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Sample records for system cns tumors

  1. Occurrence of Spontaneous Tumors in the Central Nervous System (CNS) of F344 and SD Rats

    PubMed Central

    Nagatani, Mariko; Kudo, Kayoko; Yamakawa, Seiki; Ohira, Toko; Yamaguchi, Yuko; Ikezaki, Shinichiro; Suzuki, Isamu; Saito, Tsubasa; Hoshiya, Toru; Tamura, Kazutoshi; Uchida, Kazuyuki

    2013-01-01

    In order to accurately assess the carcinogenicity of chemicals with regard to rare tumors such as rat CNS tumors, sufficient information about spontaneous tumors are very important. This paper presents the data on the type, incidence and detected age of CNS tumors in F344/DuCrlCrlj (a total of 1363 males and 1363 females) and Crl:CD(SD) rats (a total of 1650 males and 1705 females) collected from in-house background data-collection studies and control groups of carcinogenicity studies at our laboratory, together with those previously reported in F344 and SD rats. The present data on F344/DuCrlCrlj rats (F344 rats) and Crl:CD(SD) rats (SD rats) clarified the following. (1) The incidences of all CNS tumors observed in F344 rats were less than 1%. (2) The incidences of malignant astrocytoma and granular cell tumor were higher in male SD rats than in female SD rats. (3) The incidences of astrocytoma and granular cell tumor were higher in SD rats than in F344 rats. (4) Among astrocytoma, oligodendroglioma and granular cell tumor, oligodendroglioma was detected at the youngest age, followed by astrocytoma, and ultimately, granular cell tumor developed in both strains. The incidences observed in our study were almost consistent with those previously reported in F344 and SD rats. PMID:24155559

  2. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

    PubMed

    Sturm, Dominik; Orr, Brent A; Toprak, Umut H; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J; Balasubramanian, Gnanaprakash; Worst, Barbara C; Pajtler, Kristian W; Brabetz, Sebastian; Johann, Pascal D; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M; Remke, Marc; Phillips, Joanna J; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C; Schniederjan, Matthew J; Santi, Mariarita; Buccoliero, Anna M; Dahiya, Sonika; Kramm, Christof M; von Bueren, André O; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S; Taylor, Michael D; Jones, Chris; Jabado, Nada; Karajannis, Matthias A; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Ellison, David W; Korshunov, Andrey; Kool, Marcel

    2016-02-25

    Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. PMID:26919435

  3. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

    PubMed

    Sturm, Dominik; Orr, Brent A; Toprak, Umut H; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J; Balasubramanian, Gnanaprakash; Worst, Barbara C; Pajtler, Kristian W; Brabetz, Sebastian; Johann, Pascal D; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M; Remke, Marc; Phillips, Joanna J; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C; Schniederjan, Matthew J; Santi, Mariarita; Buccoliero, Anna M; Dahiya, Sonika; Kramm, Christof M; von Bueren, André O; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S; Taylor, Michael D; Jones, Chris; Jabado, Nada; Karajannis, Matthias A; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Ellison, David W; Korshunov, Andrey; Kool, Marcel

    2016-02-25

    Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

  4. Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors.

    PubMed

    Blumenthal, Deborah T; Yalon, Michal; Vainer, Gilad W; Lossos, Alexander; Yust, Shlomit; Tzach, Lior; Cagnano, Emanuela; Limon, Dror; Bokstein, Felix

    2016-09-01

    Patients with progressive primary brain tumors (PBT) are attracted to promising new treatments, even prior to convincing data. Anti-PD1 immunotherapies have been in the spotlight since publication of groundbreaking results for metastatic melanoma with pembrolizumab (PBL). Our objective was to report on the response and toxicity of PBL in patients with advanced PBT. We retrospectively reviewed the charts of 22 patients (17 adults and 5 children) with recurrent central nervous system tumors treated with PBL. We analyzed prior antineoplastic therapies, steroid usage, and outcomes. Patients received a median of two neoplastic therapies prior to PBL, and a median of three infusions of PBL in adults and four in children. Twelve patients (9 adults and 3 children) started PBL on steroids (median dose in adults 4 mg; range 2-8, and in children 1.5 mg, range 0.5-4) and five patients received steroids later during PBL treatment. Twelve patients (10 adults and 2 children) received concomitant bevacizumab with PBL. Side effects were minimal. All patients showed progressive tumor growth during therapy. Median OS from the start of PBL was 2.6 months in adults and 3.2 months in children. Two GB patients underwent tumor resection following treatment with PBL. Tumor-lymphocytic response in these cases was unremarkable, and PD-L1 immuno-staining was negative. In this series of 22 patients with recurrent primary brain tumors, PBL showed no clinical or histologic efficacy. We do not recommend further use of PBL for recurrent PBT unless convincing prospective clinical trial data are published.

  5. H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: possible diagnostic and therapeutic implications?

    PubMed

    Gessi, Marco; Gielen, Gerrit H; Hammes, Jennifer; Dörner, Evelyn; Mühlen, Anja Zur; Waha, Andreas; Pietsch, Torsten

    2013-03-01

    Pediatric glioblastomas recently have been exon sequenced with evidence that approximately 30 % of cases harbour mutations of the histone H3.3 gene. Although studies to determinate their role in risk stratification are on-going, it remains to be determined whether H3.3 mutations could be found in other tumors such as pediatric primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) and whether the presence of H3.3 mutations in glioblastomas could be used as diagnostic tool in their differential diagnosis with CNS-PNETs. We performed a large mutational pyrosequencing-based screening on 123 pediatric glioblastomas and 33 CNS-PNET. The analysis revealed that 39/123 (31.7 %) glioblastomas carry H3.3 mutations. The K27M (AAG → ATG, lysine → methionine) mutation was found in 33 glioblastomas (26 %); the G34R (GGG → AGG, glycine → arginine) was observed in 6 glioblastomas (5.5 %). However, we also identified 4 of 33 cases (11 %) of CNS-PNETs harbouring a H3.3 G34R mutation. Multiplex ligation-dependent probe amplification analysis revealed PDGFR-alpha amplification and EGFR gain in two cases and N-Myc amplification in one case of H3.3 G34R mutated CNS-PNET. None of H3.3 mutated tumors presented a CDKN2A loss. In conclusion, because pediatric patients with glioblastoma and CNS-PNET are treated according to different therapeutic protocols, these findings may raise further concerns about the reliability of the histological diagnosis in the case of an undifferentiated brain tumor harbouring G34R H3.3 mutation. In this view, additional studies are needed to determine whether H3.3 G34 mutated CNS-PNET/glioblastomas may represent a defined tumor subtype. PMID:23354654

  6. Applications of Genomic Sequencing in Pediatric CNS Tumors.

    PubMed

    Bavle, Abhishek A; Lin, Frank Y; Parsons, D Williams

    2016-05-01

    Recent advances in genome-scale sequencing methods have resulted in a significant increase in our understanding of the biology of human cancers. When applied to pediatric central nervous system (CNS) tumors, these remarkable technological breakthroughs have facilitated the molecular characterization of multiple tumor types, provided new insights into the genetic basis of these cancers, and prompted innovative strategies that are changing the management paradigm in pediatric neuro-oncology. Genomic tests have begun to affect medical decision making in a number of ways, from delineating histopathologically similar tumor types into distinct molecular subgroups that correlate with clinical characteristics, to guiding the addition of novel therapeutic agents for patients with high-risk or poor-prognosis tumors, or alternatively, reducing treatment intensity for those with a favorable prognosis. Genomic sequencing has also had a significant impact on translational research strategies in pediatric CNS tumors, resulting in wide-ranging applications that have the potential to direct the rational preclinical screening of novel therapeutic agents, shed light on tumor heterogeneity and evolution, and highlight differences (or similarities) between pediatric and adult CNS tumors. Finally, in addition to allowing the identification of somatic (tumor-specific) mutations, the analysis of patient-matched constitutional (germline) DNA has facilitated the detection of pathogenic germline alterations in cancer genes in patients with CNS tumors, with critical implications for genetic counseling and tumor surveillance strategies for children with familial predisposition syndromes. As our understanding of the molecular landscape of pediatric CNS tumors continues to advance, innovative applications of genomic sequencing hold significant promise for further improving the care of children with these cancers. PMID:27188671

  7. Risk and survival outcomes of radiation-induced CNS tumors.

    PubMed

    Lee, Jessica W; Wernicke, A Gabriella

    2016-08-01

    Patients treated with cranial radiation are at risk of developing secondary CNS tumors. Understanding the incidence, treatment, and long-term outcomes of radiation-induced CNS tumors plays a role in clinical decision-making and patient education. Additionally, as meningiomas and pituitary tumors have been detected at increasing rates across all ages and may potentially be treated with radiation, it is important to know and communicate the risk of secondary tumors in children and adults. After conducting an extensive literature search, we identified publications that report incidence and long-term outcomes of radiation-induced CNS tumors. We reviewed 14 studies in children, which reported that radiation confers a 7- to 10-fold increase in subsequent CNS tumors, with a 20-year cumulative incidence ranging from 1.03 to 28.9 %. The latency period for secondary tumors ranged from 5.5 to 30 years, with gliomas developing in 5-10 years and meningiomas developing around 15 years after radiation. We also reviewed seven studies in adults, where the two strongest studies showed no increased risk while the remaining studies found a higher risk compared to the general population. The latency period for secondary CNS tumors in adults ranged from 5 to 34 years. Treatment and long-term outcomes of radiation-induced CNS tumors have been documented in four case series, which did not conclusively demonstrate that secondary CNS tumors fared worse than primary CNS tumors. Radiation-induced CNS tumors remain a rare occurrence that should not by itself impede radiation treatment. Additional investigation is needed on the risk of radiation-induced tumors in adults and the long-term outcomes of these tumors. PMID:27209188

  8. Emerging tumor entities and variants of CNS neoplasms.

    PubMed

    Cenacchi, Giovanna; Giangaspero, Felice

    2004-03-01

    Since the appearance in 2000 of the World Health Organization (WHO) classification for central nervous system (CNS) neoplasms, numerous descriptions of new entities or variants have appeared in the literature. In the group of neuronal and mixed glioneuronal neoplasms are lesions with distinctive morphological features that are still not included in a precise classification, including extraventricular neurocytoma, papillary glioneuronal tumor, rosette-forming glioneuronal of the fourth ventricle, glioneuronal with neuropil-like rosette, and DNT-like tumor of the septum pellucidum. The glioneuronal tumor with neuropil-like rosette and oligodendroglioma with neurocytic differentiation represent morphological variants of genetically proven diffuse gliomas. The lipoastrocytoma and the pilomixoid astrocytoma enlarge the group of astrocytic lesions. Rare, low-grade gliomas of the spinal cord with extensive leptomeningeal dissemination associated with unusual neuroimaging are described. The chordoid glioma of the third ventricle and the papillary tumor of the pineal region seem to be correlated by a common histogenesis from the specialized ependyma of the subcommissural organ. An embryonal tumor with neuropil and true rosettes combining features of neuroblastoma and ependymoblastoma is discussed. These new, recently described lesions indicate that the complex morphologic spectrum of CNS tumors is far from being completely delineated.

  9. SU-E-T-587: Monte Carlo Versus Ray-Tracing for Treatment Planning Involving CNS Tumors On the MultiPlan System for CyberKnife Radiosurgery

    SciTech Connect

    Forbang, R Teboh

    2014-06-01

    Purpose: MultiPlan, the treatment planning system for the CyberKnife Robotic Radiosurgery system offers two approaches to dose computation, namely Ray-Tracing (RT), the default technique and Monte Carlo (MC), an option. RT is deterministic, however it accounts for primary heterogeneity only. MC on the other hand has an uncertainty associated with the calculation results. The advantage is that in addition, it accounts for heterogeneity effects on the scattered dose. Not all sites will benefit from MC. The goal of this work was to focus on central nervous system (CNS) tumors and compare dosimetrically, treatment plans computed with RT versus MC. Methods: Treatment plans were computed using both RT and MC for sites covering (a) the brain (b) C-spine (c) upper T-spine (d) lower T-spine (e) L-spine and (f) sacrum. RT was first used to compute clinically valid treatment plans. Then the same treatment parameters, monitor units, beam weights, etc., were used in the MC algorithm to compute the dose distribution. The plans were then compared for tumor coverage to illustrate the difference if any. All MC calculations were performed at a 1% uncertainty. Results: Using the RT technique, the tumor coverage for the brain, C-spine (C3–C7), upper T-spine (T4–T6), lower T-spine (T10), Lspine (L2) and sacrum were 96.8%, 93.1%, 97.2%, 87.3%, 91.1%, and 95.3%. The corresponding tumor coverage based on the MC approach was 98.2%, 95.3%, 87.55%, 88.2%, 92.5%, and 95.3%. It should be noted that the acceptable planning target coverage for our clinical practice is >95%. The coverage can be compromised for spine tumors to spare normal tissues such as the spinal cord. Conclusion: For treatment planning involving the CNS, RT and MC appear to be similar for most sites but for the T-spine area where most of the beams traverse lung tissue. In this case, MC is highly recommended.

  10. Auto Transplant for High Risk or Relapsed Solid or CNS Tumors

    ClinicalTrials.gov

    2016-08-15

    Ewing's Family Tumors; Renal Tumors; Hepatoblastoma; Rhabdomyosarcoma; Soft Tissue Sarcoma; Primary Malignant Brain Neoplasms; Retinoblastoma; Medulloblastoma; Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET); Atypical Teratoid/Rhabdoid Tumor (AT/RT); CNS Tumors; Germ Cell Tumors

  11. Age–incidence patterns of primary CNS tumors in children, adolescents, and adults in England

    PubMed Central

    Arora, Ramandeep S.; Alston, Robert D.; Eden, Tim O.B.; Estlin, Edward J.; Moran, Anthony; Birch, Jillian M.

    2009-01-01

    Around 25% of all tumors in those 0–14 years of age and 9% in those 15–24 years of age involve the CNS. They are the most common cause of cancer-related deaths in both age groups. In adults 25–84 years of age, the proportion of CNS tumors is 2%; 5-year overall survival is 10%–15%; and survivors have considerable morbidity. Comprehensive up-to-date population-based incidence data on these tumors are lacking. We present incidence rates for primary CNS tumors based on data derived from the high-quality national cancer registration system in England. A total of 54,336 CNS tumors of malignant, benign, and uncertain behavior were registered across the whole of England from 1995 through 2003. The age-standardized rates for all ages (0–84 years) was 9.21 per 100,000 person-years. This is higher than previously reported for England because it includes nonmalignant CNS tumors and hence gives a more accurate picture of burden of disease. The age-standardized rates for those 0–14 years of age, 15–24 years of age, and 25–84 years of age were 3.56, 3.26, and 14.57 per 100,000 person-years, respectively. In this article, we describe the changing patterns in the epidemiology of primary CNS tumors in these three age groups with respect to sex, tumor behavior, and histology using the current WHO classification. This information will provide a reference for future studies nationally and internationally and make comparisons relevant and meaningful. PMID:19033157

  12. Solitary Fibrous Tumor/Hemangiopericytoma Dichotomy Revisited: A Restless Family of Neoplasms in the CNS.

    PubMed

    Yalcin, Can Ege; Tihan, Tarik

    2016-03-01

    Solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) both entered the literature as separate entities in the early to mid 1900s. In contrast to their central nervous system (CNS) counterparts, there has been a tendency to consider these 2 entities as 1 since the early 1990s, as soft tissue SFT gradually included the tumors previously diagnosed as HPC. The most recent World Health Organization (WHO) classification of the tumors of soft tissue considered the term HPC obsolete, and places all such tumors within the extrapleural SFT category. In contrast, CNS SFT and HPC continue to be regarded as different entities in the latest version of the WHO CNS tumor classification. A change in this approach is currently being considered for the upcoming revision of the WHO scheme, but it is not quite clear whether such a change will be as drastic as the one adopted by the soft tissue and bone tumor working group. This article focuses on the historical evolution of these 2 labels as primary CNS neoplasms, and reviews their differences and similarities in terms of clinical, pathologic, and molecular features. PMID:26849816

  13. Solitary Fibrous Tumor/Hemangiopericytoma Dichotomy Revisited: A Restless Family of Neoplasms in the CNS.

    PubMed

    Yalcin, Can Ege; Tihan, Tarik

    2016-03-01

    Solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) both entered the literature as separate entities in the early to mid 1900s. In contrast to their central nervous system (CNS) counterparts, there has been a tendency to consider these 2 entities as 1 since the early 1990s, as soft tissue SFT gradually included the tumors previously diagnosed as HPC. The most recent World Health Organization (WHO) classification of the tumors of soft tissue considered the term HPC obsolete, and places all such tumors within the extrapleural SFT category. In contrast, CNS SFT and HPC continue to be regarded as different entities in the latest version of the WHO CNS tumor classification. A change in this approach is currently being considered for the upcoming revision of the WHO scheme, but it is not quite clear whether such a change will be as drastic as the one adopted by the soft tissue and bone tumor working group. This article focuses on the historical evolution of these 2 labels as primary CNS neoplasms, and reviews their differences and similarities in terms of clinical, pathologic, and molecular features.

  14. Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Is Constitutively Expressed in Adult Central Nervous System (CNS) and Associated with Astrocyte-mediated Glial Scar Formation following Spinal Cord Injury*

    PubMed Central

    Coulson-Thomas, Vivien J.; Lauer, Mark E.; Soleman, Sara; Zhao, Chao; Hascall, Vincent C.; Day, Anthony J.; Fawcett, James W.

    2016-01-01

    Tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) binds to hyaluronan and can reorganize/stabilize its structure, also enhancing the binding of this glycosaminoglycan to its cell surface receptor, CD44. TSG-6 is rapidly up-regulated in response to inflammatory cytokines protecting tissues from the damaging effects of inflammation. Despite TSG-6 treatment having been shown to improve outcomes in an experimental model of traumatic brain injury, TSG-6 expression has not been extensively studied in the central nervous system (CNS). We hereby analyzed the expression profile of TSG-6 in the developing CNS and following injury. We show that TSG-6 is expressed in the rat CNS by GFAP+ and CD44+ astrocytes, solely in the mature brain and spinal cord, and is not present during the development of the CNS. TSG-6−/− mice present a reduced number of GFAP+ astrocytes when compared with the littermate TSG-6+/− mice. TSG-6 expression is drastically up-regulated after injury, and the TSG-6 protein is present within the glial scar, potentially coordinating and stabilizing the formation of this hyaluronan-rich matrix. This study shows that TSG-6 is expressed in the CNS, suggesting a role for TSG-6 in astrocyte activation and tissue repair. We hypothesize that within this context TSG-6 could participate in the formation of the glial scar and confer anti-inflammatory properties. Further studies are required to elucidate the therapeutic potential of targeting TSG-6 after CNS injury to promote its protective effects while reducing the inhibitory properties of the glial scar in axon regeneration. PMID:27435674

  15. Treatment Options for Medulloblastoma and CNS Primitive Neuroectodermal Tumor (PNET)

    PubMed Central

    Packer, Roger J.

    2016-01-01

    The amount of residual disease after surgery better correlates with survival for medulloblastomas than for CNS PNETs. Maximal surgical resection of tumor should be done, only if additional permanent, neurologic deficits can be spared. Patients should have a staging work-up to assess the extent of disease. This includes postoperative magnetic resonance imaging (MRI) of the brain, MRI of the entire spine and lumbar cerebrospinal fluid (CSF) sampling for cytological examination, if deemed safe. Radiation therapy to the entire CNS axis is required, with a greater dose (boost) given to the region of the primary site or any bulky residual disease for older children. Adjuvant chemotherapy must be given even if no evidence of disease after radiation therapy exists, as the risk of relapse is substantial after radiation alone. Subsets of younger children with medulloblastoma, arbitrarily defined as those younger than 3 years of age in some studies and 4 or even 5 years in other studies, can be effectively treated with chemotherapy alone. Recent genomic studies have revealed further subtypes of disease than previously recognized. Clinical trials to exploit these biologic differences are required to assess potential efficacy of targeted agents. The treatment of medulloblastoma and CNS PNET can cause significant impairment in neurologic function. Evaluations by physical therapy, occupational therapy, speech therapy and neurocognitive assessments should be obtained, as needed. After therapy is completed, survivors need follow-up of endocrine function, surveillance scans and psychosocial support. PMID:23979905

  16. Obesity and Risk for Brain/CNS Tumors, Gliomas and Meningiomas: A Meta-Analysis

    PubMed Central

    Sergentanis, Theodoros N.; Tsivgoulis, Georgios; Perlepe, Christina; Ntanasis-Stathopoulos, Ioannis; Tzanninis, Ioannis-Georgios; Sergentanis, Ioannis N.; Psaltopoulou, Theodora

    2015-01-01

    Objective This meta-analysis aims to examine the association between being overweight/obese and risk of meningiomas and gliomas as well as overall brain/central nervous system (CNS) tumors. Study Design Potentially eligible publications were sought in PubMed up to June 30, 2014. Random-effects meta-analysis and dose-response meta-regression analysis was conducted. Cochran Q statistic, I-squared and tau-squared were used for the assessment of between-study heterogeneity. The analysis was performed using Stata/SE version 13 statistical software. Results A total of 22 studies were eligible, namely 14 cohort studies (10,219 incident brain/CNS tumor cases, 1,319 meningioma and 2,418 glioma cases in a total cohort size of 10,143,803 subjects) and eight case-control studies (1,009 brain/CNS cases, 1,977 meningioma cases, 1,265 glioma cases and 8,316 controls). In females, overweight status/obesity was associated with increased risk for overall brain/CNS tumors (pooled RR = 1.12, 95%CI: 1.03–1.21, 10 study arms), meningiomas (pooled RR = 1.27, 95%CI: 1.13–1.43, 16 study arms) and gliomas (pooled RR = 1.17, 95%CI: 1.03–1.32, six arms). Obese (BMI>30 kg/m2) females seemed particularly aggravated in terms of brain/CNS tumor (pooled RR = 1.19, 95%CI: 1.05–1.36, six study arms) and meningioma risk (pooled RR = 1.48, 95%CI: 1.28–1.71, seven arms). In males, overweight/obesity status correlated with increased meningioma risk (pooled RR = 1.58, 95%CI: 1.22–2.04, nine study arms), whereas the respective association with overall brain/CNS tumor or glioma risk was not statistically significant. Dose-response meta-regression analysis further validated the findings. Conclusion Our findings highlight obesity as a risk factor for overall brain/CNS tumors, meningiomas and gliomas among females, as well as for meningiomas among males. PMID:26332834

  17. Alpha6 beta4 and alpha6 beta1 integrins in astrocytomas and other CNS tumors.

    PubMed

    Previtali, S; Quattrini, A; Nemni, R; Truci, G; Ducati, A; Wrabetz, L; Canal, N

    1996-04-01

    Laminin may alter the biological behavior of gliomas. Therefore, we investigated the expression of two laminin receptors, alpha6 beta1 and alpha6 beta4 integrins in normal brain, astrogliotic brain, and astrocytomas as compared to other central nervous system (CNS) tumors. In most CNS tumors, the expression of these integrins was unchanged in neoplastic as compared to normal counterpart cells. In contrast, increased numbers of reactive and neoplastic astrocytes expressed beta4 integrin as compared to normal astrocytes, whereas alpha6 and beta1 integrin expression did not change. Conversely, lower numbers of astrocytoma blood vessels expressed beta4, whereas all blood vessels in normal brain expressed beta4. These data suggest that the profile of laminin receptors changes in neoplastic astrocytes and in astrocytoma blood vessels; this change may play an important role in astrocytoma pathogenesis.

  18. VIIP: Central Nervous System (CNS) Modeling

    NASA Technical Reports Server (NTRS)

    Vera, Jerry; Mulugeta, Lealem; Nelson, Emily; Raykin, Julia; Feola, Andrew; Gleason, Rudy; Samuels, Brian; Ethier, C. Ross; Myers, Jerry

    2015-01-01

    Current long-duration missions to the International Space Station and future exploration-class missions beyond low-Earth orbit expose astronauts to increased risk of Visual Impairment and Intracranial Pressure (VIIP) syndrome. It has been hypothesized that the headward shift of cerebrospinal fluid (CSF) and blood in microgravity may cause significant elevation of intracranial pressure (ICP), which in turn may then induce VIIP syndrome through interaction with various biomechanical pathways. However, there is insufficient evidence to confirm this hypothesis. In this light, we are developing lumped-parameter models of fluid transport in the central nervous system (CNS) as a means to simulate the influence of microgravity on ICP. The CNS models will also be used in concert with the lumped parameter and finite element models of the eye described in the related IWS works submitted by Nelson et al., Feola et al. and Ethier et al.

  19. A history of the AANS/CNS Section on Tumors Biennial Satellite Symposium.

    PubMed

    Lang, Frederick F; Barker, Fred G

    2014-09-01

    The Biennial Satellite Tumor Symposium is the flagship meeting of the AANS/CNS Section on Tumors. The year 2013 marked the 10th Tumor Section Biennial Satellite Tumor Symposium, a significant milestone warranting retrospection on the origin and development of the Satellite Tumor Symposium. This article provides a brief history of the Section on Tumors Biennial Satellite Tumor Symposium, including insights into the structure and evolution of the meeting, and recognizes some of the members of the AANS/CNS Section on Tumors who have contributed to Satellite meetings over the years.

  20. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery.

    PubMed

    Ghose, Arup K; Herbertz, Torsten; Hudkins, Robert L; Dorsey, Bruce D; Mallamo, John P

    2012-01-18

    The central nervous system (CNS) is the major area that is affected by aging. Alzheimer's disease (AD), Parkinson's disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood-brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å(2) (25-60 Å(2)), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740-970 Å(3), (vi) solvent accessible surface area of 460-580 Å(2), and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The

  1. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery.

    PubMed

    Ghose, Arup K; Herbertz, Torsten; Hudkins, Robert L; Dorsey, Bruce D; Mallamo, John P

    2012-01-18

    The central nervous system (CNS) is the major area that is affected by aging. Alzheimer's disease (AD), Parkinson's disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood-brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å(2) (25-60 Å(2)), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740-970 Å(3), (vi) solvent accessible surface area of 460-580 Å(2), and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The

  2. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery

    PubMed Central

    2011-01-01

    The central nervous system (CNS) is the major area that is affected by aging. Alzheimer’s disease (AD), Parkinson’s disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood–brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å2 (25–60 Å2), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740–970 Å3, (vi) solvent accessible surface area of 460–580 Å2, and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The

  3. Systematic comparison of MRI findings in pediatric ependymoblastoma with ependymoma and CNS primitive neuroectodermal tumor not otherwise specified

    PubMed Central

    Nowak, Johannes; Seidel, Carolin; Pietsch, Torsten; Alkonyi, Balint; Fuss, Taylor Laura; Friedrich, Carsten; von Hoff, Katja; Rutkowski, Stefan; Warmuth-Metz, Monika

    2015-01-01

    Background Ependymoblastoma (EBL), ependymoma (EP), and primitive neuroectodermal tumors of the central nervous system not otherwise specified (CNS-PNET NOS) are pediatric brain tumors that can be differentiated by histopathology in the clinical setting. Recently, we described specific MRI features of EBL. In this study, we compare standardized MRI characteristics of EBL with EP and CNS-PNET NOS in a series comprising 22 patients in each group. Methods All 66 centrally reviewed cases were obtained from the database of the German multicenter HIT trials. We systematically analyzed the initial MRI scans at diagnosis according to standardized criteria, and paired comparison was performed for EBL and EP, as well as for EBL and CNS-PNET NOS. Results We found differences between EBL and EP regarding age at diagnosis, MR signal intensity, tumor margin and surrounding edema, presence and size of cysts, and contrast enhancement pattern. Although MRI appearance of EBL shares many features with CNS-PNET NOS, we revealed significant differences in terms of age at diagnosis, tumor volume and localization, tumor margins, edema, and contrast enhancement. Conclusion This is the first study that systematically compares multiple parameters of MRI in pediatric EBL with findings in EP and CNS-PNET NOS. Although a definite differentiation by means of MRI alone might not be feasible in the individual case, we identify significant differences between these tumor entities. PMID:25916887

  4. Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins.

    PubMed

    Montesinos-Rongen, Manuel; Purschke, Frauke G; Brunn, Anna; May, Caroline; Nordhoff, Eckhard; Marcus, Katrin; Deckert, Martina

    2015-08-01

    Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-α, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-κB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS. PMID:26116512

  5. Gliosarcoma: A rare primary CNS tumor. Presentation of two cases

    PubMed Central

    Pardo, José; Murcia, Mauricio; García, Felip; Alvarado, Arnaldo

    2010-01-01

    Summary Introduction Gliosarcoma is a very rare primary mixed tumor in the central nervous system, with a biphasic pattern consisting of glial and malignant mesenchymal elements. Its onset is between the fourth and sixth decade of life, and it has a male/female ratio of 1.8/1. Here we present two cases of Gliosarcoma treated in our department. Discussion The monoclonal or biclonal origin of its biphasic nature is still subject to debate; hence the importance of its diagnosis and histogenesis. Results Standard treatment consists in surgical resection of the tumor followed in some cases by external radiotherapy and chemotherapy. PMID:24376932

  6. The impact of neural stem cell biology on CNS carcinogenesis and tumor types.

    PubMed

    Kurian, K M

    2011-01-01

    The incidence of gliomas is on the increase, according to epidemiological data. This increase is a conundrum because the brain is in a privileged protected site behind the blood-brain barrier, and therefore partially buffered from environmental factors. In addition the brain also has a very low proliferative potential compared with other parts of the body. Recent advances in neural stem cell biology have impacted on our understanding of CNS carcinogenesis and tumor types. This article considers the cancer stem cell theory with regard to CNS cancers, whether CNS tumors arise from human neural stem cells and whether glioma stem cells can be reprogrammed.

  7. Tumor-Associated CSF MicroRNAs for the Prediction and Evaluation of CNS Malignancies

    PubMed Central

    Shalaby, Tarek; Grotzer, Michael A.

    2015-01-01

    Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route for seeding metastases of CNS malignancies and its analysis could be informative for diagnosis and risk stratification of brain cancers. Recently, modern high-throughput, microRNAs (miRNAs) measuring technology has enabled sensitive detection of distinct miRNAs that are bio-chemicallystable in the CSF and can distinguish between different types of CNS cancers. Owing to the fact that a CSF specimen can be obtained with relative ease, analysis of CSF miRNAs could be a promising contribution to clinical practice. In this review, we examine the current scientific knowledge on tumor associated CSF miRNAs that could guide diagnosis of different brain cancer types, or could be helpful in predicting disease progression and therapy response. Finally, we highlight their potential applications clinically as biomarkers and discuss limitations. PMID:26690130

  8. CNS tumors and exposure to acrylonitrile: inconsistency between experimental and epidemiology studies.

    PubMed Central

    Collins, J. J.; Strother, D. E.

    1999-01-01

    Acrylonitrile is a potent CNS tumorigen in rats leading to concern that it may be a tumorigen in humans. There have been 12 epidemiology studies of 37,352 workers exposed to acrylonitrile which evaluate CNS cancers. We summarize and evaluate these epidemiology studies for CNS cancers using the methods of meta-analysis. Our analyses indicate that workers with acrylonitrile exposure have null findings for CNS cancer (relative risk = 1.1, 95% confidence interval 0.8-1.5), which are in stark contrast to the projected risk to humans using the rat findings (relative risk = 3.5, 95% confidence interval 3.0-4.0). We discuss several explanations for the inconsistency between animal and human findings, including the possibility that the acrylonitrile-induced rat CNS tumors may not be relevant to humans. Given the rarity of CNS tumors in humans and a lack of understanding of the causal mechanisms of these tumors in rats, however, a more definitive conclusion will have to await additional experimental and observational data. Nevertheless, the epidemiology evidence indicates that acrylonitrile is not a potent CNS tumorigen. PMID:11550315

  9. Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide

    PubMed Central

    Chacko, Ann-Marie; Li, Chunsheng; Pryma, Daniel A.; Brem, Steven; Coukos, George; Muzykantov, Vladimir R.

    2014-01-01

    Introduction Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID:23751126

  10. Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

    PubMed Central

    Iorio, Anna Lisa; da Ros, Martina; Fantappiè, Ornella; Lucchesi, Maurizio; Facchini, Ludovica; Stival, Alessia; Becciani, Sabrina; Guidi, Milena; Favre, Claudio; de Martino, Maurizio; Genitori, Lorenzo; Sardi, Iacopo

    2016-01-01

    The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies. The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS. In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases. PMID:26584727

  11. Quantification of Cerebral Perfusion Using the “Bookend Technique”: an Evaluation in CNS Tumors

    PubMed Central

    Carroll, Timothy J; Horowitz, Sandra; Shin, Wanyong; Mouannes, Jessy; Sawlani, Rahul; Ali, Saad; Raizer, Jeffrey; Futterer, Stephen

    2008-01-01

    We present a method of quantifying cerebral blood volume using Dynamic Susceptibility Contrast. Our approach combines T2-weighted EPI pulse sequences and reference scans that determine the parenchymal T1-changes resulting from an injection of a gadolinium chelate. This combined T2-and T1-weighted approach (The “Bookend” technique) has been shown to be effective in the quantification of Gradient-Echo (T2*-weighted) perfusion images, but has not been applied to Spin –Echo EPI (T2-weighted) images. The physics related to blood volume measurement based on T2- and T2*-weighted EPI sequences is known to be different, and there is a question as to whether the bookend approach is effective with SE-EPI. We have compared the quantitative SE-EPI with GE-EPI in a series of patients with central nervous system (CNS) tumors. We found that quantitative cerebral Blood Volume (qCBV) values for SE-EPI and GRE-EPI are in agreement with each other and with historical reference values. A subjective evaluation of image quality showed that image quality in the SE-EPI scans was high and exhibited high inter-reader agreement. We conclude that measuring qCBV using the bookend technique with SE-EPI images is possible and may be a viable alternative to GRE-EPI in the evaluation of CNS tumors. PMID:18538523

  12. Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma

    SciTech Connect

    Merchant, Thomas E. . E-mail: thomas.merchant@stjude.org; Kiehna, Erin N.; Li Chenghong; Shukla, Hemant; Sengupta, Saikat; Xiong Xiaoping; Gajjar, Amar; Mulhern, Raymond K.

    2006-05-01

    Purpose: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. Methods and Materials: Pediatric patients with CNS embryonal tumors (n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose-volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. Results: When the dose distribution was partitioned into 2 levels, both had a significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. Conclusions: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts.

  13. Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

    PubMed Central

    Upadhyay, Ravi Kant

    2014-01-01

    Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB) for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods. PMID:25136634

  14. Drug delivery systems, CNS protection, and the blood brain barrier.

    PubMed

    Upadhyay, Ravi Kant

    2014-01-01

    Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB) for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods.

  15. Awards, lectures, and fellowships sponsored by the AANS/CNS Section on Tumors.

    PubMed

    Lau, Darryl; Barker, Fred G; Aghi, Manish K

    2014-09-01

    A major goal of the Section on Tumors of the American Association of Neurological Surgery (AANS) and Congress of Neurological Surgeons (CNS) since it was founded in 1984 has been to foster both education and research in the field of brain tumor treatment and development. In support of this goal, the Section sponsors a number of awards, named lectures, and fellowships at the annual meetings of the AANS and CNS. In this article, we describe the awards given by the AANS/CNS Section on Tumors since its foundation, the recipients of the awards, and their philanthropic donors. The subsequent history of awardees and their work is briefly examined. Specifically for the Preuss and Mahaley Awards, this article also examines the rates of publication among the award-winning abstracts and achievement of grant funding by awardees.

  16. Differentiation between meningiomas and other CNS tumors by simultaneous somatostatin receptor and brain scintigraphy

    SciTech Connect

    Haldemann, A.R.; Luescher, D.; Sulzer, M.

    1994-05-01

    Since the differentiation between meningiomas and some other CNS tumors may be difficult in certain localizations, biopsy is mandatory, even in patients with meningiomas who are to be treated with percutaneous radiotherapy alone. The high density of somatostatin receptors (SSR) in meningiomas has led us to compare patients with meningiomas and other CNS tumors by simultaneous SSR and brain scintigraphy (BS) using 74 MBq 111In octreotide and 740 MBq 99mTc DTPA injected two hours later. SPECT was performed on a 3-head gamma camera 4 hours after 111In octreotide injection in multiple peak acquisition mode in 35 patients with radiologically documented CNS tumors. In positive scans, a tumor ROI was defined manually in the transverse 111In slice with highest tumor contrast and the identical tumor ROI was transferred to the corresponding 99mTc slice. A SSR to BS index was then calculated from the ratio of 111In to 99mTc counts after normalizing for identical total counts in the slices. in negative scans, the SSR to BS index was set to be 1.0. In 7 meningiomas, the SSR to BS index was 2.64{plus_minus}0.76. In 28 other CNS tumors (7 gliomas I-111, 4 neurinomas, 3 glial reactions, 3 metastases, 3 gliomas IV, 2 ependymomas, 1 chordoma, 1 NHL; plus 4 inoperable, radiologically diagnosed glioblastomas) 1.06{plus_minus}0.13. Thus, a highly significant difference was found between these two groups (p<0.0001). It is concluded that combined SSR and BS allows excellent discrimination between meningiomas and other CNS tumors and may become a non-invasive alternative to biopsy in selected clinical situations.

  17. The Use of Anthracyclines for Therapy of CNS Tumors

    PubMed Central

    da Ros, Martina; Iorio, Anna Lisa; Lucchesi, Maurizio; Stival, Alessia; de Martino, Maurizio; Sardi, Iacopo

    2015-01-01

    Despite being long lived, anthracyclines remain the “evergreen” drugs in clinical practice of oncology, showing a potent effect in inhibiting cell growth in many types of tumors, including brain neoplasms. Unfortunately, they suffer from a poor penetration into the brain when intravenously administered due to multidrug resistance mechanism, which hampers their delivery across the blood brain barrier. In this paper, we summarize the current literature on the role of anthracyclines in cancer therapy and highlight recent efforts on 1) development of tumor cell resistance to anthracyclines and 2) the new approaches to brain drug delivery across the blood brain barrier. PMID:25846760

  18. Slice Culture Modeling of Central Nervous System (CNS) Viral Infection

    PubMed Central

    Dionne, Kalen R.; Tyler, Kenneth L.

    2016-01-01

    The complexity of the central nervous system (CNS) is not recapitulated in cell culture models. Thin slicing and subsequent culture of CNS tissue has become a valued means to study neuronal and glial biology within the context of the physiologically relevant tissue milieu. Modern membrane-interface slice culturing methodology allows straightforward access to both CNS tissue and feeding medium, enabling experimental manipulations and analyses that would otherwise be impossible in vivo. CNS slices can be successfully maintained in culture for up to several weeks for investigation of evolving pathology and long-term intervention in models of chronic neurologic disease. Herein, membrane-interface slice culture models for studying viral encephalitis and myelitis are detailed, with emphasis on the use of these models for investigation of pathogenesis and evaluation of novel treatment strategies. We describe techniques to (1) generate brain and spinal cord slices from rodent donors, (2) virally infect slices, (3) monitor viral replication, (4) assess virally induced injury/apoptosis, (5) characterize “CNS-specific” cytokine production, and (6) treat slices with cytokines/pharmaceuticals. Although our focus is on CNS viral infection, we anticipate that the described methods can be adapted to address a wide range of investigations within the fields of neuropathology, neuroimmunology, and neuropharmacology. PMID:23975824

  19. [Antiangiogenic treatment of pediatric CNS tumors in Hungary with the Kieran schedule].

    PubMed

    Hauser, Péter; Vancsó, Ildikó; Pócza, Tímea; Schuler, Dezső; Garami, Miklós

    2013-12-01

    In Hungary a new oral antiangiogenic treatment was introduced in cases of primary chemoresistant or recurrent pediatric CNS tumors, called Kieran schedule. The early results of this treatment were analyzed. From 2010 at Semmelweis University on individual decisions a daily combined per oral treatment was introduced in pediatric patients with recurrent or progressive CNS tumor (Kieran schedule: thalidomid, celecoxib, etoposid and cyclophosphamid). Efficacy of therapy was analyzed in terms of demographic data, histology, side effects and tolerability in a retrospective manner. From 2010 through 2013, twenty patients were treated with Kieran schedule (medulloblastoma: 3, ependymoma: 5, anaplastic astrocytoma: 2, GBM: 4, plexus choroideus carcinoma: 1, central primitive neuroectodermal tumor: 1, optic glioma: 2, brainstem tumor: 2). Median treatment time and median progression-free survival were 0.60 and 0.61 years, respectively. Based on the preliminary analysis of a limited cohort of patients, the therapy was efficient in those cases of medulloblastoma, ependymoma, high-grade and optic gliomas, where the expected survival time was more than 3 months at start of treatment. Side effects were slight myelosuppresion in terms of previous therapy, 16% transient ischemic attack (TIA)-like episodes. During therapy patients could live their everyday life. Kieran schedule was well-tolerable and efficient with good quality of life in certain cases of pediatric CNS tumors.

  20. [Current status of therapy of CNS metastases of germ cell tumors].

    PubMed

    Clemm, C; Gerl, A; Wendt, T G; Pöllinger, B; Winkler, P A; Wilmanns, W

    1993-05-01

    The incidence of CNS metastases in germ cell tumors is 2-5% and in very advanced disease over 20%. We report on 37 patients in whom CNS metastases were diagnosed with the CAT scanner. Twenty-nine patients were subsequently treated. In 19 cases, treatment consisted of radiotherapy, 1 patient was only operated on, and in 9 cases patients received combined surgery and radiotherapy. Two patients had seminomatous germ cell tumors, 27 patients non-seminomatous tumors. HCG levels were high in 11 cases. In 31 patients the disease was in the advanced stages; in 6 the disease was at the early stage. If there was just a solitary tumor, operation was the preferred mode of treatment. Radiotherapy consisted of 50 GY whole-brain irradiation, with a tumor saturation up to 60 GY. In 2 cases we suspected radiogenic necrosis. There were no other severe side effects. Of the 37 patients, 4 obtained a long-term cure (observation time 34-90 months). Therapy must take all methods of treatment into consideration and should only be carried out in fully equipped medical centers. Only then can we hope to obtain long-term cures in individuals with this usually fatal disease.

  1. Sorafenib/Regorafenib and Lapatinib interact to kill CNS tumor cells

    PubMed Central

    Hamed, Hossein A.; Tavallai, Seyedmehrad; Grant, Steven; Poklepovic, Andrew; Dent, Paul

    2014-01-01

    The present studies were to determine whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with the ERBB1/ERBB2 inhibitor lapatinib to kill CNS tumor cells. In multiple CNS tumor cell types sorafenib and lapatinib interacted in a greater than additive fashion to cause tumor cell death. Tumor cells lacking PTEN, and anoikis or lapatinib resistant cells were as sensitive to the drug combination as cells expressing PTEN or parental cells, respectively. Similar data were obtained using regorafenib. Treatment of brain cancer cells with [sorafenib + lapatinib] enhanced radiation toxicity. The drug combination increased the numbers of LC3-GFP vesicles; this correlated with a reduction in endogenous LC3II, and p62 and LAMP2 degradation. Knock down of Beclin1 or ATG5 significantly suppressed drug combination lethality. Expression of c-FLIP-s, BCL-XL or dominant negative caspase 9 reduced drug combination toxicity; knock down of FADD or CD95 was protective. Expression of both activated AKT and activated MEK1 or activated mTOR was required to strongly suppress drug combination lethality. As both lapatinib and sorafenib are FDA approved agents, our data argue for further determination as to whether lapatinib and sorafenib is a useful glioblastoma therapy. PMID:24911215

  2. [CNS primitive neuroectodermal tumor suspected as a secondary recurrence after radiation therapy for medulloblastoma:a case report].

    PubMed

    Sato, Hiroyuki; Shibuya, Kouhei; Koizumi, Takayuki; Kato, Shunichi; Endo, Shin

    2014-07-01

    We report a case of a suspected secondary central nervous system(CNS)primitive neuroectodermal tumor(PNET)that developed 25 years after radiation therapy for a medulloblastoma of the cerebellum. At 5 years of age, the patient underwent craniotomy and subsequent radiation therapy of the whole brain(39Gy), whole spinal cord(9Gy), and posterior fossa(49Gy)for the treatment of a medulloblastoma of the cerebellum;the patient did not receive chemotherapy. After radiation therapy, the medulloblastoma completely receded and did not recur. Twenty-five years later, at 30 years of age, the patient visited our institution experiencing right-sided hemiparesis and aphasia that had arisen approximately 1 month prior and had gradually worsened. The patient was subsequently hospitalized after experiencing disturbed consciousness and a generalized convulsion seizure. Gadolinium-enhanced magnetic resonance imaging(MRI)revealed a mass accompanied by a large cyst in the left frontal lobe. Complete tumor resection was achieved via macroscopic surgery, and the histopathological findings were indicative of CNS PNET. Considering the tumor occurred in the same site where radiation therapy had been previously administered to treat a medulloblastoma, additional radiotherapy was avoided in favor of combination chemotherapy with ifosfamide, cisplatin, and etoposide. Tumor recurrence was not observed in a follow-up MRI after 6 courses of ICE therapy, and the patient has resumed a normal life. The present case, a CNS PNET, is suspected as a secondary brain tumor induced by radiation therapy previously used to treat a medulloblastoma, and it represents a rare late-onset complication of radiation therapy. For the treatment of PNET, we believe that maximal safe surgical resection of the tumor and post-operative radiation therapy are typically necessary for long-term survival. However, taking into account the risks of repeated exposure to radiation, we did not perform post-operative radiation therapy

  3. Pretherapeutic radioembolization of CNS tumors: Methods, dosimetry and first clinical experience

    SciTech Connect

    Haldemann, A.R.; Roesler, H.; Noelpp, U.

    1994-05-01

    Our experience with transarterial radioembolization using 90Y resin particles ({null} 45-75 {mu}m) after selective catheterization of malignant tumors has shown good palliative results in patients with inoperable hepatocellular carcinoma. This method may be applicable for many inoperable tumors or symptomatic metastases, but selective tumor embolization must be documented prior to therapy. We have started examining highly vascularized tumors of the CNS that are routinely embolized mechanically with microparticles of different sizes in order to reduce the perioperative risk of hemorrhage. In 13 patients (5 meningiomas, 3 dural angiomas, 2 metastasis, 2 chemodectomas and 1 dural fibrosarcoma) 100 MBq 99mTc labelled macroaggregates of albumin ({null} 25-50 {mu}m) were injected intraarterially after transfemoral cathererization of the tumor-feeding artery. The activity in the area of embolization and in the lungs was then recorded using a gamma camera, and the pulmonary shunt rates calculated. In this ongoing study, we found three different patterns of embolization: (1) embolization with pulmonary shunt (up to 76% of injected activity; 3 patients), (2) embolization without pulmonary shunt but sometimes considerable peritumoral embolization (6 patients) and (3) superselective embolization without significant pulmonary or peritumoral embolization (5 patients). In patients of group (3) who would qualify for therapeutic radioembolization, dosimetric calculations resulted in tumor doses of 200-1000 Gy for 370 MBq 90Y resin particles.

  4. Atypical clinical features of children with central nervous system tumor: Delayed diagnosis and switch in handedness.

    PubMed

    Yokoi, Kentaro; Yamaoka, Masayoshi; Miyata, Ichiro; Nonaka, Yuichiro; Yuza, Yuki; Kawata, Shoko; Akiyama, Masaharu; Yanagisawa, Takaaki; Ida, Hiroyuki

    2016-09-01

    Herein is described the cases of three children with central nervous system (CNS) tumor, who had switch in handedness occurring before diagnostic confirmation. Although the onset, age, tumor location, and histology were heterogeneous, the diagnosis of CNS tumor was delayed in all three patients. The present experience indicates that switch in handedness should be recognized as a sign of CNS tumor in pediatric patients, and which might prevent delay in diagnosis. Pediatricians should carefully examine such patients who present with some suggestive symptoms of CNS tumor, even when they are unusual, in order to make a timely and appropriate diagnosis.

  5. Curcumin aggravates CNS pathology in experimental systemic lupus erythematosus.

    PubMed

    Foxley, Sean; Zamora, Marta; Hack, Bradley; Alexander, Rebecca Rashmi; Roman, Brian; Quigg, Richard John; Alexander, Jessy John

    2013-04-01

    Complement activation and inflammation are key disease features of systemic lupus erythematosus. Curcumin is an anti-inflammatory agent that inhibits the complement cascade. Therefore, we hypothesized that curcumin will be protective in CNS lupus. To assess the effect of curcumin on CNS-lupus, MRL/lpr mice were used. Brain MRI showed that curcumin (30mg/kg body wt. i.p. from 12-20 weeks) worsened regional brain atrophy. The volumes of the lateral and third ventricles are significantly increased (150%-213% and 107%-140%, without and with treatment respectively compared to MRL+/+ controls). The hippocampus was reduced further (83%-81%) by curcumin treatment. In line with increased brain atrophy, there were edematous cells (41% increase in cell size in MRL/lpr compared to MRL+/+ mice. The cell size was further increased by 28% when treated with curcumin; p<0.02) in the cortex. In line with increased atrophy and edema, there was a significant increase (p<0.02) in the mRNA and protein expression of the water channel protein, aquaporin 4 in these mice. The increase in the matrix proteins, glial fibrillary acidic protein and vimentin in lupus mice in the hippocampus was prevented by curcumin. Curcumin increased IgG deposits and decreased C3 deposits in brain with a corresponding increase in immune complexes and decrease in C3 concentration (by 60% in MRL/lpr mice Vs. MRL+/+ mice and a further 26% decrease when treated with curcumin) in circulation. Decrease in C3 could alter the transport of immune complexes leading to an increase in IgG deposits which could induce inflammatory pathways thereby leading to worsening of the disease. The neurological outcome as measured by maze performance indicates that the curcumin treated mice performed poorly compared to the untreated counterparts. Our results for the first time provide evidence that at the dose used in this study, curcumin aggravates some CNS disease manifestations in experimental lupus brain. Therefore, until a safe

  6. Lenalidomide in Treating Young Patients With Recurrent, Progressive, or Refractory CNS Tumors

    ClinicalTrials.gov

    2013-09-27

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  7. Modulation of Tumor Tolerance in Primary Central Nervous System Malignancies

    PubMed Central

    Johnson, Theodore S.; Munn, David H.; Maria, Bernard L.

    2012-01-01

    Central nervous system tumors take advantage of the unique immunology of the CNS and develop exquisitely complex stromal networks that promote growth despite the presence of antigen-presenting cells and tumor-infiltrating lymphocytes. It is precisely this immunological paradox that is essential to the survival of the tumor. We review the evidence for functional CNS immune privilege and the impact it has on tumor tolerance. In this paper, we place an emphasis on the role of tumor-infiltrating myeloid cells in maintaining stromal and vascular quiescence, and we underscore the importance of indoleamine 2,3-dioxygenase activity as a myeloid-driven tumor tolerance mechanism. Much remains to be discovered regarding the tolerogenic mechanisms by which CNS tumors avoid immune clearance. Thus, it is an open question whether tumor tolerance in the brain is fundamentally different from that of peripheral sites of tumorigenesis or whether it simply stands as a particularly strong example of such tolerance. PMID:22312408

  8. Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries.

    PubMed

    McCarthy, Bridget J; Shibui, Soichiro; Kayama, Takamasa; Miyaoka, Etsuo; Narita, Yoshitaka; Murakami, Michiko; Matsuda, Ayako; Matsuda, Tomohiro; Sobue, Tomotaka; Palis, Bryan E; Dolecek, Therese A; Kruchko, Carol; Engelhard, Herbert H; Villano, J Lee

    2012-09-01

    Intracranial germ cell tumors (GCTs) are relatively rare. Their incidence has been considered to be higher in East Asia than in the United States. This study estimates the incidence of CNS GCTs in Japan and the United States, investigates gender discrepancies in each country, and describes treatment outcomes. Data on primary CNS GCTs from 4 databases were utilized: population-based malignant incidence data from (1) the Japan Cancer Surveillance Research Group (2004-2006; 14 registries), malignant and nonmalignant incidence data from (2) the Surveillance, Epidemiology, and End Results Program (2004-2008; 17 registries), and hospital-based observed survival data from (3) the Brain Tumor Registry of Japan (1984-2000) and (4) the US National Cancer Data Base (1990-2003). Incidence rates per 100 000 for malignant GCTs were not statistically significantly different between Japan (males = 0.143, females = 0.046) and the United States (males = 0.118, females = 0.030). The malignant incidence-rate ratio was higher for pineal GCTs versus nonpineal (ie, the rest of the brain) GCTs in Japan (11.5:1 vs 1.9:1, respectively) and the United States (16.0:1 vs 1.7:1, respectively). In general, 5-year survival estimates were high: over 75% for all GCTs, and over 81% for germinomas, regardless of the type of treatment in either Japan or the United States. The incidence of primary GCTs is similar between Japan and the United States and has the same gender-based patterns by location. High rates of survival were observed in both countries.

  9. Microtubule-Targeting Agents Enter the Central Nervous System (CNS): Double-edged Swords for Treating CNS Injury and Disease

    PubMed Central

    2014-01-01

    Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs) are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS) are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases. PMID:25558415

  10. Melphalan, Carboplatin, Mannitol, and Sodium Thiosulfate in Treating Patients With Recurrent or Progressive CNS Embryonal or Germ Cell Tumors

    ClinicalTrials.gov

    2016-04-28

    Adult Central Nervous System Germ Cell Tumor; Adult Ependymoblastoma; Adult Medulloblastoma; Adult Pineoblastoma; Adult Supratentorial Primitive Neuroectodermal Tumor; Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Ependymoblastoma; Medulloepithelioma; Ototoxicity; Recurrent Adult Brain Neoplasm; Recurrent Childhood Central Nervous System Embryonal Neoplasm; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor

  11. ABT-888 and Temozolomide in Treating Young Patients With Recurrent or Refractory CNS Tumors

    ClinicalTrials.gov

    2014-07-07

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  12. AZD2171 in Treating Young Patients With Recurrent, Progressive, or Refractory Primary CNS Tumors

    ClinicalTrials.gov

    2016-03-04

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Cerebral Anaplastic Astrocytoma; Childhood Cerebral Astrocytoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway Glioma

  13. Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination.

    PubMed

    Evonuk, Kirsten S; Moseley, Carson E; Doyle, Ryan E; Weaver, Casey T; DeSilva, Tara M

    2016-01-01

    A major hallmark of the autoimmune demyelinating disease multiple sclerosis (MS) is immune cell infiltration into the brain and spinal cord resulting in myelin destruction, which not only slows conduction of nerve impulses, but causes axonal injury resulting in motor and cognitive decline. Current treatments for MS focus on attenuating immune cell infiltration into the central nervous system (CNS). These treatments decrease the number of relapses, improving quality of life, but do not completely eliminate relapses so long-term disability is not improved. Therefore, therapeutic agents that protect the CNS are warranted. In both animal models as well as human patients with MS, T cell entry into the CNS is generally considered the initiating inflammatory event. In order to assess if a drug protects the CNS, any potential effects on immune cell infiltration or proliferation in the periphery must be ruled out. This protocol describes how to determine whether CNS protection observed after drug intervention is a consequence of attenuating CNS-infiltrating immune cells or blocking death of CNS cells during inflammatory insults. The ability to examine MS treatments that are protective to the CNS during inflammatory insults is highly critical for the advancement of therapeutic strategies since current treatments reduce, but do not completely eliminate, relapses (i.e., immune cell infiltration), leaving the CNS vulnerable to degeneration. PMID:27685467

  14. A Practical Guide for Exploring Opportunities of Repurposing Drugs for CNS Diseases in Systems Biology.

    PubMed

    Mei, Hongkang; Feng, Gang; Zhu, Jason; Lin, Simon; Qiu, Yang; Wang, Yue; Xia, Tian

    2016-01-01

    Systems biology has shown its potential in facilitating pathway-focused therapy development for central nervous system (CNS) diseases. An integrated network can be utilized to explore the multiple disease mechanisms and to discover repositioning opportunities. This review covers current therapeutic gaps for CNS diseases and the role of systems biology in pharmaceutical industry. We conclude with a Multiple Level Network Modeling (MLNM) example to illustrate the great potential of systems biology for CNS diseases. The system focuses on the benefit and practical applications in pathway centric therapy and drug repositioning.

  15. Central nervous system tumors in Mexican children.

    PubMed

    De la Torre Mondragón, L; Ridaura Sanz, C; Reyes Mujica, M; Rueda Franco, F

    1993-08-01

    Five hundred and seventy primary central nervous system (CNS) tumors from the Department of Pathology at the National Institute of Pediatrics in Mexico City, collected from 1970 to 1989, were histologically reclassified in order to find out their relative incidence as well as their outstanding features. With this, we could establish a frame of reference for our local population, contributing to the epidemiological analysis of these entities. All the tumors were examined independently by two pathologists (C.R. and M.R.), using the classification of Rorke et al. Histological type, patient age and sex, and tumor location were analyzed. CNS tumors were the secondmost frequently encountered solid tumors, after lymphomas, and were increasing in incidence at a rate of 2.2 annually. Children in the age group 0-9 years were most often affected, and there was a predominance of male patients. Astrocytoma and medulloblastoma were the most common tumor types. The infratentorial region was the most frequent tumor location in the 2- to 9-year age group. By contrast, in the under 2-year-olds a supratentorial location was more frequent, and the incidence of germ cell tumors was proportionally high. In general, some histological types seemed to be associated with particular age groups. Although we found primitive neuroectodermal tumors to be the fifth most common at all ages (except for medulloblastoma), many other authors do not report a similar finding.

  16. Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

    ClinicalTrials.gov

    2016-10-13

    Retinoblastoma; Clear Cell Sarcoma; Renal Cell Carcinoma; Rhabdoid Tumor; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Germ Cell Tumors; Ewings Sarcoma; Non-rhabdomyosarcoma Soft Tissue Sarcoma; Osteosarcoma; Rhabdomyosarcoma

  17. Clinical features, outcomes, and cerebrospinal fluid findings in adult patients with central nervous system (CNS) infections caused by varicella-zoster virus: comparison with enterovirus CNS infections.

    PubMed

    Hong, Hyo-Lim; Lee, Eun Mi; Sung, Heungsup; Kang, Joong Koo; Lee, Sang-Ahm; Choi, Sang-Ho

    2014-12-01

    Varicella-zoster virus (VZV) is known to be associated with central nervous system (CNS) infections in adults. However, the clinical characteristics of VZV CNS infections are not well characterized. The aim of this study was to compare the clinical manifestations, outcomes, and cerebrospinal fluid (CSF) findings in patients with VZV CNS infections with those in patients with enterovirus (EV) CNS infections. This retrospective cohort study was performed at a 2,700-bed tertiary care hospital. Using a clinical microbiology computerized database, all adults with CSF PCR results positive for VZV or EV that were treated between January 1999 and February 2013 were identified. Thirty-eight patients with VZV CNS infection and 68 patients with EV CNS infection were included in the study. Compared with the EV group, the median age in the VZV group was higher (VZV, 35 years vs. EV, 31 years; P = 0.02), and showed a bimodal age distribution with peaks in the third and seventh decade. Encephalitis was more commonly encountered in the VZV group (VZV, 23.7% vs. EV, 4.4%; P = 0.01). The median lymphocyte percentage in the CSF (VZV, 81% vs. EV, 36%; P < 0.001) and the CSF protein level (VZV, 100 mg/dl vs. EV, 46 mg/dl; P < 0.001) were higher in the VZV group. Compared with patients with EV CNS infection, patients with VZV CNS infection developed encephalitis more often and exhibited more intense inflammatory reaction. Nevertheless, both VZV and EV CNS infections were associated with excellent long-term prognosis.

  18. Central nervous system (CNS) cancer in children and young people in the European Union and its involvements with socio-economic and environmental factors.

    PubMed

    Llopis-González, Agustín; Alcaide Capilla, Teresa; Chenlo Alonso, Unai; Rubio-López, Nuria; Alegre-Martinez, Antoni; Morales Suárez-Varela, María

    2015-12-15

    Malignant central nervous system (CNS) tumors are the leading cause of death by cancer in children and the second commonest pediatric cancer type. Despite several decades of epidemiologic research, the etiology of childhood CNS tumors is still largely unknown. A few genetic syndromes and therapeutic ionizing radiation are thought to account for 5-10% of childhood cancer, but the etiology of other cases remains unknown. Nongenetic causes, like environmental agents, are thought to explain them. However, as very few epidemiologic studies have been conducted, it is not surprising that nongenetic risk factors have not been detected. The biggest difference between cancers for which there are good etiologic clues and those for which there are none could be the number of relevant studies. This study, which covers the 1980-2011 period, identified links between CNS cancer evolution and the socio-economic and environmental indicators in the same space and time limits in the European Union.

  19. Central nervous system (CNS) cancer in children and young people in the European Union and its involvements with socio-economic and environmental factors.

    PubMed

    Llopis-González, Agustín; Alcaide Capilla, Teresa; Chenlo Alonso, Unai; Rubio-López, Nuria; Alegre-Martinez, Antoni; Morales Suárez-Varela, María

    2015-12-15

    Malignant central nervous system (CNS) tumors are the leading cause of death by cancer in children and the second commonest pediatric cancer type. Despite several decades of epidemiologic research, the etiology of childhood CNS tumors is still largely unknown. A few genetic syndromes and therapeutic ionizing radiation are thought to account for 5-10% of childhood cancer, but the etiology of other cases remains unknown. Nongenetic causes, like environmental agents, are thought to explain them. However, as very few epidemiologic studies have been conducted, it is not surprising that nongenetic risk factors have not been detected. The biggest difference between cancers for which there are good etiologic clues and those for which there are none could be the number of relevant studies. This study, which covers the 1980-2011 period, identified links between CNS cancer evolution and the socio-economic and environmental indicators in the same space and time limits in the European Union. PMID:26671105

  20. Patterns of hospital resource utilization of children with leukemia and CNS tumors: a comparison of children who survive and those who die within 3 years of diagnosis.

    PubMed

    Hendrickson, Karrie Cummings; Rimar, Joan

    2009-01-01

    Hospital admissions for children with cancer tend to be longer than admissions for adults with cancer and longer, more frequent, and more costly than other pediatric admissions. The two childhood cancers most commonly requiring hospitalization are leukemia and tumors of the central nervous system (CNS tumors). Determining the best use of limited financial resources and preparing children and their parents for what to expect requires a better understanding of the patterns and cost of hospital resource utilization by children with cancer. Both hospital administrators and third-party payers can use this understanding to better allocate resources and plan the care of children with cancer in the future. Because many parents of children with cancer struggle financially due to the high cost of treatments, time off of work, and other non-medical expenses, more education in this area may help parents to prepare, thus alleviating some of the uncertainty and unexpected financial costs associated with childhood cancer.

  1. Dealing with Danger in the CNS: The Response of the Immune System to Injury

    PubMed Central

    Gadani, Sachin P.; Walsh, James T.; Lukens, John R.; Kipnis, Jonathan

    2015-01-01

    Fighting pathogens and maintaining tissue homeostasis are prerequisites for survival. Both of these functions are upheld by the immune system, though the latter is often overlooked in the context of the CNS. The mere presence of immune cells in the CNS was long considered a hallmark of pathology, but this view has been recently challenged by studies demonstrating that immunological signaling can confer pivotal neuroprotective effects on the injured CNS. In this review we describe the temporal sequence of immunological events that follow CNS injury. Beginning with immediate changes at the injury site including death of neural cells and release of damage-associated molecular patterns (DAMPs), and progressing through innate and adaptive immune responses, we describe the cascade of inflammatory mediators and the implications of their post-injury effects. We conclude by proposing a revised interpretation of immune privilege in the brain, which takes beneficial neuro-immune communications into account. PMID:26139369

  2. Impact of radiotherapy for pediatric CNS atypical teratoid/rhabdoid tumor (single institute experience)

    SciTech Connect

    Chen, Y.-W.; Wong, T.-T.; Ho, Donald Ming-Tak; Huang, P.-I.; Chang, K.-P.; Shiau, C.-Y.; Yen, S.-H. . E-mail: shyen@vghtpe.gov.tw

    2006-03-15

    Purpose: To assess outcomes and prognostic factors in radiotherapy of pediatric central nervous system atypical teratoid/rhabdoid tumor (AT/RT). Methods and Materials: Seventeen patients with central nervous system AT/RT were retrospectively reviewed after curative radiotherapy as primary or adjuvant therapy between January 1990 and December 2003. Overall and failure-free survival rates were calculated using the Kaplan-Meier method. The log-rank method was used to compare the effects of dosage (>50 Gy or {<=}50 Gy) and treatment duration (>45 days or {<=}45 days). Multivariate analysis was performed for prognostic factors. Results: Median overall survival and failure-free survival were 17 and 11 months, respectively. The 3 longest-surviving patients were older, underwent gross tumor removal, and completed both craniospinal and focal boost irradiation. Multivariate analysis revealed a significant relationship between the following: overall survival and performance status (p = 0.019), failure-free survival and total irradiation dose (p = 0.037), time interval between surgery and radiotherapy initiation (p = 0.031), and time interval between surgery and radiotherapy end point (p = 0.047). Conclusion: Radiotherapy is crucial in the treatment of AT/RT. We recommend initiating radiotherapy immediately postoperatively and before systemic chemotherapy in pediatric patients {>=}3 years of age.

  3. Airspace Concept Evaluation System (ACES), Concept Simulations using Communication, Navigation and Surveillance (CNS) System Models

    NASA Technical Reports Server (NTRS)

    Kubat, Greg; Vandrei, Don

    2006-01-01

    Project Objectives include: a) CNS Model Development; b Design/Integration of baseline set of CNS Models into ACES; c) Implement Enhanced Simulation Capabilities in ACES; d) Design and Integration of Enhanced (2nd set) CNS Models; and e) Continue with CNS Model Integration/Concept evaluations.

  4. Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system.

    PubMed Central

    Sampson, J H; Archer, G E; Ashley, D M; Fuchs, H E; Hale, L P; Dranoff, G; Bigner, D D

    1996-01-01

    Vaccination with cytokine-producing tumor cells generates potent immune responses against tumors outside the central nervous system (CNS). The CNS, however, is a barrier to allograft and xenograft rejection, and established tumors within the CNS have failed to respond to other forms of systemic immunotherapy. To determine what barriers the "immunologically privileged" CNS would pose to cytokine-assisted tumor vaccines and what cytokines would be most efficacious against tumors within the CNS, we irradiated B16 murine melanoma cells producing murine interleukin 2 (IL-2), IL-3, IL-4, IL-6, gamma-interferon, or granulocyte-macrophage colony stimulating factor (GM-CSF) and used these cells as subcutaneous vaccines against tumors within the brain. Under conditions where untransfected B16 cells had no effect, cells producing IL-3, IL-6, or GM-CSF increased the survival of mice challenged with viable B16 cells in the brain. Vaccination with B16 cells producing IL-4 or gamma-interferon had no effect, and vaccination with B16 cells producing IL-2 decreased survival time. GM-CSF-producing vaccines were also able to increase survival in mice with pre-established tumors. The response elicited by GM-CSF-producing vaccines was found to be specific to tumor type and to be abrogated by depletion of CD8+ cells. Unlike the immunity generated against subcutaneous tumors by GM-CSF, however, the effector responses generated against tumors in the CNS were not dependent on CD4+ cells. These data suggest that cytokine-producing tumor cells are very potent stimulators of immunity against tumors within the CNS, but effector responses in the CNS may be different from those obtained against subcutaneous tumors. Images Fig. 3 PMID:8816812

  5. General Information about Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor

    MedlinePlus

    ... Teratoid/Rhabdoid Tumor Treatment (PDQ®)–Patient Version General Information About Childhood Central Nervous System (CNS) Atypical Teratoid/ ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  6. Using Ferumoxytol-Enhanced MRI to Measure Inflammation in Patients With Brain Tumors or Other Conditions of the CNS

    ClinicalTrials.gov

    2016-07-08

    Brain Injury; Central Nervous System Degenerative Disorder; Central Nervous System Infectious Disorder; Central Nervous System Vascular Malformation; Hemorrhagic Cerebrovascular Accident; Ischemic Cerebrovascular Accident; Primary Brain Neoplasm; Brain Cancer; Brain Tumors

  7. Immunohistological localization of 5-HT in the CNS and feeding system of the Stable Fly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    5-HT immunoreactive neurons were detected in the CNS of the stable fly. The finding of strong innervations of the cibarial pump muscles and the foregut by 5-HT IR neurons in the feeding-related systems suggests that 5-HT may play a crucial role in the control of the feeding behavior in both the larv...

  8. Interactions of the histamine and hypocretin systems in CNS disorders.

    PubMed

    Shan, Ling; Dauvilliers, Yves; Siegel, Jerome M

    2015-07-01

    Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system. PMID:26100750

  9. Interactions of the histamine and hypocretin systems in CNS disorders.

    PubMed

    Shan, Ling; Dauvilliers, Yves; Siegel, Jerome M

    2015-07-01

    Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system.

  10. Generalized CNS arousal: An elementary force within the vertebrate nervous system.

    PubMed

    Calderon, D P; Kilinc, M; Maritan, A; Banavar, J R; Pfaff, D

    2016-09-01

    Why do animals and humans do anything at all? Arousal is the most powerful and essential function of the brain, a continuous function that accounts for the ability of animals and humans to respond to stimuli in the environment by producing muscular responses. Following decades of psychological, neurophysiological and molecular investigations, generalized CNS arousal can now be analyzed using approaches usually applied to physical systems. The concept of "criticality" is a state that illustrates an advantage for arousal systems poised near a phase transition. This property provides speed and sensitivity and facilitates the transition of the system into different brain states, especially as the brain crosses a phase transition from less aroused to more aroused states. In summary, concepts derived from applied mathematics of physical systems will now find their application in this area of neuroscience, the neurobiology of CNS arousal. PMID:27216213

  11. Central nervous system tumors: a single center pathology review of 34,140 cases over 60 years

    PubMed Central

    2013-01-01

    Background Tumor epidemiology is a significant part of CNS (central nervous system) tumor studies. Reassessment of original sections can update our knowledge of tumor spectrum. Here, we discuss the features of CNS tumor pathology in a single center. Methods A total of 34140 cases from 1950 to 2009 were collected; sections from 1990 to 2009 were reassessed according to WHO 2007 classification, and cases from 1950 to 1989 were classified according to the previous pathological diagnosis. Results Seven CNS tumor categories during 1990 to 2009 were as follow: neuroepithelial tissue (38.0%), tumors of the meninges (36.5%), tumors of the sellar region (4.1%), germ cell tumors (1.3%), tumors of cranial and paraspinal nerves (13.3%), lymphomas and hematopoietic neoplasm (1.7%), metastatic tumors (5.1%), where histological types by age and sex were diverse. Overall, males exceeded females in distributions of most CNS tumor subtypes, while tumors of the meninges occurred more frequently in females. The case number of lymphomas and hematopoietic neoplasms grew the fastest during the past five years, and the distribution of neuroepithelial tumors remained stable over the past twenty years. Conclusions Despite the possibilities of cross sample biases, the data in this series could suggest a similar CNS tumor spectrum as might occur in other developing countries. PMID:23639346

  12. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.

    PubMed

    Louis, David N; Perry, Arie; Reifenberger, Guido; von Deimling, Andreas; Figarella-Branger, Dominique; Cavenee, Webster K; Ohgaki, Hiroko; Wiestler, Otmar D; Kleihues, Paul; Ellison, David W

    2016-06-01

    The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors. PMID:27157931

  13. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.

    PubMed

    Louis, David N; Perry, Arie; Reifenberger, Guido; von Deimling, Andreas; Figarella-Branger, Dominique; Cavenee, Webster K; Ohgaki, Hiroko; Wiestler, Otmar D; Kleihues, Paul; Ellison, David W

    2016-06-01

    The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.

  14. MicroRNA Signatures as Biomarkers and Therapeutic Target for CNS Embryonal Tumors: The Pros and the Cons

    PubMed Central

    Shalaby, Tarek; Fiaschetti, Giulio; Baumgartner, Martin; Grotzer, Michael A.

    2014-01-01

    Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients’ response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5–10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs) in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets. PMID:25421247

  15. Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

    ClinicalTrials.gov

    2014-11-04

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Gonadotroph Adenoma; Pituitary Basophilic Adenoma; Pituitary Chromophobe Adenoma; Pituitary Eosinophilic Adenoma; Prolactin Secreting Adenoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Pituitary Tumor; Recurrent/Refractory Childhood Hodgkin Lymphoma; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; TSH Secreting Adenoma; Unspecified Childhood Solid Tumor, Protocol Specific

  16. Nanomedicine in Central Nervous System (CNS) Disorders: A Present and Future Prospective

    PubMed Central

    Soni, Shringika; Ruhela, Rakesh Kumar; Medhi, Bikash

    2016-01-01

    Purpose: For the past few decades central nervous system disorders were considered as a major strike on human health and social system of developing countries. The natural therapeutic methods for CNS disorders limited for many patients. Moreover, nanotechnology-based drug delivery to the brain may an exciting and promising platform to overcome the problem of BBB crossing. In this review, first we focused on the role of the blood-brain barrier in drug delivery; and second, we summarized synthesis methods of nanomedicine and their role in different CNS disorder. Method: We reviewed the PubMed databases and extracted several kinds of literature on neuro nanomedicines using keywords, CNS disorders, nanomedicine, and nanotechnology. The inclusion criteria included chemical and green synthesis methods for synthesis of nanoparticles encapsulated drugs and, their in-vivo and in-vitro studies. We excluded nanomedicine gene therapy and nanomaterial in brain imaging. Results: In this review, we tried to identify a highly efficient method for nanomedicine synthesis and their efficacy in neuronal disorders. SLN and PNP encapsulated drugs reported highly efficient by easily crossing BBB. Although, these neuro-nanomedicine play significant role in therapeutics but some metallic nanoparticles reported the adverse effect on developing the brain. Conclusion: Although impressive advancement has made via innovative potential drug development, but their efficacy is still moderate due to limited brain permeability. To overcome this constraint,powerful tool in CNS therapeutic intervention provided by nanotechnology-based drug delivery methods. Due to its small and biofunctionalization characteristics, nanomedicine can easily penetrate and facilitate the drug through the barrier. But still, understanding of their toxicity level, optimization and standardization are a long way to go. PMID:27766216

  17. Intraoperative consultation on pediatric central nervous system tumors by squash cytology.

    PubMed

    Lacruz, César R; Catalina-Fernández, Inmaculada; Bardales, Ricardo H; Pimentel, José; López-Presa, Dolores; Sáenz-Santamaría, Javier

    2015-06-01

    Squash cytology (SC) is a very useful procedure during neurosurgical intraoperative consultation (IOC), and it is especially recommended for the evaluation of soft tumors or tumors that are highly cellular (just the characteristics of pediatric central nervous system [CNS] tumors). The aim of this review is to familiarize pathologists with the range of cytomorphologic appearances that can occur during IOC for pediatric CNS tumors and with the diagnostic dilemmas and pitfalls encountered in this setting. This article is based on the medical literature and the authors' experience with a large series of cases accrued over a 12-year period at 3 institutions. SC is a specially recommended procedure in IOC for pediatric CNS tumors; it reveals the fine cellular details and background features in a manner not seen in corresponding frozen sections. Indeed, a differential diagnosis between histologically look-alike processes can be achieved with more confidence if SC is employed. PMID:25766425

  18. Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma

    PubMed Central

    Miller, Suzanne; Rogers, Hazel A.; Lyon, Paul; Rand, Vikki; Adamowicz-Brice, Martyna; Clifford, Steven C.; Hayden, James T.; Dyer, Sara; Pfister, Stefan; Korshunov, Andrey; Brundler, Marie-Anne; Lowe, James; Coyle, Beth; Grundy, Richard G.

    2011-01-01

    Central nervous system primitive neuroectodermal tumor (CNS PNET) and pineoblastoma are highly malignant embryonal brain tumors with poor prognoses. Current therapies are based on the treatment of pediatric medulloblastoma, even though these tumors are distinct at both the anatomical and molecular level. CNS PNET and pineoblastoma have a worse clinical outcome than medulloblastoma; thus, improved therapies based on an understanding of the underlying biology of CNS PNET and pineoblastoma are needed. To this end, we characterized the genomic alterations of 36 pediatric CNS PNETs and 8 pineoblastomas using Affymetrix single nucleotide polymorphism arrays. Overall, the majority of CNS PNETs contained a greater degree of genomic imbalance than pineoblastomas, with gain of 19p (8 [27.6%] of 29), 2p (7 [24.1%] of 29), and 1q (6 [20.7%] of 29) common events in primary CNS PNETs. Novel gene copy number alterations were identified and corroborated by Genomic Identification of Significant Targets In Cancer (GISTIC) analysis: gain of PCDHGA3, 5q31.3 in 62.1% of primary CNS PNETs and all primary pineoblastomas and FAM129A, 1q25 in 55.2% of primary CNS PNETs and 50% of primary pineoblastomas. Comparison of our GISTIC data with publically available data for medulloblastoma confirmed these CNS PNET–specific copy number alterations. With use of the collection of 5 primary and recurrent CNS PNET pairs, we found that gain of 2p21 was maintained at relapse in 80% of cases. Novel gene copy number losses included OR4C12, 11p11.12 in 48.2% of primary CNS PNETs and 50% of primary pineoblastomas. Loss of CDKN2A/B (9p21.3) was identified in 14% of primary CNS PNETs and was significantly associated with older age among children (P = .05). CADPS, 3p14.2 was lost in 27.6% of primary CNS PNETs and was associated with poor prognosis (P = .043). This genome-wide analysis revealed the marked molecular heterogeneity of CNS PNETs and enabled the identification of novel genes and clinical

  19. A Novel Robust H∞ Filter Based on Krein Space Theory in the SINS/CNS Attitude Reference System.

    PubMed

    Yu, Fei; Lv, Chongyang; Dong, Qianhui

    2016-01-01

    Owing to their numerous merits, such as compact, autonomous and independence, the strapdown inertial navigation system (SINS) and celestial navigation system (CNS) can be used in marine applications. What is more, due to the complementary navigation information obtained from two different kinds of sensors, the accuracy of the SINS/CNS integrated navigation system can be enhanced availably. Thus, the SINS/CNS system is widely used in the marine navigation field. However, the CNS is easily interfered with by the surroundings, which will lead to the output being discontinuous. Thus, the uncertainty problem caused by the lost measurement will reduce the system accuracy. In this paper, a robust H∞ filter based on the Krein space theory is proposed. The Krein space theory is introduced firstly, and then, the linear state and observation models of the SINS/CNS integrated navigation system are established reasonably. By taking the uncertainty problem into account, in this paper, a new robust H∞ filter is proposed to improve the robustness of the integrated system. At last, this new robust filter based on the Krein space theory is estimated by numerical simulations and actual experiments. Additionally, the simulation and experiment results and analysis show that the attitude errors can be reduced by utilizing the proposed robust filter effectively when the measurements are missing discontinuous. Compared to the traditional Kalman filter (KF) method, the accuracy of the SINS/CNS integrated system is improved, verifying the robustness and the availability of the proposed robust H∞ filter. PMID:26999153

  20. A Novel Robust H∞ Filter Based on Krein Space Theory in the SINS/CNS Attitude Reference System

    PubMed Central

    Yu, Fei; Lv, Chongyang; Dong, Qianhui

    2016-01-01

    Owing to their numerous merits, such as compact, autonomous and independence, the strapdown inertial navigation system (SINS) and celestial navigation system (CNS) can be used in marine applications. What is more, due to the complementary navigation information obtained from two different kinds of sensors, the accuracy of the SINS/CNS integrated navigation system can be enhanced availably. Thus, the SINS/CNS system is widely used in the marine navigation field. However, the CNS is easily interfered with by the surroundings, which will lead to the output being discontinuous. Thus, the uncertainty problem caused by the lost measurement will reduce the system accuracy. In this paper, a robust H∞ filter based on the Krein space theory is proposed. The Krein space theory is introduced firstly, and then, the linear state and observation models of the SINS/CNS integrated navigation system are established reasonably. By taking the uncertainty problem into account, in this paper, a new robust H∞ filter is proposed to improve the robustness of the integrated system. At last, this new robust filter based on the Krein space theory is estimated by numerical simulations and actual experiments. Additionally, the simulation and experiment results and analysis show that the attitude errors can be reduced by utilizing the proposed robust filter effectively when the measurements are missing discontinuous. Compared to the traditional Kalman filter (KF) method, the accuracy of the SINS/CNS integrated system is improved, verifying the robustness and the availability of the proposed robust H∞ filter. PMID:26999153

  1. A Novel Robust H∞ Filter Based on Krein Space Theory in the SINS/CNS Attitude Reference System.

    PubMed

    Yu, Fei; Lv, Chongyang; Dong, Qianhui

    2016-03-18

    Owing to their numerous merits, such as compact, autonomous and independence, the strapdown inertial navigation system (SINS) and celestial navigation system (CNS) can be used in marine applications. What is more, due to the complementary navigation information obtained from two different kinds of sensors, the accuracy of the SINS/CNS integrated navigation system can be enhanced availably. Thus, the SINS/CNS system is widely used in the marine navigation field. However, the CNS is easily interfered with by the surroundings, which will lead to the output being discontinuous. Thus, the uncertainty problem caused by the lost measurement will reduce the system accuracy. In this paper, a robust H∞ filter based on the Krein space theory is proposed. The Krein space theory is introduced firstly, and then, the linear state and observation models of the SINS/CNS integrated navigation system are established reasonably. By taking the uncertainty problem into account, in this paper, a new robust H∞ filter is proposed to improve the robustness of the integrated system. At last, this new robust filter based on the Krein space theory is estimated by numerical simulations and actual experiments. Additionally, the simulation and experiment results and analysis show that the attitude errors can be reduced by utilizing the proposed robust filter effectively when the measurements are missing discontinuous. Compared to the traditional Kalman filter (KF) method, the accuracy of the SINS/CNS integrated system is improved, verifying the robustness and the availability of the proposed robust H∞ filter.

  2. Spontaneous behavioral rhythms in the isolated CNS of insects - presenting new model systems.

    PubMed

    Hustert, R; Mashaly, A M

    2013-01-01

    Three new model systems for the study of rhythm generation in the isolated insect central nervous system are presented. Natural behavioral rhythms are produced in these cases spontaneously in the isolated CNS. They can be monitored as output of motoneurons at peripheral nerves. Recording from the neurons of the pattern generating networks during this output gives insight into neural control principles of locust respiration, of hemolymph pumping in accessory pumping organs of crickets, and of crawling movements in larvae of the weevil Rhynchophorus ferrugineus. PMID:22609472

  3. System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS.

    PubMed

    Bridges, Richard J; Natale, Nicholas R; Patel, Sarjubhai A

    2012-01-01

    System x(c)(-) is an amino acid antiporter that typically mediates the exchange of extracellular l-cystine and intracellular L-glutamate across the cellular plasma membrane. Studied in a variety of cell types, the import of L-cystine through this transporter is critical to glutathione production and oxidative protection. The exchange-mediated export of L-glutamate takes on added significance within the CNS, as it represents a non-vesicular route of release through which this excitatory neurotransmitter can participate in either neuronal signalling or excitotoxic pathology. When both the import of L-cystine and the export of L-glutamate are taken into consideration, system x(c)(-) has now been linked to a wide range of CNS functions, including oxidative protection, the operation of the blood-brain barrier, neurotransmitter release, synaptic organization, viral pathology, drug addiction, chemosensitivity and chemoresistance, and brain tumour growth. The ability to selectively manipulate system x(c)(-), delineate its function, probe its structure and evaluate it as a therapeutic target is closely linked to understanding its pharmacology and the subsequent development of selective inhibitors and substrates. Towards that goal, this review will examine the current status of our understanding of system x(c)(-) pharmacology and the structure-activity relationships that have guided the development of an initial pharmacophore model, including the presence of lipophilic domains adjacent to the substrate binding site. A special emphasis is placed on the roles of system x(c)(-) within the CNS, as it is these actions that are among the most exciting as potential long-range therapeutic targets.

  4. Current Understanding of Circulating Tumor Cells – Potential Value in Malignancies of the Central Nervous System

    PubMed Central

    Adamczyk, Lukasz A.; Williams, Hannah; Frankow, Aleksandra; Ellis, Hayley Patricia; Haynes, Harry R.; Perks, Claire; Holly, Jeff M. P.; Kurian, Kathreena M.

    2015-01-01

    Detection of circulating tumor cells (CTCs) in the blood via so-called “liquid biopsies” carries enormous clinical potential in malignancies of the central nervous system (CNS) because of the potential to follow disease evolution with a blood test, without the need for repeat neurosurgical procedures with their inherent risk of patient morbidity. To date, studies in non-CNS malignancies, particularly in breast cancer, show increasing reproducibility of detection methods for these rare tumor cells in the circulation. However, no method has yet received full recommendation to use in clinical practice, in part because of lack of a sufficient evidence base regarding clinical utility. In CNS malignancies, one of the main challenges is finding a suitable biomarker for identification of these cells, because automated systems, such as the widely used Cell Search system, are reliant on markers, such as the epithelial cell adhesion molecule, which are not present in CNS tumors. This review examines methods for CTC enrichment and detection, and reviews the progress in non-CNS tumors and the potential for using this technique in human brain tumors. PMID:26322014

  5. Descriptive epidemiology and risk factors of primary central nervous system tumors: Current knowledge.

    PubMed

    Pouchieu, C; Baldi, I; Gruber, A; Berteaud, E; Carles, C; Loiseau, H

    2016-01-01

    Although comparisons are difficult due to differences in methodologies, the annual incidence rates of central nervous system (CNS) tumors range from 8.5 to 21.4/100,000 population according to cancer registries, with a predominance of neuroepithelial tumors in men and meningiomas in women. An increase in the incidence of CNS tumors has been observed during the past decades in several countries. It has been suggested that this trend could be due to aging of the population, and improvements in diagnostic imaging and healthcare access, but these factors do not explain differences in incidence by gender and histological subtypes. Several etiological hypotheses related to intrinsic (sociodemographic, anthropometric, hormonal, immunological, genetic) and exogenous (ionizing radiation, electromagnetic fields, diet, infections, pesticides, drugs) risk factors have led to analytical epidemiological studies to establish relationships with CNS tumors. The only established environmental risk factor for CNS tumors is ionizing radiation exposure. However, for other risk factors, studies have been inconsistent and inconclusive due to systematic differences in study design and difficulties in accurately measuring exposures. Thus, the etiology of CNS tumors is complex and may involve several genetic and/or environmental factors that may act differently according to histological subtype. PMID:26708326

  6. Staging Primary CNS Lymphoma

    MedlinePlus

    ... large vein near the heart. Having a weakened immune system may increase the risk of developing primary CNS ... immunodeficiency syndrome (AIDS) or other disorders of the immune system or who have had a kidney transplant . For ...

  7. The role of zinc in the pathogenesis and treatment of central nervous system (CNS) diseases. Implications of zinc homeostasis for proper CNS function.

    PubMed

    Tyszka-Czochara, Małgorzata; Grzywacz, Agata; Gdula-Argasińska, Joanna; Librowski, Tadeusz; Wiliński, Bogdan; Opoka, Włodzimierz

    2014-01-01

    Zinc, the essential trace element, is known to play multiple biological functions in human organism. This metal is a component of many structural as well as regulatory and catalytic proteins. The precise regulation of zinc homeostasis is essential for central nervous system and for the whole organism. Zinc plays a significant role in the brain development and in the proper brain function at every stage of life. This article is a review of knowledge about the role of zinc in central nervous system (CNS) function. The influence of this biometal on etiopathogenesis, prevention and treatment of selected brain diseases and disorders was discussed. Zinc imbalance can result not only from insufficient dietary intake, but also from impaired activity of zinc transport proteins and zinc dependent regulation of metabolic pathways. It is known that some neurodegenerative processes are connected with zinc dyshomeostasis and it may influence the state of Alzheimer's disease, depression and ageing-connected loss of cognitive function. The exact role of zinc and zinc-binding proteins in CNS pathogenesis processes is being under intensive investigation. The appropriate zinc supplementation in brain diseases may help in the prevention as well as in the proper treatment of several brain dysfunctions.

  8. Incidence and survival of children with central nervous system primitive tumors in the French National Registry of Childhood Solid Tumors

    PubMed Central

    Desandes, Emmanuel; Guissou, Sandra; Chastagner, Pascal; Lacour, Brigitte

    2014-01-01

    Background Central nervous system (CNS) tumors are the second most common childhood malignancy. The French National Registry of Childhood Solid Tumors (NRCST) makes it possible to describe this variety of distinct tumor types and to provide incidence and survival data in France on a nationwide basis. Methods All children aged 0–14 years, who were registered with a primary CNS tumor in the NRCST of France between 2000 and 2008, were identified. Tumors were classified according to the International Classification of Childhood Cancer, third edition. Results Approximately 57% of pediatric CNS tumors were gliomas, with astrocytomas of the pilocytic type predominating. Distributions of subtypes by age showed that primitive neuroectodermal tumors and ependymomas mainly occurred in children aged <5 years. The mean annual incidence rate of CNS tumors was 39 per million. No statistically significant change in time trends of incidence rate was observed during 2000–2008. For all tumors combined, overall survival was 84.8% (95% CI, 83.7%–85.9%) at 1 year and 72.9% (95% CI, 71.5%–74.3%) at 5 years. Survival time trends were studied in a multivariate analysis observing a reduction in the risk of death in periods of diagnosis 2003–2005 (HR = 0.8; 95% CI, 0.7–0.9) and 2006–2008 (HR = 0.7; 95% CI, 0.6–0.9) compared with 2000–2002. Conclusions The stable incidence rates during the last 10 years could indicate that major changes in environmental risk factors are unlikely, but the ongoing need for population-based surveillance remains relevant. Results indicate a positive trend in the survival probability still persistent in the 2000s. PMID:24470548

  9. Clinicopathological and immunohistochemical features of primary central nervous system germ cell tumors: a 24-years experience.

    PubMed

    Gao, Yuping; Jiang, Jiyao; Liu, Qiang

    2014-01-01

    Primary central nervous system (CNS) germ cell tumors (GCTs) are a rare heterogeneous group of lesions, which the clinicopathological features have a marked degree of heterogeneity comparing with that of gonadal GCTs. Accurately diagnosing CNS GCTs might be extremely difficult and requires immunohistochemical verification. This study was to investigate the biological feature of CNS GCTs and diagnostic value of immunohistochemical markers OCT3/4, C-kit, PLAP, and CD30 in CNS GCTs. A retrospective study was performed on 34 patients with CNS germ cell tumors between 1990 and 2014. 34 CNS GCTs account for 9.2% of all primary CNS neoplasms. The sellar region (35.3%) and pineal gland (17.6%) were the most common sites of intracranial GCTs. Hydrocephalus (82.4%) and diplopia (46.9%) were the two most common clinical presentations. The most common histological subtypes were germinoma (67.6%). PLAP, c-kit, OCT3/4 were highly expressed in gernimomas. CD30 and CK AE1/3 stainings were positive in embryonal carcinoma. Yolk sac tumor component showed positive staining for AFP and CK AE1/3. β-HCG staining was positive in choriocarcinoma and STGC. Patients with mature teratomas and germinomas had a better prognosis (a 5-year survival rate) than those with embryonal carcinoma and choriocarcinoma (a 5-year survival rates were 0). Our finding suggest that the incidences of primary CNS GCTs are higher in South China than in the West, but mixed GCTs are uncommon in our study. The judicious use of a panel of selected markers is helpful in diagnosing and predicting the prognosis for CNS GCTs.

  10. Sphingosine Lysolipids in the CNS: Endogenous Cannabinoid Antagonists or a Parallel Pain Modulatory System?

    PubMed Central

    Selley, Dana E.; Welch, Sandra P.; Sim-Selley, Laura J.

    2014-01-01

    A significant number of patients experience chronic pain and the intractable side effects of currently prescribed pain medications. Recent evidence indicates important pain modulatory roles for two classes of G-protein-coupled receptors that are activated by endogenous lipid ligands, the endocannabinoid (eCB) and sphingosine-1-phosphate (S1P) receptors, which are widely expressed in both the immune and nervous systems. In the central nervous system (CNS), CB1 cannabinoid and S1P1 receptors are most abundantly expressed and exhibit overlapping anatomical distributions and similar signaling mechanisms. The eCB system has emerged as a potential target for treatment of chronic pain, but comparatively little is known about the roles of S1P in pain regulation. Both eCB and S1P systems modulate pain perception via the central and peripheral nervous systems. In most paradigms studied, the eCB system mainly inhibits pain perception. In contrast, S1P acting peripherally at S1P1 and S1P3 receptors can enhance sensitivity to various pain stimuli or elicit spontaneous pain. However, S1P acting at S1P1 receptors and possibly other targets in the CNS can attenuate sensitivity to various pain stimuli. Interestingly, other endogenous sphingolipid derivatives might play a role in central pain sensitization. Moreover, these sphingolipids can also act as CB1 cannabinoid receptor antagonists, but the physiological relevance of this interaction is unknown. Overall, both eCB and sphingolipid systems offer promising targets for the treatment of chronic pain. This review compares and contrasts the eCB and S1P systems with a focus on their roles in pain modulation, and considers possible points of interaction between these systems. PMID:23782998

  11. Pediatric Primitive Neuroectodermal Tumors of the Central Nervous System Differentially Express Granzyme Inhibitors

    PubMed Central

    Vermeulen, Jeroen F.; van Hecke, Wim; Spliet, Wim G. M.; Villacorta Hidalgo, José; Fisch, Paul; Broekhuizen, Roel; Bovenschen, Niels

    2016-01-01

    Background Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) are malignant primary brain tumors that occur in young infants. Using current standard therapy, up to 80% of the children still dies from recurrent disease. Cellular immunotherapy might be key to improve overall survival. To achieve efficient killing of tumor cells, however, immunotherapy has to overcome cancer-associated strategies to evade the cytotoxic immune response. Whether CNS-PNETs can evade the immune response remains unknown. Methods We examined by immunohistochemistry the immune response and immune evasion strategies in pediatric CNS-PNETs. Results Here, we show that CD4+, CD8+, γδ-T-cells, and Tregs can infiltrate pediatric CNS-PNETs, although the activation status of cytotoxic cells is variable. Pediatric CNS-PNETs evade immune recognition by downregulating cell surface MHC-I and CD1d expression. Intriguingly, expression of SERPINB9, SERPINB1, and SERPINB4 is acquired during tumorigenesis in 29%, 29%, and 57% of the tumors, respectively. Conclusion We show for the first time that brain tumors express direct granzyme inhibitors (serpins) as a potential mechanism to overcome cellular cytotoxicity, which may have consequences for cellular immunotherapy. PMID:26963506

  12. CNS development: an overview

    NASA Technical Reports Server (NTRS)

    Nowakowski, R. S.; Hayes, N. L.

    1999-01-01

    The basic principles of the development of the central nervous system (CNS) are reviewed, and their implications for both normal and abnormal development of the brain are discussed. The goals of this review are (a) to provide a set of concepts to aid in understanding the variety of complex processes that occur during CNS development, (b) to illustrate how these concepts contribute to our knowledge of the normal anatomy of the adult brain, and (c) to provide a basis for understanding how modifications of normal developmental processes by traumatic injury, by environmental or experiential influences, or by genetic variations may lead to modifications in the resultant structure and function of the adult CNS.

  13. Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors

    PubMed Central

    Gounder, Mrinal M.; Nayak, Lakshmi; Sahebjam, Solmaz; Muzikansky, Alona; Sanchez, Armando J.; Desideri, Serena; Ye, Xiaobu; Ivy, S. Percy; Nabors, L. Burt; Prados, Michael; Grossman, Stuart; DeAngelis, Lisa M.; Wen, Patrick Y.

    2016-01-01

    Purpose Patients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations. Patient and Methods Individual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival. Results Our analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n = 5) and cytotoxic (n = 3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range, < one to 56 cycles), and 96% were evaluable for primary end points. During cycle 1, grade ≥ 3 nonhematologic and grade ≥ 4 hematologic toxicities were 5% (28 of 565 adverse events) and 0.9% (five of 565 adverse events), respectively, and 66% of these occurred at the highest dose level. There was one death attributed to drug. Overall response rate (complete and partial response) was 5.5%. Median progression-free and overall survival times were 1.8 and 6 months, respectively. Conclusion Patients with HGG who meet standard eligibility criteria may be good candidates for solid tumor phase I studies with single-agent molecular or cytotoxic drugs with favorable preclinical rationale and pharmacokinetic properties

  14. Solitary Fibrous Tumor of Central Nervous System: A Case Report.

    PubMed

    Kim, Jang Hoon; Yang, Kook Hee; Yoon, Pyeong Ho; Kie, Jeong Hae

    2015-10-01

    Solitary fibrous tumor (SFT) is a rare neoplasm of mesenchymal origin, especially in the central nervous system (CNS). Reported herein is a case of SFT of CNS in a 63-year-old female patient who had confused mentality, without other neurological deficit. The brain MRI showed an ovoid mass in the right frontal lobe. The tumor was surgically removed grossly and totally, and the pathologic diagnosis was SFT. At 55 months after the surgery, the tumor recurred at the primary site and at an adjacent area. A second operation was thus done, and the tumor was again surgically removed grossly and totally. The pathologic diagnosis was the same as the previous, but the Ki-67 index was elevated. Ten months later, two small recurring tumors in the right frontal skull base were found in the follow-up MRI. It was decided that radiation therapy be done, and MRI was done again 3 months later. In the follow-up MRI, the size of the recurring mass was found to have decreased, and the patient did not manifest any significant symptom. Follow-up will again be done 18 months after the second surgery.

  15. Solitary Fibrous Tumor of Central Nervous System: A Case Report.

    PubMed

    Kim, Jang Hoon; Yang, Kook Hee; Yoon, Pyeong Ho; Kie, Jeong Hae

    2015-10-01

    Solitary fibrous tumor (SFT) is a rare neoplasm of mesenchymal origin, especially in the central nervous system (CNS). Reported herein is a case of SFT of CNS in a 63-year-old female patient who had confused mentality, without other neurological deficit. The brain MRI showed an ovoid mass in the right frontal lobe. The tumor was surgically removed grossly and totally, and the pathologic diagnosis was SFT. At 55 months after the surgery, the tumor recurred at the primary site and at an adjacent area. A second operation was thus done, and the tumor was again surgically removed grossly and totally. The pathologic diagnosis was the same as the previous, but the Ki-67 index was elevated. Ten months later, two small recurring tumors in the right frontal skull base were found in the follow-up MRI. It was decided that radiation therapy be done, and MRI was done again 3 months later. In the follow-up MRI, the size of the recurring mass was found to have decreased, and the patient did not manifest any significant symptom. Follow-up will again be done 18 months after the second surgery. PMID:26605270

  16. Delayed Effects of Whole Brain Radiotherapy in Germ Cell Tumor Patients With Central Nervous System Metastases

    SciTech Connect

    Doyle, Danielle M. Einhorn, Lawrence H.

    2008-04-01

    Purpose: Central nervous system (CNS) metastases are uncommon in patients with germ cell tumors, with an incidence of 2-3%. CNS metastases have been managed with whole brain radiotherapy (WBRT) and concomitant cisplatin-based combination chemotherapy. Our previous study did not observe serious CNS toxicity (Int J Radiat Oncol Biol Phys 1991;22:17-22). We now report on 5 patients who developed delayed significant CNS toxicity. Patients and Methods: We observed 5 patients with delayed CNS toxicity. The initial diagnosis was between 1981 and 2003. All patients had poor-risk disease according to the International Germ Cell Consensus Collaborative Group criteria. Of the 5 patients, 3 had CNS metastases at diagnosis and 2 developed relapses with CNS metastases. These 5 patients underwent WBRT to 4,000-5,000 cGy in 18-28 fractions concurrently with cisplatin-based chemotherapy. Results: All 5 patients developed delayed symptoms consistent with progressive multifocal leukoencephalopathy. The symptoms included seizures, hemiparesis, cranial neuropathy, headaches, blindness, dementia, and ataxia. The median time from WBRT to CNS symptoms was 72 months (range, 9-228). Head imaging revealed multiple abnormalities consistent with gliosis and diffuse cerebral atrophy. Of the 5 patients, 3 had progressive and 2 stable symptoms. Treatment with surgery and/or steroids had modest benefit. The progressive multifocal leukoencephalopathy resulted in significant debility in all 5 patients, resulting in death (3 patients), loss of work, steroid-induced morbidity, and recurrent hospitalizations. Conclusion: Whole brain radiotherapy is not innocuous in young patients with germ cell tumors and can cause late CNS toxicity.

  17. Tumors of the Central Nervous System: An 18-Year Retrospective Review in a Tertiary Pediatric Referral Center

    PubMed Central

    AGHAYAN GOLKASHANI, Hosein; HATAMI, Hossein; FARZAN, Abdonaser; MOHAMMADI, Hassan Reza; NILIPOUR, Yalda; KHODDAMI, Maliheh; JADALI, Farzaneh

    2015-01-01

    Objective Few studies exist on the demographics and trends of pediatric central nervous system (CNS) tumors in Iran. In this study, we retrospectively reviewed all cases with confirmed CNS tumors admitted to Mofid Pediatric Hospital, Tehran, Iran during the last 18 years. Materials & Methods Data on gender, age of diagnosis, pathologic classification and tumor location were extracted from the available medical records. We used the last version of International Classification of Childhood Cancer. Result Overall, 258 (81.9%) brain tumors and 57 (18.1%) spinal tumors were identified. Our subjects comprised of 147 (46.7%) female and 168 (53.3%) male children. More male dominancy was observed in brain tumors with a male to female ratio of 1.2 compared with 1.03 of spinal tumors. Malignant CNS tumors were most common in 1-4 yr age group. The four most common brain tumors in our subjects were astrocytomas, medulloblastoma, ependymoma and craniopharyngioma. Overall, 53.1% of the brain tumors were supratentorial. Gliomas, PNET and neuroblastma were the most frequent primary spinal tumors in our study. We observed an increasing trend for both brain and spinal tumors that was moreremarkable in the last 5 years. Conclusion Our results are comparable with similar single center studies on CNS tumors during childhood. The observed disparities could be attributed to the single center nature of our study and geographical, environmental and racial variations in pediatric CNS tumors. The increasing trend of both brain and spinal tumors could warrant further investigations at provincial and national levels to investigate probable contributing environmental risk factors. PMID:26401150

  18. B Cells in the Multiple Sclerosis Central Nervous System: Trafficking and Contribution to CNS-Compartmentalized Inflammation.

    PubMed

    Michel, Laure; Touil, Hanane; Pikor, Natalia B; Gommerman, Jennifer L; Prat, Alexandre; Bar-Or, Amit

    2015-01-01

    Clinical trial results of peripheral B cell depletion indicate abnormal proinflammatory B cell properties, and particularly antibody-independent functions, contribute to relapsing MS disease activity. However, potential roles of B cells in progressive forms of disease continue to be debated. Prior work indicates that presence of B cells is fostered within the inflamed MS central nervous system (CNS) environment, and that B cell-rich immune cell collections may be present within the meninges of patients. A potential association is reported between such meningeal immune cell collections and the subpial pattern of cortical injury that is now considered important in progressive disease. Elucidating the characteristics of B cells that populate the MS CNS, how they traffic into the CNS and how they may contribute to progressive forms of the disease has become of considerable interest. Here, we will review characteristics of human B cells identified within distinct CNS subcompartments of patients with MS, including the cerebrospinal fluid, parenchymal lesions, and meninges, as well as the relationship between B cell populations identified in these subcompartments and the periphery. We will further describe the different barriers of the CNS and the possible mechanisms of migration of B cells across these barriers. Finally, we will consider the range of human B cell responses (including potential for antibody production, cytokine secretion, and antigen presentation) that may contribute to propagating inflammation and injury cascades thought to underlie MS progression. PMID:26732544

  19. ERG is a novel and reliable marker for endothelial cells in central nervous system tumors.

    PubMed

    Haber, Matthew A; Iranmahboob, Amir; Thomas, Cheddhi; Liu, Mengling; Najjar, Amanda; Zagzag, David

    2015-01-01

    ETS-related gene (ERG) is a transcription factor that has been linked to angiogenesis. Very little research has been done to assess ERG expression in central nervous system (CNS) tumors. We evaluated 57 CNS tumors, including glioblastomas (GBMs) and hemangioblastomas (HBs), as well as two arteriovenous malformations and four samples of normal brain tissue with immunohistochemistry using a specific ERG rabbit monoclonal antibody. In addition, immunostains for CD31, CD34, and α-smooth muscle actin (α-SMA) were performed on all samples. CD31 demonstrated variable and sometimes weak immunoreactivity for endothelial cells. Furthermore, in 1 case of a GBM, CD34 stained not only endothelial cells, but also tumor cells. In contrast, we observed that ERG was only expressed in the nuclei of endothelial cells, for example, in the hyperplastic vascular complexes that comprise the glomeruloid microvascular proliferation seen in GBMs. Conversely, α-SMA immunoreactivity was identified in the abluminal cells of these hyperplastic vessels. Quantitative evaluation with automated methodology and custom Matlab 2008b software was used to calculate percent staining of ERG in each case. We observed significantly higher quantitative expression of ERG in HBs than in other CNS tumors. Our results show that ERG is a novel, reliable, and specific marker for endothelial cells within CNS tumors that can be used to better study the process of neovascularization.

  20. ERG is a novel and reliable marker for endothelial cells in central nervous system tumors.

    PubMed

    Haber, Matthew A; Iranmahboob, Amir; Thomas, Cheddhi; Liu, Mengling; Najjar, Amanda; Zagzag, David

    2015-01-01

    ETS-related gene (ERG) is a transcription factor that has been linked to angiogenesis. Very little research has been done to assess ERG expression in central nervous system (CNS) tumors. We evaluated 57 CNS tumors, including glioblastomas (GBMs) and hemangioblastomas (HBs), as well as two arteriovenous malformations and four samples of normal brain tissue with immunohistochemistry using a specific ERG rabbit monoclonal antibody. In addition, immunostains for CD31, CD34, and α-smooth muscle actin (α-SMA) were performed on all samples. CD31 demonstrated variable and sometimes weak immunoreactivity for endothelial cells. Furthermore, in 1 case of a GBM, CD34 stained not only endothelial cells, but also tumor cells. In contrast, we observed that ERG was only expressed in the nuclei of endothelial cells, for example, in the hyperplastic vascular complexes that comprise the glomeruloid microvascular proliferation seen in GBMs. Conversely, α-SMA immunoreactivity was identified in the abluminal cells of these hyperplastic vessels. Quantitative evaluation with automated methodology and custom Matlab 2008b software was used to calculate percent staining of ERG in each case. We observed significantly higher quantitative expression of ERG in HBs than in other CNS tumors. Our results show that ERG is a novel, reliable, and specific marker for endothelial cells within CNS tumors that can be used to better study the process of neovascularization. PMID:25881913

  1. Functional genomics of the brain: uncovering networks in the CNS using a systems approach.

    PubMed

    Konopka, Genevieve

    2011-01-01

    The central nervous system (CNS) is undoubtedly the most complex human organ system in terms of its diverse functions, cellular composition, and connections. Attempts to capture this diversity experimentally were the foundation on which the field of neurobiology was built. Until now though, techniques were either painstakingly slow or insufficient in capturing this heterogeneity. In addition, the combination of multiple layers of information needed for a complete picture of neuronal diversity from the epigenome to the proteome requires an even more complex compilation of data. In this era of high-throughput genomics though, the ability to isolate and profile neurons and brain tissue has increased tremendously and now requires less effort. Both microarrays and next-generation sequencing have identified neuronal transcriptomes and signaling networks involved in normal brain development, as well as in disease. However, the expertise needed to organize and prioritize the resultant data remains substantial. A combination of supervised organization and unsupervised analyses are needed to fully appreciate the underlying structure in these datasets. When utilized effectively, these analyses have yielded striking insights into a number of fundamental questions in neuroscience on topics ranging from the evolution of the human brain to neuropsychiatric and neurodegenerative disorders. Future studies will incorporate these analyses with behavioral and physiological data from patients to more efficiently move toward personalized therapeutics.

  2. A fluorescence based method, exploiting lipofuscin, for the real-time detection of central nervous system (CNS) tissues on bovine carcasses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The removal of Central Nervous System (CNS) tissues as part of Bovine Spongiform Encephalopathy (BSE) risk material is one of the highest priority tasks to avoid contamination of the human food chain with BSE. No currently available method enables the real-time detection of possible CNS tissue conta...

  3. Absence of Lymphatic Vessels in PCNSL May Contribute to Confinement of Tumor Cells to the Central Nervous System.

    PubMed

    Deckert, Martina; Brunn, Anna; Montesinos-Rongen, Manuel; Siebert, Reiner

    2016-06-01

    Primary central nervous system (CNS) lymphoma (PCNSL) is a mature lymphoma of the diffuse large B-cell lymphoma (DLBCL) type confined to the CNS. Despite cytomorphological similarities between PCNSL and systemic DLBCL, molecular differences between both entities have been identified. The exclusively topographical restriction of PCNSL to the CNS is an unexplained mystery. To address the question of whether the unique lymphatic drainage system of the CNS, which differs from that of other organs, may play a role for this peculiar behavior, we investigated a series of 20 PCNSLs for the presence of lymphatic vessels by immunohistochemistry for Lyve-1, podoplanin, and Prox-1 expression. All PCNSLs lacked lymphatic vessels and, in this regard, were similar to 20 glioblastoma multiforme samples. In contrast to these tumors, all of which were located in the deep brain parenchyma, dural and meningeal DLBCL harbored lymphatic vessels that expressed Lyve-1 (3/8 tumors), podoplanin (5/8 tumors), and Prox-1 (5/8 tumors) in areas where the tumors had invaded the fibrous tissue of the dura. These data indicate that local topographical characteristics of the specific lymphatic drainage system may contribute to confinement of the tumor cells in PCNSL and malignant gliomas.

  4. Absence of Lymphatic Vessels in PCNSL May Contribute to Confinement of Tumor Cells to the Central Nervous System.

    PubMed

    Deckert, Martina; Brunn, Anna; Montesinos-Rongen, Manuel; Siebert, Reiner

    2016-06-01

    Primary central nervous system (CNS) lymphoma (PCNSL) is a mature lymphoma of the diffuse large B-cell lymphoma (DLBCL) type confined to the CNS. Despite cytomorphological similarities between PCNSL and systemic DLBCL, molecular differences between both entities have been identified. The exclusively topographical restriction of PCNSL to the CNS is an unexplained mystery. To address the question of whether the unique lymphatic drainage system of the CNS, which differs from that of other organs, may play a role for this peculiar behavior, we investigated a series of 20 PCNSLs for the presence of lymphatic vessels by immunohistochemistry for Lyve-1, podoplanin, and Prox-1 expression. All PCNSLs lacked lymphatic vessels and, in this regard, were similar to 20 glioblastoma multiforme samples. In contrast to these tumors, all of which were located in the deep brain parenchyma, dural and meningeal DLBCL harbored lymphatic vessels that expressed Lyve-1 (3/8 tumors), podoplanin (5/8 tumors), and Prox-1 (5/8 tumors) in areas where the tumors had invaded the fibrous tissue of the dura. These data indicate that local topographical characteristics of the specific lymphatic drainage system may contribute to confinement of the tumor cells in PCNSL and malignant gliomas. PMID:27142645

  5. Gravity sensing in the retinal spreading depression, an in-vitro model for the central nervous system (CNS)

    NASA Astrophysics Data System (ADS)

    Wiedemann, Meike; Piffel, Alexandra; Hanke, Wolfgang

    2005-08-01

    The retinal spreading depression (SD) was used to study the effects of altered gravity on the central nervous system (CNS). The SD is an excitation depression wave and an example of self-organization and pattern formation in neuronal tissue being an excitable media. Until now it is not much known about how changes in gravity effect the central nervous system. Here we present the results of SD experiments on a sounding rocket mission (TEXUS 41) and the comparison to earlier SD experiments on parabolic flights (2nd and 3rd DLR Parabolic flight campaign) and centrifuge experiments in our lab. The results of these experimetns show that the properties of the SD and therefore the CNS in its properties as an excitable medium reacts very sensitive to changes in gravity.

  6. Molecular stress response in the CNS of mice after systemic exposureto interferon-alpha, ionizing radiation and ketamine

    SciTech Connect

    Lowe, Xiu R.; Marchetti, Francesco; Lu, Xiaochen; Wyrobek, Andrew J.

    2009-03-03

    We previously showed that the expression of troponin T1 (Tnnt 1) was induced in the central nervous system (CNS) of adultmice 30 min after treatment with ketamine, a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist. We hypothesized that Tnnt 1 expression may be an early molecular biomarker of stress response in the CNS of mice. To further evaluate this hypothesis, we investigated the regional expression of Tnnt 1 in the mouse brain using RNA in situ hybridization 4 h after systemic exposure to interferon-a (IFN-a) and gamma ionizing radiation, both of which have be associated with wide ranges of neuropsychiatric complications. Adult B6C3F1 male mice were treated with either human IFN-a (a single i.p. injection at 1 x 105 IU/kg) or whole body gamma-radiation (10 cGy or 2 Gy). Patterns of Tnnt 1 transcript expression were compared in various CNS regions after IFN-a, radiation and ketamine treatments (previous study). Tnnt 1 expression was consistently induced in pyramidal neurons of cerebral cortex and hippocampus after all treatment regimens including 10 cGy of ionizing radiation. Regional expression of Tnnt 1 was induced in Purkinje cells of cerebellum after ionizing radiation and ketamine treatment; but not after IFN-a treatment. None of the three treatments induced Tnnt 1 expression in glial cells. The patterns of Tnnt 1 expression in pyramidal neurons of cerebral cortex andhippocampus, which are both known to play important roles in cognitive function, memory and emotion, suggest that the expression of Tnnt 1 may be an early molecular biomarker of induced CNS stress.

  7. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan.

    PubMed

    Weismann, Cara M; Ferreira, Jennifer; Keeler, Allison M; Su, Qin; Qui, Linghua; Shaffer, Scott A; Xu, Zuoshang; Gao, Guangping; Sena-Esteves, Miguel

    2015-08-01

    GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease where GLB1 gene mutations result in a reduction or absence of lysosomal acid β-galactosidase (βgal) activity. βgal deficiency leads to accumulation of GM1-ganglioside in the central nervous system (CNS). GM1 is characterized by progressive neurological decline resulting in generalized paralysis, extreme emaciation and death. In this study, we assessed the therapeutic efficacy of an adeno-associated virus (AAV) 9-mβgal vector infused systemically in adult GM1 mice (βGal(-/-)) at 1 × 10(11) or 3 × 10(11) vector genomes (vg). Biochemical analysis of AAV9-treated GM1 mice showed high βGal activity in liver and serum. Moderate βGal levels throughout CNS resulted in a 36-76% reduction in GM1-ganglioside content in the brain and 75-86% in the spinal cord. Histological analyses of the CNS of animals treated with 3 × 10(11) vg dose revealed increased presence of βgal and clearance of lysosomal storage throughout cortex, hippocampus, brainstem and spinal cord. Storage reduction in these regions was accompanied by a marked decrease in astrogliosis. AAV9 treatment resulted in improved performance in multiple tests of motor function and behavior. Also the majority of GM1 mice in the 3 × 10(11) vg cohort retained ambulation and rearing despite reaching the humane endpoint due to weight loss. Importantly, the median survival of AAV9 treatment groups (316-576 days) was significantly increased over controls (250-264 days). This study shows that moderate widespread expression of βgal in the CNS of GM1 gangliosidosis mice is sufficient to achieve significant biochemical impact with phenotypic amelioration and extension in lifespan.

  8. Characterization of the M2 autoantigen of central nervous system (CNS) myelin as a glycoproteins(s) also expressed on oligodendrocyte membrane

    SciTech Connect

    Lebar, R.; Lubetzki, C.; Vincent, C.; Lombrail, P.; Boutry, J.M.

    1986-03-01

    Guinea pigs immunized with homologous brain tissue develop an acute experimental allergic encephalomyelitis and their sera contain demyelinating antibodies. These antibodies were used to characterize the target: the unidentified autoantigen M2. Using both the Dot immunobinding technique and autoradiography of immunoprecipitates formed with radiolabelled guinea-pig myelin and analyzed in SDS acrylamide gel electrophoresis, M2 was found to be a component of CNS myelin and not peripheral nervous system (PNS) myelin. In the Dot technique anti-M2 serum did not react with myelin basic protein (BP), proteolipid and galactocerebroside (GC). On electrophoresis, in reducing and non reducing conditions, M2 appeared as two CNS myelin protein bands at the 27,000 and 54,000 molecular weight levels, distinct from the CNS myelin major protein bands of proteolipid protein and BP. Affinity chromatography of CNS myelin on wheat germ agglutinin Sepharose showed that M2 bands were of glycoprotein nature. The same M2 bands were formed with guinea pig antibodies and rat, rabbit or bovine CNS myelin. The same type of anti-M2 antibodies were induced in rabbits immunized with homologous CNS tissue. As a component of myelin, M2 was present in white matter tracts of CNS tissue sections tested by immunofluorescence. Furthermore, M2 was expressed on rat oligodendrocyte membrane in one day and 8 day in vitro cultures.

  9. Morphologic characterization of spontaneous nervous system tumors in mice and rats.

    PubMed

    Krinke, G J; Kaufmann, W; Mahrous, A T; Schaetti, P

    2000-01-01

    Spontaneous rodent nervous system tumors, in comparison to those of man, are less well differentiated. Among the central nervous system (CNS) tumors, the "embryonic" forms (medulloblastoma, pineoblastoma) occur both in rodents and humans, whereas the human "adult" forms (gliomas, ependymomas, meningiomas) have fewer counterparts in rodents. In general, the incidence of spontaneous CNS tumors is higher in rats (>1%) than in mice (>0.001%). A characteristic rat CNS tumor is the granular cell tumor. Usually it is associated with the meninges, and most meningeal tumors in rats seem to be totally or at least partly composed of granular cells, which have eosinophilic granular cytoplasm, are periodic acid-Schiff reaction (PAS)-positive, and contain lysosomes. Such tumors are frequently found on the cerebellar surface or at the brain basis. Rat astrocytomas are diffuse, frequently multifocal, and they invade perivascular spaces and meninges. The neoplastic cells with round to oval nuclei and indistinct cytoplasm grow around preexisting neurons, producing satellitosis. In large tumors, there are necrotic areas surrounded by palisading cells. Extensive damage of brain tissue is associated with the presence of scavenger cells that react positively with histiocytic/macrophage markers. The neoplastic astrocytes do not stain positively for glial fibrillary acidic protein; they probably represent an immature phenotype. In contrast to neoplastic oligodendroglia, they bind the lectin RCA-1. Astrocytomas are frequently located in the brain stem, especially the basal ganglia. Rat oligodendroglial tumors are well circumscribed and frequently grow in the walls of brain ventricles. Their cells have water-clear cytoplasm and round, dark-staining nuclei. Atypical vascular endothelial proliferation occurs, especially at the tumor periphery. Occasionally in the oligodendrogliomas, primitive glial elements with large nuclei occur in the form of cell groups that form rows and circles

  10. Clinicopathological analysis of nine consecutive central nervous system primitive neuroectodermal tumors in a single institute.

    PubMed

    Aizawa-Kohama, Misaki; Kumabe, Toshihiro; Saito, Ryuta; Kanamori, Masayuki; Yamashita, Yoji; Sonoda, Yukihiko; Watanabe, Mika; Tominaga, Teiji

    2013-01-01

    The objective of this study was to determine the outcome of central nervous system primitive neuroectodermal tumors (CNS PNETs) and to clarify the histopathological findings as prognostic factors. We performed a retrospective analysis of nine consecutive patients with CNS PNETs who underwent treatment at our institute between 1993 and 2011. All patients were treated by surgical resection followed by chemoradiotherapy. Additional treatment, including surgical resection, was performed at relapse. Expression of immunohistochemical markers was examined for neuronal, astrocytic, mesenchymal, and epithelial differentiation, and also for TP53, O(6)-methylguanine-DNA methyltransferase, and Ki-67. Five-year progression-free survival was 18.2 % and the overall survival was 52.5 %. Five the 9 patients had recurrence and 4 patients died during the median follow-up period of 41.1 months. All 4 patients died of dissemination not local recurrence. After relapses, the extent of differentiation was different in each case and TP53 changed to positive or negative, but the Ki-67 labeling index did not reveal any differences between primary and recurrent tumors. A treatment procedure to prevent and treat dissemination of CNS PNETs should be established. Because the pathological change after relapse was different in each case, definitive histopathological prognostic factors for CNS PNETs are still difficult to propose.

  11. Staging Childhood Central Nervous System Embryonal Tumors

    MedlinePlus

    ... There are four types of CNS PNETs: CNS neuroblastomas CNS neuroblastomas are a very rare type of neuroblastoma that form in the nerve tissue of the ... that cover the brain and spinal cord. CNS neuroblastomas may be large and spread to other parts ...

  12. Clinical Experience With Radiation Therapy in the Management of Neurofibromatosis-Associated Central Nervous System Tumors

    SciTech Connect

    Wentworth, Stacy; Pinn, Melva; Bourland, J. Daniel; Guzman, Allan F. de; Ekstrand, Kenneth; Ellis, Thomas L.; Glazier, Steven S.; McMullen, Kevin P.; Munley, Michael; Stieber, Volker W.; Tatter, Stephen B.; Shaw, Edward G.

    2009-01-01

    Purpose: Patients with neurofibromatosis (NF) develop tumors of the central nervous system (CNS). Radiation therapy (RT) is used to treat these lesions. To better define the efficacy of RT in these patients, we reviewed our 20-year experience. Methods and Materials: Eighteen patients with NF with CNS tumors were treated from 1986 to 2007. Median follow-up was 48 months. Progression was defined as growth or recurrence of an irradiated tumor on serial imaging. Progression-free survival (PFS) was measured from the date of RT completion to the date of last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. Results: Eighty-two tumors in 18 patients were irradiated, with an average of five tumors/patient. Median age at treatment was 25 years (range, 4.3-64 years). Tumor types included acoustic neuroma (16%), ependymoma (6%), low-grade glioma (11%), meningioma (60%), and schwanomma/neurofibroma (7%). The most common indication for treatment was growth on serial imaging. Most patients (67%) received stereotactic radiosurgery (median dose, 1,200 cGy; range, 1,000-2,400 cGy). The OS rate at 5 years was 94%. Five-year PFS rates were 75% (acoustic neuroma), 100% (ependymoma), 75% (low-grade glioma), 86% (meningioma), and 100% (schwanomma/neurofibroma). Thirteen acoustic neuromas had a local control rate of 94% with a 50% hearing preservation rate. Conclusions: RT provided local control, OS, and PFS rates similar to or better than published data for tumors in non-NF patients. Radiation therapy should be considered in NF patients with imaging progression of CNS tumors.

  13. Nanotechnological advances for the delivery of CNS therapeutics.

    PubMed

    Wong, Ho Lun; Wu, Xiao Yu; Bendayan, Reina

    2012-05-15

    Effective non-invasive treatment of neurological diseases is often limited by the poor access of therapeutic agents into the central nervous system (CNS). The majority of drugs and biotechnological agents do not readily permeate into brain parenchyma due to the presence of two anatomical and biochemical dynamic barriers: the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Therefore, one of the most significant challenges facing CNS drug development is the availability of effective brain targeting technology. Recent advances in nanotechnology have provided promising solutions to this challenge. Several nanocarriers ranging from the more established systems, e.g. polymeric nanoparticles, solid lipid nanoparticles, liposomes, micelles to the newer systems, e.g. dendrimers, nanogels, nanoemulsions and nanosuspensions have been studied for the delivery of CNS therapeutics. Many of these nanomedicines can be effectively transported across various in vitro and in vivo BBB models by endocytosis and/or transcytosis, and demonstrated early preclinical success for the management of CNS conditions such as brain tumors, HIV encephalopathy, Alzheimer's disease and acute ischemic stroke. Future development of CNS nanomedicines need to focus on increasing their drug-trafficking performance and specificity for brain tissue using novel targeting moieties, improving their BBB permeability and reducing their neurotoxicity. PMID:22100125

  14. Syndrome-Associated Tumors by Organ System.

    PubMed

    Gonzalez, Raul S; Riddle, Nicole D

    2016-06-01

    Certain tumors suggest the possibility of a patient harboring a genetic syndrome, particularly in children. Syndrome-associated tumors of the gastrointestinal tract, genitourinary tract, gynecologic tract, heart, lungs, brain, eye, endocrine organs, and hematopoietic system will be briefly discussed.

  15. Report: Central nervous system (CNS) toxicity caused by metal poisoning: Brain as a target organ.

    PubMed

    Gilani, Syeda Rubina; Zaidi, Syed Raza Ali; Batool, Madeeha; Bhatti, Amanat Ali; Durrani, Arjumand Iqbal; Mahmood, Zaid

    2015-07-01

    People relate the neural disorders with either inheritance or psychological violence but there might be some other reasons responsible for the ailment of people that do not have such a background. The present study explains the chronic effect of heavy toxic metals on nervous system. During experimentation, rabbits used as laboratory animals, were given test metals in their diet. Concentration of metals given to them in the diet was less than their tolerable dietary intake. Behavioral changes were observed during experimentation. Periodic increase in the metal concentration was seen in the blood sample of rabbits. They were slaughtered after a period of eight months of slow poisoning. Histological examination of brain tissues was performed. The brain samples were analyzed by Atomic absorption spectroscopy and Inductively Coupled Plasma Mass Spectrometry to find the retention of heavy metals in mammalian brain. Concentration of lead, mercury and cadmium in the blood samples of occupationally exposed people and patients with neurological disorders at the time of neurosurgery was determined by using the same techniques. During circulation, toxic metals passes through the nerve capillaries to settle down in the brain. Heavy metals cross the blood brain barrier and 'may retain themselves in it. Brain tumors and biopsy samples of patients with neurological disorder were also analyzed to relate neurotoxicity and heavy metal poisoning. Results obtained shows that lead, mercury and cadmium retain themselves in the brain for longer period of time and are one of the causes of neurotoxicity.

  16. Anti-aquaporin-4 autoantibodies in systemic lupus erythematosus persist for years and induce astrocytic cytotoxicity but not CNS disease.

    PubMed

    Alexopoulos, Harry; Kampylafka, Eleni I; Fouka, Penelope; Tatouli, Ioanna; Akrivou, Sofia; Politis, Panagiotis K; Moutsopoulos, Haralampos M; Tzioufas, Athanasios G; Dalakas, Marinos C

    2015-12-15

    Anti-aquaporin-4 autoantibodies are specific for the neuromyelitis optica spectrum disorders (NMOSD) and they have also been described in patients with systemic lupus erythematosus (SLE) with neurological signs consistent with NMOSD. Our objective was to test for the presence and pathogenicity of anti-AQP4 antibodies in SLE patients without neurological disease. Sera from 89 non-CNS-SLE patients were screened for anti-AQP4 autoantibodies. Two of the 89 patients were positive. Archived samples dating back 11 years were also positive. A brain and spinal cord MRI did not reveal any NMOSD-compatible lesions. An in vitro cytotoxicity assay showed that either sera or purified IgG from these patients induced a complement-mediated damage in cultured astrocytes comparable to antibodies obtained from typical NMO patients. We conclude that AQP4-antibodies can be present in SLE patients and persist for many years, without concurrent clinical or radiological NMOSD signs. It is unclear why the anti-AQP4 antibodies did not induce CNS disease.

  17. Histamine and Immune Biomarkers in CNS Disorders

    PubMed Central

    Cacabelos, Ramón; Torrellas, Clara; Fernández-Novoa, Lucía; López-Muñoz, Francisco

    2016-01-01

    Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer's disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death. PMID:27190492

  18. Rapid immunocytochemistry based on alternating current electric field using squash smear preparation of central nervous system tumors.

    PubMed

    Moriya, Jun; Tanino, Mishie Ann; Takenami, Tomoko; Endoh, Tomoko; Urushido, Masana; Kato, Yasutaka; Wang, Lei; Kimura, Taichi; Tsuda, Masumi; Nishihara, Hiroshi; Tanaka, Shinya

    2016-01-01

    The role of intraoperative pathological diagnosis for central nervous system (CNS) tumors is crucial for neurosurgery when determining the surgical procedure. Especially, treatment of carmustine (BCNU) wafers requires a conclusive diagnosis of high-grade glioma proven by intraoperative diagnosis. Recently, we demonstrated the usefulness of rapid immunohistochemistry (R-IHC) that facilitates antigen-antibody reaction under alternative current (AC) electric field in the intraoperative diagnosis of CNS tumors; however, a higher proportion of water and lipid in the brain parenchyma sometimes leads to freezing artifacts, resulting in poor quality of frozen sections. On the other hand, squash smear preparation of CNS tumors for cytology does not affect the frozen artifacts, and the importance of smear preparation is now being re-recognized as being better than that of the tissue sections. In this study, we established the rapid immunocytochemistry (R-ICC) protocol for squash smears of CNS tumors using AC electric field that takes only 22 min, and demonstrated its usefulness for semi-quantitative Ki-67/MIB-1 labeling index and CD 20 by R-ICC for intraoperative diagnosis. R-ICC by AC electric field may become a substantial tool for compensating R-IHC and will be applied for broad antibodies in the future.

  19. Solitary fibrous tumor of the central nervous system: report of 2 cases and review of literature.

    PubMed

    Wen, Ge; Li, Meifang; Xu, Lijun; Hu, Peiqian; Liao, Xin; Lin, Chuang; Zhao, Liang

    2014-01-01

    Solitary fibrous tumors (SFTs) rarely occur in the central nervous system (CNS). Involvement of the brainstem and pineal gland is rarely recorded. Herein, we represent 2 cases of SFTs and firstly report SFT of the pineal gland. Cranial MR imaging showed isointense to hypointense signal intensity, and marked enhancement. Microscopically, the tumors showed characteristic "patternless-pattern" architecture. Elongated tumour cells formed fascicles alternating with hypocellular densely collagenous stroma. Immunohistochemistry for CD34, BCL2, and CD99 favors the definitive diagnosis of SFT. It is difficult to predict prognosis in patients with intraventricular SFT. In general, complete surgical resection may offer the best chance of a favorable clinical outcome.

  20. STARs in the CNS.

    PubMed

    Ehrmann, Ingrid; Fort, Philippe; Elliott, David J

    2016-08-15

    STAR (signal transduction and activation of RNA) proteins regulate splicing of target genes that have roles in neural connectivity, survival and myelination in the vertebrate nervous system. These regulated splicing targets include mRNAs such as the Neurexins (Nrxn), SMN2 (survival of motor neuron) and MAG (myelin-associated glycoprotein). Recent work has made it possible to identify and validate STAR protein splicing targets in vivo by using genetically modified mouse models. In this review, we will discuss the importance of STAR protein splicing targets in the CNS (central nervous system). PMID:27528753

  1. Non-neuronal cardiac cholinergic system influences CNS via the vagus nerve to acquire a stress-refractory propensity.

    PubMed

    Oikawa, Shino; Kai, Yuko; Tsuda, Masayuki; Ohata, Hisayuki; Mano, Asuka; Mizoguchi, Naoko; Sugama, Shuei; Nemoto, Takahiro; Suzuki, Kenji; Kurabayashi, Atsushi; Muramoto, Kazuyo; Kaneda, Makoto; Kakinuma, Yoshihiko

    2016-11-01

    We previously developed cardiac ventricle-specific choline acetyltransferase (ChAT) gene-overexpressing transgenic mice (ChAT tgm), i.e. an in vivo model of the cardiac non-neuronal acetylcholine (NNA) system or non-neuronal cardiac cholinergic system (NNCCS). By using this murine model, we determined that this system was responsible for characteristics of resistance to ischaemia, or hypoxia, via the modulation of cellular energy metabolism and angiogenesis. In line with our previous study, neuronal ChAT-immunoreactivity in the ChAT tgm brains was not altered from that in the wild-type (WT) mice brains; in contrast, the ChAT tgm hearts were the organs with the highest expression of the ChAT transgene. ChAT tgm showed specific traits in a central nervous system (CNS) phenotype, including decreased response to restraint stress, less depressive-like and anxiety-like behaviours and anti-convulsive effects, all of which may benefit the heart. These phenotypes, induced by the activation of cardiac NNCCS, were dependent on the vagus nerve, because vagus nerve stimulation (VS) in WT mice also evoked phenotypes similar to those of ChAT tgm, which display higher vagus nerve discharge frequency; in contrast, lateral vagotomy attenuated these traits in ChAT tgm to levels observed in WT mice. Furthermore, ChAT tgm induced several biomarkers of VS responsible for anti-convulsive and anti-depressive-like effects. These results suggest that the augmentation of the NNCCS transduces an effective and beneficial signal to the afferent pathway, which mimics VS. Therefore, the present study supports our hypothesis that activation of the NNCCS modifies CNS to a more stress-resistant state through vagus nerve activity. PMID:27528769

  2. Acute Cerebrovascular Radiation Syndrome: Radiation Neurotoxicity , mechanisms of CNS radiation injury, advanced countermeasures for Radiation Protection of Central Nervous System.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Jones, Jeffrey; Maliev, Slava

    Key words: Cerebrovascular Acute Radiation Syndrome (Cv ARS), Radiation Neurotoxins (RNT), Neurotransmitters, Radiation Countermeasures, Antiradiation Vaccine (ArV), Antiradiation Blocking Antibodies, Antiradiation Antidote. Psychoneuroimmunology, Neurotoxicity. ABSTRACT: To review the role of Radiation Neurotoxins in triggering, developing of radiation induced central nervous system injury. Radiation Neurotoxins - rapidly acting blood toxic lethal agent, which activated after irradiation and concentrated, circulated in interstitial fluid, lymph, blood with interactions with cell membranes, receptors and cell compartments. Radiation Neurotoxins - biological molecules with high enzymatic activity and/or specific lipids and activated or modified after irradiation. The Radiation Neurotoxins induce increased permeability of blood vessels, disruption of the blood-brain barrier, blood-cerebrospinal fluid (CSF) barrier and developing severe disorder of blood macro- and micro-circulation. Principles of Radiation Psychoneuro-immunology and Psychoneuro-allergology were applied for determination of pathological processes developed after irradiation or selective administration of Radiation Neurotoxins to radiation naïve mammals. Effects of radiation and exposure to radiation can develop severe irreversible abnormalities of Central Nervous System, brain structures and functions. Antiradiation Vaccine - most effective, advanced methods of protection, prevention, mitigation and treatment and was used for of Acute Radiation Syndromes and elaboration of new technology for immune-prophylaxis and immune-protection against ϒ, Heavy Ion, Neutron irradiation. Results of experiments suggested that blocking, antitoxic, antiradiation antibodies can significantly reduce toxicity of Radiation Toxins. New advanced technology include active immune-prophylaxis with Antiradiation Vaccine and Antiradiation therapy that included specific blocking antibodies to Radiation Neurotoxins

  3. CNS Diseases and Uveitis

    PubMed Central

    Allegri, Pia; Rissotto, Roberto; Herbort, Carl P.; Murialdo, Ugo

    2011-01-01

    A number of inflammatory, infectious, neoplastic and idiopathic disorders affect the eye and the central nervous system (CNS) concurrently or at different time frames. These conditions pose a diagnostic challenge to the clinician since they may present with similar ocular and neurological manifestations. The purpose of this review is to describe major neurological syndromes including multiple sclerosis, Vogt-Koyanagi-Harada disease, other autoimmune syndromes, and several infectious diseases which may affect the eye. This article may serve as a guide for the diagnosis and treatment of such disorders. It should be noted that these conditions have been viewed from a neurologist’s perspective thereby neurologic involvement is stressed. PMID:22454751

  4. Development of a Novel 3D Culture System for Screening Features of a Complex Implantable Device for CNS Repair

    PubMed Central

    2013-01-01

    Tubular scaffolds which incorporate a variety of micro- and nanotopographies have a wide application potential in tissue engineering especially for the repair of spinal cord injury (SCI). We aim to produce metabolically active differentiated tissues within such tubes, as it is crucially important to evaluate the biological performance of the three-dimensional (3D) scaffold and optimize the bioprocesses for tissue culture. Because of the complex 3D configuration and the presence of various topographies, it is rarely possible to observe and analyze cells within such scaffolds in situ. Thus, we aim to develop scaled down mini-chambers as simplified in vitro simulation systems, to bridge the gap between two-dimensional (2D) cell cultures on structured substrates and three-dimensional (3D) tissue culture. The mini-chambers were manipulated to systematically simulate and evaluate the influences of gravity, topography, fluid flow, and scaffold dimension on three exemplary cell models that play a role in CNS repair (i.e., cortical astrocytes, fibroblasts, and myelinating cultures) within a tubular scaffold created by rolling up a microstructured membrane. Since we use CNS myelinating cultures, we can confirm that the scaffold does not affect neural cell differentiation. It was found that heterogeneous cell distribution within the tubular constructs was caused by a combination of gravity, fluid flow, topography, and scaffold configuration, while cell survival was influenced by scaffold length, porosity, and thickness. This research demonstrates that the mini-chambers represent a viable, novel, scale down approach for the evaluation of complex 3D scaffolds as well as providing a microbioprocessing strategy for tissue engineering and the potential repair of SCI. PMID:24279373

  5. Treatment of primary CNS lymphoma (PCNSL) following successful treatment of systemic non-Hodgkin's lymphoma (NHL): a case series.

    PubMed

    Chamberlain, Marc C

    2013-05-01

    Management of PCNSL occurring after successful treatment of systemic non-Hodgkin's lymphoma (NHL) is poorly defined. Illustrate a treatment approach for PCNSL following prior treatment of a systemic NHL. A retrospective case series of 6 patients (mean age 60 years; range 46-65) diagnosed with a diffuse large B cell lymphoma of the CNS following prior successful treatment of a systemic NHL (low-grade in 2; high-grade in 4). Mean interval to diagnosis of PCNSL after diagnosis of systemic NHL was 12 months (range 7-18). In 4/6 patients in whom genetic analysis could be performed, the PCNSL and NHL differed. Treatment utilized high-dose methotrexate and rituximab (immunochemotherapy) followed in patients with a radiographic complete response by autologous peripheral stem cell transplant (ASCT) with total body irradiation (TBI) and multi-agent conditioning chemotherapy (BEAM: carmustine, etoposide, cytarabine, melphalan). 5/6 patients had a radiographic complete response to immunochemotherapy and were treated with ASCT. 4/5 patients were free of disease following ASCT with a mean follow-up of 3 years (range 0.5-4 years). There were no toxic deaths and all patients transplanted successfully engrafted within 28 days (mean 18). Using a treatment paradigm similar to that utilized for recurrent systemic NHL (induction chemotherapy followed by ASCT) for PCNSL occurring metachronously after successful treatment of systemic NHL appears safe and effective. PMID:23456654

  6. Perispinal Delivery of CNS Drugs.

    PubMed

    Tobinick, Edward Lewis

    2016-06-01

    Perispinal injection is a novel emerging method of drug delivery to the central nervous system (CNS). Physiological barriers prevent macromolecules from efficiently penetrating into the CNS after systemic administration. Perispinal injection is designed to use the cerebrospinal venous system (CSVS) to enhance delivery of drugs to the CNS. It delivers a substance into the anatomic area posterior to the ligamentum flavum, an anatomic region drained by the external vertebral venous plexus (EVVP), a division of the CSVS. Blood within the EVVP communicates with the deeper venous plexuses of the CSVS. The anatomical basis for this method originates in the detailed studies of the CSVS published in 1819 by the French anatomist Gilbert Breschet. By the turn of the century, Breschet's findings were nearly forgotten, until rediscovered by American anatomist Oscar Batson in 1940. Batson confirmed the unique, linear, bidirectional and retrograde flow of blood between the spinal and cerebral divisions of the CSVS, made possible by the absence of venous valves. Recently, additional supporting evidence was discovered in the publications of American neurologist Corning. Analysis suggests that Corning's famous first use of cocaine for spinal anesthesia in 1885 was in fact based on Breschet's anatomical findings, and accomplished by perispinal injection. The therapeutic potential of perispinal injection for CNS disorders is highlighted by the rapid neurological improvement in patients with otherwise intractable neuroinflammatory disorders that may ensue following perispinal etanercept administration. Perispinal delivery merits intense investigation as a new method of enhanced delivery of macromolecules to the CNS and related structures.

  7. A prognostic analysis of pediatrics central nervous system small cell tumors: evaluation of EGFR family gene amplification and overexpression

    PubMed Central

    2014-01-01

    Background Central nervous system (CNS) tumors are the most common solid tumors that occur in children, however there were few big-data follow-up analysis published in China. Overexpression of epidermal growth factor receptor (EGFR) family members was reported on glioblastoma (GBM) and medulloblastoma (MB) before. However, the correlation between EGFR family members expression with prognosis of MB, supratentorial primitive neuroectodermal tumor (PNET) and small cell GBM is unclear in Chinese children. Methods A retrospective and survival analysis was performed on children (age ≤ 16 years) diagnosed as CNS primary small cell tumors in the Affiliated Provincial Hospital, Shandong University from 2000 to 2012, including MB (n = 44), PNET (n = 8) and small cell GBM (n = 19). The expression of EGFR, ERBB-2, ERBB-3 and ERBB-4 were detected by immunohistochemistry (IHC). The fluorescence in situ hybridization (FISH) was used to observe the amplification of EGFR and ERBB-2 gene. Results Median survival times of MBs, small GBMs and PNETs were 23 ± 6.7 months, 8 ± 4.7 months and 10 ± 1.4 months. Expression and amplification of ERBB-2, ERBB-3 and ERBB-4 were not observed in all tumor samples. The multiply Cox regression suggested the overexpression and amplification of EGFR were negative prognostic factors for MB. Radiotherapy had the positive function for all pediatric patients. Conclusion Overexpression of EGFR predicts poor outcomes of MBs, small cell GBMs and PNETs, suggesting those three CNS tumor subtypes can be considered as one group for the potential common mechanism. The current individual treatment and big data analysis of pediatric CNS embryonal tumors and GBM continues to be very challenging in China. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7649640001237474 PMID:24986561

  8. Proton Radiotherapy for Pediatric Central Nervous System Germ Cell Tumors: Early Clinical Outcomes

    SciTech Connect

    MacDonald, Shannon M.; Trofimov, Alexei; Safai, Sairos; Adams, Judith; Fullerton, Barbara; Ebb, David; Tarbell, Nancy J.; Yock, Torunn I.

    2011-01-01

    Purpose: To report early clinical outcomes for children with central nervous system (CNS) germ cell tumors treated with protons; to compare dose distributions for intensity-modulated photon radiotherapy (IMRT), three-dimensional conformal proton radiation (3D-CPT), and intensity-modulated proton therapy with pencil beam scanning (IMPT) for whole-ventricular irradiation with and without an involved-field boost. Methods and Materials: All children with CNS germinoma or nongerminomatous germ cell tumor who received treatment at the Massachusetts General Hospital between 1998 and 2007 were included in this study. The IMRT, 3D-CPT, and IMPT plans were generated and compared for a representative case. Results: Twenty-two patients were treated with 3D-CPT. At a median follow-up of 28 months, there were no CNS recurrences; 1 patient had a recurrence outside the CNS. Local control, progression-free survival, and overall survival rates were 100%, 95%, and 100%, respectively. Comparable tumor volume coverage was achieved with IMRT, 3D-CPT, and IMPT. Substantial normal tissue sparing was seen with any form of proton therapy as compared with IMRT. The use of IMPT may yield additional sparing of the brain and temporal lobes. Conclusions: Preliminary disease control with proton therapy compares favorably to the literature. Dosimetric comparisons demonstrate the advantage of proton radiation over IMRT for whole-ventricle radiation. Superior dose distributions were accomplished with fewer beam angles utilizing 3D-CPT and scanned protons. Intensity-modulated proton therapy with pencil beam scanning may improve dose distribution as compared with 3D-CPT for this treatment.

  9. Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease.

    PubMed

    Spencer, Brian; Potkar, Rewati; Metcalf, Jeff; Thrin, Ivy; Adame, Anthony; Rockenstein, Edward; Masliah, Eliezer

    2016-01-22

    Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of Aβ. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with Aβ accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-Aβ therapeutic.

  10. Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report

    PubMed Central

    UMEDA, KATSUTSUGU; SAIDA, SATOSHI; YAMAGUCHI, HIDEKI; OKAMOTO, SHINYA; OKAMOTO, TAKESHI; KATO, ITARU; HIRAMATSU, HIDEFUMI; IMAI, TSUYOSHI; KODAIRA, TAKESHI; HEIKE, TOSHIO; ADACHI, SOUICHI; WATANABE, KEN-ICHIRO

    2016-01-01

    Patients with desmoplastic small round cell tumors (DSRCTs) have an extremely poor outcome despite the use of aggressive therapy. The current study presents the case of 16-year-old male with metastatic DSRCT, in which multimodal therapy, including intensive chemotherapies using frequent autologous stem cell support, gross resection of primary and metastatic lesions, and whole abdominopelvic intensity-modulated radiation therapy, was administered. Subsequent to these treatments, there was no evidence of active disease. However, cerebellar and pineal body lesions, and bone metastasis to the left humerus were detected 1 year and 2 months after the initial diagnosis. Combination chemotherapy with irinotecan and temozolomide was initially effective against the central nervous system (CNS) metastatic lesions; however, the patient succumbed due to progressive CNS disease after seven courses of combination chemotherapy. Additional studies are required to accumulate information regarding CNS recurrence of DSRCT. PMID:26870296

  11. Ontogeny and functions of CNS macrophages

    PubMed Central

    Katsumoto, Atsuko; Lu, Haiyan; Miranda, Aline S.; Ransohoff, Richard M.

    2014-01-01

    Microglia, the only non-neuroepithelial cells found in the parenchyma of the central nervous system (CNS), originate during embryogenesis from the yolk sac and enter the CNS quite early (embryonic day 9.5-10 in mice). Thereafter, microglia are maintained independently of any input from the blood and in particular do not require hematopoietic stem cells as a source of replacement for senescent cells. Monocytes are hematopoietic cells, derived from bone marrow. The ontogeny of microglia and monocytes is important for understanding CNS pathologies. Microglial functions are distinct from those of blood-derived monocytes, which invade the CNS only under pathological conditions. Recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis and synaptic interactions. Here we discuss physiology of microglia and the functions of monocytes in CNS pathology. We address the roles of microglia and monocytes in neurodegenerative diseases as an example of CNS pathology. PMID:25193935

  12. Syndrome-Associated Tumors by Organ System.

    PubMed

    Gonzalez, Raul S; Riddle, Nicole D

    2016-06-01

    Certain tumors suggest the possibility of a patient harboring a genetic syndrome, particularly in children. Syndrome-associated tumors of the gastrointestinal tract, genitourinary tract, gynecologic tract, heart, lungs, brain, eye, endocrine organs, and hematopoietic system will be briefly discussed. PMID:27617151

  13. TOPP in the CNS

    NASA Astrophysics Data System (ADS)

    Smart, R. L.; Lattanzi, M. G.; Jahreiss, H.; Bucciarelli, B.; Massone, G.

    2006-08-01

    Introduction: We present the Torino Observatory Parallax Program (TOPP) results for 22 candidates for the Catalog of Nearby Stars (CNS). Methods: Observations were made with the Torino OTAP 1.05m telescope over the period 1996-2001. Results: For the 22 objects examined 12 are within the CNS limit. Discussion: We discuss at length the objects out side the CNS limits which are either misclassified or objects with incorrect trigonometric parallaxes.

  14. Comparison of A-SMGCS Requirements with Observed Performance of an Integrated Airport CNS System

    NASA Technical Reports Server (NTRS)

    Young, Steven D.

    1997-01-01

    The International Civil Aviation Organization (ICAO) has recently drafted a reference document describing the operational requirements for Advanced Surface Movement Guidance and Control Systems (A-SMGCS). During the summer of 1997, NASA, the FAA, industry, and academia partners demonstrated a holistic system approach that has the potential to meet many of the proposed A-SMGCS requirements. An assessment of the field tested system and data resulting from the field testing is presented to determine its compliance with A-SMGCS requirements. In those areas where compliance was not demonstrated, a recommendation is presented suggesting further research or a modification of the system architecture.

  15. Basic Concepts of CNS Development.

    ERIC Educational Resources Information Center

    Nowakowski, R. S.

    1987-01-01

    The goals of this review are to: (1) provide a set of concepts to aid in the understanding of complex processes which occur during central nervous system (CNS) development; (2) illustrate how they contribute to our knowlege of adult brain anatomy; and (3) delineate how modifications of normal developmental processes may affect the structure and…

  16. Targeting gene therapy vectors to CNS malignancies.

    PubMed

    Spear, M A; Herrlinger, U; Rainov, N; Pechan, P; Weissleder, R; Breakefield, X O

    1998-04-01

    Gene therapy offers significant advantages to the field of oncology with the addition of specifically and uniquely engineered mechanisms of halting malignant proliferation through cytotoxicity or reproductive arrest. To confer a true benefit to the therapeutic ratio (the relative toxicity to tumor compared to normal tissue) a vector or the transgene it carries must selectively affect or access tumor cells. Beyond the selective toxicities of many transgene products, which frequently parallel that of contemporary chemotherapeutic agents, lies the potential utility of targeting the vector. This review presents an overview of current and potential methods for designing vectors targeted to CNS malignancies through selective delivery, cell entry, transport or transcriptional regulation. The topic of delivery encompasses physical and pharmaceutic means of increasing the relative exposure of tumors to vector. Cell entry based methodologies are founded on increasing relative uptake of vector through the chemical or recombinant addition of ligand and antibody domains which selectively bind receptors expressed on target cells. Targeted transport involves the potential for using cells to selectively carry vectors or transgenes into tumors. Finally, promoter and enhancer systems are discussed which have potential for selectivity activating transcription to produce targeted transgene expression or vector propagation. PMID:9584951

  17. Aromatherapy and the central nerve system (CNS): therapeutic mechanism and its associated genes.

    PubMed

    Lv, Xiao Nan; Liu, Zhu Jun; Zhang, Huan Jing; Tzeng, Chi Meng

    2013-07-01

    Molecular medical research on aromatherapy has been steadily increasing for use as an adjuvant therapy in managing psychiatric disorders and to examine its therapeutic mechanisms. Most studies, as well as clinically applied experience, have indicated that various essential oils, such as lavender, lemon and bergamot can help to relieve stress, anxiety, depression and other mood disorders. Most notably, inhalation of essential oils can communicate signals to the olfactory system and stimulate the brain to exert neurotransmitters (e.g. serotonin and dopamine) thereby further regulating mood. However, little research has been done on the molecular mechanisms underlying these effects, thus their mechanism of action remains ambiguous. Several hypotheses have been proposed regarding the therapeutic mechanism of depression. These have mainly centered on possible deficiencies in monoamines, neurotrophins, the neuroendocrine system, c-AMP, cation channels as well as neuroimmune interactions and epigenetics, however the precise mechanism or mechanisms related to depression have yet to be elucidated. In the current study, the effectiveness of aromatherapy for alleviating psychiatric disorders was examined using data collected from previously published studies and our unpublished data. A possible signaling pathway from olfactory system to the central nerve system and the associated key molecular elements of aromatherapy are also proposed.

  18. Phase II study of central nervous system (CNS)-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation for CNS relapse of aggressive lymphomas

    PubMed Central

    Korfel, Agnieszka; Elter, Thomas; Thiel, Eckhard; Hänel, Matthias; Möhle, Robert; Schroers, Roland; Reiser, Marcel; Dreyling, Martin; Eucker, Jan; Scholz, Christian; Metzner, Bernd; Röth, Alexander; Birkmann, Josef; Schlegel, Uwe; Martus, Peter; Illerhaus, Gerard; Fischer, Lars

    2013-01-01

    The prognosis of patients with central nervous system relapse of aggressive lymphoma is very poor with no therapy established so far. In a prospective multicenter phase II study, we evaluated a potentially curative chemotherapy-only regimen in these patients. Adult immunocompetent patients 65 years of age or under received induction chemotherapy with MTX/IFO/DEP (methotrexate 4 g/m2 intravenously (i.v.) Day 1, ifosfamide 2 g/m2 i.v. Days 3– 5 and liposomal cytarabine 50 mg intrathecally (i.th) Day 6) and AraC/TT/DEP (cytarabine 3g/m2 i.v. Days 1–2, thiotepa 40 mg/m2 i.v. Day 2 and i.th. liposomal cytarabine 50 mg i.th. Day 3) followed by high-dose chemotherapy with carmustine 400 mg/m2 i.v. Day −5, thiotepa 2×5 mg/kg i.v. Days −4 to −3 and etoposide 150 mg/m2 i.v. Days −5 to −3, and autologous stem cell transplantation Day 0 (HD-ASCT). Thirty eligible patients (median age 58 years) were enrolled. After HD-ASCT (n=24), there was a complete remission in 15 (63%), partial remission in 2 (8%) and progressive disease in 7 (29%) patients. Myelotoxicity was the most adverse event with CTC grade 3/4 infections in 12% of MTX/IFO/DEP courses, 21% of AraC/TT/DEP courses and 46% of HD-ASCT courses. The 2-year time to treatment failure was 49%±19 for all patients and 58%±22 for patients completing HD-ASCT. The protocol assessed proved feasible and highly active with long-lasting remissions in a large proportion of patients. (ClinicalTrials.govIdentifier NCT01148173) PMID:23242601

  19. Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors

    SciTech Connect

    Pulsifer, Margaret B.; Sethi, Roshan V.; Kuhlthau, Karen A.; MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.

    2015-10-01

    Purpose: To report, from a longitudinal study, cognitive outcome in pediatric patients treated with proton radiation therapy (PRT) for central nervous system (CNS) tumors. Methods and Materials: Sixty patients receiving PRT for medulloblastoma (38.3%), gliomas (18.3%), craniopharyngioma (15.0%), ependymoma (11.7%), and other CNS tumors (16.7%) were administered age-appropriate measures of cognitive abilities at or near PRT initiation (baseline) and afterward (follow-up). Patients were aged ≥6 years at baseline to ensure consistency in neurocognitive measures. Results: Mean age was 12.3 years at baseline; mean follow-up interval was 2.5 years. Treatment included prior surgical resection (76.7%) and chemotherapy (61.7%). Proton radiation therapy included craniospinal irradiation (46.7%) and partial brain radiation (53.3%). At baseline, mean Wechsler Full Scale IQ was 104.6; means of all 4 Index scores were also in the average range. At follow-up, no significant change was observed in mean Wechsler Full Scale IQ, Verbal Comprehension, Perceptual Reasoning/Organization, or Working Memory. However, Processing Speed scores declined significantly (mean 5.2 points), with a significantly greater decline for subjects aged <12 years at baseline and those with the highest baseline scores. Cognitive outcome was not significantly related to gender, extent of radiation, radiation dose, tumor location, histology, socioeconomic status, chemotherapy, or history of surgical resection. Conclusions: Early cognitive outcomes after PRT for pediatric CNS tumors are encouraging, compared with published outcomes from photon radiation therapy.

  20. Health-Related Quality of Life of Adolescent and Young Adult Survivors of Central Nervous System Tumors: Identifying Domains From a Survivor Perspective.

    PubMed

    Kuhlthau, Karen; Luff, Donna; Delahaye, Jennifer; Wong, Alicia; Yock, Torunn; Huang, Mary; Park, Elyse R

    2015-01-01

    This article uses qualitative methods to describe the domains of health-related quality of life (HRQoL) that adolescent and young adult (AYA) survivors of central nervous system (CNS) tumors identify as important. Survivors clearly attributed aspects of their current HRQoL to their disease or its treatment. We identified 7 key domains of AYA CNS tumor survivorship: physical health, social well-being, mental health, cognitive functioning, health behaviors, sexual and reproductive health, and support systems. Although most aspects of HRQoL that survivors discussed represented new challenges, there were several areas where survivors pointed out positive outcomes. There is a need for a HRQoL tool designed for this population of survivors, given their unique treatment and survivorship experience. Aspects of HRQoL related to cognition, sexual and reproductive health, health behaviors, and support systems are not typically included in generic HRQoL tools but should be assessed for this population. Developing HRQoL measurement instruments that capture the most significant aspects of HRQoL will improve the ability to track HRQoL in AYA CNS tumor survivors and in the long-term management of common sequelae from CNS tumors and their treatments.

  1. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity.

    PubMed

    Shaw, C A; Tomljenovic, L

    2013-07-01

    We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome. PMID:23609067

  2. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity.

    PubMed

    Shaw, C A; Tomljenovic, L

    2013-07-01

    We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome.

  3. A Phenotypic Culture System for the Molecular Analysis of CNS Myelination in the Spinal Cord

    PubMed Central

    Davis, Hedvika; Gonzalez, Mercedes; Stancescu, Maria; Love, Rachal; Hickman, James J.; Lambert, Stephen

    2014-01-01

    Studies of central nervous system myelination lack defined in vitro models which would effectively dissect molecular mechanisms of myelination that contain cells of the correct phenotype. Here we describe a co-culture of purified motoneurons and oligodendrocyte progenitor cells, isolated from rat embryonic spinal cord using a combination of immunopanning techniques. This model illustrates differentiation of oligodendrocyte progenitors into fully functional mature oligodendrocytes that myelinate axons. It also illustrates a contribution of axons to the rate of oligodendrocyte maturation and myelin gene expression. The defined conditions used allow molecular analysis of distinct stages of myelination and precise manipulation of inductive cues affecting axonal–oligodendrocyte interactions. This phenotypic in vitro myelination model can provide valuable insight into our understanding of demyelinating disorders, such as multiple sclerosis and traumatic diseases such as spinal cord injury where demyelination represents a contributing factor to the pathology of the disorder. PMID:25064806

  4. A phenotypic culture system for the molecular analysis of CNS myelination in the spinal cord.

    PubMed

    Davis, Hedvika; Gonzalez, Mercedes; Stancescu, Maria; Love, Rachal; Hickman, James J; Lambert, Stephen

    2014-10-01

    Studies of central nervous system myelination lack defined in vitro models which would effectively dissect molecular mechanisms of myelination that contain cells of the correct phenotype. Here we describe a co-culture of purified motoneurons and oligodendrocyte progenitor cells, isolated from rat embryonic spinal cord using a combination of immunopanning techniques. This model illustrates differentiation of oligodendrocyte progenitors into fully functional mature oligodendrocytes that myelinate axons. It also illustrates a contribution of axons to the rate of oligodendrocyte maturation and myelin gene expression. The defined conditions used allow molecular analysis of distinct stages of myelination and precise manipulation of inductive cues affecting axonal-oligodendrocyte interactions. This phenotypic in vitro myelination model can provide valuable insight into our understanding of demyelinating disorders, such as multiple sclerosis and traumatic diseases such as spinal cord injury where demyelination represents a contributing factor to the pathology of the disorder.

  5. Operational characteristics of the helium refrigeration system at HANARO-CNS

    NASA Astrophysics Data System (ADS)

    Lee, Mun; Choi, Ho Young; Han, Jae Sam; Cho, Sung Hwan; Kim, Min Su; Hur, Soon Ock; Son, Wu Jung; Ahn, Guk Hoon; Lim, In-Cheol

    2012-06-01

    The HANARO research reactor produced the first cold neutron sources through the neutron guide tube on Nov 3. 2009. Cold sources are produced by scattering method in the moderator cell that is filled with liquid hydrogen to maintain a sub-cooled state by a helium refrigeration system (HRS). The helium refrigerator has a capacity of 1500 watts at a supply temperature of 14 Kelvin. The hydrogen pressure to produce cold sources on a cold mode operation drops down to 152±3 kPa(a). Normally, the HRS should be operated before starting up the reactor. For this, the HRS should be turned on at least 12 hours before the reactor; 6 hours for removing impurities in helium, 4 hours and 20 minutes for the cold mode operation to cool down, and 1 hour and 20 minutes for stabilizing the hydrogen pressure. The helium purification should be done before the cold mode operation of the HRS. To get rid of impurities, we use a cryogenic adsorbent, activated charcoal with LH2. The gas analyzer monitors impurities such as H2O, N2, and hydrocarbon etc. The operational limit for them is below 1 ppm which is less than one tenth of the manufacturer's manual.

  6. Tumor Types

    MedlinePlus

    ... acoustic neuroma is also known as a schwannoma, vestibular schwannoma, or neurilemmoma. Characteristics Arises from cells that ... multiple CNS tumors, including neurofibromas, multiple meningiomas, bilateral vestibular schwannomas, optic nerve gliomas, and spinal cord tumors. ...

  7. General Information about Childhood Central Nervous System Embryonal Tumors

    MedlinePlus

    ... System Embryonal Tumors Treatment (PDQ®)–Patient Version General Information About Childhood Central Nervous System Embryonal Tumors Go ... in patients with a high-risk tumor. The information from tests and procedures done to detect (find) ...

  8. Treatment Option Overview (Primary CNS Lymphoma)

    MedlinePlus

    ... large vein near the heart. Having a weakened immune system may increase the risk of developing primary CNS ... immunodeficiency syndrome (AIDS) or other disorders of the immune system or who have had a kidney transplant . For ...

  9. Treatment Options for Primary CNS Lymphoma

    MedlinePlus

    ... large vein near the heart. Having a weakened immune system may increase the risk of developing primary CNS ... immunodeficiency syndrome (AIDS) or other disorders of the immune system or who have had a kidney transplant . For ...

  10. CNS disease triggering Takotsubo stress cardiomyopathy.

    PubMed

    Finsterer, Josef; Wahbi, Karim

    2014-12-15

    There are a number of hereditary and non-hereditary central nervous system (CNS) disorders, which directly or indirectly affect the heart (brain-heart disorders). The most well-known of these CNS disorders are epilepsy, stroke, infectious or immunological encephalitis/meningitis, migraine, and traumatic brain injury. In addition, a number of hereditary and non-hereditary neurodegenerative disorders may impair cardiac functions. Affection of the heart may manifest not only as arrhythmias, myocardial infarction, autonomic impairment, systolic dysfunction/heart failure, arterial hypertension, or pulmonary hypertension, but also as stress cardiomyopathy (Takotsubo syndrome, TTS). CNS disease triggering TTS includes subarachnoid bleeding, epilepsy, ischemic stroke, intracerebral bleeding, migraine, encephalitis, traumatic brain injury, PRES syndrome, or ALS. Usually, TTS is acutely precipitated by stress triggered by various different events. TTS is one of the cardiac abnormalities most frequently induced by CNS disorders. Appropriate management of TTS from CNS disorders is essential to improve the outcome of affected patients. PMID:25213573

  11. Pathology of CNS parasitic infections.

    PubMed

    Pittella, José Eymard Homem

    2013-01-01

    Parasitic infections of the central nervous system (CNS) include two broad categories of infectious organisms: single-celled protozoa and multicellular metazoa. The protozoal infections include malaria, American trypanosomiasis, human African trypanosomiasis, toxoplasmosis, amebiasis, microsporidiasis, and leishmaniasis. The metazoal infections are grouped into flatworms, which include trematoda and cestoda, and roundworms or nematoda. Trematoda infections include schistosomiasis and paragonimiasis. Cestoda infections include cysticercosis, coenurosis, hydatidosis, and sparganosis. Nematoda infections include gnathostomiasis, angiostrongyliasis, toxocariasis, strongyloidiasis, filariasis, baylisascariasis, dracunculiasis, micronemiasis, and lagochilascariasis. The most common route of CNS invasion is through the blood. In some cases, the parasite invades the olfactory neuroepithelium in the nasal mucosa and penetrates the brain via the subarachnoid space or reaches the CNS through neural foramina of the skull base around the cranial nerves or vessels. The neuropathological changes vary greatly, depending on the type and size of the parasite, geographical strain variations in parasitic virulence, immune evasion by the parasite, and differences in host immune response. Congestion of the leptomeninges, cerebral edema, hemorrhage, thrombosis, vasculitis, necrosis, calcification, abscesses, meningeal and perivascular polymorphonuclear and mononuclear inflammatory infiltrate, microglial nodules, gliosis, granulomas, and fibrosis can be found affecting isolated or multiple regions of the CNS, or even diffusely spread. Some infections may be present as an expanding mass lesion. The parasites can be identified by conventional histology, immunohistochemistry, in situ hybridization, and PCR.

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

    PubMed

    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.

  13. Primitive neuroectodermal tumor of the central nervous system with glial differentiation: a FISH study of an adult case.

    PubMed

    Alameda, F; Lloreta, J; Ariza, A; Salido, M; Espinet, B; Baro, T; Garcia-Fructoso, G; Galito, E; Munne, A; Cruz Sanchez, F F; Sole, F; Serrano, S

    2007-01-01

    Primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS), a rare occurrence in adults, may show glial differentiation and can be misinterpreted as pure astrocytic neoplasms. Few fluorescence in situ hybridization (FISH) studies have been carried out on these tumors; isochromosome 17q was found to be the major chromosomal abnormality. We present the case of an adult in which we performed a FISH study of both the glial and neuronal components. A complex array of FISH changes, not including an isochromosome 17q were identified.

  14. Bevacizumab in Reducing CNS Side Effects in Patients Who Have Undergone Radiation Therapy to the Brain for Primary Brain Tumor, Meningioma, or Head and Neck Cancer

    ClinicalTrials.gov

    2014-04-21

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Central Nervous System Germ Cell Tumor; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Malignant Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineocytoma; Malignant Neoplasm; Meningeal Melanocytoma; Radiation Toxicity; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Brain Tumor; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Basal Cell Carcinoma of the Lip; Stage I Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage I Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage I Lymphoepithelioma of the Nasopharynx; Stage I Lymphoepithelioma of the Oropharynx; Stage I Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Salivary Gland Cancer; Stage I Squamous Cell Carcinoma

  15. Systemic inflammation disrupts oligodendrocyte gap junctions and induces ER stress in a model of CNS manifestations of X-linked Charcot-Marie-Tooth disease.

    PubMed

    Olympiou, Margarita; Sargiannidou, Irene; Markoullis, Kyriaki; Karaiskos, Christos; Kagiava, Alexia; Kyriakoudi, Styliana; Abrams, Charles K; Kleopa, Kleopas A

    2016-01-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is a common form of inherited neuropathy resulting from different mutations affecting the gap junction (GJ) protein connexin32 (Cx32). A subset of CMT1X patients may additionally present with acute fulminant CNS dysfunction, typically triggered by conditions of systemic inflammation and metabolic stress. To clarify the underlying mechanisms of CNS phenotypes in CMT1X we studied a mouse model of systemic inflammation induced by lipopolysaccharide (LPS) injection to compare wild type (WT), connexin32 (Cx32) knockout (KO), and KO T55I mice expressing the T55I Cx32 mutation associated with CNS phenotypes. Following a single intraperitoneal LPS or saline (controls) injection at the age of 40-60 days systemic inflammatory response was documented by elevated TNF-α and IL-6 levels in peripheral blood and mice were evaluated 1 week after injection. Behavioral analysis showed graded impairment of motor performance in LPS treated mice, worse in KO T55I than in Cx32 KO and in Cx32 KO worse than WT. Iba1 immunostaining revealed widespread inflammation in LPS treated mice with diffusely activated microglia throughout the CNS. Immunostaining for the remaining major oligodendrocyte connexin Cx47 and for its astrocytic partner Cx43 revealed widely reduced expression of Cx43 and loss of Cx47 GJs in oligodendrocytes. Real-time PCR and immunoblot analysis indicated primarily a down regulation of Cx43 expression with secondary loss of Cx47 membrane localization. Inflammatory changes and connexin alterations were most severe in the KO T55I group. To examine why the presence of the T55I mutant exacerbates pathology even more than in Cx32 KO mice, we analyzed the expression of ER-stress markers BiP, Fas and CHOP by immunostaining, immunoblot and Real-time PCR. All markers were increased in LPS treated KO T55I mice more than in other genotypes. In conclusion, LPS induced neuroinflammation causes disruption of the main astrocyte

  16. H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas.

    PubMed

    Gielen, Gerrit H; Gessi, Marco; Hammes, Jennifer; Kramm, Christof M; Waha, Andreas; Pietsch, Torsten

    2013-03-01

    Brain tumors are one of the most common childhood malignancies. Diffuse high-grade gliomas represent approximately 10% of pediatric brain tumors. Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors. We performed a pyrosequencing-based analysis for the identification of H3F3A codon 27 and codon 34 mutations in 338 pediatric brain tumors. The K27M mutation occurred in 35 of 129 glioblastomas (27.1%) and in 5 of 28 (17.9%) anaplastic astrocytomas. None of the other tumor entities showed H3F3A K27M mutation. Because H3F3A K27M mutations occur exclusively in pediatric diffuse high-grade astrocytomas, analysis of codon 27 mutational status could be useful in the differential diagnosis of these neoplasms. PMID:23429371

  17. Neurotrauma and Inflammation: CNS and PNS Responses

    PubMed Central

    Mietto, Bruno Siqueira; Mostacada, Klauss; Martinez, Ana Maria Blanco

    2015-01-01

    Traumatic injury to the central nervous system (CNS) or the peripheral nervous system (PNS) triggers a cascade of events which culminate in a robust inflammatory reaction. The role played by inflammation in the course of degeneration and regeneration is not completely elucidated. While, in peripheral nerves, the inflammatory response is assumed to be essential for normal progression of Wallerian degeneration and regeneration, CNS trauma inflammation is often associated with poor recovery. In this review, we discuss key mechanisms that trigger the inflammatory reaction after nervous system trauma, emphasizing how inflammations in both CNS and PNS differ from each other, in terms of magnitude, cell types involved, and effector molecules. Knowledge of the precise mechanisms that elicit and maintain inflammation after CNS and PNS tissue trauma and their effect on axon degeneration and regeneration is crucial for the identification of possible pharmacological drugs that can positively affect the tissue regenerative capacity. PMID:25918475

  18. Ionotropic Glutamate Receptors & CNS Disorders

    PubMed Central

    Bowie, Derek

    2008-01-01

    Disorders of the central nervous system (CNS) are complex disease states that represent a major challenge for modern medicine. Although etiology is often unknown, it is established that multiple factors such as defects in genetics and/or epigenetics, the environment as well as imbalance in neurotransmitter receptor systems are all at play in determining an individual’s susceptibility to disease. Gene therapy is currently not available and therefore, most conditions are treated with pharmacological agents that modify neurotransmitter receptor signaling. Here, I provide a review of ionotropic glutamate receptors (iGluRs) and the roles they fulfill in numerous CNS disorders. Specifically, I argue that our understanding of iGluRs has reached a critical turning point to permit, for the first time, a comprehensive re-evaluation of their role in the cause of disease. I illustrate this by highlighting how defects in AMPA receptor trafficking are important to Fragile X mental retardation and ectopic expression of kainate (KA) receptor synapses contributes to the pathology of temporal lobe epilepsy. Finally, I discuss how parallel advances in studies of other neurotransmitter systems may allow pharmacologists to work towards a cure for many CNS disorders rather than developing drugs to treat their symptoms. PMID:18537642

  19. Application of Nanomedicine to the CNS Diseases.

    PubMed

    Carradori, D; Gaudin, A; Brambilla, D; Andrieux, K

    2016-01-01

    Drug delivery to the brain is a challenge because of the many mechanisms that protect the brain from the entry of foreign substances. Numerous molecules which could be active against brain disorders are not clinically useful due to the presence of the blood-brain barrier. Nanoparticles can be used to deliver these drugs to the brain. Encapsulation within colloidal systems can allow the passage of nontransportable drugs across this barrier by masking their physicochemical properties. It should be noted that the status of the blood-brain barrier is different depending on the brain disease. In fact, in some pathological situations such as tumors or inflammatory disorders, its permeability is increased allowing very easy translocation of carriers. This chapter gathers the promising results obtained by using nanoparticles as drug delivery systems with the aim to improve the therapy of some CNS diseases such as brain tumor, Alzheimer's disease, and stroke. The data show that several approaches can be investigated: (1) carrying drug through a permeabilized barrier, (2) crossing the barrier thanks to receptor-mediated transcytosis pathway in order to deliver drug into the brain parenchyma, and also (3) targeting and treating the endothelial cells themselves to preserve locally the brain tissue. The examples given in this chapter contribute to demonstrate that delivering drugs into the brain is one of the most promising applications of nanotechnology in clinical neuroscience. PMID:27678175

  20. Air Pollution: Mechanisms of Neuroinflammation & CNS Disease

    PubMed Central

    Block, Michelle L.; Calderón-Garcidueñas, Lilian

    2009-01-01

    Emerging evidence implicates air pollution as a chronic source of neuroinflammation, reactive oxygen species (ROS), and neuropathology instigating central nervous system (CNS) disease. Stroke incidence, and Alzheimer’s and Parkinson’s disease pathology are linked to air pollution. Recent reports reveal that air pollution components reach the brain. Further, systemic effects known to impact lung and cardiovascular disease also impinge upon CNS health. While mechanisms driving air pollution-induced CNS pathology are poorly understood, new evidence suggests that activation of microglia and changes in the blood brain barrier may be key to this process. Here, we summarize recent findings detailing the mechanisms through which air pollution reaches the brain and activates the resident innate immune response to become a chronic source of pro-inflammatory factors and ROS culpable in CNS disease. PMID:19716187

  1. Clinical Applications Involving CNS Gene Transfer

    PubMed Central

    Kantor, Boris; McCown, Thomas; Leone, Paola; Gray, Steven J.

    2015-01-01

    Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood–brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying protein for a disease such as Parkinson's. Gene therapy approaches for CNS disorders has evolved considerably over the last two decades. Although a breakthrough treatment has remained elusive, current strategies are now considerably safer and potentially much more effective. This chapter will explore the past, current, and future status of CNS gene therapy, focusing on clinical trials utilizing adeno-associated virus and lentiviral vectors. PMID:25311921

  2. Sublime microglia: expanding roles for the guardians of the CNS.

    PubMed

    Salter, Michael W; Beggs, Simon

    2014-07-01

    Recent findings challenge the concept that microglia solely function in disease states in the central nervous system (CNS). Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity. These physiological functions of microglia in the normal CNS begin during development and persist into maturity. Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS.

  3. Which drug or drug delivery system can change clinical practice for brain tumor therapy?

    PubMed Central

    Siegal, Tali

    2013-01-01

    The prognosis and treatment outcome for primary brain tumors have remained unchanged despite advances in anticancer drug discovery and development. In clinical trials, the majority of promising experimental agents for brain tumors have had limited impact on survival or time to recurrence. These disappointing results are partially explained by the inadequacy of effective drug delivery to the CNS. The impediments posed by the various specialized physiological barriers and active efflux mechanisms lead to drug failure because of inability to reach the desired target at a sufficient concentration. This perspective reviews the leading strategies that aim to improve drug delivery to brain tumors and their likelihood to change clinical practice. The English literature was searched for defined search items. Strategies that use systemic delivery and those that use local delivery are critically reviewed. In addition, challenges posed for drug delivery by combined treatment with anti-angiogenic therapy are outlined. To impact clinical practice and to achieve more than just a limited local control, new drugs and delivery systems must adhere to basic clinical expectations. These include, in addition to an antitumor effect, a verified favorable adverse effects profile, easy introduction into clinical practice, feasibility of repeated or continuous administration, and compatibility of the drug or delivery system with any tumor size and brain location. PMID:23502426

  4. Pharmacology of Glutamate Transport in the CNS: Substrates and Inhibitors of Excitatory Amino Acid Transporters (EAATs) and the Glutamate/Cystine Exchanger System x c -

    NASA Astrophysics Data System (ADS)

    Bridges, Richard J.; Patel, Sarjubhai A.

    As the primary excitatory neurotransmitter in the mammalian CNS, l-glutamate participates not only in standard fast synaptic communication, but also contributes to higher order signal processing, as well as neuropathology. Given this variety of functional roles, interest has been growing as to how the extracellular concentrations of l-glutamate surrounding neurons are regulated by cellular transporter proteins. This review focuses on two prominent systems, each of which appears capable of influencing both the signaling and pathological actions of l-glutamate within the CNS: the sodium-dependent excitatory amino acid transporters (EAATs) and the glutamate/cystine exchanger, system x c - (Sx c -). While the family of EAAT subtypes limit access to glutamate receptors by rapidly and efficiently sequestering l-glutamate in neurons and glia, Sxc - provides a route for the export of glutamate from cells into the extracellular environment. The primary intent of this work is to provide an overview of the inhibitors and substrates that have been developed to delineate the pharmacological specificity of these transport systems, as well as be exploited as probes with which to selectively investigate function. Particular attention is paid to the development of small molecule templates that mimic the structural properties of the endogenous substrates, l-glutamate, l-aspartate and l-cystine and how strategic control of functional group position and/or the introduction of lipophilic R-groups can impact multiple aspects of the transport process, including: subtype selectivity, inhibitory potency, and substrate activity.

  5. Differential expression of utrophin-A and -B promoters in the central nervous system (CNS) of normal and dystrophic mdx mice.

    PubMed

    Baby, Santhosh M; Bogdanovich, Sasha; Willmann, Gabriel; Basu, Utpal; Lozynska, Olga; Khurana, Tejvir S

    2010-03-01

    Utrophin (Utrn) is the autosomal homolog of dystrophin, the Duchene Muscular Dystrophy (DMD) locus product and of therapeutic interest, as its overexpression can compensate dystrophin's absence. Utrn is transcribed by Utrn-A and -B promoters with mRNAs differing at their 5' ends. However, previous central nervous system (CNS) studies used C-terminal antibodies recognizing both isoforms. As this distinction may impact upregulation strategies, we generated Utrn-A and -B promoter-specific antibodies, Taqman Polymerase chain reaction (PCR)-based absolute copy number assays, and luciferase-reporter constructs to study CNS of normal and dystrophic mdx mice. Differential expression of Utrn-A and -B was noted in microdissected and capillary-enriched fractions. At the protein level, Utrn-B was predominantly expressed in vasculature and ependymal lining, whereas Utrn-A was expressed in neurons, astrocytes, choroid plexus and pia mater. mRNA quantification demonstrated matching patterns of differential expression; however, transcription-translation mismatch was noted for Utrn-B in caudal brain regions. Utrn-A and Utrn-B proteins were significantly upregulated in olfactory bulb and cerebellum of mdx brain. Differential promoter activity, mRNA and protein expressions were studied in cultured C2C12, bEnd3, neurons and astrocytes. Promoter activity ranking for Utrn-A and -B was neurons > astrocytes > C2C12 > bEnd3 and bEnd3 > astrocytes > neurons > C2C12, respectively. Our results identify promoter usage patterns for therapeutic targeting and define promoter-specific differential distribution of Utrn isoforms in normal and dystrophic CNS.

  6. The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures*

    PubMed Central

    Qin, Weiping; Sun, Li; Cao, Jay; Peng, Yuanzhen; Collier, Lauren; Wu, Yong; Creasey, Graham; Li, Jianhua; Qin, Yiwen; Jarvis, Jonathan; Bauman, William A.; Zaidi, Mone; Cardozo, Christopher

    2013-01-01

    Muscle and bone work as a functional unit. Cellular and molecular mechanisms underlying effects of muscle activity on bone mass are largely unknown. Spinal cord injury (SCI) causes muscle paralysis and extensive sublesional bone loss and disrupts neural connections between the central nervous system (CNS) and bone. Muscle contraction elicited by electrical stimulation (ES) of nerves partially protects against SCI-related bone loss. Thus, application of ES after SCI provides an opportunity to study the effects of muscle activity on bone and roles of the CNS in this interaction, as well as the underlying mechanisms. Using a rat model of SCI, the effects on bone of ES-induced muscle contraction were characterized. The SCI-mediated increase in serum C-terminal telopeptide of type I collagen (CTX) was completely reversed by ES. In ex vivo bone marrow cell cultures, SCI increased the number of osteoclasts and their expression of mRNA for several osteoclast differentiation markers, whereas ES significantly reduced these changes; SCI decreased osteoblast numbers, but increased expression in these cells of receptor activator of NF-κB ligand (RANKL) mRNA, whereas ES increased expression of osteoprotegerin (OPG) and the OPG/RANKL ratio. A microarray analysis revealed that ES partially reversed SCI-induced alterations in expression of genes involved in signaling through Wnt, FSH, parathyroid hormone (PTH), oxytocin, and calcineurin/nuclear factor of activated T-cells (NFAT) pathways. ES mitigated SCI-mediated increases in mRNA levels for the Wnt inhibitors DKK1, sFRP2, and sclerostin in ex vivo cultured osteoblasts. Our results demonstrate an anti-bone-resorptive activity of muscle contraction by ES that develops rapidly and is independent of the CNS. The pathways involved, particularly Wnt signaling, suggest future strategies to minimize bone loss after immobilization. PMID:23530032

  7. Differential expression of utrophin-A and -B promoters in the central nervous system (CNS) of normal and dystrophic mdx mice.

    PubMed

    Baby, Santhosh M; Bogdanovich, Sasha; Willmann, Gabriel; Basu, Utpal; Lozynska, Olga; Khurana, Tejvir S

    2010-03-01

    Utrophin (Utrn) is the autosomal homolog of dystrophin, the Duchene Muscular Dystrophy (DMD) locus product and of therapeutic interest, as its overexpression can compensate dystrophin's absence. Utrn is transcribed by Utrn-A and -B promoters with mRNAs differing at their 5' ends. However, previous central nervous system (CNS) studies used C-terminal antibodies recognizing both isoforms. As this distinction may impact upregulation strategies, we generated Utrn-A and -B promoter-specific antibodies, Taqman Polymerase chain reaction (PCR)-based absolute copy number assays, and luciferase-reporter constructs to study CNS of normal and dystrophic mdx mice. Differential expression of Utrn-A and -B was noted in microdissected and capillary-enriched fractions. At the protein level, Utrn-B was predominantly expressed in vasculature and ependymal lining, whereas Utrn-A was expressed in neurons, astrocytes, choroid plexus and pia mater. mRNA quantification demonstrated matching patterns of differential expression; however, transcription-translation mismatch was noted for Utrn-B in caudal brain regions. Utrn-A and Utrn-B proteins were significantly upregulated in olfactory bulb and cerebellum of mdx brain. Differential promoter activity, mRNA and protein expressions were studied in cultured C2C12, bEnd3, neurons and astrocytes. Promoter activity ranking for Utrn-A and -B was neurons > astrocytes > C2C12 > bEnd3 and bEnd3 > astrocytes > neurons > C2C12, respectively. Our results identify promoter usage patterns for therapeutic targeting and define promoter-specific differential distribution of Utrn isoforms in normal and dystrophic CNS. PMID:19486009

  8. Report on a conference analyzing the role of cerebrospinal fluid prophylaxis for brain tumors

    PubMed Central

    Glantz, Michael; Johanson, Conrad

    2008-01-01

    This is a report of a meeting sponsored by MundiPharma International to identify ways to exploit the cerebrospinal fluid system pharmacologically, for more effective management and prevention of primary and metastatic CNS tumors. PMID:18366751

  9. Practical molecular pathology and histopathology of embryonal tumors.

    PubMed

    Phillips, Joanna; Tihan, Tarik; Fuller, Gregory

    2015-03-01

    There have been significant improvements in understanding of embryonal tumors of the central nervous system (CNS) in recent years. These advances are most likely to influence the diagnostic algorithms and methodology currently proposed by the World Health Organization (WHO) classification scheme. Molecular evidence suggests that the tumors presumed to be specific entities within the CNS/primitive neuroectodermal tumors spectrum are likely to be reclassified. All these developments compel reassessing current status and expectations from the upcoming WHO classification efforts. This review provides a synopsis of current developments and a practical algorithm for the work-up of these tumors in practice.

  10. Comparative integrated molecular analysis of intraocular medulloepitheliomas and central nervous system embryonal tumors with multilayered rosettes confirms that they are distinct nosologic entities.

    PubMed

    Korshunov, Andrey; Jakobiec, Frederick A; Eberhart, Charles G; Hovestadt, Volker; Capper, David; Jones, David T W; Sturm, Dominik; Stagner, Anna M; Edward, Deepak P; Eagle, Ralph C; Proia, Alan D; Koch, Arend; Ryzhova, Marina; Ektova, Anastasia; Schüller, Ulrich; Zheludkova, Olga; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Kool, Marcel

    2015-12-01

    Intraocular medulloepithelioma (IO MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. These ocular neoplasms have been compared with intracranial medulloepitheliomas or other histologic variants of CNS embryonal tumor with multilayered rosettes (CNS ETMR) due to their morphological mimicry. We performed comprehensive molecular analysis to explore the histogenetic and biologic relationships between 22 IO MEPL and 68 CNS ETMR. Routinely prepared paraffin-embedded samples were assessed for genome-wide methylation profiles using the Illumina Methylation 450k BeadChip array. We identified strong cytogenetic and epigenetic differences between ocular neoplasms and CNS ETMR. None of the IO MEPL cases displayed the ETMR-specific amplification of the C19MC locus. Instead, cytogenetic analysis of the IO MEPL showed numerous copy number aberrations which involved either whole chromosomes or chromosomal arms; recurrent aberrations in these tumors affected chromosomes 1p, 4, 8 and 16p. DNA methylation patterns were also strikingly different between these two tumor entities, suggesting that they do not share common origins and biological behaviors. Comparative cluster analysis of 198 pediatric CNS tumors and 22 IO MEPL revealed a clear demarcation of the CNS ETMR and IO MEPL profiles from other CNS entities. In conclusion, although IO MEPL shares some histopathological features with CNS ETMR, they manifest striking molecular diversity at the cytogenetic and epigenetic levels. Consequently they deserve a separate nosologic designation in future tumor classifications, where CNS MEPL could be designated as a histological variant of CNS ETMR.

  11. Treatment Option Overview (Childhood Central Nervous System Embryonal Tumors)

    MedlinePlus

    ... There are four types of CNS PNETs: CNS neuroblastomas CNS neuroblastomas are a very rare type of neuroblastoma that form in the nerve tissue of the ... that cover the brain and spinal cord. CNS neuroblastomas may be large and spread to other parts ...

  12. The effect of mouse strain on herpes simplex virus type 1 (HSV-1) infection of the central nervous system (CNS)

    PubMed Central

    2012-01-01

    Background Mice infected with HSV-1 can develop lethal encephalitis or virus induced CNS demyelination. Multiple factors affect outcome including route of infection, virus and mouse strain. When infected with a sub-lethal dose of HSV-1 strain 2 via the oral mucosa, susceptible SJL/J, A/J, and PL/J mice develop demyelinating lesions throughout the brain. In contrast, lesions are restricted to the brainstem (BST) in moderately resistant BALB/c mice and are absent in resistant BL/6 mice. The reasons for the strain differences are unknown. Methods In this study, we combine histology, immunohistochemistry, and in-situ hybridization to investigate the relationship between virus and the development of lesions during the early stage (< 24 days PI) of demyelination in different strains of mice. Results Initially, viral DNA and antigen positive cells appear sequentially in non-contiguous areas throughout the brains of BALB/c, SJL/J, A/J, and PL/J mice but are restricted to an area of the BST of BL/6 mice. In SJL/J, A/J, and PL/J mice, this is followed by the development of 'focal' areas of virus infected neuronal and non-neuronal cells throughout the brain. The 'focal' areas follow a hierarchical order and co-localize with developing demyelinating lesions. When antigen is cleared, viral DNA positive cells can remain in areas of demyelination; consistent with a latent infection. In contrast, 'focal' areas are restricted to the BST of BALB/c mice and do not occur in BL/6 mice. Conclusions The results of this study indicate that susceptible mouse strains, infected with HSV-1 via the oral mucosa, develop CNS demyelination during the first 24 days PI in several stages. These include: the initial spread of virus and infection of cells in non-contiguous areas throughout the brain, the development of 'focal' areas of virus infected neuronal and non-neuronal cells, the co-localization of 'focal' areas with developing demyelinating lesions, and latent infection in a number of the

  13. Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor.

    PubMed

    Zimmerman, Mary Ann; Goumnerova, Liliana C; Proctor, Mark; Scott, R Michael; Marcus, Karen; Pomeroy, Scott L; Turner, Christopher D; Chi, Susan N; Chordas, Christine; Kieran, Mark W

    2005-03-01

    Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant lesions of childhood that carry a very poor prognosis. AT/RT can occur in the central nervous system (CNS AT/RT) and disease in this location carries an even worse prognosis with a median survival of 7 months. In spite of multiple treatment regimens consisting of maximal surgical resection (including second look surgery), radiation therapy (focal and craniospinal), and multi-agent intravenous, oral and intrathecal chemotherapy, with or without high-dose therapy and stem cell rescue, only seven long-term survivors of CNS AT/RT have been reported, all in patients with newly diagnosed disease. For this reason, many centers now direct such patients, particularly those under 5 years of age, or those with recurrent disease, towards comfort care rather than attempt curative therapy. We now report on four children, two with newly diagnosed CNS AT/RT and two with progressive disease after multi-agent chemotherapy who are long term survivors (median follow-up of 37 months) using a combination of surgery, radiation therapy, and intensive chemotherapy. The chemotherapy component was modified from the Intergroup Rhabdomyosarcoma Study Group (IRS III) parameningeal protocol as three of the seven reported survivors in the literature were treated using this type of therapy. Our four patients, when added to the three reported survivors in the literature using this approach, suggest that patients provided this aggressive therapy can significantly alter the course of their disease. More importantly, we report on the first two survivors after relapse with multi-agent intravenous and intrathecal chemotherapy treated with this modified regimen. PMID:15803379

  14. Five novel cell surface antigens of CNS neoplasms.

    PubMed

    Jennings, M T; Jennings, V D; Asadourian, L L; Rosenblum, M; Albino, A P; Cairncross, J G; Old, L J

    1989-01-01

    Optimal monoclonal antibody-mediated immunotherapy requires the identification of tumor-restricted cell surface antigens. We have identified and partially characterized 5 new monoclonal antibodies generated against malignant astrocytoma, medulloblastoma, neuroblastoma and melanoma which were used to define 5 neuroectodermal tumor antigenic systems. CNT/1 identifies a 57-kDa, heat-stable, trypsin-sensitive neuroblastoma surface antigen, which is expressed intracellularly in many malignant gliomas, medulloblastomas, ependymomas, breast and ovarian carcinomas. CNT/2 reacts with a 130-kDa, heat-labile, trypsin- and neuraminidase-resistant antigen restricted to low-grade astrocytomas and malignant gliomas. CNT/11 reacts with a 70-kDa, heat-labile, trypsin-sensitive antigen coded for by a gene on chromosome 12, and is restricted to astrocytomas, neuroblastomas and sarcomas. CNT/8 identifies a heat-labile, trypsin-sensitive antigen whose gene has been localized to chromosome 15 and is expressed by neuroectodermal and mesodermally derived tumors and few epithelial cancers. The B2.6 antigen is identified only in terms of serologic reactivity with a subset of cultured astrocytomas and melanomas. Neuroectodermal tumor-associated antigens may be categorized as lineage-consistent, lineage-independent and putatively tumor-restricted in their expression. These restricted antibodies may be potentially useful reagents to consider for monoclonal antibody-mediated immunotherapy of CNS neoplasms.

  15. The Zebrafish Homologue of the Human DYT1 Dystonia Gene Is Widely Expressed in CNS Neurons but Non-Essential for Early Motor System Development

    PubMed Central

    Sager, Jonathan J.; Torres, Gonzalo E.; Burton, Edward A.

    2012-01-01

    DYT1 dystonia is caused by mutation of the TOR1A gene, resulting in the loss of a single glutamic acid residue near the carboxyl terminal of TorsinA. The neuronal functions perturbed by TorsinA[ΔE] are a major unresolved issue in understanding the pathophysiology of dystonia, presenting a critical roadblock to developing effective treatments. We identified and characterized the zebrafish homologue of TOR1A, as a first step towards elucidating the functions of TorsinA in neurons, in vivo, using the genetically-manipulable zebrafish model. The zebrafish genome was found to contain a single alternatively-spliced tor1 gene, derived from a common ancestral locus shared with the dual TOR1A and TOR1B paralogues found in tertrapods. tor1 was expressed ubiquitously during early embryonic development and in multiple adult tissues, including the CNS. The 2.1 kb tor1 mRNA encodes Torsin1, which is 59% identical and 78% homologous to human TorsinA. Torsin1 was expressed as major 45 kDa and minor 47 kDa glycoproteins, within the cytoplasm of neurons and neuropil throughout the CNS. Similar to previous findings relating to human TorsinA, mutations of the ATP hydrolysis domain of Torsin1 resulted in relocalization of the protein in cultured cells from the endoplasmic reticulum to the nuclear envelope. Zebrafish embryos lacking tor1 during early development did not show impaired viability, overt morphological abnormalities, alterations in motor behavior, or developmental defects in the dopaminergic system. Torsin1 is thus non-essential for early development of the motor system, suggesting that important CNS functions may occur later in development, consistent with the critical time window in late childhood when dystonia symptoms usually emerge in DYT1 patients. The similarities between Torsin1 and human TorsinA in domain organization, expression pattern, and cellular localization suggest that the zebrafish will provide a useful model to understand the neuronal functions of Torsins

  16. Recent advances in systemic therapy for gastrointestinal neuroendocrine tumors.

    PubMed

    Pelley, R J; Bukowski, R M

    1999-01-01

    Neuroendocrine tumors of the gastrointestinal tract are rare tumors which can be classified as amine precursor uptake and decarboxylation tumors (APU-Domas). Although the majority of clinically apparent tumors are malignant, they are frequently slow growing. Despite this characteristic, they may generate disabling hormonal syndromes requiring aggressive treatment to achieve palliation. Recent advances in understanding the pathophysiology of these tumors has led to better medical therapy with chemotherapeutic agents, somatostatin analogues, and biologic therapies. This review will update the recent efforts in systemic therapies of the gastrointestinal neuroendocrine tumors.

  17. Correlation between clinical severity of central nervous system (CNS) lupus and findings on single photon emission computed tomographic (SPECT) images of the brain; preliminary results

    SciTech Connect

    Silverman, I.E.; Zeit, R.M.; Von Feldt, J.M.

    1994-05-01

    Systemic Lupus Erythematosis (SLE) commonly causes significant neuropsychiatric disorders. The purpose of this study was to review the brain SPECT studies of SLE patients with clinical evidence of CNS involvement and determine whether there is a correlation between the findings on SPECT images and the clinical manifestations of this serious phase of the disease. We enrolled 19 SLE patients and 12 normal controls in this study. The level of each patient`s disease activity was determined by the SLE Disease Activity Index (SLEDAI), an established method of scoring disease severity which is heavily weighted toward neuropsychiatric symptomatology, for 15 of the 19 SLE patients. The SLEDAI was calculated within a 10 day window of the date when the SPECT scan was obtained. SPECT scans were performed 30 minutes following the intravenous administration of 99mTc-HMPAO. Results are discussed.

  18. CNS involvement in hemophagocytic lymphohistiocytosis: CT and MR findings.

    PubMed

    Chung, Tae Woong

    2007-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder that is characterized by proliferation of benign histiocytes, and this commonly involves the liver, spleen, lymph nodes, bone marrow and central nervous system (CNS). We report here on the CT and MR imaging findings in a case of CNS HLH that showed multiple ring enhancing masses mimicking abscess or another mass on the CT and MR imaging.

  19. Mechanisms of Hypothermia, Delayed Hyperthermia and Fever Following CNS Injury

    EPA Science Inventory

    Central nervous system (CNS) damage is often associated with robust body temperature changes, such as hypothermia and delayed hyperthermia. Hypothermia is one of the most common body temperature changes to CNS insults in rodents and is often associated with improved outcome. Alth...

  20. Intraventricular CNS lesions: A pictorial essay.

    PubMed

    Watts, Jane; Yap, Kelvin K; Ou, Daniel; Tartaglia, Con; Trost, Nicholas; Sutherland, Tom

    2015-08-01

    Intraventricular lesions of the central nervous system (CNS) can present a diagnostic challenge due to a range of differential diagnoses and radiological appearances. Both CT and MRI imaging findings, in combination with location and patient's age, can help limit the differentials. This pictorial essay presents the salient radiological features, location and demographics of the more common intraventricular lesions of the brain.

  1. Pharmacotherapy for Adults with Tumors of the Central Nervous System

    PubMed Central

    Schor, Nina F.

    2009-01-01

    Tumors of the adult central nervous system are among the most common and most chemoresistant neoplasms. Malignant tumors of the brain and spinal cord collectively account for approximately 1.3% of all cancers and 2.2% of all cancer-related deaths. Novel pharmacological approaches to nervous system tumors are urgently needed. This review presents the current approaches and challenges to successful pharmacotherapy of adults with malignant tumors of the central nervous system and discusses novel approaches aimed at overcoming these challenges. PMID:19091301

  2. Immune surveillance of the CNS following infection and injury

    PubMed Central

    Russo, Matthew; McGavern, Dorian B.

    2015-01-01

    The central nervous system (CNS) contains a sophisticated neural network that must be constantly surveyed in order to detect and mitigate a diverse array of challenges. The innate and adaptive immune systems actively participate in this surveillance, which is critical for the maintenance of CNS homeostasis and can facilitate the resolution of infections, degeneration, and tissue damage. Infections and sterile injuries represent two common challenges imposed on the CNS that require a prompt immune response. While the inducers of these two challenges differ in origin, the resultant responses orchestrated by the CNS share some overlapping features. Here, we review how the CNS immunologically discriminates between pathogens and sterile injuries, mobilizes an immune reaction, and, ultimately, regulates local and peripherally-derived immune cells to provide a supportive milieu for tissue repair. PMID:26431941

  3. Treatment of Children With Central Nervous System Primitive Neuroectodermal Tumors/Pinealoblastomas in the Prospective Multicentric Trial HIT 2000 Using Hyperfractionated Radiation Therapy Followed by Maintenance Chemotherapy

    SciTech Connect

    Gerber, Nicolas U.; Hoff, Katja von; Resch, Anika; Ottensmeier, Holger; Kwiecien, Robert; Faldum, Andreas; Matuschek, Christiane; Hornung, Dagmar; Bremer, Michael; Benesch, Martin; Pietsch, Torsten; Warmuth-Metz, Monika; Kuehl, Joachim; Rutkowski, Stefan; Kortmann, Rolf D.

    2014-07-15

    Purpose: The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4. Methods and Materials: After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine). Results: Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (±standard error [SE]) were each 58% (±10%) for the entire cohort: CNS-PNET was 53% (±13); pinealoblastoma was 64% (±15%; P=.524 and P=.627, respectively). Conclusions: Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.

  4. Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers

    PubMed Central

    Zhang, Fan; Mastorakos, Panagiotis; Mishra, Manoj K.; Mangraviti, Antonella; Hwang, Lee; Zhou, Jinyuan; Hanes, Justin; Brem, Henry; Olivi, Alessandro; Tyler, Betty; Kannan, Rangaramanujam M.

    2015-01-01

    Effective blood–brain tumor barrier penetration and uniform solid tumor distribution can significantly enhance therapeutic delivery to brain tumors. Hydroxyl-functionalized, generation-4 poly(amidoamine) (PAMAM) dendrimers, with their small size, near-neutral surface charge, and the ability to selectively localize in cells associated with neuroinflammation may offer new opportunities to address these challenges. In this study we characterized the intracranial tumor biodistribution of systemically delivered PAMAM dendrimers in an intracranial rodent gliosarcoma model using fluorescence-based quantification methods and high resolution confocal microscopy. We observed selective and homogeneous distribution of dendrimer throughout the solid tumor (~6 mm) and peritumoral area within fifteen minutes after systemic administration, with subsequent accumulation and retention in tumor associated microglia/macrophages (TAMs). Neuroinflammation and TAMs have important growth promoting and pro-invasive effects in brain tumors. The rapid clearance of systemically administered dendrimers from major organs promises minimal off-target adverse effects of conjugated drugs. Therefore, selective delivery of immunomodulatory molecules to TAM, using hydroxyl PAMAM dendrimers, may hold promise for therapy of glioblastoma. PMID:25818456

  5. Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers.

    PubMed

    Zhang, Fan; Mastorakos, Panagiotis; Mishra, Manoj K; Mangraviti, Antonella; Hwang, Lee; Zhou, Jinyuan; Hanes, Justin; Brem, Henry; Olivi, Alessandro; Tyler, Betty; Kannan, Rangaramanujam M

    2015-06-01

    Effective blood-brain tumor barrier penetration and uniform solid tumor distribution can significantly enhance therapeutic delivery to brain tumors. Hydroxyl-functionalized, generation-4 poly(amidoamine) (PAMAM) dendrimers, with their small size, near-neutral surface charge, and the ability to selectively localize in cells associated with neuroinflammation may offer new opportunities to address these challenges. In this study we characterized the intracranial tumor biodistribution of systemically delivered PAMAM dendrimers in an intracranial rodent gliosarcoma model using fluorescence-based quantification methods and high resolution confocal microscopy. We observed selective and homogeneous distribution of dendrimer throughout the solid tumor (∼6 mm) and peritumoral area within fifteen minutes after systemic administration, with subsequent accumulation and retention in tumor associated microglia/macrophages (TAMs). Neuroinflammation and TAMs have important growth promoting and pro-invasive effects in brain tumors. The rapid clearance of systemically administered dendrimers from major organs promises minimal off-target adverse effects of conjugated drugs. Therefore, selective delivery of immunomodulatory molecules to TAM, using hydroxyl PAMAM dendrimers, may hold promise for therapy of glioblastoma.

  6. Chemokines in CNS injury and repair.

    PubMed

    Jaerve, Anne; Müller, Hans Werner

    2012-07-01

    Recruitment of inflammatory cells is known to drive the secondary damage cascades that are common to injuries of the central nervous system (CNS). Cell activation and infiltration to the injury site is orchestrated by changes in the expression of chemokines, the chemoattractive cytokines. Reducing the numbers of recruited inflammatory cells by the blocking of the action of chemokines has turned out be a promising approach to diminish neuroinflammation and to improve tissue preservation and neovascularization. In addition, several chemokines have been shown to be essential for stem/progenitor cell attraction, their survival, differentiation and cytokine production. Thus, chemokines might indirectly participate in remyelination, neovascularization and neuroprotection, which are important prerequisites for CNS repair after trauma. Moreover, CXCL12 promotes neurite outgrowth in the presence of growth inhibitory CNS myelin and enhances axonal sprouting after spinal cord injury (SCI). Here, we review current knowledge about the exciting functions of chemokines in CNS trauma, including SCI, traumatic brain injury and stroke. We identify common principles of chemokine action and discuss the potentials and challenges of therapeutic interventions with chemokines. PMID:22700007

  7. How Do Meningeal Lymphatic Vessels Drain the CNS?

    PubMed

    Raper, Daniel; Louveau, Antoine; Kipnis, Jonathan

    2016-09-01

    The many interactions between the nervous and the immune systems, which are active in both physiological and pathological states, have recently become more clearly delineated with the discovery of a meningeal lymphatic system capable of carrying fluid, immune cells, and macromolecules from the central nervous system (CNS) to the draining deep cervical lymph nodes. However, the exact localization of the meningeal lymphatic vasculature and the path of drainage from the cerebrospinal fluid (CSF) to the lymphatics remain poorly understood. Here, we discuss the potential differences between peripheral and CNS lymphatic vessels and examine the purported mechanisms of CNS lymphatic drainage, along with how these may fit into established patterns of CSF flow.

  8. Tumor tracking and motion compensation with an adaptive tumor tracking system (ATTS): System description and prototype testing

    SciTech Connect

    Wilbert, Juergen; Meyer, Juergen; Baier, Kurt; Guckenberger, Matthias; Herrmann, Christian; Hess, Robin; Janka, Christian; Ma Lei; Mersebach, Torben; Richter, Anne; Roth, Michael; Schilling, Klaus; Flentje, Michael

    2008-09-15

    A novel system for real-time tumor tracking and motion compensation with a robotic HexaPOD treatment couch is described. The approach is based on continuous tracking of the tumor motion in portal images without implanted fiducial markers, using the therapeutic megavoltage beam, and tracking of abdominal breathing motion with optical markers. Based on the two independently acquired data sets the table movements for motion compensation are calculated. The principle of operation of the entire prototype system is detailed first. In the second part the performance of the HexaPOD couch was investigated with a robotic four-dimensional-phantom capable of simulating real patient tumor trajectories in three-dimensional space. The performance and limitations of the HexaPOD table and the control system were characterized in terms of its dynamic behavior. The maximum speed and acceleration of the HexaPOD were 8 mm/s and 34.5 mm/s{sup 2} in the lateral direction, and 9.5 mm/s and 29.5 mm/s{sup 2} in longitudinal and anterior-posterior direction, respectively. Base line drifts of the mean tumor position of realistic lung tumor trajectories could be fully compensated. For continuous tumor tracking and motion compensation a reduction of tumor motion up to 68% of the original amplitude was achieved. In conclusion, this study demonstrated that it is technically feasible to compensate breathing induced tumor motion in the lung with the adaptive tumor tracking system.

  9. [A case of an anti-Ma2 antibody-positive patient presenting with variable CNS symptoms mimicking multiple system atrophy with a partial response to immunotherapy].

    PubMed

    Shiraishi, Wataru; Iwanaga, Yasutaka; Yamamoto, Akifumi

    2015-01-01

    A 70-year-old man with a 5-month history of progressive bradykinesia of the bilateral lower extremities was admitted to our hospital. At the age of 64, he underwent proximal gastrectomy for gastric cancer. He also had a history of subacute combined degeneration of the spinal cord since the age of 67, which was successfully treated with vitamin B12 therapy. Four weeks before admission to our hospital, he admitted himself to his former hospital complaining of walking difficulty. Two weeks later, however, his symptoms progressed rapidly; he was immobilized for two weeks and did not respond to the vitamin therapy. On admission to our hospital, he showed moderate paralysis of the lower extremities, cog-wheel rigidity of the four extremities, and dystonic posture of his left hand. He also showed orthostatic hypotension and vesicorectal disorders. Blood examination and cerebrospinal fluid analysis revealed no remarkable abnormalities. Electroencephalography showed frontal dominant, high voltage, sharp waves. His brain and spinal MRI revealed no notable abnormalities. We suspected autoimmune disease and commenced one course of intravenous methylprednisolone therapy, resulting in improvement of the parkinsonism and orthostatic hypotension. Based on these results, we investigated possible neural antigens and detected anti-Ma2 antibody. In addition to limbic encephalitis, anti-Ma2 antibody-positive neural disorders are characterized by rapid eye movement sleep behavior disorders or parkinsonism. Here, we report an anti-Ma2 antibody positive patient presenting variable CNS symptoms mimicking multiple system atrophy, who responded to immunotherapy. PMID:25746072

  10. Cell encapsulation technology as a therapeutic strategy for CNS malignancies.

    PubMed Central

    Visted, T.; Bjerkvig, R.; Enger, P. O.

    2001-01-01

    Gene therapy using viral vectors has to date failed to reveal its definitive clinical usefulness. Cell encapsulation technology represents an alternative, nonviral approach for the delivery of biologically active compounds to tumors. This strategy involves the use of genetically engineered producer cells that secrete a protein with therapeutic potential. The cells are encapsulated in an immunoisolating material that makes them suitable for transplantation. The capsules, or bioreactors, permit the release of recombinant proteins that may assert their effects in the tumor microenvironment. During the last decades, there has been significant progress in the development of encapsulation technologies that comprise devices for both macro- and microencapsulation. The polysaccharide alginate is the most commonly used material for cell encapsulation and is well tolerated by various tissues. A wide spectrum of cells and tissues has been encapsulated and implanted, both in animals and humans, indicating the general applicability of this approach for both research and medical purposes, including CNS malignancies. Gliomas most frequently recur at the resection site. To provide local and sustained drug delivery, the bioreactors can be implanted in the brain parenchyma or in the ventricular system. The development of comprehensive analyses of geno- and phenotypic profiles of a tumor (genomics and proteomics) may provide new and important guidelines for choosing the optimal combination of bioreactors and recombinant proteins for therapeutic use. PMID:11465401

  11. Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system.

    PubMed

    Salinas Tejedor, Laura; Berner, Gabriel; Jacobsen, Kristin; Gudi, Viktoria; Jungwirth, Nicole; Hansmann, Florian; Gingele, Stefan; Prajeeth, Chittappen K; Baumgärtner, Wolfgang; Hoffmann, Andrea; Skripuletz, Thomas; Stangel, Martin

    2015-11-01

    Remyelination is the natural repair mechanism in demyelinating disorders such as multiple sclerosis (MS) and it was proposed that it might protect from axonal loss. For unknown reasons, remyelination is often incomplete or fails in MS lesions and therapeutic treatments to enhance remyelination are not available. Recently, the transplantation of exogenous mesenchymal stem cells (MSC) has emerged as a promising tool to enhance repair processes. This included the animal model experimental autoimmune encephalomyelitis (EAE), a commonly used model for the autoimmune mechanisms of MS. However, in EAE it is not clear if the beneficial effect of MSC derives from a direct influence on brain resident cells or if this is an indirect phenomenon via modulation of the peripheral immune system. The aim of this study was to determine potential regenerative functions of MSC in the toxic cuprizone model of demyelination that allows studying direct effects on de- and remyelination without the influence of the peripheral immune system. MSC from three different species (human, murine, canine) were transplanted either intraventricularly into the cerebrospinal fluid or directly into the lesion of the corpus callosum at two time points: at the onset of oligodendrocyte progenitor cell (OPC) proliferation or the peak of OPC proliferation during cuprizone induced demyelination. Our results show that MSC did not exert any regenerative effects after cuprizone induced demyelination and oligodendrocyte loss. During remyelination, MSC did not influence the dynamics of OPC proliferation and myelin formation. In conclusion, MSC did not exert direct regenerative functions in a mouse model where peripheral immune cells and especially T lymphocytes do not play a role. We thus suggest that the peripheral immune system is required for MSC to exert their effects and this is independent from a direct influence of the central nervous system.

  12. Treatment of newly diagnosed B-cell origin primary CNS lymphoma with systemic R-IDARAM chemotherapy and intrathecal immunochemotherapy

    PubMed Central

    Qian, Liren; Zhou, Chunhui; Shen, Jianliang; Cen, Jian; Yin, Wenjie

    2016-01-01

    Background Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin's lymphoma (NHL). The aim was to evaluate response rate, progression free survival (PFS), overall survival (OS), and toxicity in PCNSL after systemic R-IDARAM and intrathecal immunochemotherapy with deferred radiotherapy. Results The response rate was 94% with 17 (89%) complete responses and 1 (5%) partial responses. Follow-up time is from 5 to 63 months (median, 39 months). Median survival has not been reached. 3-year overall survival and progression-free survival rates were 84.2% (CI 72.6% to 99.8%) and 63.2% (CI 41.4% to 73.8%). Systemic toxicity was mainly hematologic. Neurocognitive and neuromotor deterioration as a result of treatment occurred in only one patient (5%). Patients and Methods From September 2010 to June 2015, 19 consecutive patients with PCNSL (median age, 54 years) were enrolled into a pilot phase II study evaluating immunochemotherapy without radiotherapy. The patients were accrued to a chemotherapy regimen that incorporated rituximab, idarubicin, dexamethasone, cytarabine (Ara-c) and methotrexate (MTX) combined with intrathecal rituximab, MTX, dexamethasone and Ara-c. Conclusions The results indicate that R-IDARAM regimen with intrathecal immunochemotherapy is generally well tolerated and produces a high complete response rate and survival rate. PMID:27029056

  13. Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases.

    PubMed

    Bar-Or, Amit; Hintzen, Rogier Q; Dale, Russell C; Rostasy, Kevin; Brück, Wolfgang; Chitnis, Tanuja

    2016-08-30

    Elucidating pathophysiologic mechanisms underlying the spectrum of pediatric-onset CNS demyelinating diseases, particularly those that may distinguish multiple sclerosis (MS) from other entities, promises to both improve diagnostics and guide more-informed therapeutic decisions. Observations that pediatric- and adult-onset MS share the same genetic and environmental risk factors support the view that these conditions represent essentially the same illness manifesting at different ages. Nonetheless, special consideration must be given when CNS inflammation manifests in early life, at a time when multiple organs (including immune and nervous systems) are actively maturing. CSF analysis in pediatric-onset MS points to chronic CNS inflammation, supported by observations from limited pathologic material available for study. Emerging results implicate abnormalities in both effector and regulatory T cell subsets, and potentially immune senescence, in children with MS. Although CNS-directed antibodies (including antibodies recognizing myelin antigens; Kir4.1) can be documented in pediatric-onset MS, their pathophysiologic significance (as in adults) remains unclear. This is in contrast to the presence of serum and/or CSF antibodies recognizing aquaporin-4, which, when measured using validated cell-based assays, supports the diagnosis of a neuromyelitis optica spectrum disorder, distinct from MS. Presence of anti-myelin oligodendrocyte glycoprotein antibodies documented with similar cell-based assays may also be associated with pathophysiologically distinct disease phenotypes in children. The substantial impact of pediatric-onset MS on normal brain development and function underscores the importance of elucidating both the immunobiology and neurobiology of disease. Ongoing efforts are aimed at developing and validating biological measures that define pathophysiologically distinct monophasic and chronic forms of pediatric CNS demyelination. PMID:27572856

  14. CNS Anticancer Drug Discovery and Development Conference White Paper.

    PubMed

    Levin, Victor A; Tonge, Peter J; Gallo, James M; Birtwistle, Marc R; Dar, Arvin C; Iavarone, Antonio; Paddison, Patrick J; Heffron, Timothy P; Elmquist, William F; Lachowicz, Jean E; Johnson, Ted W; White, Forest M; Sul, Joohee; Smith, Quentin R; Shen, Wang; Sarkaria, Jann N; Samala, Ramakrishna; Wen, Patrick Y; Berry, Donald A; Petter, Russell C

    2015-11-01

    Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward.

  15. Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control

    PubMed Central

    de Kloet, Annette D.; Liu, Meng; Rodríguez, Vermalí; Krause, Eric G.

    2015-01-01

    Despite tremendous research efforts, hypertension remains an epidemic health concern, leading often to the development of cardiovascular disease. It is well established that in many instances, the brain plays an important role in the onset and progression of hypertension via activation of the sympathetic nervous system. Further, the activity of the renin-angiotensin system (RAS) and of glial cell-mediated proinflammatory processes have independently been linked to this neural control and are, as a consequence, both attractive targets for the development of antihypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS, ANG II, activates its type-1 receptor on neurons to mediate some of its hypertensive actions, additional nuances of this brain RAS control of blood pressure are constantly being uncovered. One of these complexities is that the RAS is now thought to impact cardiovascular control, in part, via facilitating a glial cell-dependent proinflammatory milieu within cardiovascular control centers. Another complexity is that the newly characterized antihypertensive limbs of the RAS are now recognized to, in many cases, antagonize the prohypertensive ANG II type 1 receptor (AT1R)-mediated effects. That being said, the mechanism by which the RAS, glia, and neurons interact to regulate blood pressure is an active area of ongoing research. Here, we review the current understanding of these interactions and present a hypothetical model of how these exchanges may ultimately regulate cardiovascular function. PMID:26084692

  16. Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control.

    PubMed

    de Kloet, Annette D; Liu, Meng; Rodríguez, Vermalí; Krause, Eric G; Sumners, Colin

    2015-09-01

    Despite tremendous research efforts, hypertension remains an epidemic health concern, leading often to the development of cardiovascular disease. It is well established that in many instances, the brain plays an important role in the onset and progression of hypertension via activation of the sympathetic nervous system. Further, the activity of the renin-angiotensin system (RAS) and of glial cell-mediated proinflammatory processes have independently been linked to this neural control and are, as a consequence, both attractive targets for the development of antihypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS, ANG II, activates its type-1 receptor on neurons to mediate some of its hypertensive actions, additional nuances of this brain RAS control of blood pressure are constantly being uncovered. One of these complexities is that the RAS is now thought to impact cardiovascular control, in part, via facilitating a glial cell-dependent proinflammatory milieu within cardiovascular control centers. Another complexity is that the newly characterized antihypertensive limbs of the RAS are now recognized to, in many cases, antagonize the prohypertensive ANG II type 1 receptor (AT1R)-mediated effects. That being said, the mechanism by which the RAS, glia, and neurons interact to regulate blood pressure is an active area of ongoing research. Here, we review the current understanding of these interactions and present a hypothetical model of how these exchanges may ultimately regulate cardiovascular function.

  17. CNS activation and regional connectivity during pantomime observation: No engagement of the mirror neuron system for deaf signers

    PubMed Central

    Emmorey, Karen; Xu, Jiang; Gannon, Patrick; Goldin-Meadow, Susan; Braun, Allen

    2009-01-01

    Deaf signers have extensive experience using their hands to communicate. Using fMRI, we examined the neural systems engaged during the perception of manual communication in 14 deaf signers and 14 hearing non-signers. Participants passively viewed blocked video clips of pantomimes (e.g., peeling an imaginary banana) and action verbs in American Sign Language (ASL) that were rated as meaningless by non-signers (e.g., TO-DANCE). In contrast to visual fixation, pantomimes strongly activated fronto-parietal regions (the mirror neuron system, MNS) in hearing non-signers, but only bilateral middle temporal regions in deaf signers. When contrasted with ASL verbs, pantomimes selectively engaged inferior and superior parietal regions in hearing non-signers, but right superior temporal cortex in deaf signers. The perception of ASL verbs recruited similar regions as pantomimes for deaf signers, with some evidence of greater involvement of left inferior frontal gyrus for ASL verbs. Functional connectivity analyses with left hemisphere seed voxels (ventral premotor, inferior parietal lobule, fusiform gyrus) revealed robust connectivity with the MNS for the hearing non-signers. Deaf signers exhibited functional connectivity with the right hemisphere that was not observed for the hearing group for the fusiform gyrus seed voxel. We suggest that life-long experience with manual communication, and/or auditory deprivation, may alter regional connectivity and brain activation when viewing pantomimes. We conclude that the lack of activation within the MNS for deaf signers does not support an account of human communication that depends upon automatic sensorimotor resonance between perception and action. PMID:19679192

  18. Changes in the nitric oxide system in the shore crab Hemigrapsus sanguineus (Crustacea, Decapoda) CNS induced by a nociceptive stimulus.

    PubMed

    Dyuizen, Inessa V; Kotsyuba, Elena P; Lamash, Nina E

    2012-08-01

    Using NADPH-diaphorase (NADPH-d) histochemistry, inducible nitric oxide synthase (iNOS)-immunohistochemistry and immunoblotting, we characterized the nitric oxide (NO)-producing neurons in the brain and thoracic ganglion of a shore crab subjected to a nociceptive chemical stimulus. Formalin injection into the cheliped evoked specific nociceptive behavior and neurochemical responses in the brain and thoracic ganglion of experimental animals. Within 5-10 min of injury, the NADPH-d activity increased mainly in the neuropils of the olfactory lobes and the lateral antenna I neuropil on the side of injury. Later, the noxious-induced expression of NADPH-d and iNOS was detected in neurons of the brain, as well as in segmental motoneurons and interneurons of the thoracic ganglion. Western blotting analysis showed that an iNOS antiserum recognized a band at 120 kDa, in agreement with the expected molecular mass of the protein. The increase in nitrergic activity induced by nociceptive stimulation suggests that the NO signaling system may modulate nociceptive behavior in crabs.

  19. Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems: a review.

    PubMed

    Bicker, Joana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

    2014-08-01

    During the research and development of new drugs directed at the central nervous system, there is a considerable attrition rate caused by their hampered access to the brain by the blood-brain barrier. Throughout the years, several in vitro models have been developed in an attempt to mimic critical functionalities of the blood-brain barrier and reliably predict the permeability of drug candidates. However, the current challenge lies in developing a model that retains fundamental blood-brain barrier characteristics and simultaneously remains compatible with the high throughput demands of pharmaceutical industries. This review firstly describes the roles of all elements of the neurovascular unit and their influence on drug brain penetration. In vitro models, including non-cell based and cell-based models, and in vivo models are herein presented, with a particular emphasis on their methodological aspects. Lastly, their contribution to the improvement of brain drug delivery strategies and drug transport across the blood-brain barrier is also discussed.

  20. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

    PubMed Central

    Marrone, Gina F.; Grinnell, Steven G.; Lu, Zhigang; Rossi, Grace C.; Le Rouzic, Valerie; Xu, Jin; Majumdar, Susruta; Pan, Ying-Xian; Pasternak, Gavril W.

    2016-01-01

    The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia. PMID:26976581

  1. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS.

    PubMed

    Marrone, Gina F; Grinnell, Steven G; Lu, Zhigang; Rossi, Grace C; Le Rouzic, Valerie; Xu, Jin; Majumdar, Susruta; Pan, Ying-Xian; Pasternak, Gavril W

    2016-03-29

    The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3'-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50, 488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia. PMID:26976581

  2. Connexin36 expression in major centers of the auditory system in the CNS of mouse and rat: Evidence for neurons forming purely electrical synapses and morphologically mixed synapses

    PubMed Central

    Rubio, M.E.; Nagy, J.I.

    2015-01-01

    Electrical synapses formed by gap junctions composed of connexin36 (Cx36) are widely distributed in the mammalian central nervous system (CNS). Here, we used immunofluorescence methods to document the expression of Cx36 in the cochlear nucleus and in various structures of the auditory pathway of rat and mouse. Labelling of Cx36 visualized exclusively as Cx36-puncta was densely distributed primarily on the somata and initial dendrites of neuronal populations in the ventral cochlear nucleus, and was abundant in superficial layers of the dorsal cochlear nucleus. Other auditory centers displaying Cx36-puncta included the medial nucleus of the trapezoid body (MNTB), regions surrounding the lateral superior olivary nucleus, the dorsal nucleus of the medial lemniscus, the nucleus sagulum, all subnuclei of the inferior colliculus, and the auditory cerebral cortex. In EGFP-Cx36 transgenic mice, EGFP reporter was detected in neurons located in each of auditory centers that harboured Cx36-puncta. In the ventral cochlear nuclei and the MNTB, many neuronal somata were heavily innervated by nerve terminals containing vesicular glutamate transporter-1 (vglut1) and Cx36 was frequently localized at these terminals. Cochlear ablation caused a near total depletion of vglut1-positive terminals in the ventral cochlear nuclei, with a commensurate loss of labelling for Cx36 around most neuronal somata, but preserved Cx36-puncta at somatic neuronal appositions. The results suggest that electrical synapses formed by Cx36-containing gap junctions occur in most of the widely distributed centers of the auditory system. Further, it appears that morphologically mixed chemical/electrical synapses formed by nerve terminals are abundant in the ventral cochlear nucleus, including those at endbulbs of Held formed by cochlear primary afferent fibers, and those at calyx of Held synapses on MNTB neurons. PMID:26188286

  3. FDTD analysis of a noninvasive hyperthermia system for brain tumors

    PubMed Central

    2012-01-01

    Background Hyperthermia is considered one of the new therapeutic modalities for cancer treatment and is based on the difference in thermal sensitivity between healthy tissues and tumors. During hyperthermia treatment, the temperature of the tumor is raised to 40–45°C for a definite period resulting in the destruction of cancer cells. This paper investigates design, modeling and simulation of a new non-invasive hyperthermia applicator system capable of effectively heating deep seated as well as superficial brain tumors using inexpensive, simple, and easy to fabricate components without harming surrounding healthy brain tissues. Methods The proposed hyperthermia applicator system is composed of an air filled partial half ellipsoidal chamber, a patch antenna, and a head model with an embedded tumor at an arbitrary location. The irradiating antenna is placed at one of the foci of the hyperthermia chamber while the center of the brain tumor is placed at the other focus. The finite difference time domain (FDTD) method is used to compute both the SAR patterns and the temperature distribution in three different head models due to two different patch antennas at a frequency of 915 MHz. Results The obtained results suggest that by using the proposed noninvasive hyperthermia system it is feasible to achieve sufficient and focused energy deposition and temperature rise to therapeutic values in deep seated as well as superficial brain tumors without harming surrounding healthy tissue. Conclusions The proposed noninvasive hyperthermia system proved suitable for raising the temperature in tumors embedded in the brain to therapeutic values by carefully selecting the systems components. The operator of the system only needs to place the center of the brain tumor at a pre-specified location and excite the antenna at a single frequency of 915 MHz. Our study may provide a basis for a clinical applicator prototype capable of heating brain tumors. PMID:22891953

  4. Necrosis After Craniospinal Irradiation: Results From a Prospective Series of Children With Central Nervous System Embryonal Tumors

    SciTech Connect

    Murphy, Erin S.; Merchant, Thomas E.; Wu Shengjie; Xiong Xiaoping; Lukose, Renin; Wright, Karen D.; Qaddoumi, Ibrahim; Armstrong, Gregory T.; Broniscer, Alberto; Gajjar, Amar

    2012-08-01

    Purpose: Necrosis of the central nervous system (CNS) is a known complication of craniospinal irradiation (CSI) in children with medulloblastoma and similar tumors. We reviewed the incidence of necrosis in our prospective treatment series. Patients and Methods: Between 1996 and 2009, 236 children with medulloblastoma (n = 185) or other CNS embryonal tumors (n = 51) received postoperative CSI followed by dose-intense cyclophosphamide, vincristine, and cisplatin. Average risk cases (n = 148) received 23.4 Gy CSI, 36 Gy to the posterior fossa, and 55.8 Gy to the primary; after 2003, the treatment was 23.4 Gy CSI and 55.8 Gy to the primary. All high-risk cases (n = 88) received 36-39.6 Gy CSI and 55.8 Gy primary. The primary site clinical target volume margin was 2 cm (pre-2003) or 1 cm (post-2003). With competing risk of death by any cause, we determined the cumulative incidence of necrosis. Results: With a median follow-up of 52 months (range, 4-163 months), eight cases of necrosis were documented. One death was attributed. The median time to the imaging evidence was 4.8 months and to symptoms 6.0 months. The cumulative incidence at 5 years was 3.7% {+-} 1.3% (n = 236) for the entire cohort and 4.4% {+-} 1.5% (n = 196) for infratentorial tumor location. The mean relative volume of infratentorial brain receiving high-dose irradiation was significantly greater for patients with necrosis than for those without: {>=}50 Gy (92.12% {+-} 4.58% vs 72.89% {+-} 1.96%; P=.0337), {>=}52 Gy (88.95% {+-} 5.50% vs 69.16% {+-} 1.97%; P=.0275), and {>=}54 Gy (82.28% {+-} 7.06% vs 63.37% {+-} 1.96%; P=.0488), respectively. Conclusions: Necrosis in patients with CNS embryonal tumors is uncommon. When competing risks are considered, the incidence is 3.7% at 5 years. The volume of infratentorial brain receiving greater than 50, 52, and 54 Gy, respectively, is predictive for necrosis.

  5. A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study.

    PubMed

    Salloum, Ralph; Hummel, Trent R; Kumar, Shiva Senthil; Dorris, Kathleen; Li, Shaoyu; Lin, Tong; Daryani, Vinay M; Stewart, Clinton F; Miles, Lili; Poussaint, Tina Young; Stevenson, Charles; Goldman, Stewart; Dhall, Girish; Packer, Roger; Fisher, Paul; Pollack, Ian F; Fouladi, Maryam; Boyett, James; Drissi, Rachid

    2016-09-01

    Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

  6. CNS Vasculitis Associated with Waldenström Macroglobulinemia

    PubMed Central

    Riangwiwat, Tanawan; Wu, Chris Y.; Santos-Ocampo, Alberto S.; Liu, Randal J.

    2016-01-01

    Waldenström macroglobulinemia (WM) is an indolent B cell lymphoproliferative disorder with monoclonal IgM secretion. We present a patient with WM who presented with multifocal acute cortical ischemic strokes and was found to have central nervous system (CNS) vasculitis. Workup was negative for cryoglobulins and hyperviscosity syndrome. Immunosuppression with intravenous steroids and cyclophosphamide stabilized the patient's mental status and neurologic deficits. On followup over 7 years, patient gained independence from walking aids and experienced no recurrences of CNS vasculitis. To our knowledge, CNS vasculitis in a WM patient, in the absence of cryoglobulins, has not been reported. Immunosuppression is the preferred treatment.

  7. Regional astrocyte allocation regulates CNS synaptogenesis and repair.

    PubMed

    Tsai, Hui-Hsin; Li, Huiliang; Fuentealba, Luis C; Molofsky, Anna V; Taveira-Marques, Raquel; Zhuang, Helin; Tenney, April; Murnen, Alice T; Fancy, Stephen P J; Merkle, Florian; Kessaris, Nicoletta; Alvarez-Buylla, Arturo; Richardson, William D; Rowitch, David H

    2012-07-20

    Astrocytes, the most abundant cell population in the central nervous system (CNS), are essential for normal neurological function. We show that astrocytes are allocated to spatial domains in mouse spinal cord and brain in accordance with their embryonic sites of origin in the ventricular zone. These domains remain stable throughout life without evidence of secondary tangential migration, even after acute CNS injury. Domain-specific depletion of astrocytes in ventral spinal cord resulted in abnormal motor neuron synaptogenesis, which was not rescued by immigration of astrocytes from adjoining regions. Our findings demonstrate that region-restricted astrocyte allocation is a general CNS phenomenon and reveal intrinsic limitations of the astroglial response to injury.

  8. Treatment of diffuse large B-cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS-penetrating R-IDARAM chemotherapy.

    PubMed

    Maciocia, Paul; Badat, Mohsin; Cheesman, Simon; D'Sa, Shirley; Joshi, Rahul; Lambert, Jonathan; Mohamedbhai, Sajir; Pule, Martin; Linch, David; Ardeshna, Kirit

    2016-02-01

    Diffuse large B-cell lymphoma with secondary involvement of the central nervous system (SCNS-DLBCL) is a rare condition carrying a poor prognosis. No optimal therapeutic regimen has been identified. We retrospectively analysed 23 patients with SCNS-DLBCL treated with R-IDARAM (rituximab 375 mg/m(2) IV day 1; methotrexate 12·5 mg by intrathecal injection day 1; idarubicin 10 mg/m(2) /day IV days 1 and 2; dexamethasone 100 mg/day IV infusion over 12 h days 1-3; cytosine arabinoside 1000 mg/m(2) /day IV over 1 h days 1 and 2; and methotrexate 2000 mg/m(2) IV over 2 h day 3. Ten out of 23 (44%) patients had CNS involvement at initial presentation ('new disease'), 10/23 (44%) had relapsed disease and 3/23 (13%) had primary refractory disease. 14/23 (61%) of patients responded - 6 (26%) complete response, 8 (35%) partial response. Grade 3-4 haematological toxicity was seen in all cycles, with no grade 3-4 or long-term neurological toxicity. Median follow-up for surviving patients was 49 months. At 2 years, estimated progression-free survival (PFS) was 39% and overall survival (OS) was 52%. Encouraging outcomes were reported in patients with new disease, with 5-year estimated PFS of 50% and OS 75%. R-IDARAM is a well-tolerated regimen with encouraging efficacy in patients with SCNS-DLBCL, although patients with relapsed or refractory disease continue to fare poorly. PMID:26684148

  9. CNS-disease affecting the heart: brain-heart disorders.

    PubMed

    Finsterer, Josef; Wahbi, Karim

    2014-10-15

    There are a number of hereditary and non-hereditary central nervous system (CNS) disorders, which directly or indirectly affect the heart (brain-heart disorders). The most well-known of these CNS-disorders are epilepsy, stroke, subarachanoid bleeding, bacterial meningitis, and head injury. In addition, a number of hereditary and non-hereditary neurodegenerative disorders may impair cardiac functions. Affection of the heart may manifest as arrhythmias, cardiomyopathy, or autonomic dysfunction. Rarer cardiac complications of CNS disorders include heart failure, systolic or diastolic dysfunction, myocardial infarction, arterial hypertension, or pulmonary hypertension. Cardiomyopathy induced by hereditary CNS disease mainly include stress-induced myocardial dysfunction, known as Takotsubo syndrome (TTS). CNS disease triggering TTS includes epilepsy, ischemic stroke, subarachnoid bleeding, or PRES syndrome. Arrhythmias induced by hereditary CNS disease include supraventricular or ventricular arrhythmias leading to palpitations, dizziness, vertigo, fainting, syncope, (near) sudden cardiac death, or sudden unexplained death in epilepsy (SUDEP). Appropriate management of cardiac involvement in CNS-disorders is essential to improve outcome of affected patients. PMID:25034054

  10. A Systems Approach for Tumor Pharmacokinetics

    PubMed Central

    Thurber, Greg Michael; Weissleder, Ralph

    2011-01-01

    Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design. PMID:21935441

  11. A systems approach for tumor pharmacokinetics.

    PubMed

    Thurber, Greg Michael; Weissleder, Ralph

    2011-01-01

    Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design. PMID:21935441

  12. Interneuron Progenitor Transplantation to Treat CNS Dysfunction

    PubMed Central

    Chohan, Muhammad O.; Moore, Holly

    2016-01-01

    Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field. PMID:27582692

  13. Cerebral blood flow variations in CNS lupus

    SciTech Connect

    Kushner, M.J.; Tobin, M.; Fazekas, F.; Chawluk, J.; Jamieson, D.; Freundlich, B.; Grenell, S.; Freemen, L.; Reivich, M. )

    1990-01-01

    We studied the patterns of cerebral blood flow (CBF), over time, in patients with systemic lupus erythematosus and varying neurologic manifestations including headache, stroke, psychosis, and encephalopathy. For 20 paired xenon-133 CBF measurements, CBF was normal during CNS remissions, regardless of the symptoms. CBF was significantly depressed during CNS exacerbations. The magnitude of change in CBF varied with the neurologic syndrome. CBF was least affected in patients with nonspecific symptoms such as headache or malaise, whereas patients with encephalopathy or psychosis exhibited the greatest reductions in CBF. In 1 patient with affective psychosis, without clinical or CT evidence of cerebral ischemia, serial SPECT studies showed resolution of multifocal cerebral perfusion defects which paralleled clinical recovery.

  14. Dendrimer Advances for the Central Nervous System Delivery of Therapeutics

    PubMed Central

    2013-01-01

    The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included. PMID:24274162

  15. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

    PubMed

    Alimoradi, Houman; Matikonda, Siddharth S; Gamble, Allan B; Giles, Gregory I; Greish, Khaled

    2016-01-01

    Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems.

  16. Glioma migration: clues from the biology of neural progenitor cells and embryonic CNS cell migration.

    PubMed

    Dirks, P B

    2001-06-01

    Neural stem cells have recently come to the forefront in neurobiology because of the possibilities for CNS repair by transplantation. Further understanding of the biology of these cells is critical for making their use in CNS repair possible. It is likely that these discoveries will also have spin-offs for neuro-oncology as primary brain tumors may arise from a CNS progenitor cell. An understanding of the normal migratory ability of these cells is also likely to have a very important impact on the knowledge of brain tumor invasion.

  17. Agile Delivery of Protein Therapeutics to CNS

    PubMed Central

    Yi, Xiang; Manickam, Devika S.; Brynskikh, Anna; Kabanov, Alexander V.

    2014-01-01

    A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics. PMID:24956489

  18. Agile delivery of protein therapeutics to CNS.

    PubMed

    Yi, Xiang; Manickam, Devika S; Brynskikh, Anna; Kabanov, Alexander V

    2014-09-28

    A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics.

  19. CNS drug design: balancing physicochemical properties for optimal brain exposure.

    PubMed

    Rankovic, Zoran

    2015-03-26

    The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.

  20. The Processing of Airspace Concept Evaluations Using FASTE-CNS as a Pre- or Post-Simulation CNS Analysis Tool

    NASA Technical Reports Server (NTRS)

    Mainger, Steve

    2004-01-01

    As NASA speculates on and explores the future of aviation, the technological and physical aspects of our environment increasing become hurdles that must be overcome for success. Research into methods for overcoming some of these selected hurdles have been purposed by several NASA research partners as concepts. The task of establishing a common evaluation environment was placed on NASA's Virtual Airspace Simulation Technologies (VAST) project (sub-project of VAMS), and they responded with the development of the Airspace Concept Evaluation System (ACES). As one examines the ACES environment from a communication, navigation or surveillance (CNS) perspective, the simulation parameters are built with assumed perfection in the transactions associated with CNS. To truly evaluate these concepts in a realistic sense, the contributions/effects of CNS must be part of the ACES. NASA Glenn Research Center (GRC) has supported the Virtual Airspace Modeling and Simulation (VAMS) project through the continued development of CNS models and analysis capabilities which supports the ACES environment. NASA GRC initiated the development a communications traffic loading analysis tool, called the Future Aeronautical Sub-network Traffic Emulator for Communications, Navigation and Surveillance (FASTE-CNS), as part of this support. This tool allows for forecasting of communications load with the understanding that, there is no single, common source for loading models used to evaluate the existing and planned communications channels; and that, consensus and accuracy in the traffic load models is a very important input to the decisions being made on the acceptability of communication techniques used to fulfill the aeronautical requirements. Leveraging off the existing capabilities of the FASTE-CNS tool, GRC has called for FASTE-CNS to have the functionality to pre- and post-process the simulation runs of ACES to report on instances when traffic density, frequency congestion or aircraft spacing

  1. Survival of European patients with central nervous system tumors.

    PubMed

    Sant, Milena; Minicozzi, Pamela; Lagorio, Susanna; Børge Johannesen, Tom; Marcos-Gragera, Rafael; Francisci, Silvia

    2012-07-01

    We present estimates of population-based 5-year relative survival for adult Europeans diagnosed with central nervous system tumors, by morphology (14 categories based on cell lineage and malignancy grade), sex, age at diagnosis and region (UK and Ireland, Northern, Central, Eastern and Southern Europe) for the most recent period with available data (2000-2002). Sources were 39 EUROCARE cancer registries with continuous data from 1996 to 2002. Survival time trends (1988 to 2002) were estimated from 24 cancer registries with continuous data from 1988. Overall 5-year relative survival was 85.0% for benign, 19.9% for malignant tumors. Benign tumor survival ranged from 90.6% (Northern Europe) to 77.4% (UK and Ireland); for malignant tumors the range was 25.1% (Northern Europe) to 15.6% (UK and Ireland). Survival decreased with age at diagnosis and was slightly better for women (malignant tumors only). For glial tumors, survival varied from 83.5% (ependymoma and choroid plexus) to 2.7% (glioblastoma); and for non-glioma tumors from 96.5% (neurinoma) to 44.9% (primitive neuroectoderm tumor/medulloblastoma). Survival differences between regions narrowed after adjustment for morphology and age, and were mainly attributable to differences in morphology mix; however UK and Ireland and Eastern Europe patients still had 40% and 30% higher excess risk of death, respectively, than Northern Europe patients (reference). Survival for benign tumors increased from 69.3% (1988-1990) to 77.1% (2000-2002); but survival for malignant tumors did not improve indicating no useful advances in treatment over the 14-year study period, notwithstanding major improvement in the diagnosis and treatment of other solid cancers.

  2. Clinical epidemiology for childhood primary central nervous system tumors.

    PubMed

    Bauchet, Luc; Rigau, Valérie; Mathieu-Daudé, Hélène; Fabbro-Peray, Pascale; Palenzuela, Gilles; Figarella-Branger, Dominique; Moritz, Jorge; Puget, Stéphanie; Bauchet, Fabienne; Pallusseau, Lorelei; Duffau, Hugues; Coubes, Philippe; Trétarre, Brigitte; Labrousse, François; Dhellemmes, Patrick

    2009-03-01

    This work was conducted by the French Brain Tumor Data Bank (FBTDB) and aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. Results concerning children are presented. This study analyzes the childhood cases (0-19 years) of newly diagnosed and histologically confirmed PCNST (during the years 2004-2006) which have been recorded by the FBTDB. All French neuropathology and neurosurgery departments participated in this program. Neurosurgeons and neuropathologists completed a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault was authorized to compile the data files with personal identifiers. About 1,017 cases (533 boys and 484 girls) of newly diagnosed childhood PCNST have been recorded (gliomas: 52%, all other neuroepithelial tumors: 31%, craniopharyngioma: 5%, germ cell tumors, meningioma and neurinoma: approximately 3% each, all histological subtypes have been detailed). Tumor resections were performed in 83.3%, and biopsies in 16.7%. The distributions by histology, cryopreservation of the samples, age, sex, tumor site and surgery have been detailed. To our knowledge, this work is the first databank in Europe dedicated to PCNST that includes the collection of clinical, radiological and histological data (including cryopreservation of the specimen). The long term goals of the FBTDB are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to evaluate and harmonize the healthcare of children and adult patients affected by PCNST. PMID:19020806

  3. Atypical presentations of solitary fibrous tumors of the central nervous system: an analysis of unusual clinicopathological and outcome patterns in three new cases with a review of the literature.

    PubMed

    Pakasa, Nestor M; Pasquier, Basile; Chambonnière, Marie-Laure; Morrison, Alan L; Khaddage, Abir; Perret, Anne Gentil; Dumollard, Jean Marc; Barral, Fabrice G; Péoc'h, Michel

    2005-07-01

    Central nervous system (CNS) solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms recognized less than a decade ago. Approximately 60 cases of SFT have been reported in the central nervous system. We describe three atypical SFTs of the CNS, two intracranial and one within the spine. One intracranial SFT arose from the sella turcica and expanded into the suprasellar areas. It relapsed twice during the 3 years following partial resection, and the MiB 1 labeling index steadily increased without obvious malignant transformation. The second SFT arose from the confluence of the sinuses, widely invaded the lateral sinus and adjacent bones, had a low MiB 1 index and has not recurred after 5 years. The intraspinal tumor occurred at T5-T7 in a patient with multiple café-au-lait spots, was predominantly myxoid and developed a second similar lesion at S3-S5 14 years later. The MiB 1 index was lower in the second tumor. Immunohistochemistry confirmed that all were SFTs. These atypical presentations gave us an opportunity to provide further information about the natural histological course of CNS SFTs.

  4. Controlling cytoplasmic c-Fos controls tumor growth in the peripheral and central nervous system.

    PubMed

    Gil, Germán A; Silvestre, David C; Tomasini, Nicolás; Bussolino, Daniela F; Caputto, Beatriz L

    2012-06-01

    Some 20 years ago c-Fos was identified as a member of the AP-1 family of inducible transcription factors (Angel and Karin in Biochim Biophys Acta 1072:129-157, 1991). More recently, an additional activity was described for this protein: it associates to the endoplasmic reticulum and activates the biosynthesis of phospholipids (Bussolino et al. in FASEB J 15:556-558, 2001), (Gil et al. in Mol Biol Cell 15:1881-1894, 2004), the quantitatively most important components of cellular membranes. This latter activity of c-Fos determines the rate of membrane genesis and consequently of growth in differentiating PC12 cells (Gil et al. in Mol Biol Cell 15:1881-1894, 2004). In addition, it has been shown that c-Fos is over-expressed both in PNS and CNS tumors (Silvestre et al. in PLoS One 5(3):e9544, 2010). Herein, it is shown that c-Fos-activated phospholipid synthesis is required to support membrane genesis during the exacerbated growth characteristic of brain tumor cells. Specifically blocking c-Fos-activated phospholipid synthesis significantly reduces proliferation of tumor cells in culture. Blocking c-Fos expression also prevents tumor progression in mice intra-cranially xeno-grafted human brain tumor cells. In NPcis mice, an animal model of the human disease Neurofibromatosis Type I (Cichowski and Jacks in Cell 104:593-604, 2001), animals spontaneously develop tumors of the PNS and the CNS, provided they express c-Fos (Silvestre et al. in PLoS One 5(3):e9544, 2010). Treatment of PNS tumors with an antisense oligonucleotide that specifically blocks c-Fos expression also blocks tumor growth in vivo. These results disclose cytoplasmic c-Fos as a new target for effectively controlling brain tumor growth.

  5. A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies.

    PubMed

    Chadwick, Emily J; Yang, David P; Filbin, Mariella G; Mazzola, Emanuele; Sun, Yu; Behar, Oded; Pazyra-Murphy, Maria F; Goumnerova, Liliana; Ligon, Keith L; Stiles, Charles D; Segal, Rosalind A

    2015-11-07

    Brain tumors are a major cause of cancer-related morbidity and mortality. Developing new therapeutics for these cancers is difficult, as many of these tumors are not easily grown in standard culture conditions. Neurosphere cultures under serum-free conditions and orthotopic xenografts have expanded the range of tumors that can be maintained. However, many types of brain tumors remain difficult to propagate or study. This is particularly true for pediatric brain tumors such as pilocytic astrocytomas and medulloblastomas. This protocol describes a system that allows primary human brain tumors to be grown in culture. This quantitative assay can be used to investigate the effect of microenvironment on tumor growth, and to test new drug therapies. This protocol describes a system where fluorescently labeled brain tumor cells are grown on an organotypic brain slice from a juvenile mouse. The response of tumor cells to drug treatments can be studied in this assay, by analyzing changes in the number of cells on the slice over time. In addition, this system can address the nature of the microenvironment that normally fosters growth of brain tumors. This brain tumor organotypic slice co-culture assay provides a propitious system for testing new drugs on human tumor cells within a brain microenvironment.

  6. Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the 'Head Start' trials, 1991-2009.

    PubMed

    Altshuler, C; Haley, K; Dhall, G; Vasquez, L; Gardner, S L; Stanek, J; Finlay, J L

    2016-07-01

    Since 1991, three sequential prospective clinical trials have been conducted by the 'Head Start' (HS) Consortium in which young children with newly-diagnosed malignant central nervous system (CNS) tumors were treated with induction chemotherapy followed by single-cycle marrow-ablative chemotherapy and autologous hematopoietic rescue as a means of improving disease cure rate and quality of survival through avoidance (<6 years old at diagnosis) or reduction (6-10 years old) of brain irradiation. Bone Marrow (HS I) or filgrastim-mobilized peripheral hematopoietic cells (HS II and III) were obtained following recovery from the first and/or second induction cycles. Radiotherapy was administered following all chemotherapy only for patients with residual tumor following completion of induction or with age greater than 6 years at diagnosis. Two hundred and twenty-six children were enrolled on three consecutive HS trials with primary malignant CNS tumors and underwent marrow-ablative chemotherapy. The 100-day treatment-related mortality (TRM) steadily declined as did grade IV transplant-related oropharyngeal mucositis. Factors most likely associated with the decrease in TRM and morbidity are increasing experience with the marrow-ablative chemotherapy regimen combined with improved leukapheresis and post-reinfusion supportive care techniques, contributing toward improved overall survival. PMID:26950375

  7. Viral antibodies in the CSF after acute CNS infections.

    PubMed

    Cappel, R; Thiry, L; Clinet, G

    1975-09-01

    Viral antibodies were measured in the cerebrospinal fluid (CSF) and serum from 25 patients having acute viral central nervous system (CNS) infections, and from 39 control patients. The results, collected two weeks after the clinical onset, revealed the presence of antibodies in nine of 13 (69%) CSF specimens from patients suffering from encephalitis of myelitis, and in only one of nine (11%) of the CSF samples of those presenting a viral meningitis infection. This difference was statistically significant and suggests that the titration of viral antibodies in the CSF can be helpful in establishing the diagnosis of viral CNS infection. Our data also suggest that localized production of antibodies occurs during the course of acute CNS infections, and that the respiratory syncytial virus can be associated with CNS infections in man.

  8. Receptor Tyrosine Kinases: Molecular Switches Regulating CNS Axon Regeneration

    PubMed Central

    Vigneswara, Vasanthy; Kundi, Sarina; Ahmed, Zubair

    2012-01-01

    The poor or lack of injured adult central nervous system (CNS) axon regeneration results in devastating consequences and poor functional recovery. The interplay between the intrinsic and extrinsic factors contributes to robust inhibition of axon regeneration of injured CNS neurons. The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury. In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands. This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration. PMID:22848811

  9. A pretargeting system for tumor PET imaging and radioimmunotherapy

    PubMed Central

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Frampas, Eric; Faivre-Chauvet, Alain; Rauscher, Aurore; Sharkey, Robert M.; Goldenberg, David M.; Chatal, Jean-François; Barbet, Jacques

    2015-01-01

    Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed. PMID:25873896

  10. CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia.

    PubMed

    Zimmermann, Julian; Krauthausen, Marius; Hofer, Markus J; Heneka, Michael T; Campbell, Iain L; Müller, Marcus

    2013-01-01

    Interleukin-17A (IL-17A) is a key cytokine modulating the course of inflammatory diseases. Whereas effector functions of IL-17A like induction of antimicrobial peptides and leukocyte infiltration could clearly be demonstrated for peripheral organs, CNS specific effects are not well defined and appear controversial. To further clarify the functional significance of IL-17A in the CNS, we generated a transgenic mouse line with astrocyte-restricted expression of the IL-17A gene. GFAP/IL-17A transgenic mice develop normally and do not show any signs of neurological dysfunction. However, histological characterization revealed astrocytosis and activation of microglia. Demyelination, neurodegeneration or prominent tissue damage was not observed but a vascular pathology mimicking microangiopathic features was evident. Histological and flow cytometric analysis demonstrated the absence of parenchymal infiltration of immune cells into the CNS of GFAP/IL-17A transgenic mice. In GFAP/IL-17A mice, LPS-induced endotoxemia led to a more pronounced microglial activation with expansion of a distinct CD45(high)/CD11b(+) population and increased induction of proinflammatory cytokines compared with controls. Our data argues against a direct role of IL-17A in mediating tissue damage during neuroinflammation. More likely IL-17A acts as a modulating factor in the network of induced cytokines. This novel mouse model will be a very useful tool to further characterize the role of IL-17A in neuroinflammatory disease models.

  11. Insights into the physiological role of CNS regeneration inhibitors

    PubMed Central

    Baldwin, Katherine T.; Giger, Roman J.

    2015-01-01

    The growth inhibitory nature of injured adult mammalian central nervous system (CNS) tissue constitutes a major barrier to robust axonal outgrowth and functional recovery following trauma or disease. Prototypic CNS regeneration inhibitors are broadly expressed in the healthy and injured brain and spinal cord and include myelin-associated glycoprotein (MAG), the reticulon family member NogoA, oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans (CSPGs). These structurally diverse molecules strongly inhibit neurite outgrowth in vitro, and have been most extensively studied in the context of nervous system injury in vivo. The physiological role of CNS regeneration inhibitors in the naïve, or uninjured, CNS remains less well understood, but has received growing attention in recent years and is the focus of this review. CNS regeneration inhibitors regulate myelin development and axon stability, consolidate neuronal structure shaped by experience, and limit activity-dependent modification of synaptic strength. Altered function of CNS regeneration inhibitors is associated with neuropsychiatric disorders, suggesting crucial roles in brain development and health. PMID:26113809

  12. Transport processes in biological systems: Tumoral cells and human brain

    NASA Astrophysics Data System (ADS)

    Lucia, Umberto

    2014-01-01

    The entropy generation approach has been developed for the analysis of complex systems, with particular regards to biological systems, in order to evaluate their stationary states. The entropy generation is related to the transport processes related to exergy flows. Moreover, cancer can be described as an open complex dynamic and self-organizing system. Consequently, it is used as an example useful to evaluate the different thermo-chemical quantities of the transport processes in normal and in tumoral cells systems.

  13. Epigenetics, Nervous System Tumors, and Cancer Stem Cells

    PubMed Central

    Qureshi, Irfan A.; Mehler, Mark F.

    2011-01-01

    Recent advances have begun to elucidate how epigenetic regulatory mechanisms are responsible for establishing and maintaining cell identity during development and adult life and how the disruption of these processes is, not surprisingly, one of the hallmarks of cancer. In this review, we describe the major epigenetic mechanisms (i.e., DNA methylation, histone and chromatin modification, non-coding RNA deployment, RNA editing, and nuclear reorganization) and discuss the broad spectrum of epigenetic alterations that have been uncovered in pediatric and adult nervous system tumors. We also highlight emerging evidence that suggests epigenetic deregulation is a characteristic feature of so-called cancer stem cells (CSCs), which are thought to be present in a range of nervous system tumors and responsible for tumor maintenance, progression, treatment resistance, and recurrence. We believe that better understanding how epigenetic mechanisms operate in neural cells and identifying the etiologies and consequences of epigenetic deregulation in tumor cells and CSCs, in particular, are likely to promote the development of enhanced molecular diagnostics and more targeted and effective therapeutic agents for treating recalcitrant nervous system tumors. PMID:24212967

  14. [Symptoms and diagnosis of neuroendocrine tumors of the digestive system].

    PubMed

    Gyökeres, Tibor

    2011-03-01

    Neuroendocrine tumors of the digestive system can cause very diverse clinical symptoms. Due to the secretion of biogenic amines, peptides and hormones secreted by the tumor cells, various paraneoplastic syndromes can evolve, on the other hand, the growth and spreading of hormonally inactive tumors can result in different local symptoms. Patients can be symptom-free for a long time or aspecific, often periodical symptoms can prevent recognition or lead to misdiagnosis for years. The symptomatology of hormonally active tumors, derived mainly from the pancreas is very characteristic. Carcinoid syndrome can be seen in 10-18% of patients with neuroendocrine tumors. In this review, the critical appreciation of laboratory and imaging modalities is discussed. Among the major new developments in this field, the introduction of serum chromogranin A assay and new small bowel examination methods should be mentioned. Capsule endoscopy and balloon enteroscopy can provide possibility of much more earlier diagnosis, as previously. The worldwide spreading of endoscopic ultrasound and fine needle biopsy allows the detection and clear localization of pancreatic neuroendocrine tumors.

  15. Multimodal system for in vivo tumor imaging in mice

    NASA Astrophysics Data System (ADS)

    Autiero, Maddalena; Celentano, Luigi; Cozzolino, Rosanna; Laccetti, Paolo; Marotta, Marcello; Mettivier, Giovanni; Montesi, Maria Cristina; Riccio, Patrizia; Roberti, Giuseppe; Russo, Paolo

    2006-04-01

    We devised a multimodal planar imaging system for in vivo mouse imaging, employing four modalities: optical imaging, green and red fluorescence reflectance imaging, radionuclide imaging and X-ray radiography. We are testing separately, and then in a combined way, each detection mode, via in vivo mouse imaging, with the final purpose of identifying small implanted tumor masses, of providing early tumor detection and following metastatic dissemination. We describe the multimodal system and summarize its main performance, as assessed in our research work in the various stages of the development, in fluorescence and radionuclide tests on healthy or tumor bearing mice. For gamma-ray detection we used a semiconductor pixel detector (Medipix1 or Medipix2) that works in single photon counting. Laser-induced fluorescence reflectance imaging was performed in vivo using a pulsed light source to excite the fluorescence emission of injected hematoporphyrin (HP) compound, a CCD camera, a low pass filter and a commercial image analysis system. The bimodal system was used for the acquisition of combined images of the tumor area (fluorescence: animal top view; radionuclide: bottom view). It was shown that the tumor area can be imaged in a few minutes, with a few millimeter resolution (1 mm pinhole diameter), radioactively ( 99mTc radiotracer), and with the fluorescence system and that, in one case, only one of the two modalities is able to recognize the tumor. A phantom study for thyroid imaging with 125I source embedded in a simulated tissue indicated a spatial resolution of 1.25 mm FWHM with a 1 mm pinhole.

  16. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by viruses are: Cervical cancer (human papillomavirus) Hepatocellular carcinoma (hepatitis B and hepatitis C ...

  17. Histamine pharmacology and new CNS drug targets.

    PubMed

    Tiligada, Ekaterini; Kyriakidis, Konstantinos; Chazot, Paul L; Passani, M Beatrice

    2011-12-01

    During the last decade, the identification of a number of novel drug targets led to the development of promising new compounds which are currently under evaluation for their therapeutic prospective in CNS related disorders. Besides the established pleiotropic regulatory functions in the periphery, the interest in the potential homeostatic role of histamine in the brain was revived following the identification of H(3) and H(4) receptors some years ago. Complementing classical CNS pharmacology, the development of selective histamine receptor agonists, antagonists, and inverse agonists provides the lead for the potential exploitation of the histaminergic system in the treatment of brain pathologies. Although no CNS disease entity has been associated directly to brain histamine dysfunction until now, the H(3) receptor is recognized as a drug target for neuropathic pain, sleep-wake disorders, including narcolepsy, and cognitive impairment associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimer's, or Parkinson's disease, while the first H(3) receptor ligands have already entered phase I-III clinical trials. Interestingly, the localization of the immunomodulatory H(4) receptor in the nervous system exposes attractive perspectives for the therapeutic exploitation of this new drug target in neuroimmunopharmacology. This review focuses on a concise presentation of the current "translational research" approach that exploits the latest advances in histamine pharmacology for the development of beneficial drug targets for the treatment of neuronal disorders, such as neuropathic pain, cognitive, and sleep-wake pathologies. Furthermore, the role of the brain histaminergic system(s) in neuroprotection and neuroimmunology/inflammation remains a challenging research area that is currently under consideration.

  18. Novel treatment strategies for brain tumors and metastases

    PubMed Central

    El-Habashy, Salma E.; Nazief, Alaa M.; Adkins, Chris E.; Wen, Ming Ming; El-Kamel, Amal H.; Hamdan, Ahmed M.; Hanafy, Amira S.; Terrell, Tori O.; Mohammad, Afroz S.; Lockman, Paul R.; Nounou, Mohamed Ismail

    2015-01-01

    This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood–brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application. PMID:24998288

  19. [Central nervous system tumors in pregnancy].

    PubMed

    Podciechowski, Lech; Nowakowska, Dorota; Bielak, Adam; Nowosławska, Emilia; Szymański, Wojciech; Polis, Lech; Krasomski, Grzechorz; Fiks, Tomasz; Wilczyński, Jan

    2003-12-01

    Central nervous system tumour in pregnancy constitutes a serious complication. Considering frequent difficulties in diagnostics and therapy, the aim of the study was to present our experience in management with pregnant women with brain and spinal cord tumours. Between 1988-2000, in The Research Institute Polish Mother's Memorial Hospital in Lodzi, 4 pregnant women had been diagnosed with brain and spinal cord tumours. The incidence of tumours complicating pregnancy was 1/11460. Two patients diagnosed at 29 weeks' gestation, underwent craniotomy and tumour resection during pregnancy. Two other women with central nervous system tumours diagnosed at 39 weeks' gestation, were operated in the postpartum period. The analysis of the postoperative period, gestation and/or postpartum period in all women and well-being of their new-borns confirm undertaken medical decisions. PMID:15029742

  20. Angiogenic inhibitors delivered by the type III secretion system of tumor-targeting Salmonella typhimurium safely shrink tumors in mice.

    PubMed

    Shi, Lei; Yu, Bin; Cai, Chun-Hui; Huang, Jian-Dong

    2016-12-01

    Despite of a growing number of bacterial species that apparently exhibit intrinsic tumor-targeting properties, no bacterium is able to inhibit tumor growth completely in the immunocompetent hosts, due to its poor dissemination inside the tumors. Oxygen and inflammatory reaction form two barriers and restrain the spread of the bacteria inside the tumors. Here, we engineered a Salmonella typhimurium strain named ST8 which is safe and has limited ability to spread beyond the anaerobic regions of tumors. When injected systemically to tumor-bearing immunocompetent mice, ST8 accumulated in tumors at levels at least 100-fold greater than parental obligate anaerobic strain ST4. ST8/pSEndo harboring therapeutic plasmids encoding Endostatin fused with a secreted protein SopA could target vasculature at the tumor periphery, can stably maintain and safely deliver a therapeutic vector, release angiogenic inhibitors through a type III secretion system (T3SS) to interfere with the pro-angiogenic action of growth factors in tumors. Mice with murine CT26 colon cancer that had been injected with ST8/pSEndo showed efficient tumor suppression by inducing more severe necrosis and inhibiting blooding vessel density within tumors. Our findings provide a therapeutic platform for indirectly acting therapeutic strategies such as anti-angiogenesis and immune therapy. PMID:27558018

  1. Neurotrophin and neurotrophin receptor proteins in medulloblastomas and other primitive neuroectodermal tumors of the pediatric central nervous system.

    PubMed Central

    Washiyama, K.; Muragaki, Y.; Rorke, L. B.; Lee, V. M.; Feinstein, S. C.; Radeke, M. J.; Blumberg, D.; Kaplan, D. R.; Trojanowski, J. Q.

    1996-01-01

    Primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS) are poorly understood childhood neoplasms, and medulloblastomas are the most common pediatric PNETs. Neoplastic cells in medulloblastomas and other PNETs resemble progenitor cells of the developing central nervous system, but they also may exhibit the molecular phenotype of immature neurons or glia. As neurotrophins play a role in regulating differentiation, proliferation, and cell death in the normal developing central nervous system, and recent evidence suggests that neurotrophins may influence the behavior of medulloblastomas, we studied 29 PNET biopsy samples (27 of which were posterior fossa medulloblastomas) by immunobistochemistry using antibodies specific for each of the major high affinity neurotrophin receptor proteins, ie, TrkA, TrkB, and TrkC. A subset of these tumors also was examined by Western blot. Immunoreactive TrkA, TrkB, and TrkC were observed in neoplastic cells in 8 (27%), 18 (62%), and 14 (48%) of these PNETs, respectively. Additional immunohistochemical studies of a subset of these PNETs using antibodies to neurotrophins that primarily activate TrkB and TrkC, ie, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5, showed that immunoreactive brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 were detected in 22, 9, and 19% of these PNET biopsies, respectively. Finally, 19 pediatric brain tumors other than these PNETs also were studied here, and they expressed these neurotrophins and their receptors to a variable extent. The demonstration here that neurotrophins and their cognate receptor proteins are expressed in PNETs as well as in other pediatric brain tumors may imply that signal transduction pathways mediated by neurotrophins and/or their receptors influence the induction or progression of these common childhood neoplasms. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8774147

  2. Epithelioid solitary fibrous tumor of the central nervous system.

    PubMed

    Fu, Jing; Zhang, Rui; Zhang, Hongying; Bu, Hong; Chen, Huijiao; Yin, Xiangli; Zhang, Zhang; Wei, Bing

    2012-01-01

    Epithelioid solitary fibrous tumor (SFT) has recently been reported and is an extremely rare soft-tissue neoplasm. Herein we present an epithelioid SFT attached to the falx cerebri occurring in a Chinese woman. This patient underwent gross-total tumor resection at the age of 30 years and recurred 68 months following the initial total resection. Histologically, the initial lesion exhibited features of classic spindle cell SFT. In contrast, the recurrent tumor demonstrated exclusively epithelioid morphology with significant atypia. Both the original and recurrent lesions showed positivity for vimentin, CD34, Bcl-2, and CD99, whereas were negative for all the remaining antibodies. The epithelioid feature in SFT seems to be associated with a more aggressive clinical behavior in this case and more cases are awaited to verify this possibility. To the best of authors' knowledge, the present case is the first published example of SFT with epithelioid feature in the central nervous system.

  3. Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma

    ClinicalTrials.gov

    2013-07-01

    Childhood Burkitt Lymphoma; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Medulloepithelioma; Childhood Meningioma; Childhood Mixed Glioma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Oligodendroglioma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  4. [Chemotherapy of brain tumors].

    PubMed

    Kuratsu, J; Ushio, Y

    1994-10-01

    Despite recent attempts to improve chemotherapeutic approaches for the treatment of malignant gliomas, results remain limited and palliative. The development of effective chemotherapy for tumors of the central nervous system (CNS) is complicated in that the blood-brain barrier (B.B.B.) hampers the penetration of most drugs into the brain and cerebrospinal fluid. The factors governing delivery in the brain are the drug's molecular weight, lipophilicity and degree of ionization. Now the standard therapy for malignant glioma is maximal tumor resection followed by combination radiotherapy plus chemotherapy. Nitrosoureas are representative drugs which easily cross the B.B.B.. It has been shown that nitrosourea compounds have an additive effect to radiotherapy. The toxicity profile of nitrosoureas is leukocytopenia and thrombocytopenia as a dose-limiting factor. Furthermore, the great heterogeneity of malignant glioma tissues offered a rationale for the use of multiple drugs. Many studies were reported to show a substantial advantage for the multidrug regimen over control series utilizing single drugs alone. Despite clear examples of the effectiveness of chemotherapy, we are still far from improving the cure rate for the vast majority of patients with primary malignancies of the CNS. Further improvement in patient survival may depend upon understanding and manipulating the pathways that regulate aberrant growth in these tumors. The development of new anticancer agents, which are sensitive to malignant glioma and can reach a high concentration in glioma tissue, is warranted. PMID:7986118

  5. How Do Meningeal Lymphatic Vessels Drain the CNS?

    PubMed

    Raper, Daniel; Louveau, Antoine; Kipnis, Jonathan

    2016-09-01

    The many interactions between the nervous and the immune systems, which are active in both physiological and pathological states, have recently become more clearly delineated with the discovery of a meningeal lymphatic system capable of carrying fluid, immune cells, and macromolecules from the central nervous system (CNS) to the draining deep cervical lymph nodes. However, the exact localization of the meningeal lymphatic vasculature and the path of drainage from the cerebrospinal fluid (CSF) to the lymphatics remain poorly understood. Here, we discuss the potential differences between peripheral and CNS lymphatic vessels and examine the purported mechanisms of CNS lymphatic drainage, along with how these may fit into established patterns of CSF flow. PMID:27460561

  6. Cerebrospinal fluid may mediate CNS ischemic injury

    PubMed Central

    Wang, Yanming F; Gwathmey, Judith K; Zhang, Guorong; Soriano, Sulpicio G; He, Shunli; Wang, Yanguang

    2005-01-01

    Background The central nervous system (CNS) is extremely vulnerable to ischemic injury. The details underlying this susceptibility are not completely understood. Since the CNS is surrounded by cerebrospinal fluid (CSF) that contains a low concentration of plasma protein, we examined the effect of changing the CSF in the evolution of CNS injury during ischemic insult. Methods Lumbar spinal cord ischemia was induced in rabbits by cross-clamping the descending abdominal aorta for 1 h, 2 h or 3 h followed by 7 d of reperfusion. Prior to ischemia, rabbits were subjected to the following procedures; 1) CSF depletion, 2) CSF replenishment at 0 mmHg intracranial pressure (ICP), and 3) replacement of CSF with 8% albumin- or 1% gelatin-modified artificial CSF, respectively. Motor function of the hind limbs and histopathological changes of the spinal cord were scored. Post-ischemic microcirculation of the spinal cord was visualized by fluorescein isothiocyanate (FITC) albumin. Results The severity of histopathological damage paralleled the neurological deficit scores. Paraplegia and associated histopathological changes were accompanied by a clear post-ischemic deficit in blood perfusion. Spinal cord ischemia for 1 h resulted in permanent paraplegia in the control group. Depletion of the CSF significantly prevented paraplegia. CSF replenishment with the ICP reduced to 0 mmHg, did not prevent paraplegia. Replacement of CSF with albumin- or gelatin-modified artificial CSF prevented paraplegia in rabbits even when the ICP was maintained at 10–15 mmHg. Conclusion We conclude that the presence of normal CSF may contribute to the vulnerability of the spinal cord to ischemic injury. Depletion of the CSF or replacement of the CSF with an albumin- or gelatin-modified artificial CSF can be neuroprotective. PMID:16174300

  7. Curcumin and tumor immune-editing: resurrecting the immune system.

    PubMed

    Bose, Sayantan; Panda, Abir Kumar; Mukherjee, Shravanti; Sa, Gaurisankar

    2015-01-01

    Curcumin has long been known to posses medicinal properties and recent scientific studies have shown its efficacy in treating cancer. Curcumin is now considered to be a promising anti-cancer agent and studies continue on its molecular mechanism of action. Curcumin has been shown to act in a multi-faceted manner by targeting the classical hallmarks of cancer like sustained proliferation, evasion of apoptosis, sustained angiogenesis, insensitivity to growth inhibitors, tissue invasion and metastasis etc. However, one of the emerging hallmarks of cancer is the avoidance of immune system by tumors. Growing tumors adopt several strategies to escape immune surveillance and successfully develop in the body. In this review we highlight the recent studies that show that curcumin also targets this process and helps restore the immune activity against cancer. Curcumin mediates several processes like restoration of CD4(+)/CD8(+) T cell populations, reversal of type-2 cytokine bias, reduction of Treg cell population and suppression of T cell apoptosis; all these help to resurrect tumor immune surveillance that leads to tumor regression. Thus interaction of curcumin with the immune system is also an important feature of its multi-faceted modes of action against cancer. Finally, we also point out the drawbacks of and difficulties in curcumin administration and indicate the use of nano-formulations of curcumin for better therapeutic efficacy. PMID:26464579

  8. A Computer System for Processing Tumor Registry Data

    PubMed Central

    Leahey, Charles F.

    1981-01-01

    An interactive computer system for processing tumor registry data has been developed by the Washington, D.C. VA Medical Center Systems Development Group. The automated registry system replaces a manual registry, which had been implemented according to the guidelines established for Cancer Programs by the American College of Surgeons. A permanent on-line data base of patient data is maintained by a minicomputer at the medical center. A user oriented application program provides entry, edit, and retrieval of patient data in the following formats - Suspense, Master, Accession, and Follow-up registers, and in Abstract form. Data entered in any of the formats is stored in a common file, and is available as needed in any other format. The programs were written in the standard Mumps Language. Construction of the Tumor Registry application was greatly assisted by use of the File Manager, a data base file management package written in the standard Mumps language.

  9. Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms.

    PubMed

    Dodick, D W; Martin, V

    2004-06-01

    Triptans are the treatment of choice for acute migraine. While seemingly a homogenous group of drugs, results from a meta-analysis reveal significant differences in efficacy and tolerability among oral triptans. The incidence of drug-related central nervous system (CNS) side-effects with some triptans is as high as 15% and may be associated with functional impairment and reduced productivity. The occurrence of adverse events associated with triptans in general, and CNS side-effects in particular, may lead to a delay in initiating or even avoidance of an otherwise effective treatment. Potential explanations for differences among triptans in the incidence of CNS side-effects may relate to pharmacological and pharmacokinetic differences, including receptor binding, lipophilicity, and the presence of active metabolites. Of the triptans reviewed, at clinically relevant doses, almotriptan 12.5 mg, naratriptan 2.5 mg and sumatriptan 50 mg had the lowest incidence of CNS side-effects, while eletriptan 40 and 80 mg, rizatriptan 10 mg and zolmitriptan 2.5 and 5 mg had the highest incidence. The most likely explanations for the differences in CNS side-effects among triptans are the presence of active metabolites and high lipophilicity of the parent compound and active metabolites. Eletriptan, rizatriptan and zolmitriptan have active metabolites, while lipophilicity is lowest for almotriptan and sumatriptan. If CNS side-effects are a clinically relevant concern in the individual patient, use of a triptan with a low incidence of CNS side-effects may offer the potential for earlier initiation of treatment and more effective outcomes. PMID:15154851

  10. Toll-like Receptor 4 in CNS Pathologies

    PubMed Central

    Buchanan, Madison M.; Hutchinson, Mark; Watkins, Linda R.; Yin, Hang

    2010-01-01

    The responses of the brain to infection, ischemia and trauma share remarkable similarities. These and other conditions of the CNS coordinate an innate immune response marked by activation of microglia, the macrophage-like cells of the nervous system. An important contributor to microglial activation is toll-like receptor 4 (TLR4), a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli. The present review traces new efforts to characterize and control the contribution of TLR4 to inflammatory etiologies of the nervous system. PMID:20402965

  11. High Intensity Focused Ultrasound Tumor Therapy System and Its Application

    NASA Astrophysics Data System (ADS)

    Sun, Fucheng; He, Ye; Li, Rui

    2007-05-01

    At the end of last century, a High Intensity Focused Ultrasound (HIFU) tumor therapy system was successfully developed and manufactured in China, which has been already applied to clinical therapy. This article aims to discuss the HIFU therapy system and its application. Detailed research includes the following: power amplifiers for high-power ultrasound, ultrasound transducers with large apertures, accurate 3-D mechanical drives, a software control system (both high-voltage control and low-voltage control), and the B-mode ultrasonic diagnostic equipment used for treatment monitoring. Research on the dosage of ultrasound required for tumour therapy in multiple human cases has made it possible to relate a dosage formula, presented in this paper, to other significant parameters such as the volume of thermal tumor solidification, the acoustic intensity (I), and the ultrasound emission time (tn). Moreover, the HIFU therapy system can be applied to the clinical treatment of both benign and malignant tumors in the pelvic and abdominal cavity, such as uterine fibroids, liver cancer and pancreatic carcinoma.

  12. Magnetic nanoparticle drug delivery systems for targeting tumor

    NASA Astrophysics Data System (ADS)

    Mody, Vicky V.; Cox, Arthur; Shah, Samit; Singh, Ajay; Bevins, Wesley; Parihar, Harish

    2014-04-01

    Tumor hypoxia, or low oxygen concentration, is a result of disordered vasculature that lead to distinctive hypoxic microenvironments not found in normal tissues. Many traditional anti-cancer agents are not able to penetrate into these hypoxic zones, whereas, conventional cancer therapies that work by blocking cell division are not effective to treat tumors within hypoxic zones. Under these circumstances the use of magnetic nanoparticles as a drug delivering agent system under the influence of external magnetic field has received much attention, based on their simplicity, ease of preparation, and ability to tailor their properties for specific biological applications. Hence in this review article we have reviewed current magnetic drug delivery systems, along with their application and clinical status in the field of magnetic drug delivery.

  13. Applications of a novel tumor-grading-metastasis staging system for pancreatic neuroendocrine tumors

    PubMed Central

    Yang, Min; Tan, Chun-Lu; Zhang, Yi; Ke, Neng-Wen; Zeng, Lin; Li, Ang; Zhang, Hao; Xiong, Jun-Jie; Guo, Zi-Heng; Tian, Bo-Le; Liu, Xu-Bao

    2016-01-01

    Abstract The ability to stratify patients with pancreatic neuroendocrine tumors (p-NETs) into prognostic groups has been hindered by the absence of a commonly accepted staging system. Both the 7th tumor-node-metastasis (TNM) staging guidelines by the American Joint Committee on Cancer (AJCC) and the 2010 grading classifications by the World Health Organization (WHO) were validated to be unsatisfactory. We aim to evaluate the feasibility of combining the latest AJCC and WHO criteria to devise a novel tumor-grading-metastasis (TGM) staging system. We also sought to examine the stage-specific survival rates and the prognostic value of this new TGM system for p-NETs. Data of 120 patients with surgical resection and histopathological diagnosis of p-NETs from January 2004 to February 2014 in our institution were retrospectively collected and analyzed. Based on the AJCC and WHO criteria, we replaced the stage N0 and N1 with stage Ga (NET G1 and NET G2) and Gb (NET G3 and MANEC) respectively, without changes of the definition of T or M stage. The present novel TGM staging system was grouped as follows: stage I was defined as T1–2, Ga, M0; stage II as T3, Ga, M0 or as T1–3, Gb, M0; stage III as T4, Ga–b, M0 and stage IV as any T, M1. The new TGM staging system successfully distributed 55, 42, 12, and 11 eligible patients in stage I to IV, respectively. Differences of survival compared stage I with III and IV for patients with p-NETs were both statistically significant (P < 0.001), as well as those of stage II with III and IV (P < 0.001). Patients in stage I showed better a survival than those in stage II, whereas difference between stages III and IV was not notable (P = 0.001, P = 0.286, respectively). In multivariate models, when the TGM staging system was evaluated in place of the individual T, G, and M variables, this new criteria were proven to be an independent predictor of survival for surgically resected p-NETs (P < 0.05). Stratifying patients well

  14. Targeting anti-HIV drugs to the CNS

    PubMed Central

    Rao, Kavitha S; Ghorpade, Anuja; Labhasetwar, Vinod

    2009-01-01

    The development of antiretroviral drugs over the past couple of decades has been commendable due to the identification of several new targets within the overall Human Immunodeficiency Virus (HIV) replication cycle. However, complete control over HIV/Acquired Immune Deficiency Syndrome is yet to be achieved. This is because the current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. This occurs because most anti-HIV drugs do not accumulate in certain cellular and anatomical reservoirs including the Central Nervous System (CNS). Insufficient delivery of anti-HIV drugs to the CNS is attributed to their low permeability across the blood-brain-barrier (BBB). Hence, low and sustained viral replication within the CNS continues even during prolonged antiretroviral drug therapy. Therefore, developing novel approaches that are targeted at enhancing the CNS delivery of anti-HIV drugs are required. In this review, we discussed the potential of nanocarriers and the role of cell-penetrating peptides in enhancing drug delivery to the CNS. Such drug delivery approaches could also lead to higher drug delivery to other cellular and anatomical reservoirs where the virus harbor than with conventional treatment, thus providing an effective therapy to eliminate the virus completely from the body. PMID:19566446

  15. Rare Primary Central Nervous System Tumors Encountered in Pediatrics.

    PubMed

    Kramer, Kim

    2016-10-01

    As part of the special issue on Pediatric Neuro-Oncology, this article will focus on 4 of the rarer tumors in this spectrum, including atypical teratoid rhabdoid tumors, embryonal tumors with multilayered rosettes, choroid plexus tumors, and pleomorphic xanthoastrocytoma. Incidence and current understanding of the molecular pathogenesis of these tumors are discussed, and avenues of therapy both current and prospective are explored.

  16. [The activity of redox-regulatory systems in the tumor and its surrounding tissues in various histological types of tumor].

    PubMed

    Surikova, E I; Goroshinskaja, I A; Nerodo, G A; Frantsiyants, E M; Malejko, M L; Shalashnaja, E V; Kachesova, P; Nemashkalova, L A; Leonova, A V

    2016-01-01

    According to modern concepts cancer is a complex dynamic system having multiple relationships with both the immediate environment and with remote nonmalignant tissues and organs. Changes in the redox balance in them can result in disruption of the normal tissue control. Understanding of the biology of redox processes in a particular tumor and its surroundings, and of their functioning mechanisms is necessary for the development of new anti-cancer strategies based on the effects on the redox state of the tumor and surrounding tissue. Thus the aim of this work was to investigate activity of enzymatic systems influencing the redox state in the tumor tissue, peritumoral area and nonmalignant tissue (taken along the line of resection) for different histological types of tumors. The data obtained showed a similar level of reduced glutathione (GSH) in tumor tissues of gastric adenocarcinoma and vulvar squamous cell carcinoma, but its dynamics in the tissues surrounding the tumor was different. In contrast to the gastric adenocarcinoma the carcinoma of the vulva had a significant level of GSH and higher activity of glutathione dependent enzymes in the tumor tissue and its peritumoral area compared with the surrounding nonmalignant tissue. The results indicate that there are differences in the functioning of the redox regulatory systems in the tumor tissue and its surrounding tissues of various histological origin and localization, possibly due to different mechanisms involved in maintenance of the redox balance in the originally nonmalignant tissue. PMID:27143378

  17. [The activity of redox-regulatory systems in the tumor and its surrounding tissues in various histological types of tumor].

    PubMed

    Surikova, E I; Goroshinskaja, I A; Nerodo, G A; Frantsiyants, E M; Malejko, M L; Shalashnaja, E V; Kachesova, P; Nemashkalova, L A; Leonova, A V

    2016-01-01

    According to modern concepts cancer is a complex dynamic system having multiple relationships with both the immediate environment and with remote nonmalignant tissues and organs. Changes in the redox balance in them can result in disruption of the normal tissue control. Understanding of the biology of redox processes in a particular tumor and its surroundings, and of their functioning mechanisms is necessary for the development of new anti-cancer strategies based on the effects on the redox state of the tumor and surrounding tissue. Thus the aim of this work was to investigate activity of enzymatic systems influencing the redox state in the tumor tissue, peritumoral area and nonmalignant tissue (taken along the line of resection) for different histological types of tumors. The data obtained showed a similar level of reduced glutathione (GSH) in tumor tissues of gastric adenocarcinoma and vulvar squamous cell carcinoma, but its dynamics in the tissues surrounding the tumor was different. In contrast to the gastric adenocarcinoma the carcinoma of the vulva had a significant level of GSH and higher activity of glutathione dependent enzymes in the tumor tissue and its peritumoral area compared with the surrounding nonmalignant tissue. The results indicate that there are differences in the functioning of the redox regulatory systems in the tumor tissue and its surrounding tissues of various histological origin and localization, possibly due to different mechanisms involved in maintenance of the redox balance in the originally nonmalignant tissue.

  18. Tumor infiltrating immune cells in gliomas and meningiomas.

    PubMed

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Miranda, David; Ruiz, Laura; Sousa, Pablo; Ciudad, Juana; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2016-03-01

    Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors-gliomas and meningiomas-, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control.

  19. Prospects for the development of epigenetic drugs for CNS conditions.

    PubMed

    Szyf, Moshe

    2015-07-01

    Advances in our understanding of the epigenetic mechanisms that control gene expression in the central nervous system (CNS) and their role in neuropsychiatric disorders are paving the way for a potential new therapeutic approach that is focused on reversing the epigenetic underpinnings of neuropsychiatric conditions. In this article, the complexity of epigenetic processes and the current level of proof for their involvement in CNS disorders are discussed. The preclinical evidence for efficacy of pharmacological approaches that target epigenetics in the CNS and the particular challenges of this approach are also examined. Finally, strategies to address these challenges through the development of improved evidence-based epigenetic therapeutics and through combining pharmacological and behavioural approaches are presented.

  20. 21 CFR 866.6010 - Tumor-associated antigen immunological test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Tumor-associated antigen immunological test system... SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Tumor Associated Antigen immunological Test Systems § 866.6010 Tumor-associated antigen immunological test system. (a) Identification....

  1. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma.

    PubMed

    Kramer, Kim; Kushner, Brian H; Modak, Shakeel; Pandit-Taskar, Neeta; Smith-Jones, Peter; Zanzonico, Pat; Humm, John L; Xu, Hong; Wolden, Suzanne L; Souweidane, Mark M; Larson, Steven M; Cheung, Nai-Kong V

    2010-05-01

    Innovation in the management of brain metastases is needed. We evaluated the addition of compartmental intrathecal antibody-based radioimmunotherapy (cRIT) in patients with recurrent metastatic central nervous system (CNS) neuroblastoma following surgery, craniospinal irradiation, and chemotherapy. Twenty one patients treated for recurrent neuroblastoma metastatic to the CNS, received a cRIT-containing salvage regimen incorporating intrathecal (131)I-monoclonal antibodies (MoAbs) targeting GD2 or B7H3 following surgery and radiation. Most patients also received outpatient craniospinal irradiation, 3F8/GMCSF immunotherapy, 13-cis-retinoic acid and oral temozolomide for systemic control. Seventeen of 21 cRIT-salvage patients are alive 7-74 months (median 33 months) since CNS relapse, with all 17 remaining free of CNS neuroblastoma. One patient died of infection at 22 months with no evidence of disease at autopsy, and one of lung and bone marrow metastases at 15 months, and one of progressive bone marrow disease at 30 months. The cRIT-salvage regimen was well tolerated, notable for myelosuppression minimized by stem cell support (n = 5), and biochemical hypothyroidism (n = 5). One patient with a 7-year history of metastatic neuroblastoma is in remission from MLL-associated secondary leukemia. This is significantly improved to published results with non-cRIT based where relapsed CNS NB has a median time to death of approximately 6 months. The cRIT-salvage regimen for CNS metastases was well tolerated by young patients, despite their prior history of intensive cytotoxic therapies. It has the potential to increase survival with better than expected quality of life.

  2. Brain and Spinal Cord Tumors in Adults

    MedlinePlus

    ... saved articles window. My Saved Articles » My ACS » Brain and Spinal Cord Tumors in Adults Download Printable ... the topics below to get started. What Is Brain/CNS Tumors In Adults? What are adult brain ...

  3. Safety Evaluation of CNS Administered Biologics-Study Design, Data Interpretation, and Translation to the Clinic.

    PubMed

    Vuillemenot, Brian R; Korte, Sven; Wright, Teresa L; Adams, Eric L; Boyd, Robert B; Butt, Mark T

    2016-07-01

    Many central nervous system (CNS) diseases are inadequately treated by systemically administered therapies due to the blood brain barrier (BBB), which prevents achieving adequate drug concentrations at sites of action. Due to the increasing prevalence of neurodegenerative diseases and the inability of most systemically administered therapies to cross the BBB, direct CNS delivery will likely play an increasing role in treatment. Administration of large molecules, cells, viral vectors, oligonucleotides, and other novel therapies directly to the CNS via the subarachnoid space, ventricular system, or parenchyma overcomes this obstacle. Clinical experience with direct CNS administration of small molecule therapies suggests that this approach may be efficacious for the treatment of neurodegenerative disorders using biological therapies. Risks of administration into the brain tissue or cerebrospinal fluid include local damage from implantation of the delivery system and/or administration of the therapeutic and reactions affecting the CNS. Preclinical safety studies on CNS administered compounds must differentiate between the effects of the test article, the delivery device, and/or the vehicle, and assess exacerbations of reactions due to combinations of effects. Animal models characterized for safety assessment of CNS administered therapeutics have enabled human trials, but interpretation can be challenging. This manuscript outlines the challenges of preclinical intrathecal/intracerebroventricular/intraparenchymal studies, evaluation of results, considerations for special endpoints, and translation of preclinical findings to enable first-in-human trials. Recommendations will be made based on the authors' collective experience with conducting these studies to enable clinical development of CNS-administered biologics. PMID:27354708

  4. Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM

    PubMed Central

    Zhu, Yuwen; Yao, Sheng; Augustine, Mathew M.; Xu, Haiying; Wang, Jun; Sun, Jingwei; Broadwater, Megan; Ruff, William; Luo, Liqun; Zhu, Gefeng; Tamada, Koji; Chen, Lieping

    2016-01-01

    The central nervous system (CNS) is an immune-privileged organ with the capacity to prevent excessive inflammation. Aside from the blood-brain barrier, active immunosuppressive mechanisms remain largely unknown. We report that a neuron-specific molecule, synaptic adhesion-like molecule 5 (SALM5), is a crucial contributor to CNS immune privilege. We found that SALM5 suppressed lipopolysaccharide-induced inflammatory responses in the CNS and that a SALM-specific monoclonal antibody promoted inflammation in the CNS, and thereby aggravated clinical symptoms of mouse experimental autoimmune encephalomyelitis. In addition, we identified herpes virus entry mediator as a functional receptor that mediates SALM5’s suppressive function. Our findings reveal a molecular link between the neuronal system and the immune system, and provide potential therapeutic targets for the control of CNS diseases. PMID:27152329

  5. Gene therapy for CNS diseases - Krabbe disease.

    PubMed

    Rafi, Mohammad A

    2016-01-01

    This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS) Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV) alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases. PMID:27525222

  6. On the resemblance of synapse formation and CNS myelination.

    PubMed

    Almeida, R G; Lyons, D A

    2014-09-12

    The myelination of axons in the central nervous system (CNS) is essential for nervous system formation, function and health. CNS myelination continues well into adulthood, but not all axons become myelinated. Unlike the peripheral nervous system, where we know of numerous axon-glial signals required for myelination, we have a poor understanding of the nature or identity of such molecules that regulate which axons are myelinated in the CNS. Recent studies have started to elucidate cell behavior during myelination in vivo and indicate that the choice of which axons are myelinated is made prior to myelin sheath generation. Here we propose that interactions between axons and the exploratory processes of oligodendrocyte precursor cells (OPCs) lead to myelination and may be similar to those between dendrites and axons that prefigure and lead to synapse formation. Indeed axons and OPCs form synapses with striking resemblance to those of neurons, suggesting a similar mode of formation. We discuss families of molecules with specific functions at different stages of synapse formation and address studies that implicate the same factors during axon-OPC synapse formation and myelination. We also address the possibility that the function of such synapses might directly regulate the myelinating behavior of oligodendrocyte processes in vivo. In the future it may be of benefit to consider these similarities when taking a candidate-based approach to dissect mechanisms of CNS myelination.

  7. Primary CNS T-cell Lymphomas: A Clinical, Morphologic, Immunophenotypic, and Molecular Analysis.

    PubMed

    Menon, Madhu P; Nicolae, Alina; Meeker, Hillary; Raffeld, Mark; Xi, Liqiang; Jegalian, Armin G; Miller, Douglas C; Pittaluga, Stefania; Jaffe, Elaine S

    2015-12-01

    Primary central nervous system (CNS) lymphomas are relatively rare with the most common subtype being diffuse large B-cell lymphoma. Primary CNS T-cell lymphomas (PCNSTL) account for <5% of CNS lymphomas. We report the clinical, morphologic, immunophenotypic, and molecular characteristics of 18 PCNSTLs. Fifteen cases were classified as peripheral T-cell lymphoma, not otherwise specified, 2 of which were of γδ T-cell derivation and 1 was TCR silent; there was 1 anaplastic large cell lymphoma, ALK-positive and 2 anaplastic large cell lymphoma, ALK-negative. Median age was 58.5 years (range, 21 to 81 y), with an M:F ratio of 11:7. Imaging results showed that 15 patients had supratentorial lesions. Regardless of subtype, necrosis and perivascular cuffing of tumor cells were frequently observed (11/18 cases). CD3 was positive in all cases but 1; 10/17 were CD8-positive, and 5/17 were CD4-positive. Most cases studied had a cytotoxic phenotype with expression of TIA1 (13/15) and granzyme-B (9/13). Polymerase chain reaction analysis of T-cell receptor γ rearrangement confirmed a T-cell clone in 14 cases with adequate DNA quality. Next-generation sequencing showed somatic mutations in 36% of cases studied; 2 had >1 mutation, and none showed overlapping mutations. These included mutations in DNMT3A, KRAS, JAK3, STAT3, STAT5B, GNB1, and TET2 genes, genes implicated previously in other T-cell neoplasms. The outcome was heterogenous; 2 patients are alive without disease, 4 are alive with disease, and 6 died of disease. In conclusion, PCNSTLs are histologically and genomically heterogenous with frequent phenotypic aberrancy and a cytotoxic phenotype in most cases. PMID:26379152

  8. Treatment Options for Childhood Central Nervous System Embryonal Tumors and Childhood Pineoblastoma

    MedlinePlus

    ... There are four types of CNS PNETs: CNS neuroblastomas CNS neuroblastomas are a very rare type of neuroblastoma that form in the nerve tissue of the ... that cover the brain and spinal cord. CNS neuroblastomas may be large and spread to other parts ...

  9. Coefficient of Energy Balance: Effective Tool for Early Differential Diagnosis of CNS Diseases

    PubMed Central

    Sobek, Ondřej; Hajduková, Lenka; Lánská, Věra; Nekola, Petr

    2013-01-01

    Urgent examination of cerebrospinal fluid (CSF) provides immediate important information about the character of central nervous system (CNS) impairment. Although this examination includes energy parameters such as glucose and lactate concentrations, it does not commonly use Coefficient of Energy Balance (CEB). In this study, we focused on CEB because it enables more exact assessment of actual energy state in the CSF compartment than glucose and lactate alone. CEB informs about the actual functioning condition of present cells, and it does not require any other analysis or costs. Using Kruskal-Wallis ANOVA, we examined a large CSF sample (n = 8183) and we compared CEB values among groups with different cytological syndromes. We found a statistically significant difference of CEB between the group with granulocyte pleocytosis and the control group. These results indicate a high degree of anaerobic metabolism caused by the oxidative burst of neutrophils. Similarly, we found a statistically significant difference of CEB between the control group and groups with tumorous oligocytosis plus pleocytosis and monocyte pleocytosis. This difference can be attributed to the oxidative burst of macrophages. Our findings suggest that CEB combined with CSF cytology has a great importance for diagnosis, differential diagnosis, and early therapy of CNS diseases. PMID:23865063

  10. Expression of α5 integrin rescues fibronectin responsiveness in NT2N CNS neuronal cells

    PubMed Central

    Meland, Marit N.; Herndon, Mary E.; Stipp, Christopher S.

    2010-01-01

    The extracellular matrix protein fibronectin is implicated in neuronal regeneration in the peripheral nervous system. In the central nervous system (CNS), fibronectin is upregulated at sites of penetrating injuries and stroke; however, CNS neurons downregulate the fibronectin receptor, α5β1 integrin, during differentiation and generally respond poorly to fibronectin. NT2N CNS neuron-like cells (derived from NT2 precursor cells) have been used in pre-clinical and clinical studies for treatment of stroke and a variety of CNS injury and disease models. Here we show that, like primary CNS neurons, NT2N cells downregulate α5β1 integrin during differentiation and respond poorly to fibronectin. The poor neurite outgrowth by NT2N cells on fibronectin can be rescued by transducing NT2 precursors with a retroviral vector expressing α5 integrin under the control of the Murine Stem Cell Virus 5′ long terminal repeat. Sustained α5 integrin expression is compatible with the CNS-like neuronal differentiation of NT2N cells and does not prevent robust neurite outgrowth on other integrin ligands. Thus, α5 integrin expression in CNS neuronal precursor cells may provide a strategy for enhancing the outgrowth and survival of implanted cells in cell replacement therapies for CNS injury and disease. PMID:19598247

  11. Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence

    PubMed Central

    Abid, Muhammad Bilal; De Mel, Sanjay; Abid, Muhammad Abbas; Tan, Kong Bing; Chng, Wee Joo

    2016-01-01

    ABSTRACT Background: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. Case presentation: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. Discussion: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. Conclusion: In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration. PMID:27105248

  12. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, [corrected] TNF-α and IL-6 challenges in C57BL/6 mice.

    PubMed

    Skelly, Donal T; Hennessy, Edel; Dansereau, Marc-Andre; Cunningham, Colm

    2013-01-01

    It is increasingly clear that systemic inflammation has both adaptive and deleterious effects on the brain. However, detailed comparisons of brain effects of systemic challenges with different pro-inflammatory cytokines are lacking. In the present study, we challenged female C57BL/6 mice intraperitoneally with LPS (100 µg/kg), IL-1β (15 or 50 µg/kg), TNF-α (50 or 250 µg/kg) or IL-6 (50 or 125 µg/kg). We investigated effects on core body temperature, open field activity and plasma levels of inflammatory markers at 2 hours post injection. We also examined levels of hepatic, hypothalamic and hippocampal inflammatory cytokine transcripts. Hypothermia and locomotor hypoactivity were induced by LPS>IL-1β>TNF-α>IL-6. Systemic LPS, IL-1β and TNF-α challenges induced robust and broadly similar systemic and central inflammation compared to IL-6, which showed limited effects, but did induce a hepatic acute phase response. Important exceptions included IFNβ, which could only be induced by LPS. Systemic IL-1β could not induce significant blood TNF-α, but induced CNS TNF-α mRNA, while systemic TNF-α could induce IL-1β in blood and brain. Differences between IL-1β and TNF-α-induced hippocampal profiles, specifically for IL-6 and CXCL1 prompted a temporal analysis of systemic and central responses at 1, 2, 4, 8 and 24 hours, which revealed that IL-1β and TNF-α both induced the chemokines CXCL1 and CCL2 but only IL-1β induced the pentraxin PTX3. Expression of COX-2, CXCL1 and CCL2, with nuclear localisation of the p65 subunit of NFκB, in the cerebrovasculature was demonstrated by immunohistochemistry. Furthermore, we used cFOS immunohistochemistry to show that LPS, IL-1β and to a lesser degree, TNF-α activated the central nucleus of the amygdala. Given the increasing attention in the clinical literautre on correlating specific systemic inflammatory mediators with neurological or neuropsychiatric conditions and complications, these data will provide a useful

  13. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, [corrected] TNF-α and IL-6 challenges in C57BL/6 mice.

    PubMed

    Skelly, Donal T; Hennessy, Edel; Dansereau, Marc-Andre; Cunningham, Colm

    2013-01-01

    It is increasingly clear that systemic inflammation has both adaptive and deleterious effects on the brain. However, detailed comparisons of brain effects of systemic challenges with different pro-inflammatory cytokines are lacking. In the present study, we challenged female C57BL/6 mice intraperitoneally with LPS (100 µg/kg), IL-1β (15 or 50 µg/kg), TNF-α (50 or 250 µg/kg) or IL-6 (50 or 125 µg/kg). We investigated effects on core body temperature, open field activity and plasma levels of inflammatory markers at 2 hours post injection. We also examined levels of hepatic, hypothalamic and hippocampal inflammatory cytokine transcripts. Hypothermia and locomotor hypoactivity were induced by LPS>IL-1β>TNF-α>IL-6. Systemic LPS, IL-1β and TNF-α challenges induced robust and broadly similar systemic and central inflammation compared to IL-6, which showed limited effects, but did induce a hepatic acute phase response. Important exceptions included IFNβ, which could only be induced by LPS. Systemic IL-1β could not induce significant blood TNF-α, but induced CNS TNF-α mRNA, while systemic TNF-α could induce IL-1β in blood and brain. Differences between IL-1β and TNF-α-induced hippocampal profiles, specifically for IL-6 and CXCL1 prompted a temporal analysis of systemic and central responses at 1, 2, 4, 8 and 24 hours, which revealed that IL-1β and TNF-α both induced the chemokines CXCL1 and CCL2 but only IL-1β induced the pentraxin PTX3. Expression of COX-2, CXCL1 and CCL2, with nuclear localisation of the p65 subunit of NFκB, in the cerebrovasculature was demonstrated by immunohistochemistry. Furthermore, we used cFOS immunohistochemistry to show that LPS, IL-1β and to a lesser degree, TNF-α activated the central nucleus of the amygdala. Given the increasing attention in the clinical literautre on correlating specific systemic inflammatory mediators with neurological or neuropsychiatric conditions and complications, these data will provide a useful

  14. Mathematical Modeling of Tumor Cell Growth and Immune System Interactions

    NASA Astrophysics Data System (ADS)

    Rihan, Fathalla A.; Safan, Muntaser; Abdeen, Mohamed A.; Abdel-Rahman, Duaa H.

    In this paper, we provide a family of ordinary and delay differential equations to describe the dynamics of tumor-growth and immunotherapy interactions. We explore the effects of adoptive cellular immunotherapy on the model and describe under what circumstances the tumor can be eliminated. The possibility of clearing the tumor, with a strategy, is based on two parameters in the model: the rate of influx of the effector cells, and the rate of influx of IL2. The critical tumor-growth rate, below which endemic tumor does not exist, has been found. One can use the model to make predictions about tumor-dormancy.

  15. EFFICACY OF THE ENNEKING STAGING SYSTEM IN RELATION TO TREATING BENIGN BONE TUMORS AND TUMOR-LIKE BONE LESIONS

    PubMed Central

    Nogueira Drumond, José Marcos

    2015-01-01

    Objective: To evaluate the efficacy of the Enneking staging system for determining the prognosis, planning surgical treatment and indicating adjuvant therapy for benign bone tumors (BBT) and tumor-like bone lesions (TBL). Methods: A retrospective multicenter, descriptive, nonrandomized study was carried out on a representative sample comprising a large series of 165 patients with a total of 168 benign bone tumors and tumor-like bone lesions. The patient sample was typical, and matched the literature in all respects. All the patients were classified according to the Enneking staging system, and the initial staging of each lesion was correlated with its behavior after either conservative or surgical treatment, in order to determine the efficacy of the system. The treatment options and complications were described and analyzed. Results: The results from the treatment provided 95.2% agreement with the Enneking staging system, with a 95% confidence interval of between 90.8 and 97.9%. Of the 168 tumors treated, only eight (4.8%) could not be controlled in relation to the initial treatment indicated by the Enneking staging system. Tumors classified as active were the most prevalent, comprising 73.2% of the lesions. Tumor recurrence was significantly more frequent (p < 0.001) in the aggressive stage. All the patients staged as latent evolved to cure. The study suggested that surgery with wide margins, for aggressive lesions, could provide better lesion control, with a lower recurrence rate (p > 0.001). For latent and active lesions, the study demonstrated the efficacy of both expectant treatment and excision, with or without autogenous bone graft. Conclusion: The results confirm that the Enneking staging system was very efficient in determining the prognosis, enabling surgical planning and indicating adjuvant therapy for treatment of BBT and TBL. PMID:27019838

  16. The mast cells of the mammalian central nervous system. V. The effect of compound 48/80 on the neurolipomastocytoid cells and related areas of the CNS: early changes.

    PubMed

    Ibrahim, M Z; Uthman, M A; Tenekjian, V; Wiedman, T

    1980-01-01

    The response of the neurolipomastocytoid cells (NLMs) and elements in their vicinity within the central nervous system of various animal species was studied following injection of the animals with the specific mast cell (MC)-discharger compound 48/80. The observed alterations were grouped into those occurring early (0--21 days) and later (up to 18 months). In the present report, only the acute changes are described, light and electron microscopically. Most experimental animals developed prostration, scratching, acral-type reaction, signs of respiratory distress and salivation, and, in the monkey, uncontrollable somnolence. Within about 2 weeks after the injection some animals (especially guinea pigs) manifested various degrees of limb paralysis. The NLMs, like MCs outside the CNS, responded to injection by various degrees of degranulation, vacuolation, marked variation in granule size, apparent cell loss and sometimes an increase in number. Electron microscopically, particulate breakdown products of the granules of the NLMs appeared in the cytoplasm; occasionally there was suggestive evidence that they had passed inward across the vessel wall to reach the lumen, and also outward through the outermost basal lamina. Perivascular astrocytic feet showed swelling and vacuolation shortly after the injection, which was followed by evidence of gliosis and later scarring; occasionally, alterations in the mitochondria were observed. In the spinal cord of the guinea pig, capillary neoformation was observed with endothelial cells and adjacent NLMs taking up tritiated thymidine. The discussion centers on the partial similarity of response to compound 48/80 of the NLMs to that of MCs outside the CNS, and the probable involvement of NLM-damage in the parenchymal changes.

  17. Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity.

    PubMed

    Sonar, Sandip; Lal, Girdhari

    2015-01-01

    Tumor necrosis factor superfamily (TNFSF) molecules play an important role in the activation, proliferation, differentiation, and migration of immune cells into the central nervous system (CNS). Several TNF superfamily molecules are known to control alloimmunity, autoimmunity, and immunity. Development of transgenic and gene knockout animals, and monoclonal antibodies against TNFSF molecules have increased our understanding of individual receptor-ligand interactions, and their intracellular signaling during homeostasis and neuroinflammation. A strong clinical association has been observed between TNFSF members and CNS autoimmunity such as multiple sclerosis and also in its animal model experimental autoimmune encephalomyelitis. Therefore, they are promising targets for alternative therapeutic options to control autoimmunity. Although, TNFSF ligands are widely distributed and have diverse functions, we have restricted the discussions in this review to TNFSF receptor-ligand interactions and their role in the pathogenesis of neuroinflammation and CNS autoimmunity.

  18. CNS development under altered gravity

    NASA Astrophysics Data System (ADS)

    Sajdel-Sulkowska, E.

    The future of space exploration depends on a solid understanding of the developmental process under microgravity. In furtherance of this goal, the present studies assessed the impact of altered gravity on the developing rat cerebellum. Specifically, the expression of selected cerebellar proteins and corresponding genes was compared in rat neonates exposed to hypergravity (1.5G) from embryonic day (E) 11 to postnatal day (P) 6 and P9 against their expression in rat neonates developing under normal gravity. Cerebellar proteins were analyzed by quantitative western blots of cerebellar homogenates; RNA analysis was performed in the same samples using ribonuclease protection assay (RPA). Densitometric analysis of western blots suggested 21% to 31% reduction in neuronal cell adhesion molecule (NCAM) and 31% to 45% reduction in glial acidic protein (GFAP). RPA results suggested a small reduction (<10%) in NCAM mRNA and a moderate reduction (<25%) in GFAP mRNA. These data indicate that the expression of selected cerebellar proteins may be affected at both the transcriptional and translational/postranslational level. Furthermore, these results suggest that changes in expression of selected genes may underlie hypergravity's effect on the developing CNS. (Supported by NASA grant NCC2-1042 and BWH Psychiatry Fund).

  19. Clitoria ternatea and the CNS.

    PubMed

    Jain, Neeti N; Ohal, C C; Shroff, S K; Bhutada, R H; Somani, R S; Kasture, V S; Kasture, S B

    2003-06-01

    The present investigation was aimed at determining the spectrum of activity of the methanolic extract of Clitoria ternatea (CT) on the CNS. The CT was studied for its effect on cognitive behavior, anxiety, depression, stress and convulsions induced by pentylenetetrazol (PTZ) and maximum electroshock (MES). To explain these effects, the effect of CT was also studied on behavior mediated by dopamine (DA), noradrenaline, serotonin and acetylcholine. The extract decreased time required to occupy the central platform (transfer latency, TL) in the elevated plus maze (EPM) and increased discrimination index in the object recognition test, indicating nootropic activity. The extract was more active in the object recognition test than in the EPM. The extract increased occupancy in the open arm of EPM by 160% and in the lit box of the light/dark exploration test by 157%, indicating its anxiolytic activity. It decreased the duration of immobility in tail suspension test (suggesting its antidepressant activity), reduced stress-induced ulcers and reduced the convulsing action of PTZ and MES. The extract exhibited tendency to reduce the intensity of behavior mediated via serotonin and acetylcholine. The effect on DA- and noradrenaline-mediated behavior was not significant. In conclusion, the extract was found to possess nootropic, anxiolytic, antidepressant, anticonvulsant and antistress activity. Further studies are necessary to isolate the active principle responsible for the activities and to understand its mode of action. PMID:12895670

  20. HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

    PubMed Central

    Paveliev, Mikhail; Fenrich, Keith K.; Kislin, Mikhail; Kuja-Panula, Juha; Kulesskiy, Evgeny; Varjosalo, Markku; Kajander, Tommi; Mugantseva, Ekaterina; Ahonen-Bishopp, Anni; Khiroug, Leonard; Kulesskaya, Natalia; Rougon, Geneviève; Rauvala, Heikki

    2016-01-01

    Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries. PMID:27671118

  1. [MicroRNAs in microglia polarization and CNS diseases: mechanism and functions].

    PubMed

    Fang, Xue; Tan, Wei-Xing; He, Cheng; Cao, Li

    2015-02-25

    Microglia are resident macrophages of central nervous system (CNS), and thus act as the crucial stuff of immune response and play very important roles in the progress of various CNS diseases. There are two different polarization statuses of activated microglia, M1 and M2 phenotypes. M1 polarized microglia are important for eradicating bacterial and promoting inflammation, whereas M2 cells are characterized by anti-inflammation and tissue remodeling. Recently, more and more evidence indicated that different polarized microglia showed diverse microRNA (miRNA) expression profiles. MiRNAs regulate microglia polarization, and thus affect the progress of CNS diseases. Fully exploring the polarization status of microglia during CNS diseases and the role of miRNAs in microglia polarization will be very helpful for a deep understanding of the roles of microglia in immunopathologic mechanism of different CNS diseases and offer the theoretical foundation of searching more effective therapies for these disorders. PMID:25672624

  2. Current approaches to enhance CNS delivery of drugs across the brain barriers

    PubMed Central

    Lu, Cui-Tao; Zhao, Ying-Zheng; Wong, Ho Lun; Cai, Jun; Peng, Lei; Tian, Xin-Qiao

    2014-01-01

    Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. PMID:24872687

  3. Recent advances in lymphatic targeted drug delivery system for tumor metastasis

    PubMed Central

    Zhang, Xiao-Yu; Lu, Wei-Yue

    2014-01-01

    The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the specificity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers. PMID:25610710

  4. B7-1/CD80-transduced tumor cells elicit better systemic immunity than wild-type tumor cells admixed with Corynebacterium parvum.

    PubMed

    Chen, L; McGowan, P; Ashe, S; Johnston, J V; Hellström, I; Hellström, K E

    1994-10-15

    Tumor cells genetically modified by transduction of B7 (B7-1/CD80), a natural ligand for the T-cell costimulatory molecules CD28 and CTLA-4, can elicit potent tumor immunity, and they can be effective for treatment of established cancers in animal models. In this study, three tumor lines, the EL4 lymphoma, the P815 mastocytoma, and the MCA102 sarcoma were transduced with recombinant retrovirus containing the murine B7 gene, and their potency to induce systemic immunity protective against challenge with wild-type tumor was compared to that of the same tumor cells admixed with the commonly used adjuvant Corynebacterium parvum. While admixture of tumor cells with C. parvum resulted in complete regression of tumors in syngeneic mice, it did not induce protective immunity against a subsequent challenge of wild-type cells from any of the 3 tumors tested. In contrast, B7-transduced EL4 and P815 tumors regressed locally and induced a potent systemic immunity to wild-type tumors and a higher level of cytotoxic T-cell activity than did tumor cells admixed with C. parvum. No systemic immunity was induced by B7-transduced nonimmunogenic MCA102 sarcoma cells. Our results demonstrate that immunogenic tumor cells transduced with the B7 gene are superior to tumor cells mixed with C. parvum for the induction of systemic tumor immunity. PMID:7522958

  5. Diffuse endocrine system, neuroendocrine tumors and immunity: what's new?

    PubMed

    Ameri, Pietro; Ferone, Diego

    2012-01-01

    During the last two decades, research into the modulation of immunity by the neuroendocrine system has flourished, unravelling significant effects of several neuropeptides, including somatostatin (SRIH), and especially cortistatin (CST), on immune cells. Scientists have learnt that the diffuse neuroendocrine system can regulate the immune system at all its levels: innate immunity, adaptive immunity, and maintenance of immune tolerance. Compelling studies with animal models have demonstrated that some neuropeptides may be effective in treating inflammatory disorders, such as sepsis, and T helper 1-driven autoimmune diseases, like Crohn's disease and rheumatoid arthritis. Here, the latest findings concerning the neuroendocrine control of the immune system are discussed, with emphasis on SRIH and CST. The second part of the review deals with the immune response to neuroendocrine tumors (NETs). The anti-NET immune response has been described in the last years and it is still being characterized, similarly to what is happening for several other types of cancer. In parallel with investigations addressing the mechanisms by which the immune system contrasts NET growth and spreading, ground-breaking clinical trials of dendritic cell vaccination as immunotherapy for metastatic NETs have shown in principle that the immune reaction to NETs can be exploited for treatment.

  6. Myelin damage and repair in pathologic CNS: challenges and prospects

    PubMed Central

    Alizadeh, Arsalan; Dyck, Scott M.; Karimi-Abdolrezaee, Soheila

    2015-01-01

    Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for

  7. Myelin damage and repair in pathologic CNS: challenges and prospects.

    PubMed

    Alizadeh, Arsalan; Dyck, Scott M; Karimi-Abdolrezaee, Soheila

    2015-01-01

    Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for

  8. Myelin damage and repair in pathologic CNS: challenges and prospects.

    PubMed

    Alizadeh, Arsalan; Dyck, Scott M; Karimi-Abdolrezaee, Soheila

    2015-01-01

    Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for

  9. Use of a relational database program for quantification of the CNS role.

    PubMed

    Picella, D V

    1996-11-01

    In the current state of flux and economic retrenchment in the healthcare system, clinical nurse specialists (CNSs) are challenged to clearly define their contribution to high quality patient care services. Systems for documenting and reporting on CNS activities that are flexible, easy to use, and do not require extensive time commitments to use are needed. A systematic approach for developing a tool to collect data about the CNS role is presented. This tool can be used with an adaptation of computerized relational database technology that can handle the inputting, managing, and reporting of data collected about the CNS roles and associated activities. A relational database computer software application can run on a personal computer or laptop. When applied to structural evaluation of the CNS role, this system has potential for quickly and effectively performing periodic evaluations that clearly document how CNS time is spent. An accurate and usable database of CNS activities is a critical step toward demonstrating whether or not the CNS is performing appropriate functions and establishes a foundation of critical information for further evaluation of process and outcome data. Further exploration of this technology through experience in its applied use is needed.

  10. Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview.

    PubMed

    Liu, Hao-Li; Fan, Ching-Hsiang; Ting, Chien-Yu; Yeh, Chih-Kuang

    2014-01-01

    Malignant glioma is one of the most challenging central nervous system (CNS) diseases, which is typically associated with high rates of recurrence and mortality. Current surgical debulking combined with radiation or chemotherapy has failed to control tumor progression or improve glioma patient survival. Microbubbles (MBs) originally serve as contrast agents in diagnostic ultrasound but have recently attracted considerable attention for therapeutic application in enhancing blood-tissue permeability for drug delivery. MB-facilitated focused ultrasound (FUS) has already been confirmed to enhance CNS-blood permeability by temporally opening the blood-brain barrier (BBB), thus has potential to enhance delivery of various kinds of therapeutic agents into brain tumors. Here we review the current preclinical studies which demonstrate the reports by using FUS with MB-facilitated drug delivery technology in brain tumor treatment. In addition, we review newly developed multifunctional theranostic MBs for FUS-induced BBB opening for brain tumor therapy.

  11. Combining Microbubbles and Ultrasound for Drug Delivery to Brain Tumors: Current Progress and Overview

    PubMed Central

    Liu, Hao-Li; Fan, Ching-Hsiang; Ting, Chien-Yu; Yeh, Chih-Kuang

    2014-01-01

    Malignant glioma is one of the most challenging central nervous system (CNS) diseases, which is typically associated with high rates of recurrence and mortality. Current surgical debulking combined with radiation or chemotherapy has failed to control tumor progression or improve glioma patient survival. Microbubbles (MBs) originally serve as contrast agents in diagnostic ultrasound but have recently attracted considerable attention for therapeutic application in enhancing blood-tissue permeability for drug delivery. MB-facilitated focused ultrasound (FUS) has already been confirmed to enhance CNS-blood permeability by temporally opening the blood-brain barrier (BBB), thus has potential to enhance delivery of various kinds of therapeutic agents into brain tumors. Here we review the current preclinical studies which demonstrate the reports by using FUS with MB-facilitated drug delivery technology in brain tumor treatment. In addition, we review newly developed multifunctional theranostic MBs for FUS-induced BBB opening for brain tumor therapy. PMID:24578726

  12. Brain and Spinal Tumors: Hope through Research

    MedlinePlus

    ... of the CNS. Some tools used in the operating room include a surgical microscope, the endoscope (a ... cells, which support other brain function. central nervous system (CNS)—the brain and spinal cord. cerebrospinal fluid ( ...

  13. Roles of F-box proteins in human digestive system tumors (Review).

    PubMed

    Gong, Jian; Lv, Liang; Huo, Jirong

    2014-12-01

    F-box proteins (FBPs), the substrate-recognition subunit of E3 ubiquitin (Ub) ligase, are the important components of Ub proteasome system (UPS). FBPs are involved in multiple cellular processes through ubiquitylation and subsequent degradation of their target proteins. Many studies have described the roles of FBPs in human cancers. Digestive system tumors account for a large proportion of all the tumors, and their mortality is very high. This review summarizes for the first time the roles of FBPs in digestive system tumorige-nesis and tumor progression, aiming at finding new routes for the rational design of targeted anticancer therapies in digestive system tumors.

  14. 21 CFR 866.6010 - Tumor-associated antigen immunological test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Tumor-associated antigen immunological test system. 866.6010 Section 866.6010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... immunological Test Systems § 866.6010 Tumor-associated antigen immunological test system. (a) Identification....

  15. 21 CFR 866.6010 - Tumor-associated antigen immunological test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Tumor-associated antigen immunological test system. 866.6010 Section 866.6010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... immunological Test Systems § 866.6010 Tumor-associated antigen immunological test system. (a) Identification....

  16. Bioavailability of dietary polyphenols: Factors contributing to their clinical application in CNS diseases.

    PubMed

    Pandareesh, M D; Mythri, R B; Srinivas Bharath, M M

    2015-10-01

    The anatomical location of the central nervous system (CNS) renders it immunologically and pharmacologically privileged due to the blood brain barrier (BBB). Although this limits the transport of unfavorable molecules to the CNS, the ensuing privilege could be disadvantageous for therapeutic compounds. Hence, the greatest challenge in the pharmacotherapy of CNS diseases is to ensure efficient brain targeting and drug delivery. Research evidences indicate that dietary polyphenols have neuroprotective potential against CNS diseases. However, their selective permeability across BBB, poor absorption, rapid metabolism and systemic elimination limit their bioavailability and therapeutic efficacy. Consequently, the beneficial effects of these orally administered agents in the CNS still remain a subject of debate. This has also limited its clinical application either as independent or adjunctive therapy. Improving the in vivo bioavailability by novel methods could improve the therapeutic feasibility of polyphenols and assist in evolving novel drugs and their derivatives with improved efficacy in vivo. Here we review the mechanistic and pharmacological issues related to the bioavailability of polyphenols with therapeutic implications for CNS diseases. We surmise that improving the bioavailability of polyphenols entails efficient in vivo transport across BBB, biochemical stability, improved half-life and persistent neuroprotection in the CNS.

  17. Developmental and pathological angiogenesis in the central nervous system

    PubMed Central

    Vallon, Mario; Chang, Junlei; Zhang, Haijing

    2014-01-01

    Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood–brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases. PMID:24760128

  18. Unusual CNS presentation of thyroid cancer.

    PubMed

    Heery, Christopher R; Engelhard, Herbert H; Slavin, Konstantin V; Michals, Edward A; Villano, J Lee

    2012-09-01

    As advanced therapies allow cancer patients to live longer, disease failure in the central nervous system increases from limited therapeutic penetration. Primary thyroid malignancies rarely metastasize to the brain and have a small number of investigations in literature on the subject. The majority of brain metastases involve the brain parenchyma, reflecting the mass and blood distribution within the brain and central nervous system. Here, we report two cases of the most common differentiated thyroid cancers; follicular thyroid cancer having brain involvement from extra-axial growth and papillary thyroid cancer having brain involvement from a single intraventricular metastasis, presumed as metastasis from the vascular choroid plexus. Both of our cases had widespread systemic involvement. For our follicular thyroid cancer, brain involvement was a result of extra-axial growth from cavarial bone, and our papillary thyroid cancer had brain involvement from a single intraventricular metastasis that was initially resected and nearly a year later developed extensive brain involvement. Unlike the usual gray-white junction metastases seen in the majority of metastatic brain tumors, including thyroid, our cases are uncommon. They reflect differences in tumor biology that allows for spread and growth in the brain. Although there is growing genetic knowledge on tumors that favor brain metastases, little is known about tumors that rarely involve the brain. PMID:22296651

  19. A philosophy for CNS radiotracer design.

    PubMed

    Van de Bittner, Genevieve C; Ricq, Emily L; Hooker, Jacob M

    2014-10-21

    Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test-retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available

  20. Coupling Immunodeficiency factors to a normal cell system growing conjointly with tumor cells

    NASA Astrophysics Data System (ADS)

    Shojania Feizabadi, Mitra; Witten, Tarynn M.

    2014-03-01

    In this work, we modify Witten's conjoint normal-tumor cell model in order to incorporate the presence of a simple immune system. We first examine the behavior of normal and tumor cells when tumor cells interact with surrounding normal cells. We then extend our model and add the effects of a simple immune system, immune-suppression factors and immune-chemotherapeutics agents. The evolution of the system variables is investigated via computer simulation. We show that the evolution of normal and tumor cells population is significantly affected by the choice of drug or immunodeficiency.

  1. Pathogenesis and management of primary CNS lymphoma.

    PubMed

    Roth, Patrick; Korfel, Agnieszka; Martus, Peter; Weller, Michael

    2012-05-01

    Primary CNS lymphoma (PCNSL), a rare variant of extranodal non-Hodgkin's lymphoma, may cause various neurological symptoms and signs. The best therapeutic strategy is still a matter of debate. High-dose methotrexate (HD-MTX) is the most active compound and should be used as the backbone for any chemotherapy applied. Several other chemotherapeutic drugs have been assessed in combination with HD-MTX, but no standard has yet been defined. Whole-brain radiotherapy is active against PCNSL, but typically does not confer long-lasting remission and is associated with significant neurotoxicity in many patients. The recently published G-PCNSL-SG1 trial has shown that consolidating whole-brain radiotherapy after HD-MTX-based chemotherapy does not prolong overall survival and may therefore be deferred. Combined systemic and intraventricular polychemotherapy, or high-dose chemotherapy followed by stem cell transplantation may offer cures to younger patients. Improving treatment regimens without adding significant (neuro-)toxicity should be the focus of ongoing and future studies.

  2. The Endocannabinoid System as Pharmacological Target Derived from Its CNS Role in Energy Homeostasis and Reward. Applications in Eating Disorders and Addiction

    PubMed Central

    Viveros, Maria-Paz; Bermúdez-Silva, Francisco-Javier; Lopez-Rodriguez, Ana-Belén; Wagner, Edward J.

    2011-01-01

    The endocannabinoid system (ECS) has been implicated in many physiological functions, including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses). We first introduce this important regulatory system and chronicle what is known concerning the signal transduction pathways activated upon the binding of endogenous cannabinoid ligands to the Gi/0-coupled CB1 cannabinoid receptor, as well as its interactions with other hormones and neuromodulators which can modify endocannabinoid signaling in the brain. Anorexia nervosa (AN) and bulimia nervosa (BN) are severe and disabling psychiatric disorders, characterized by profound eating and weight alterations and body image disturbances. Since endocannabinoids modulate eating behavior, it is plausible that endocannabinoid genes may contribute to the biological vulnerability to these diseases. We present and discuss data suggesting an impaired endocannabinoid signaling in these eating disorders, including association of endocannabinoid components gene polymorphisms and altered CB1-receptor expression in AN and BN. Then we discuss recent findings that may provide new avenues for the identification of therapeutic strategies based on the endocannabinod system. In relation with its implications as a reward-related system, the endocannabinoid system is not only a target for cannabis but it also shows interactions with other drugs of abuse. On the other hand, there may be also a possibility to point to the ECS as a potential target for treatment of drug-abuse and addiction. Within this framework we will focus on enzymatic machinery involved in endocannabinoid inactivation (notably fatty acid amide hydrolase or FAAH) as a particularly interesting potential target. Since a deregulated endocannabinoid system may be also related to depression, anxiety and pain symptomatology accompanying drug

  3. Compartmentalized intrathecal immunoglobulin synthesis during HIV infection - a model of chronic CNS inflammation?

    PubMed

    Bonnan, Mickael; Barroso, Bruno; Demasles, Stéphanie; Krim, Elsa; Marasescu, Raluca; Miquel, Marie

    2015-08-15

    HIV infects the central nervous system (CNS) during primary infection and persists in resident macrophages. CNS infection initiates a strong local immune response that fails to control the virus but is responsible for by-stander lesions involved in neurocognitive disorders. Although highly active anti-retroviral therapy now offers an almost complete control of CNS viral proliferation, low-grade CNS inflammation persists. This review focuses on HIV-induced intrathecal immunoglobulin (Ig) synthesis. Intrathecal Ig synthesis early occurs in more than three-quarters of patients in response to viral infection of the CNS and persists throughout the course of the disease. Viral antigens are targeted but this specific response accounts for <5% of the whole intrathecal synthesis. Although the nature and mechanisms leading to non-specific synthesis are unknown, this prominent proportion is comparable to that observed in various CNS viral infections. Cerebrospinal fluid-floating antibody-secreting cells account for a minority of the whole synthesis, which mainly takes place in perivascular inflammatory infiltrates of the CNS parenchyma. B-cell traffic and lineage across the blood-brain-barrier have not yet been described. We review common technical pitfalls and update the pending questions in the field. Moreover, since HIV infection is associated with an intrathecal chronic oligoclonal (and mostly non-specific) Ig synthesis and associates with low-grade axonal lesions, this could be an interesting model of the chronic intrathecal synthesis occurring during multiple sclerosis. PMID:26198917

  4. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation.

    PubMed

    Ou, Sai-Hong Ignatius; Weitz, Michael; Jalas, John R; Kelly, Daniel F; Wong, Vanessa; Azada, Michele C; Quines, Oliver; Klempner, Samuel J

    2016-06-01

    Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment. PMID:27133743

  5. Secreted Phospholipases A2 of Snake Venoms: Effects on the Peripheral Neuromuscular System with Comments on the Role of Phospholipases A2 in Disorders of the CNS and Their Uses in Industry

    PubMed Central

    Harris, John B.; Scott-Davey, Tracey

    2013-01-01

    Neuro- and myotoxicological signs and symptoms are significant clinical features of envenoming snakebites in many parts of the world. The toxins primarily responsible for the neuro and myotoxicity fall into one of two categories—those that bind to and block the post-synaptic acetylcholine receptors (AChR) at the neuromuscular junction and neurotoxic phospholipases A2 (PLAs) that bind to and hydrolyse membrane phospholipids of the motor nerve terminal (and, in most cases, the plasma membrane of skeletal muscle) to cause degeneration of the nerve terminal and skeletal muscle. This review provides an introduction to the biochemical properties of secreted sPLA2s in the venoms of many dangerous snakes and a detailed discussion of their role in the initiation of the neurologically important consequences of snakebite. The rationale behind the experimental studies on the pharmacology and toxicology of the venoms and isolated PLAs in the venoms is discussed, with particular reference to the way these studies allow one to understand the biological basis of the clinical syndrome. The review also introduces the involvement of PLAs in inflammatory and degenerative disorders of the central nervous system (CNS) and their commercial use in the food industry. It concludes with an introduction to the problems associated with the use of antivenoms in the treatment of neuro-myotoxic snakebite and the search for alternative treatments. PMID:24351716

  6. Systems biology of tumor dormancy: linking biology and mathematics on multiple scales to improve cancer therapy.

    PubMed

    Enderling, Heiko; Hahnfeldt, Philip; Hlatky, Lynn; Almog, Nava

    2012-05-01

    For many decades, it has been appreciated that tumor progression is not monotonic, and development of a cancer cell does not equate to inevitable cancer presentation in the clinic. Tumor progression is challenged by numerous intrinsic and extrinsic bottlenecks that can hold the tumor in dormant stages for prolonged periods. Given the complex, multiscale nature of these bottlenecks, the Center of Cancer Systems Biology organized a workshop on critical issues of systems biology of tumor dormancy. The program for the meeting this past July, chaired by N. Almog and H. Enderling, included discussions and interactive breakout sessions on regulation of tumor dormancy by angiogenesis, tumor-immune system interactions, cancer stem cell kinetics, and cell signaling pathways. Three important conclusions emerged from the meeting. The first was the urgent need to differentiate between tumor cell and tumor population dormancy of the primary tumor and metastatic deposits, the second was the continued need for interdisciplinary dialogs, and the third was the need to bring cross-scale mechanistic thinking to the field to achieve a more robust understanding of tumor dormancy and its clinical implications. PMID:22414579

  7. Reactive gliosis in the pathogenesis of CNS diseases.

    PubMed

    Pekny, Milos; Pekna, Marcela

    2016-03-01

    Astrocytes maintain the homeostasis of the central nervous system (CNS) by e.g. recycling of neurotransmitters and providing nutrients to neurons. Astrocytes function also as key regulators of synaptic plasticity and adult neurogenesis. Any insult to the CNS tissue triggers a range of molecular, morphological and functional changes of astrocytes jointly called reactive (astro)gliosis. Reactive (astro)gliosis is highly heterogeneous and also context-dependent process that aims at the restoration of homeostasis and limits tissue damage. However, under some circumstances, dysfunctional (astro)gliosis can become detrimental and inhibit adaptive neural plasticity mechanisms needed for functional recovery. Understanding the multifaceted and context-specific functions of astrocytes will contribute to the development of novel therapeutic strategies that, when applied at the right time-point, will improve the outcome of diverse neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

  8. Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

    PubMed Central

    Maze, Ian; Noh, Kyung-Min; Allis, C David

    2013-01-01

    Postmitotic neurons are subject to a vast array of environmental influences that require the nuclear integration of intracellular signaling events to promote a wide variety of neuroplastic states associated with synaptic function, circuit formation, and behavioral memory. Over the last decade, much attention has been paid to the roles of transcription and chromatin regulation in guiding fundamental aspects of neuronal function. A great deal of this work has centered on neurodevelopmental and adulthood plasticity, with increased focus in the areas of neuropharmacology and molecular psychiatry. Here, we attempt to provide a broad overview of chromatin regulation, as it relates to central nervous system (CNS) function, with specific emphasis on the modes of histone posttranslational modifications, chromatin remodeling, and histone variant exchange. Understanding the functions of chromatin in the context of the CNS will aid in the future development of pharmacological therapeutics aimed at alleviating devastating neurological disorders. PMID:22828751

  9. Delivery of AAV-IGF-1 to the CNS Extends Survival in ALS Mice Through Modification of Aberrant Glial Cell Activity

    PubMed Central

    Dodge, James C; Haidet, Amanda M; Yang, Wendy; Passini, Marco A; Hester, Mark; Clarke, Jennifer; Roskelley, Eric M; Treleaven, Christopher M; Rizo, Liza; Martin, Heather; Kim, Soo H; Kaspar, Rita; Taksir, Tatyana V; Griffiths, Denise A; Cheng, Seng H; Shihabuddin, Lamya S; Kaspar, Brian K

    2009-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. Recent work in rodent models of ALS has shown that insulin-like growth factor-1 (IGF-1) slows disease progression when delivered at disease onset. However, IGF-1’s mechanism of action along the neuromuscular axis remains unclear. In this study, symptomatic ALS mice received IGF-1 through stereotaxic injection of an IGF-1-expressing viral vector to the deep cerebellar nuclei (DCN), a region of the cerebellum with extensive brain stem and spinal cord connections. We found that delivery of IGF-1 to the central nervous system (CNS) reduced ALS neuropathology, improved muscle strength, and significantly extended life span in ALS mice. To explore the mechanism of action of IGF-1, we used a newly developed in vitro model of ALS. We demonstrate that IGF-1 is potently neuroprotective and attenuates glial cell–mediated release of tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Our results show that delivering IGF-1 to the CNS is sufficient to delay disease progression in a mouse model of familial ALS and demonstrate for the first time that IGF-1 attenuates the pathological activity of non-neuronal cells that contribute to disease progression. Our findings highlight an innovative approach for delivering IGF-1 to the CNS. PMID:18388910

  10. Origin, fate and dynamics of macrophages at CNS interfaces

    PubMed Central

    Goldmann, Tobias; Jordão, Marta Joana Costa; Wieghofer, Peter; Prutek, Fabiola; Hagemeyer, Nora; Frenzel, Kathrin; Staszewski, Ori; Kierdorf, Katrin; Amann, Lukas; Krueger, Martin; Locatelli, Giuseppe; Hochgarner, Hannah; Zeiser, Robert; Epelman, Slava; Geissmann, Frederic; Priller, Josef; Rossi, Fabio; Bechmann, Ingo; Kerschensteiner, Martin; Linnarsson, Sten; Jung, Steffen; Prinz, Marco

    2016-01-01

    Perivascular, meningeal and choroid plexus macrophages are non-parenchymal macrophages that mediate immune responses at brain boundaries. Although the origin of parenchymal microglia has recently been elucidated, much less is known about the precursors, the underlying transcriptional program and the dynamics of the other macrophages in the central nervous system (CNS). It has been assumed that they have a high turnover with blood-borne monocytes. However, large scale single-cell RNA-sequencing reveals a striking molecular overlap between perivascular macrophages and microglia but not monocytes. Using several fate mapping approaches and parabiosis we demonstrate that CNS macrophages arise from yolk sac precursors during embryonic development and remain a stable population. Notably, the generation of CNS macrophages relies on the transcription factor Pu.1 whereas myb, Batf3 and Nr4a1 are not required. Upon autoimmune inflammation, macrophages undergo extensive self-renewal by local proliferation. Our data provide challenging new insights into brains innate immune system. PMID:27135602

  11. Nanotechnology for CNS Delivery of Bio-Therapeutic Agents

    PubMed Central

    Shah, Lipa; Yadav, Sunita; Amiji, Mansoor

    2013-01-01

    The current therapeutic strategies are not efficient in treating disorders related to the central nervous system (CNS) and have only shown partial alleviation of symptoms, as opposed to, disease modifying effects. With change in population demographics, the incidence of CNS disorders, especially neurodegenerative diseases, is expected to rise dramatically. Current treatment regimens are associated with severe side-effects, especially given that most of these are chronic therapies and involve elderly population. In this review, we highlight the challenges and opportunities in delivering newer and more effective bio-therapeutic agents for the treatment of CNS disorders. Bio-therapeutics like proteins, peptides, monoclonal antibodies, growth factors, and nucleic acids are thought to have a profound effect on halting the progression of neurodegenerative disorders and also provide a unique function of restoring damaged cells. We provide a review of the nano-sized formulation-based drug delivery systems and alternate modes of delivery, like the intranasal route, to carry bio-therapeutics effectively to the brain. PMID:23894728

  12. Pharmacological approaches to CNS vasculitis: where are we at now?

    PubMed

    Pagnoux, Christian; Hajj-Ali, Rula A

    2016-01-01

    The diagnosis and treatment of central nervous system (CNS) vasculitis is extremely challenging. Several conditions can mimic CNS vasculitis and require totally different treatment. CNS vasculitis, once confirmed, may result from infections or systemic diseases that will warrant specific treatments, or, more rarely, be primary and isolated (PCNSV). Prospective trials to help determine the optimal treatment for PCNSV are lacking, but data from several cohorts have provided seminal data on its management. The consensus is to use glucocorticoids as first-line agents, combined with additional immunosuppressants for the most severe cases, mainly cyclophosphamide for induction, followed by less-toxic maintenance therapy with azathioprine, methotrexate, or mycophenolate mofetil. The recent identification of PCNSV subgroups and predictors of outcomes might help in deciding the adequate treatment for each patient, keeping in mind that these data are based on a small number of patients. Other agents and biologics can be considered for patients with relapsing and/or refractory disease, but evidence is limited. In practice, the diagnosis must be re-questioned in patients with PCNSV refractory to standard treatment, especially with diagnoses not based on pathology. PMID:26559201

  13. Cranial radiation necessary for CNS prophylaxis in pediatric NHL

    SciTech Connect

    Mandell, L.R.; Wollner, N.; Fuks, Z.

    1987-03-01

    The records of 95 consecutive children less than or equal to 21 years of age with previously untreated diffuse histology NHL registered in our protocols from 1978 to 1983 were reviewed. Seventy-nine patients were considered eligible for analysis. The histologic subtypes represented included lymphoblastic (LB) 37%; histiocytic (DHL) 29%; undifferentiated (DU) 19%; poorly differentiated (DPDL) 9%; and unclassified (UNHL) 6%. Distribution of the patients according to stage showed Stage I, 0%; Stage II, 11%; Stage III, 53%; Stage IV, 36%. Four different Memorial Hospital protocols for systemic chemotherapy were used (LSA2L2 73%; L10 9%; L17 10%; L17M 8%); however, the IT (intrathecal) chemotherapy was uniform (Methotrexate: 6.0-6.25 mg/M2 per treatment course) and was included in the induction, consolidation, and maintenance phases of all treatment protocols. Cranial radiation was included in the induction, consolidation, and maintenance phases of all treatment protocols. Cranial radiation was not included in the CNS prophylaxis program. The overall median time of follow-up was 43 months. The overall CNS relapse rate was 6.3%; however, the incidence of CNS lymphoma presenting as the first isolated site of relapse in patients in otherwise complete remission (minimum follow-up of 19 months with 97% of patients off treatment) was only 1/58 (1.7%). Our data suggest that IT chemotherapy when given in combination with modern aggressive systemic combination chemotherapy, and without cranial radiation appears to be a highly effective modality for CNS prophylaxis regardless of stage, histology, or bone marrow or mediastinal involvement. (Abstract Truncated)

  14. Hyperbaric oxygen preconditioning protects rats against CNS oxygen toxicity.

    PubMed

    Arieli, Yehuda; Kotler, Doron; Eynan, Mirit; Hochman, Ayala

    2014-06-15

    We examined the hypothesis that repeated exposure to non-convulsive hyperbaric oxygen (HBO) as preconditioning provides protection against central nervous system oxygen toxicity (CNS-OT). Four groups of rats were used in the study. Rats in the control and the negative control (Ctl-) groups were kept in normobaric air. Two groups of rats were preconditioned to non-convulsive HBO at 202 kPa for 1h once every other day for a total of three sessions. Twenty-four hours after preconditioning, one of the preconditioned groups and the control rats were exposed to convulsive HBO at 608 kPa, and latency to CNS-OT was measured. Ctl- rats and the second preconditioned group (PrC-) were not subjected to convulsive HBO exposure. Tissues harvested from the hippocampus and frontal cortex were evaluated for enzymatic activity and nitrotyrosine levels. In the group exposed to convulsive oxygen at 608 kPa, latency to CNS-OT increased from 12.8 to 22.4 min following preconditioning. A significant decrease in the activity of glutathione reductase and glucose-6-phosphate dehydrogenase, and a significant increase in glutathione peroxidase activity, was observed in the hippocampus of preconditioned rats. Nitrotyrosine levels were significantly lower in the preconditioned animals, the highest level being observed in the control rats. In the cortex of the preconditioned rats, a significant increase was observed in glutathione S-transferase and glutathione peroxidase activity. Repeated exposure to non-convulsive HBO provides protection against CNS-OT. The protective mechanism involves alterations in the enzymatic activity of the antioxidant system and lower levels of peroxynitrite, mainly in the hippocampus.

  15. Observations at the CNS-PNS Border of Ventral Roots Connected to a Neuroma.

    PubMed

    Remahl, Sten; Angeria, Maria; Remahl, Ingela Nilsson; Carlstedt, Thomas; Risling, Mårten

    2010-01-01

    Previous studies have shown that numerous sprouts originating from a neuroma, after nerve injury in neonatal animals, can invade spinal nerve roots. However, no study with a focus on how such sprouts behave when they reach the border between the central and peripheral nervous system (CNS-PNS border) has been published. In this study we have in detail examined the CNS-PNS border of ventral roots in kittens with light and electron microscopy after early postnatal sciatic nerve resection. A transient ingrowth of substance P positive axons was observed into the CNS, but no spouts remained 6 weeks after the injury. Using serial sections and electron microscopy it was possible to identify small bundles of unmyelinated axons that penetrated from the root fascicles for a short distance into the CNS. These axons ended blindly, sometimes with a growth cone-like terminal swelling filled with vesicles. The axon bundles were accompanied by p75 positive cells in both the root fascicles and the pia mater, but not in the CNS. It may thus be suggested that neurotrophin presenting p75 positive cells could facilitate axonal growth into the pia mater and that the lack of such cells in the CNS compartment might contribute to the failure of growth into the CNS. A maldevelopment of myelin sheaths at the CNS-PNS border of motor axons was observed and it seems possible that this could have consequences for the propagation of action potential across this region after neonatal nerve injury. Thus, in this first detailed study on the behavior of recurrent sprouts at the CNS-PNS border.

  16. Intracerebral Mycobacterium bovis bacilli Calmette-Guerin infection-induced immune responses in the CNS 1

    PubMed Central

    Lee, JangEun; Ling, Changying; Kosmalski, Michelle M.; Hulseberg, Paul; Schreiber, Heidi A.; Sandor, Matyas; Fabry, Zsuzsanna

    2010-01-01

    To study whether cerebral mycobacterial infection induces granuloma and protective immunity similar to systemic infection, we intracerebrally infected mice with Mycobacterium bovis bacilli Calmette-Guerin. Granuloma and IFN-γ+CD4+ T cell responses are induced in the central nervous system (CNS) similar to periphery, but the presence of IFN-γIL-17 double-positive CD4+ T cells is unique to the CNS. The major CNS source of TNF-α is microglia, with modest production by CD4+ T cells and macrophage. Protective immunity is accompanied by accumulation of Foxp3+CD4+ T cells and PD-L2+ dendritic cells, suggesting that both inflammatory and anti-inflammatory responses develop in the CNS following mycobacterial infection. PMID:19535154

  17. Central Nervous System Lymphoma in a 3-Year-Old Male Suffering from a Severe Juvenile Xanthogranuloma – the Usefulness of Perfusion Weighted Imaging and Diffusion Weighted Imaging in the Diagnostics of Pediatric Brain Tumors

    PubMed Central

    Neska-Matuszewska, Małgorzata; Zimny, Anna; Kałwak, Krzysztof; Sąsiadek, Marek J.

    2015-01-01

    Summary Background Primary Central Nervous System Lymphomas (PCNSLs) are rare, malignant brain tumors derived from lymphocytes B. Juvenile xanthogranuloma (JXG) is a non-Langerhans histiocytic cell disorder in children which mostly affects the skin. Rare fatalities have been reported in extracutaneous manifestation. Brain magnetic resonance imaging (MRI) is a method of choice in the diagnostics of all neoplastic CNS lesions. Perfusion weighted imaging (PWI) and diffusion weighted imaging (DWI) allow for more detailed analysis of brain tumors including the rate of neoangiogenesis and cellularity. We presented a pediatric patient suffering from JXG with CNS involvement and the role of brain MRI including DWI and PWI in the evaluation of brain focal lesions. Case Report A 3-year-old male with severe JXG underwent two stem cell transplantations with a development of neurological complications. The patient underwent emergency CT and MRI which revealed a non-specific enhancing focal brain lesion. In DWI it showed restricted diffusion while PWI revealed low values of rCBV and the signal intensity curve returning above the baseline level. Advanced MRI techniques such as DWI and PWI suggested PCNSL. Stereotactic biopsy confirmed PCNSL due to Ebstein-Barr virus reactivation. Conclusions The use of advanced MRI sequences is important to differentiate brain lesions in pediatric patients. The use of PWI and DWI facilitated the diagnosis of PCNSL. It is important to remember that PCNSLs show a very typical pattern of changes visualized with MRI such as: usually strong homogenous enhancement, restricted diffusion and low perfusion. PMID:25624957

  18. Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL.

    PubMed

    Savage, Kerry J; Slack, Graham W; Mottok, Anja; Sehn, Laurie H; Villa, Diego; Kansara, Roopesh; Kridel, Robert; Steidl, Christian; Ennishi, Daisuke; Tan, King L; Ben-Neriah, Susana; Johnson, Nathalie A; Connors, Joseph M; Farinha, Pedro; Scott, David W; Gascoyne, Randy D

    2016-05-01

    Dual expression of MYC and BCL2 by immunohistochemistry (IHC) is associated with poor outcome in diffuse large B-cell lymphoma (DLBCL). Dual translocation of MYC and BCL2, so-called "double-hit lymphoma," has been associated with a high risk of central nervous system (CNS) relapse; however, the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown. Pretreatment formalin-fixed paraffin-embedded DLBCL biopsies derived from patients subsequently treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were assembled on tissue microarrays from 2 studies and were evaluated for expression of MYC and BCL2 by IHC. In addition, cell of origin was determined by IHC and the Lymph2Cx gene expression assay in a subset of patients. We identified 428 patients who met the inclusion criteria. By the recently described CNS risk score (CNS-International Prognostic Index [CNS-IPI]), 34% were low risk (0 to 1), 45% were intermediate risk (2 to 3), and 21% were high risk (4 or greater). With a median follow-up of 6.8 years, the risk of CNS relapse was higher in dual expressers compared with non-dual expressers (2-year risk, 9.7% vs 2.2%; P = .001). Patients with activated B-cell or non-germinal center B-cell type DLBCL also had an increased risk of CNS relapse. However, in multivariate analysis, only dual expresser status and CNS-IPI were associated with CNS relapse. Dual expresser MYC(+) BCL2(+) DLBCL defines a group at high risk of CNS relapse, independent of CNS-IPI score and cell of origin. Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies.

  19. Systemic Inflammation in Cachexia – Is Tumor Cytokine Expression Profile the Culprit?

    PubMed Central

    de Matos-Neto, Emidio M.; Lima, Joanna D. C. C.; de Pereira, Welbert O.; Figuerêdo, Raquel G.; Riccardi, Daniela M. dos R.; Radloff, Katrin; das Neves, Rodrigo X.; Camargo, Rodolfo G.; Maximiano, Linda F.; Tokeshi, Flávio; Otoch, José P.; Goldszmid, Romina; Câmara, Niels O. S.; Trinchieri, Giorgio; de Alcântara, Paulo S. M.; Seelaender, Marília

    2015-01-01

    Cachexia affects about 80% of gastrointestinal cancer patients. This multifactorial syndrome resulting in involuntary and continuous weight loss is accompanied by systemic inflammation and immune cell infiltration in various tissues. Understanding the interactions among tumor, immune cells, and peripheral tissues could help attenuating systemic inflammation. Therefore, we investigated inflammation in the subcutaneous adipose tissue and in the tumor, in weight stable and cachectic cancer patients with same diagnosis, in order to establish correlations between tumor microenvironment and secretory pattern with adipose tissue and systemic inflammation. Infiltrating monocyte phenotypes of subcutaneous and tumor vascular-stromal fraction were identified by flow cytometry. Gene and protein expression of inflammatory and chemotactic factors was measured with qRT-PCR and Multiplex Magpix® system, respectively. Subcutaneous vascular-stromal fraction exhibited no differences in regard to macrophage subtypes, while in the tumor, the percentage of M2 macrophages was decreased in the cachectic patients, in comparison to weight-stable counterparts. CCL3, CCL4, and IL-1β expression was higher in the adipose tissue and tumor tissue in the cachectic group. In both tissues, chemotactic factors were positively correlated with IL-1β. Furthermore, positive correlations were found for the content of chemoattractants and cytokines in the tumor and adipose tissue. The results strongly suggest that the crosstalk between the tumor and peripheral tissues is more pronounced in cachectic patients, compared to weight-stable patients with the same tumor diagnosis. PMID:26732354

  20. Roles for the sympathetic nervous system, renal nerves, and CNS melanocortin-4 receptor in the elevated blood pressure in hyperandrogenemic female rats

    PubMed Central

    Maranon, Rodrigo; Lima, Roberta; Spradley, Frank T.; do Carmo, Jussara M.; Zhang, Howei; Smith, Andrew D.; Bui, Elizabeth; Thomas, R. Lucas; Moulana, Mohadetheh; Hall, John E.; Granger, Joey P.

    2015-01-01

    Women with polycystic ovary syndrome (PCOS) have hyperandrogenemia and increased prevalence of risk factors for cardiovascular disease, including elevated blood pressure. We recently characterized a hyperandrogenemic female rat (HAF) model of PCOS [chronic dihydrotestosterone (DHT) beginning at 4 wk of age] that exhibits similar characteristics as women with PCOS. In the present studies we tested the hypotheses that the elevated blood pressure in HAF rats is mediated in part by sympathetic activation, renal nerves, and melanocortin-4 receptor (MC4R) activation. Adrenergic blockade with terazosin and propranolol or renal denervation reduced mean arterial pressure (MAP by telemetry) in HAF rats but not controls. Hypothalamic MC4R expression was higher in HAF rats than controls, and central nervous system MC4R antagonism with SHU-9119 (1 nmol/h icv) reduced MAP in HAF rats. Taking a genetic approach, MC4R null and wild-type (WT) female rats were treated with DHT or placebo from 5 to 16 wk of age. MC4R null rats were obese and had higher MAP than WT control rats, and while DHT increased MAP in WT controls, DHT failed to further increase MAP in MC4R null rats. These data suggest that increases in MAP with chronic hyperandrogenemia in female rats are due, in part, to activation of the sympathetic nervous system, renal nerves, and MC4R and may provide novel insights into the mechanisms responsible for hypertension in women with hyperandrogenemia such as PCOS. PMID:25695289

  1. Prediction of methotrexate CNS distribution in different species - influence of disease conditions.

    PubMed

    Westerhout, Joost; van den Berg, Dirk-Jan; Hartman, Robin; Danhof, Meindert; de Lange, Elizabeth C M

    2014-06-16

    Children and adults with malignant diseases have a high risk of prevalence of the tumor in the central nervous system (CNS). As prophylaxis treatment methotrexate is often given. In order to monitor methotrexate exposure in the CNS, cerebrospinal fluid (CSF) concentrations are often measured. However, the question is in how far we can rely on CSF concentrations of methotrexate as appropriate surrogate for brain target site concentrations, especially under disease conditions. In this study, we have investigated the spatial distribution of unbound methotrexate in healthy rat brain by parallel microdialysis, with or without inhibition of Mrp/Oat/Oatp-mediated active transport processes by a co-administration of probenecid. Specifically, we have focused on the relationship between brain extracellular fluid (brainECF) and CSF concentrations. The data were used to develop a systems-based pharmacokinetic (SBPK) brain distribution model for methotrexate. This model was subsequently applied on literature data on methotrexate brain distribution in other healthy and diseased rats (brainECF), healthy dogs (CSF) and diseased children (CSF) and adults (brainECF and CSF). Important differences between brainECF and CSF kinetics were found, but we have found that inhibition of Mrp/Oat/Oatp-mediated active transport processes does not significantly influence the relationship between brainECF and CSF fluid methotrexate concentrations. It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, combined with advanced mathematical modeling is a most valid approach to develop SBPK models that allow for revealing the mechanisms underlying the relationship between brainECF and CSF concentrations in health and disease.

  2. A requirement of serotonergic p38α mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors

    PubMed Central

    Baganz, N L; Lindler, K M; Zhu, C B; Smith, J T; Robson, M J; Iwamoto, H; Deneris, E S; Hewlett, W A; Blakely, R D

    2015-01-01

    Alterations in central serotonin (5-hydroxytryptamine, 5-HT) neurotransmission and peripheral immune activation have been linked to multiple neuropsychiatric disorders, including depression, schizophrenia and autism. The antidepressant-sensitive 5-HT transporter (SERT, SLC6A4), a critical determinant of synaptic 5-HT inactivation, can be regulated by pro-inflammatory cytokine signaling. Systemic innate immune system activation via intraperitoneal lipopolysaccharide (LPS) injection rapidly elevates brain SERT activity and 5-HT clearance. Moreover, the pro-inflammatory cytokine interleukin (IL)-1β rapidly stimulates SERT activity in raphe nerve terminal preparations ex vivo, effects that are attenuated by pharmacological p38 MAPK inhibition. To establish a role of serotonergic p38α MAPK signaling in LPS/IL-1β-induced SERT regulation and attendant behavioral responses, we pursued studies in mice that afford conditional elimination of p38α MAPK in 5-HT neurons (p38α5HT−). We found p38α5HT− and control (p38α5HT+) littermates to be indistinguishable in viability and growth and to express equivalent levels of SERT protein and synaptosomal 5-HT transport activity. Consistent with pharmacological studies, however, IL-1β fails to increase SERT activity in midbrain synaptosomes prepared from p38α5HT− animals. Moreover, although LPS elevated plasma corticosterone and central/peripheral pro-inflammatory cytokines in p38α5HT− animals, elevations in midbrain SERT activity were absent nor were changes in depressive and anxiety-like behaviors observed. Our studies support an obligate role of p38α MAPK signaling in 5-HT neurons for the translation of immune activation to SERT regulation and 5-HT-modulated behaviors. PMID:26529424

  3. Maternal and Birth Characteristics and Childhood Embryonal Solid Tumors: A Population-Based Report from Brazil

    PubMed Central

    de Paula Silva, Neimar; de Souza Reis, Rejane; Garcia Cunha, Rafael; Pinto Oliveira, Júlio Fernando; Santos, Marceli de Oliveira; Pombo-de-Oliveira, Maria S.; de Camargo, Beatriz

    2016-01-01

    Background Several maternal and birth characteristics have been reported to be associated with an increased risk of many childhood cancers. Our goal was to evaluate the risk of childhood embryonal solid tumors in relation to pre- and perinatal characteristics. Methods A case-cohort study was performed using two population-based datasets, which were linked through R software. Tumors were classified as central nervous system (CNS) or non-CNS-embryonal (retinoblastoma, neuroblastoma, renal tumors, germ cell tumors, hepatoblastoma and soft tissue sarcoma). Children aged <6 years were selected. Adjustments were made for potential confounders. Odds ratios (OR) with 95% confidence intervals (CI) were computed by unconditional logistic regression analysis using SPSS. Results Males, high maternal education level, and birth anomalies were independent risk factors. Among children diagnosed older than 24 months of age, cesarean section (CS) was a significant risk factor. Five-minute Apgar ≤8 was an independent risk factor for renal tumors. A decreasing risk with increasing birth order was observed for all tumor types except for retinoblastoma. Among children with neuroblastoma, the risk decreased with increasing birth order (OR = 0.82 (95% CI 0.67–1.01)). Children delivered by CS had a marginally significantly increased OR for all tumors except retinoblastoma. High maternal education level showed a significant increase in the odds for all tumors together, CNS tumors, and neuroblastoma. Conclusion This evidence suggests that male gender, high maternal education level, and birth anomalies are risk factors for childhood tumors irrespective of the age at diagnosis. Cesarean section, birth order, and 5-minute Apgar score were risk factors for some tumor subtypes. PMID:27768709

  4. Glibenclamide for the Treatment of Acute CNS Injury

    PubMed Central

    Kurland, David B.; Tosun, Cigdem; Pampori, Adam; Karimy, Jason K.; Caffes, Nicholas M.; Gerzanich, Volodymyr; Simard, J. Marc

    2013-01-01

    First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options. PMID:24275850

  5. Changes in the endocannabinoid signaling system in CNS structures of TDP-43 transgenic mice: relevance for a neuroprotective therapy in TDP-43-related disorders.

    PubMed

    Espejo-Porras, Francisco; Piscitelli, Fabiana; Verde, Roberta; Ramos, José A; Di Marzo, Vincenzo; de Lago, Eva; Fernández-Ruiz, Javier

    2015-06-01

    Because of their neuroprotective properties, cannabinoids are being investigated in neurodegenerative disorders, mainly in preclinical studies. These disorders also include amyotrophic lateral sclerosis (ALS), a degenerative disease produced by the damage of the upper and lower motor neurons leading to muscle denervation, atrophy and paralysis. The studies with cannabinoids in ALS have been conducted exclusively in a transgenic mouse model bearing mutated forms of human superoxide dismutase-1, the first gene that was identified in relation with ALS. The present study represents the first attempt to investigate the endocannabinoid system in an alternative model, the transgenic mouse model of TAR-DNA binding protein-43 (TDP-43), a protein related to ALS and also to frontotemporal dementia. We used these mice for behavioral and histological characterization at an early symptomatic phase (70-80 days of age) and at a post-symptomatic stage (100-110 days of age). TDP-43 transgenic mice exhibited a worsened rotarod performance at both disease stages. This was accompanied by a loss of motor neurons in the spinal cord (measured by Nissl staining) and by reactive microgliosis (measured by Iba-1 immunostaining) at the post-symptomatic stage. We also detected elevated levels of the CB2 receptor (measured by qRT-PCR and western blotting) in the spinal cord of these animals. Double-staining studies confirmed that this up-regulation occurs in microglial cells in the post-symptomatic stage. Some trends towards an increase were noted also for the levels of endocannabinoids, which in part correlate with a small reduction of FAAH. Some of these parameters were also analyzed in the cerebral cortex of TDP-43 transgenic mice, but we did not observe any significant change, in agreement with the absence of anomalies in cognitive tests. In conclusion, our data support the idea that the endocannabinoid signaling system, in particular the CB2 receptor, may serve for the development of a

  6. Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

    ClinicalTrials.gov

    2016-11-04

    Atypical Carcinoid Tumor; Foregut Carcinoid Tumor; Hindgut Carcinoid Tumor; Lung Carcinoid Tumor; Metastatic Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Midgut Carcinoid Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Regional Digestive System Neuroendocrine Tumor G1

  7. Causation of nervous system tumors in children: insights from traditional and genetically engineered animal models.

    PubMed

    Rice, Jerry M

    2004-09-01

    Pediatric neurogenic tumors include primitive neuroectodermal tumors (PNETs), especially medulloblastoma; ependymomas and choroid plexus papillomas; astrocytomas; retinoblastoma; and sympathetic neuroblastoma. Meningiomas and nerve sheath tumors, although uncommon in childhood, are also significant because they can result from exposures of children to ionizing radiation. Specific chromosomal loci and specific genes are related to each of these tumor types. Virtually all these genes appear to act as tumor suppressor genes, which are inactivated in tumor cells by mutations or by chromosomal loss. In genetically engineered mice, some genes that are clearly associated with specific human tumors (e.g., RB1 in retinoblastoma and NF2 in meningiomas and schwannomas) have no such effect. Other genetic constructs in mice involving the genes p53, ptc1, and Nf1 have produced tumors remarkably similar to some of the human pediatric neoplasms. Some of these tumors become clinically apparent after only a few weeks, while the mice are still juveniles, especially when two or more tumor suppressor genes are inactivated in the same genetic construct. Conversely, at least one genetic pathway in rodents involving point mutation in the coding region of a transforming gene (neu in malignant schwannomas) does not appear to operate in any human tumors. The nervous system is markedly susceptible to experimental carcinogenesis during early life in rodents, dogs, primates, and other nonhuman species, and there is no obvious reason why this generalization should not also apply to humans. However, except for therapeutic ionizing radiation, no physical, chemical, or biological cause of human pediatric nervous system tumors is known. The failure of experimental transplacental carcinogenesis to mirror human pediatric experience more closely may reflect the need for multiple mutational events in target cells, and for experimental carcinogens that are capable of causing the full spectrum of

  8. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage

    PubMed Central

    Crane, Genevieve M.; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E.; Burger, Peter C.; Ambinder, Richard F.; Swinnen, Lode J.; Borowitz, Michael J.; Duffield, Amy S.

    2015-01-01

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data file. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011–2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  9. MAG, myelin and overcoming growth inhibition in the CNS

    PubMed Central

    McKerracher, Lisa; Rosen, Kenneth M.

    2015-01-01

    While neurons in the central nervous system (CNS) have the capacity to regenerate their axons after injury, they fail to do so, in part because regeneration is limited by growth inhibitory proteins present in CNS myelin. Myelin-associated glycoprotein (MAG) was the first myelin-derived growth inhibitory protein identified, and its inhibitory activity was initially elucidated in 1994 independently by the Filbin lab and the McKerracher lab using cell-based and biochemical techniques, respectively. Since that time we have gained a wealth of knowledge concerning the numerous growth inhibitory proteins that are present in myelin, and we also have dissected many of the neuronal signaling pathways that act as stop signs for axon regeneration. Here we give an overview of the early research efforts that led to the identification of myelin-derived growth inhibitory proteins, and the importance of this family of proteins for understanding neurotrauma and CNS diseases. We further provide an update on how this knowledge has been translated towards current clinical studies in regenerative medicine. PMID:26441514

  10. Enhancing Psychosocial Outcomes for Young Adult Childhood CNS Cancer Survivors: Importance of Addressing Vocational Identity and Community Integration

    ERIC Educational Resources Information Center

    Strauser, David R.; Wagner, Stacia; Wong, Alex W. K.

    2012-01-01

    The purpose of this study was to examine the relationship between vocational identity, community integration, positive and negative affect, and satisfaction with life in a group of young adult central nervous system (CNS) cancer survivors. Participants in this study included 45 young adult CNS cancer survivors who ranged in age from 18 to 30 years…

  11. Non-Viral, Lipid-Mediated DNA and mRNA Gene Therapy of the Central Nervous System (CNS): Chemical-Based Transfection.

    PubMed

    Hecker, James G

    2016-01-01

    Appropriate gene delivery systems are essential for successful gene therapy in clinical medicine. Cationic lipid-mediated delivery is an alternative to viral vector-mediated gene delivery. Lipid-mediated delivery of DNA or mRNA is usually more rapid than viral-mediated delivery, offers a larger payload, and has a nearly zero risk of incorporation. Lipid-mediated delivery of DNA or RNA is therefore preferable to viral DNA delivery in those clinical applications that do not require long-term expression for chronic conditions. Delivery of RNA may be preferable to non-viral DNA delivery in some clinical applications, because transit across the nuclear membrane is not necessary and onset of expression with RNA is therefore even faster than with DNA, although both are faster than most viral vectors. Here, we describe techniques for cationic lipid-mediated delivery of nucleic acids encoding reporter genes in a variety of cell lines. We describe optimized formulations and transfection procedures that we previously assessed by bioluminescence and flow cytometry. RNA transfection demonstrates increased efficiency relative to DNA transfection in non-dividing cells. Delivery of mRNA results in onset of expression within 1 h after transfection and a peak in expression 5-7 h after transfection. Duration of expression in eukaryotic cells after mRNA transcript delivery depends on multiple factors, including transcript stability, protein turnover, and cell type. Delivery of DNA results in onset of expression within 5 h after transfection, a peak in expression 24-48 h after transfection, and a return to baseline that can be as long as several weeks after transfection. In vitro results are consistent with our in vivo delivery results, techniques for which are described as well. RNA delivery is suitable for short-term transient gene expression due to its rapid onset, short duration of expression and greater efficiency, particularly in non-dividing cells, while the longer duration and

  12. Emerging insights into barriers to effective brain tumor therapeutics.

    PubMed

    Woodworth, Graeme F; Dunn, Gavin P; Nance, Elizabeth A; Hanes, Justin; Brem, Henry

    2014-01-01

    There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM. PMID:25101239

  13. Emerging Insights into Barriers to Effective Brain Tumor Therapeutics

    PubMed Central

    Woodworth, Graeme F.; Dunn, Gavin P.; Nance, Elizabeth A.; Hanes, Justin; Brem, Henry

    2014-01-01

    There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM. PMID:25101239

  14. A Tumor-specific MicroRNA Recognition System Facilitates the Accurate Targeting to Tumor Cells by Magnetic Nanoparticles

    PubMed Central

    Yu, Yingting; Yao, Yi; Yan, Hao; Wang, Rui; Zhang, Zhenming; Sun, Xiaodan; Zhao, Lingyun; Ao, Xiang; Xie, Zhen; Wu, Qiong

    2016-01-01

    Targeted therapy for cancer is a research area of great interest, and magnetic nanoparticles (MNPs) show great potential as targeted carriers for therapeutics. One important class of cancer biomarkers is microRNAs (miRNAs), which play a significant role in tumor initiation and progression. In this study, a cascade recognition system containing multiple plasmids, including a Tet activator, a lacI repressor gene driven by the TetOn promoter, and a reporter gene repressed by the lacI repressor and influenced by multiple endogenous miRNAs, was used to recognize cells that display miRNA signals that are characteristic of cancer. For this purpose, three types of signal miRNAs with high proliferation and metastasis abilities were chosen (miR-21, miR-145, and miR-9). The response of this system to the human breast cancer MCF-7 cell line was 3.2-fold higher than that to the human breast epithelial HBL100 cell line and almost 7.5-fold higher than that to human embryonic kidney HEK293T cells. In combination with polyethyleneimine-modified MNPs, this recognition system targeted the tumor location in situ in an animal model, and an ~42% repression of tumor growth was achieved. Our study provides a new combination of magnetic nanocarrier and gene therapy based on miRNAs that are active in vivo, which has potential for use in future cancer therapies. PMID:27138178

  15. From fish to man: understanding endogenous remyelination in CNS demyelinating diseases

    PubMed Central

    Dubois-Dalcq, Monique; Williams, Anna; Stadelmann, Christine; Stankoff, Bruno; Zalc, Bernard; Lubetzki, Catherine

    2008-01-01

    In the central nervous system (CNS) of man, evolutionary pressure has preserved some capability for remyelination while axonal regeneration is very limited. In contrast, two efficient programmes of regeneration exist in the adult fish CNS, neurite regrowth and remyelination. The rapidity of CNS remyelination is critical since it not only restores fast conduction of nerve impulses but also maintains axon integrity. If myelin repair fails, axons degenerate, leading to increased disability. In the human CNS demyelinating disease Multiple Sclerosis (MS), remyelination often takes place in the midst of inflammation. Here, we discuss recent studies that address the innate repair capabilities of the axon-glia unit from fish to man. We propose that expansion of this research field will help find ways to maintain or enhance spontaneous remyelination in man. PMID:18474520

  16. Compartmentalization, Viral Evolution, and Viral Latency of HIV in the CNS.

    PubMed

    Bednar, Maria M; Sturdevant, Christa Buckheit; Tompkins, Lauren A; Arrildt, Kathryn Twigg; Dukhovlinova, Elena; Kincer, Laura P; Swanstrom, Ronald

    2015-06-01

    Human immunodeficiency virus type 1 (HIV-1) infection occurs throughout the body and can have dramatic physical effects, such as neurocognitive impairment in the central nervous system (CNS). Furthermore, examining the virus that resides in the CNS is challenging due to its location and can only be done using samples collected either at autopsy, indirectly form the cerebral spinal fluid (CSF), or through the use of animal models. The unique milieu of the CNS fosters viral compartmentalization as well as evolution of viral sequences, allowing for new cell types, such as macrophages and microglia, to be infected. Treatment must also cross the blood-brain barrier adding additional obstacles in eliminating viral populations in the CNS. These long-lived infected cell types and treatment barriers may affect functional cure strategies in people on highly active antiretroviral therapy (HAART). PMID:25914150

  17. SWIFT-MRI imaging and quantitative assessment of IONPs in murine tumors following intra-tumor and systemic delivery

    NASA Astrophysics Data System (ADS)

    Reeves, Russell; Petryk, Alicia A.; Kastner, Elliot J.; Zhang, Jinjin; Ring, Hattie; Garwood, Michael; Hoopes, P. Jack

    2015-03-01

    Although preliminary clinical trials are ongoing, successful the use of iron-oxide magnetic nanoparticles (IONP) for heatbased cancer treatments will depend on advancements in: 1) nanoparticle platforms, 2) delivery of a safe and effective alternating magnetic field (AMF) to the tumor, and 3) development of non-invasive, spatially accurate IONP imaging and quantification technique. This imaging technique must be able to assess tumor and normal tissue anatomy as well as IONP levels and biodistribution. Conventional CT imaging is capable of detecting and quantifying IONPs at tissue levels above 10 mg/gram; unfortunately this level is not clinically achievable in most situations. Conventional MRI is capable of imaging IONPs at tissue levels of 0.05 mg/gm or less, however this level is considered to be below the therapeutic threshold. We present here preliminary in vivo data demonstrating the ability of a novel MRI technique, Sweep Imaging with Fourier Transformation (SWIFT), to accurately image and quantify IONPs in tumor tissue in the therapeutic concentration range (0.1-1.0 mg/gm tissue). This ultra-short, T2 MRI method provides a positive Fe contrast enhancement with a reduced signal to noise ratio. Additional IONP signal enhancement techniques such as inversion recovery spectroscopy and variable flip angle (VFA) are also being studied for potential optimization of SWIFT IONP imaging. Our study demonstrates the use of SWIFT to assess IONP levels and biodistribution, in murine flank tumors, following intra-tumoral and systemic IONP administration. ICP-MS and quantitative histological techniques are used to validate the accuracy and sensitivity of SWIFT-based IONP imaging and quantification.

  18. TLR5 signaling, commensal microbiota and systemic tumor promoting inflammation: the three parcae of malignant progression

    PubMed Central

    Rutkowski, Melanie R; Conejo-Garcia, Jose R

    2015-01-01

    We have reported that TLR5-mediated recognition of commensal microbiota modulates systemic tumor-promoting inflammation and malignant progression of tumors at distal locations. Approximately 7–10% of the general population harbors a deleterious single nucleotide polymorphism in TLR5, implicating a novel role for genetic variation during the initiation and progression of cancer. PMID:26405577

  19. Neurocognitive Outcomes and School Performance in Solid Tumor Cancer Survivors Lacking Therapy to the Central Nervous System

    PubMed Central

    Mohrmann, Caroline; Henry, Jennifer; Hauff, Marnie; Hayashi, Robert J.

    2015-01-01

    School performance in patients who have received therapy for childhood cancers has been studied in depth. Risk factors have historically included cranial radiation, intrathecal chemotherapy, and high doses of chemotherapy, including methotrexate and cytarabine. Leukemia and brain tumor survivors who receive such therapy have been the primary focus of this area of investigation. Extracranial solid tumor cancer patients lacking such risk factors have historically been expected to have normal school performance. We examined the medical records of 58 young pediatric extracranial solid tumor patients who lacked CNS-directed therapy or other known risk factors for cognitive impairment to evaluate the incidence of reported difficulties or abnormalities in neuropsychological testing. Thirty-one percent of patients were found to have at least one reported difficulty or abnormality. Of note, 34% of patients with Wilms tumor possessed difficulties compared to 23% of patients with other extracranial solid tumors. Extracranial solid tumor cancer survivors without known risk factors for school performance difficulties appear to have a higher incidence of problems than expected. PMID:25867598

  20. CNS demyelination in fibrodysplasia ossificans progressiva.

    PubMed

    Kan, Lixin; Kitterman, Joseph A; Procissi, Daniele; Chakkalakal, Salin; Peng, Chian-Yu; McGuire, Tammy L; Goldsby, Robert E; Pignolo, Robert J; Shore, Eileen M; Kaplan, Frederick S; Kessler, John A

    2012-12-01

    Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of progressive heterotopic ossification (HO) caused by a recurrent activating mutation of ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. FOP is characterized by progressive HO, which is associated with inflammation in the setting of dysregulated BMP signaling, however, a variety of atypical neurologic symptoms are also reported by FOP patients. The main objective of this study is to investigate the potential underlying mechanism that is responsible for the observed atypical neurologic symptoms. We evaluated two mouse models of dysregulated BMP signaling for potential CNS pathology through non-invasive magnetic resonance imaging (MRI) studies and histological and immunohistochemical approaches. In one model, BMP4 is over-expressed under the control of the neuron-specific enolase promoter; the second model is a knock-in of a recurrent FOP mutation of ACVR1/ALK2. We also retrospectively examined MRI scans of four FOP patients. We consistently observed demyelinated lesions and focal inflammatory changes of the CNS in both mouse models but not in wild-type controls, and also found CNS white matter lesions in each of the four FOP patients examined. These findings suggest that dysregulated BMP signaling disturbs normal homeostasis of target tissues, including CNS where focal demyelination may manifest as the neurologic symptoms frequently observed in FOP.

  1. Grading system for blood vessel tumor emboli of invasive ductal carcinoma of the breast.

    PubMed

    Sugiyama, Michiko; Hasebe, Takahiro; Shimada, Hiroko; Takeuchi, Hideki; Shimizu, Kyoko; Shimizu, Michio; Yasuda, Masanori; Ueda, Shigeto; Shigekawa, Takashi; Osaki, Akihiko; Saeki, Toshiaki

    2015-06-01

    We previously reported that the number of mitotic and apoptotic figures in tumor cells in blood vessel tumor emboli had the greatest significant power for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. The purpose of the present study was to devise a grading system for blood vessel tumor emboli based on the mitotic and apoptotic figures of tumor cells in blood vessel tumor emboli, enabling accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 263 invasive ductal carcinomas into the following 3 grades according to the numbers of mitotic and apoptotic figures in tumor cells located in blood vessels within 1 high-power field: grade 0, no blood vessel invasion; grade 1, absence of mitotic figures and presence of any number of apoptotic figures, or 1 mitotic figure and 0 to 2 apoptotic figures; and grade 2, 1 mitotic figure and 3 or more apoptotic figures, or 2 or more mitotic figures and 1 or more apoptotic figures. Multivariate analyses with well-known prognostic factors demonstrated that grade 2 blood vessel tumor emboli significantly increased the hazard ratios for tumor recurrence independent of the nodal status, pathological TNM stage, hormone receptor status, or HER2 status. The presently reported grading system for blood vessel tumor emboli is the strongest histologic factor for accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast.

  2. CNS-expressed cathepsin D prevents lymphopenia in a murine model of congenital neuronal ceroid lipofuscinosis.

    PubMed

    Shevtsova, Zinayida; Garrido, Manuel; Weishaupt, Jochen; Saftig, Paul; Bähr, Mathias; Lühder, Fred; Kügler, Sebastian

    2010-07-01

    Deficiency in Cathepsin D (CtsD), the major cellular lysosomal aspartic proteinase, causes the congenital form of neuronal ceroid lipofuscinoses (NCLs). CtsD-deficient mice show severe visceral lesions like lymphopenia in addition to their central nervous system (CNS) phenotype of ceroid accumulation, microglia activation, and seizures. Here we demonstrate that re-expression of CtsD within the CNS but not re-expression of CtsD in visceral organs prevented both central and visceral pathologies of CtsD(-/-) mice. Our results suggest that CtsD was substantially secreted from CNS neurons and drained from CNS to periphery via lymphatic routes. Through this drainage, CNS-expressed CtsD acts as an important modulator of immune system maintenance and peripheral tissue homeostasis. These effects depended on enzymatic activity and not on proposed functions of CtsD as an extracellular ligand. Our results furthermore demonstrate that the prominent accumulation of ceroid/lipofuscin and activation of microglia in brains of CtsD(-/-) are not lethal factors but can be tolerated by the rodent CNS. PMID:20489146

  3. Rapid immunohistochemistry based on alternating current electric field for intraoperative diagnosis of brain tumors.

    PubMed

    Tanino, Mishie; Sasajima, Toshio; Nanjo, Hiroshi; Akesaka, Shiori; Kagaya, Masami; Kimura, Taichi; Ishida, Yusuke; Oda, Masaya; Takahashi, Masataka; Sugawara, Taku; Yoshioka, Toshiaki; Nishihara, Hiroshi; Akagami, Yoichi; Goto, Akiteru; Minamiya, Yoshihiro; Tanaka, Shinya

    2015-01-01

    Rapid immunohistochemistry (R-IHC) can contribute to the intraoperative diagnosis of central nervous system (CNS) tumors. We have recently developed a new IHC method based on an alternating current electric field to facilitate the antigen-antibody reaction. To ensure the requirement of R-IHC for intraoperative diagnosis, 183 cases of CNS tumors were reviewed regarding the accuracy rate of diagnosis without R-IHC. The diagnostic accuracy was 90.7 % (166/183 cases) [corrected] in which definitive diagnoses were not provided in 17 cases because of the failure of glioma grading and differential diagnosis of lymphoma and glioma. To establish the clinicopathological application, R-IHC for frozen specimens was compared with standard IHC for permanent specimens. 33 gliomas were analyzed, and the Ki-67/MIB-1 indices of frozen specimens by R-IHC were consistent with the grade and statistically correlated with those of permanent specimens. Thus, R-IHC provided supportive information to determine the grade of glioma. For discrimination between glioma and lymphoma, R-IHC was able to provide clear results of CD20 and Ki-67/MIB-1 in four frozen specimens of CNS lymphoma as well as standard IHC. We conclude that the R-IHC for frozen specimens can provide important information for intraoperative diagnosis of CNS tumors.

  4. CNS Remyelination and the Innate Immune System.

    PubMed

    McMurran, Christopher E; Jones, Clare A; Fitzgerald, Denise C; Franklin, Robin J M

    2016-01-01

    A misguided inflammatory response is frequently implicated in myelin damage. Particularly prominent among myelin diseases, multiple sclerosis (MS) is an autoimmune condition, with immune-mediated damage central to its etiology. Nevertheless, a robust inflammatory response is also essential for the efficient regeneration of myelin sheaths after such injury. Here, we discuss the functions of inflammation that promote remyelination, and how these have been experimentally disentangled from the pathological facets of the immune response. We focus on the contributions that resident microglia and monocyte-derived macrophages make to remyelination and compare the roles of these two populations of innate immune cells. Finally, the current literature is framed in the context of developing therapies that manipulate the innate immune response to promote remyelination in clinical myelin disease.

  5. CNS Remyelination and the Innate Immune System

    PubMed Central

    McMurran, Christopher E.; Jones, Clare A.; Fitzgerald, Denise C.; Franklin, Robin J. M.

    2016-01-01

    A misguided inflammatory response is frequently implicated in myelin damage. Particularly prominent among myelin diseases, multiple sclerosis (MS) is an autoimmune condition, with immune–mediated damage central to its etiology. Nevertheless, a robust inflammatory response is also essential for the efficient regeneration of myelin sheaths after such injury. Here, we discuss the functions of inflammation that promote remyelination, and how these have been experimentally disentangled from the pathological facets of the immune response. We focus on the contributions that resident microglia and monocyte-derived macrophages make to remyelination and compare the roles of these two populations of innate immune cells. Finally, the current literature is framed in the context of developing therapies that manipulate the innate immune response to promote remyelination in clinical myelin disease. PMID:27200350

  6. Safety Design and Mock-Up Tests on the Combustion of Hydrogen-Air Mixture in the Vertical CNS Channel of the CARR-CNS

    SciTech Connect

    Qingfeng Yu; Quanke Feng

    2006-07-01

    A two-phase thermo-siphon loop is applied to the Cold Neutron Source (CNS) of China Advanced Research Reactor (CARR). The moderator is liquid hydrogen. The two-phase thermo-siphon consists of the crescent-shape moderator cell, the moderator transfer tube, and the condenser. The hydrogen is supplied from the buffer tank to the condenser. The most characteristic point is that the cold helium gas is introduced into the helium sub-cooling system covering the moderator cell and then flows up through the tube covering the moderator transfer tube into the condenser. The helium sub-cooling system also reduces the void fraction of the liquid hydrogen and takes a role of the helium barrier for preventing air from intruding into the hydrogen system. We call the two-phase thermo-siphon the hydrogen cold system. The main part of this system is installed in the CNS channel made of 6061 aluminum alloy (6061A) of 6 mm in thickness, 270 mm in outer diameter and about 6 m in height. For confirming the safety of the CNS, the combustion tests were carried out using the hydrogen-air mixture under the conditions in which air is introduced into the tube at 1 atmosphere, and then hydrogen gas is supplied from the gas cylinder up to the test pressures. And maximum test pressure is 0.140 MPa Gauge (G). This condition includes the design accident of the CNS. The peak pressure due to combustion is 1.09 MPa, and the design strength of the CNS channel is 3 MPa. The safety of the CNS was thus verified even if the design basis accident occurs. The pressure distribution, the stress, and the displacement of the tube were also measured. (authors)

  7. On Study of Immune Response to Tumor Cells in Prey-Predator System

    PubMed Central

    2014-01-01

    This paper aims to develop the mathematical model that explores the immune response to a tumor system as a prey-predator system. A deterministic model defining the dynamics of tumor growth progression and regression has been analyzed. Our analysis indicates the tumor recurring and dormancy on the cellular level in combination with resting and hunting cells. The model considered in the present study is a generalization of El-Gohary (2008) by introducing the Michaelis-Menten function. This function describes the stimulation process of the resting cells by the tumor cells in the presence of tumor specific antigens. Local and global stability analysis have been performed along with the numerical simulation to support our findings. PMID:27355046

  8. The gateway theory: bridging neural and immune interactions in the CNS

    PubMed Central

    Kamimura, Daisuke; Yamada, Moe; Harada, Masaya; Sabharwal, Lavannya; Meng, Jie; Bando, Hidenori; Ogura, Hideki; Atsumi, Toru; Arima, Yasunobu; Murakami, Masaaki

    2013-01-01

    The central nervous system (CNS) is considered an immune-privileged tissue protected by a specific vessel structure, the blood-brain barrier (BBB). Upon infection or traumatic injury in the CNS, the BBB is breached, and various immune cells are recruited to the affected area. In the case of autoimmune diseases in the CNS like multiple sclerosis (MS), autoreactive T cells against some CNS-specific antigens can theoretically attack neurons throughout the CNS. The affected CNS regions in MS patients can be detected as multiple focal plaques in the cerebrum, thoracic cord, and other regions. Vision problems are often associated with the initial phase of MS, suggesting a disturbance in the optic nerves. These observations raise the possibility that there exist specific signals that direct autoreactive T cells past the BBB and into particular sites of the CNS. Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we recently defined the mechanism of the pathogenesis in which regional neural stimulations modulate the status of the blood vessel endothelium to allow the invasion of autoreactive T cells into specific sites of the CNS via the fifth lumbar cord. This gate for autoreactive T cells can be artificially manipulated by removing gravity forces on the hind legs or by electric pulses to the soleus muscles, quadriceps, and triceps of mice, resulting in an accumulation of autoreactive T cells in the intended regions via the activation of regional neurons. Gating blood vessels by regional neural stimulations, a phenomenon we call the gateway theory, has potential therapeutic value not only in preventing autoimmunity, but also in augmenting the effects of cancer immunotherapies. PMID:24194696

  9. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4

    PubMed Central

    Walsh, James T.; Hendrix, Sven; Boato, Francesco; Smirnov, Igor; Zheng, Jingjing; Lukens, John R.; Gadani, Sachin; Hechler, Daniel; Gölz, Greta; Rosenberger, Karen; Kammertöns, Thomas; Vogt, Johannes; Vogelaar, Christina; Siffrin, Volker; Radjavi, Ali; Fernandez-Castaneda, Anthony; Gaultier, Alban; Gold, Ralf; Kanneganti, Thirumala-Devi; Nitsch, Robert; Zipp, Frauke; Kipnis, Jonathan

    2015-01-01

    A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell–mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4–producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4–deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4–deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell–derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4–producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration. PMID:25607842

  10. Indian data on central nervous tumors: A summary of published work.

    PubMed

    Dasgupta, Archya; Gupta, Tejpal; Jalali, Rakesh

    2016-01-01

    Tumors of the central nervous system (CNS) constitute approximately 2% of all malignancies. Although relatively rare, the associated morbidity and mortality and the significant proportion of affected young and middle-aged individuals has a major bearing on the death-adjusted life years compared to other malignancies. CNS tumors encompass a very broad spectrum with regards to age, location, histology, and clinical outcomes. Advances in diagnostic imaging, surgical techniques, radiotherapy equipment, and generation of newer chemotherapeutic and targeted agents over the past few years have helped improving treatment outcome. Further insights into the molecular pathways leading to the development of tumors made in the past decade are being incorporated into routine clinical practice. Several focused groups within India have been working on a range of topics related to CNS tumors, and a significant body of work from India, in the recent years, is being increasingly recognized throughout the world. The present article summarizes key published work with particular emphasis on gliomas and medulloblastoma, the two commonly encountered tumors. PMID:27606302

  11. Indian data on central nervous tumors: A summary of published work

    PubMed Central

    Dasgupta, Archya; Gupta, Tejpal; Jalali, Rakesh

    2016-01-01

    Tumors of the central nervous system (CNS) constitute approximately 2% of all malignancies. Although relatively rare, the associated morbidity and mortality and the significant proportion of affected young and middle-aged individuals has a major bearing on the death-adjusted life years compared to other malignancies. CNS tumors encompass a very broad spectrum with regards to age, location, histology, and clinical outcomes. Advances in diagnostic imaging, surgical techniques, radiotherapy equipment, and generation of newer chemotherapeutic and targeted agents over the past few years have helped improving treatment outcome. Further insights into the molecular pathways leading to the development of tumors made in the past decade are being incorporated into routine clinical practice. Several focused groups within India have been working on a range of topics related to CNS tumors, and a significant body of work from India, in the recent years, is being increasingly recognized throughout the world. The present article summarizes key published work with particular emphasis on gliomas and medulloblastoma, the two commonly encountered tumors. PMID:27606302

  12. Indian data on central nervous tumors: A summary of published work

    PubMed Central

    Dasgupta, Archya; Gupta, Tejpal; Jalali, Rakesh

    2016-01-01

    Tumors of the central nervous system (CNS) constitute approximately 2% of all malignancies. Although relatively rare, the associated morbidity and mortality and the significant proportion of affected young and middle-aged individuals has a major bearing on the death-adjusted life years compared to other malignancies. CNS tumors encompass a very broad spectrum with regards to age, location, histology, and clinical outcomes. Advances in diagnostic imaging, surgical techniques, radiotherapy equipment, and generation of newer chemotherapeutic and targeted agents over the past few years have helped improving treatment outcome. Further insights into the molecular pathways leading to the development of tumors made in the past decade are being incorporated into routine clinical practice. Several focused groups within India have been working on a range of topics related to CNS tumors, and a significant body of work from India, in the recent years, is being increasingly recognized throughout the world. The present article summarizes key published work with particular emphasis on gliomas and medulloblastoma, the two commonly encountered tumors.

  13. Embryonic Medaka Model of Microglia in the Developing CNS Allowing In Vivo Analysis of Their Spatiotemporal Recruitment in Response to Irradiation

    PubMed Central

    Yasuda, Takako; Oda, Shoji; Hibi, Yusuke; Satoh, Satomi; Nagata, Kento; Hirakawa, Kei; Kutsuna, Natsumaro; Sagara, Hiroshi; Mitani, Hiroshi

    2015-01-01

    Radiation therapy (RT) is pivotal in the treatment of many central nervous system (CNS) pathologies; however, exposure to RT in children is associated with a higher risk of secondary CNS tumors. Although recent research interest has focused on the reparative and therapeutic role of microglia, their recruitment following RT has not been elucidated, especially in the developing CNS. Here, we investigated the spatiotemporal dynamics of microglia during tissue repair in the irradiated embryonic medaka brain by whole-mount in situ hybridization using a probe for Apolipoprotein E (ApoE), a marker for activated microglia in teleosts. Three-dimensional imaging of the distribution of ApoE-expressing microglia in the irradiated embryonic brain clearly showed that ApoE-expressing microglia were abundant only in the late phase of phagocytosis during tissue repair induced by irradiation, while few microglia expressed ApoE in the initial phase of phagocytosis. This strongly suggests that ApoE has a significant function in the late phase of phagocytosis by microglia in the medaka brain. In addition, the distribution of microglia in p53-deficient embryos at the late phase of phagocytosis was almost the same as in wild-type embryos, despite the low numbers of irradiation-induced apoptotic neurons, suggesting that constant numbers of activated microglia were recruited at the late phase of phagocytosis irrespective of the extent of neuronal injury. This medaka model of microglia demonstrated specific recruitment after irradiation in the developing CNS and could provide a useful potential therapeutic strategy to counteract the detrimental effects of RT. PMID:26061282

  14. Immunosuppression promotes CNS remyelination in chronic virus-induced demyelinating disease.

    PubMed

    Rodriguez, M; Lindsley, M D

    1992-02-01

    Immunosuppression using cyclophosphamide or anti-T cell monoclonal antibodies (mAbs) directed at CD4 or CD8 promoted remyelination of CNS axons in the spinal cords of mice infected chronically with Theiler's virus. Treatment with a mAb directed at class II major histocompatibility gene products did not increase the extent of CNS remyelination. Following immunosuppressive treatment, quantitative morphometry revealed a five- to sevenfold increase in new myelin synthesis. Proliferating nervous system cells were identified at the edges of remyelinated lesions by their incorporation of [3H]thymidine. CNS remyelination occurred in mice depleted of selected subsets of T lymphocytes despite the local persistence of viral antigen. These findings indicate that CNS remyelination occurs as a normal consequence of primary myelin injury, but factors associated with immune T cells somehow impair remyelination. Interference with the function of immune T cells enhances CNS remyelination by oligodendrocytes. Similar depletion of immune T cells may allow for enhanced remyelination in the CNS of patients with chronic multiple sclerosis.

  15. Chondroitin sulfate glycosaminoglycans for CNS homeostasis-implications for material design.

    PubMed

    Karumbaiah, Lohitash; Saxena, Tarun; Betancur, Martha; Bellamkonda, Ravi V

    2014-01-01

    Chondroitin sulfate proteoglycans (CSPGs) are complex biomolecules that are known to facilitate patterning of axonal direction and cell migration during the early growth and development phase of the mammalian central nervous system (CNS). In adults, they continue to control neuronal plasticity as major constituents of the "peri-neuronal nets" (PNNs) that surround adult CNS neurons. CSPGs are also barrier-forming molecules that are selectively upregulated by invading reactive astroglia after injury to the CNS, and are responsible for the active repulsion of regenerating neurons post-injury. Recent evidence however suggests that the diverse sulfated glycosaminoglycan (GAG) side chains attached to CSPGs are key components that play paradoxical roles in influencing nerve regeneration post-injury to the CNS. Sulfated GAG repeats attached to the CSPG core protein help mediate cell migration, neuritogenesis, axonal pathfinding, and axonal repulsion by directly trapping and presenting a whole host of growth factors to cells locally, or by binding to specific membrane bound proteins on the cell surface to influence cellular function. In this review, we will present the current gamut of interventional strategies used to bridge CNS deficits, and discuss the potential advantages of using sulfated GAG based biomaterials to facilitate the repair and regeneration of the injured CNS. PMID:25139544

  16. CNS manifestations of HPNS: revisited.

    PubMed

    Talpalar, A E; Grossman, Y

    2006-01-01

    Exposure to high pressures (HP) has been associated with the development of the high pressure neurological syndrome (HPNS) in deep-divers and experimental animals. In contrast, many diving mammals are naturally able to withstand very high pressures. Although at a certain pressure range humans are also able to perform to some extent, the severe signs of HPNS at higher pressures motivated the research on the pathophysiology underlying this syndrome rather than on possible adaptive mechanisms. Thermodynamically, high pressure resembles cooling. Both conditions usually involve reduction in the entropy and slowing down of kinetic rates. We have observed in rat corticohippocampal brain slices that high pressure slows and reduces excitatory synaptic activity. However, this was associated with increased gain of the system, allowing the depressed inputs to elicit regular firing in their target cells. This increased gain was partially mediated by elevated excitability of their dendrites and reduction in the background inhibition. This compensation is efficient at low-medium frequencies. However, it induces abnormal spike reverberation at the high frequency band (> 50 Hz). Synaptic depression that requires less vesicles/transmitter turn over may serve as an energy-saving mechanism when enzymes and membrane pumps activity are slowed down at pressure. It is even more efficient if a similar reduction is induced in inhibitory synaptic activity. Unfortunately, the frequency response characteristics at this mode of operation may make the system vulnerable to external signals (noise, auditory, visual, etc) at frequencies that elicit 'resonance' responses. Therefore, it is expected that humans exposed to pressures above 1.5 MPa display lethargy and fatigue, certain reduction in cognitive and memory functions when the system is working in an 'economic' mode. The more serious signs of HPNS such as nausea, vomiting, severe tremor, disturbance of motor coordination, and seizures, may be

  17. Breast Cancer Metastasis to the Central Nervous System

    PubMed Central

    Weil, Robert J.; Palmieri, Diane C.; Bronder, Julie L.; Stark, Andreas M.; Steeg, Patricia S.

    2005-01-01

    Clinically symptomatic metastases to the central nervous system (CNS) occur in ∼10 to 15% of patients with metastatic beast cancer. CNS metastases are traditionally viewed as a late complication of systemic disease, for which few effective treatment options exist. Recently, patients with Her-2-positive breast tumors who were treated with trastuzumab have been reported to develop CNS metastases at higher rates, often while responding favorably to treatment. The blood:brain barrier and the unique brain microenvironment are hypothesized to promote distinct molecular features in CNS metastases that may require tailored therapeutic approaches. New research approaches using cell lines that reliably and preferentially metastasize in vivo to the brain have been reported. Using such model systems, as well as in vitro analogs of blood-brain barrier penetration and tissue-based studies, new molecular leads into this disease are unfolding. PMID:16192626

  18. Breast cancer metastasis to the central nervous system.

    PubMed

    Weil, Robert J; Palmieri, Diane C; Bronder, Julie L; Stark, Andreas M; Steeg, Patricia S

    2005-10-01

    Clinically symptomatic metastases to the central nervous system (CNS) occur in approximately 10 to 15% of patients with metastatic beast cancer. CNS metastases are traditionally viewed as a late complication of systemic disease, for which few effective treatment options exist. Recently, patients with Her-2-positive breast tumors who were treated with trastuzumab have been reported to develop CNS metastases at higher rates, often while responding favorably to treatment. The blood:brain barrier and the unique brain microenvironment are hypothesized to promote distinct molecular features in CNS metastases that may require tailored therapeutic approaches. New research approaches using cell lines that reliably and preferentially metastasize in vivo to the brain have been reported. Using such model systems, as well as in vitro analogs of blood-brain barrier penetration and tissue-based studies, new molecular leads into this disease are unfolding. PMID:16192626

  19. Phase I study of a systemically delivered p53 nanoparticle in advanced solid tumors.

    PubMed

    Senzer, Neil; Nemunaitis, John; Nemunaitis, Derek; Bedell, Cynthia; Edelman, Gerald; Barve, Minal; Nunan, Robert; Pirollo, Kathleen F; Rait, Antonina; Chang, Esther H

    2013-05-01

    Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions.

  20. Effect of immunomodulation on the fate of tumor cells in the central nervous system and systemic organs of mice. Distribution of (/sup 125/I)5-iodo-2'-deoxyuridine-labeled KHT tumor cells after left intracardial injection

    SciTech Connect

    Conley, F.K.

    1982-08-01

    The effect of systemic immunomodulation on tumor cell arrest and retention in the central nervous system was studied by following radioactively labeled tumor cells. KHT mouse sarcoma tumor cells were labeled in vitro with (/sup 125/I)IdUrd, and 1x10/sup 5/ tumor cells were injected into the left side of the hearts of syngeneic C3H mice. Experimental groups consisted of untreated normal mice, mice pretreated iv with Corynebacterium parvum, and mice chronically infected with Toxoplasma gondii; in this model both groups of immunomodulated mice are protected from developing systemic metastatic tumor, but only Toxoplasma-infected mice have protection against metastatic brain tumor. At time intervals from 1 to 96 hours, groups of mice from each experimental group were killed, and the brain and other organs were monitored for radioactivity to determine the number of viable tumor cells that had been present at the time of death. Normal mice demonstrated significant retention of tumor cells in the brain and kidneys plus adrenals at 96 hours. By contrast, in both groups of immunomodulated mice tumor cells were rapidly eliminated from systemic organs, but tumor cells were significantly retained in the central nervous system even at 96 hours after tumor cell injections. The results indicated that generalized immunomodulation had more effect in elimination of tumor cells from systemic organs than from the brain and that the elimination of tumor cells from the brain in Toxoplasma-infected mice was a delayed phenomenon.

  1. A prototype system of microwave induced thermo-acoustic tomography for breast tumor.

    PubMed

    Zhu, Xiaozhang; Zhao, Zhiqin; Yang, Kai; Nie, Zaiping; Liu, Qinghuo

    2012-01-01

    Microwave-induced thermo-acoustic tomography (MITAT) is an innovative technique for tumor's detection. Due to there has high contrast in terms with permittivity and electrical conductivity of tumor versus normal tissue, even if the tumor still in the early phase it can be imaged clearly. For the proposed MITAT system, low energy microwave pulses are used as the irradiating signals, while the received signals are ultrasound, high contrast and high resolution images can be obtained. After some theoretical research and basic fundamental experiments, the first prototype of experimental system is designed and built. It includes the microwave radiator, the arrayed sensor bowl, the circular scanning platform, the system controller and the signal processor. Based on the experimental results using this integral MITAT clinic system, the images contrast can be reached higher than 383:1; while the sub-millimeter special resolution is obtained for a 1cm(3) scale tumor mimic. PMID:23365929

  2. Coordinated Noninvasive Studies (CNS) Project

    NASA Astrophysics Data System (ADS)

    Lauter, Judith

    1988-11-01

    Research activities during this period include: data collection related to the interface between complex-sound production and perception, specifically, studies on speech acoustics including two experiments on voice-onset-time variability in productions by speakers of several languages, and a series on acoustical characteristics of emotional expression; data collection regarding individual differences in the effect of stimulus characteristic on relative ear advantages; continuing data analysis and new collections documenting individual differences in auditory evoked potentials, with details related to auditory-systems asymmetries preliminary tests regarding the match between behavioral measures of relative ear advantages and quantitative-electroencephalographic asymmetries observed during auditory stimulation; pilot testing using a combination of Nuclear Magnetic Resonance's (NMR) anatomical-imaging and chemical-spectral-analysis capabilities to study physiological activation in the human brain.

  3. Neurosteroid regulation of CNS development

    PubMed Central

    Mellon, Synthia H.

    2007-01-01

    Neurosteroids are a relatively new class of neuroactive compounds, brought to prominence in the past two decades. Despite knowing of their presence in the nervous system of various species for over twenty years and knowing of their functions as GABAA and NMDA ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of four distinct neurosteroids – pregnenolone, progesterone, allopregnanolone and dehydroepiandrosterone. PMID:17651807

  4. Systemic elevation of PTEN induces a tumor suppressive metabolic state

    PubMed Central

    Garcia-Cao, Isabel; Song, Min Sup; Hobbs, Robin M.; Laurent, Gaelle; Giorgi, Carlotta; de Boer, Vincent C.J.; Anastasiou, Dimitrios; Ito, Keisuke; Sasaki, Atsuo T.; Rameh, Lucia; Carracedo, Arkaitz; Vander Heiden, Matthew G.; Cantley, Lewis C.; Pinton, Paolo; Haigis, Marcia C.; Pandolfi, Pier Paolo

    2012-01-01

    SUMMARY Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect. PMID:22401813

  5. [A brain tumor automatic assisted-diagnostic system based on medical image shape analysis].

    PubMed

    Wang, Li-Li; Yang, Jie

    2005-03-01

    This paper covers a brain tumor assisted diagnosis system based on medical image analysis. The system supplements the PACS functions such as display of medical images and database inquiry, segments slice in real-time using the algorithm of fuzzy region competition, extracts shape feature factors such as contour label, compactness, moment, Fourier Descriptor, chord length, radius and other medical data on the brain tumor image with irregular contour feature after segmentation and then feeds to Bayesian network in order to sort the brain tumor for the implementation of automatic assisted diagnosis. PMID:16011110

  6. A noninvasive eye fixation monitoring system for CyberKnife radiotherapy of choroidal and orbital tumors

    SciTech Connect

    Daftari, I. K.; Petti, P. L.; Larson, D. A.; O'Brien, J. M.; Phillips, T. L.

    2009-03-15

    A new noninvasive monitoring system for fixing the eye has been developed to treat orbital and choroidal tumors with CyberKnife-based radiotherapy. This device monitors the eye during CT/MRI scanning and during treatment. The results of this study demonstrate the feasibility of the fixation light system for CyberKnife-based treatments of orbital and choroidal tumors and supports the idea that larger choroidal melanomas and choroidal metastases could be treated with CyberKnife without implanting fiducial markers.

  7. Experimental Study of Stellar Reactions at CNS

    SciTech Connect

    Kubono, S.; Yamaguchi, H.; Wakabayashi, Y.; Amadio, G.; Hayakawa, S.; He, J. J.; Saito, A.; Teranishi, T.; Nishimura, S.; Fukunishi, N.; Iwasa, N.; Inafuku, K.; Kato, S.; Tanaka, M. H.; Fuchi, Y.; Moon, J. Y.; Kwon, K.; Lee, C. S.; Khiem, Le Hong; Chen, A.

    2006-11-02

    After a brief review on low-energy RI beam production technology, nuclear astrophysics programs at CNS are presented including a scope of the field in the Wako campus. The CRIB project involves a total development of the whole facility to maximize the low-energy RI beam intensities, including the ion source, the AVF cyclotron and the low-energy RI beam separator CRIB, Some recent nuclear astrophysics experiments performed with the RI beams were discussed, including the measurement of the 14O({alpha},p)17F reaction, the key stellar reaction for the onset of the high-temperature rp-process. The first experiment performed with a newly installed high-resolution magnetic spectrograph PA of CNS was also presented. Collaboration possibilities for nuclear astrophysics in the RIKEN campus are also touched.

  8. Experimental Study of Stellar Reactions at CNS

    NASA Astrophysics Data System (ADS)

    Kubono, S.; Yamaguchi, H.; Wakabayashi, Y.; Amadio, G.; Hayakawa, S.; He, J. J.; Saito, A.; Teranishi, T.; Nishimura, S.; Fukunishi, N.; Iwasa, N.; Inafuku, K.; Kato, S.; Tanaka, M. H.; Fuchi, Y.; Moon, J. Y.; Kwon, K.; Lee, C. S.; Khiem, Le Hong; Chen, A.; Pearson, J.

    2006-11-01

    After a brief review on low-energy RI beam production technology, nuclear astrophysics programs at CNS are presented including a scope of the field in the Wako campus. The CRIB project involves a total development of the whole facility to maximize the low-energy RI beam intensities, including the ion source, the AVF cyclotron and the low-energy RI beam separator CRIB, Some recent nuclear astrophysics experiments performed with the RI beams were discussed, including the measurement of the 14O(α,p)17F reaction, the key stellar reaction for the onset of the high-temperature rp-process. The first experiment performed with a newly installed high-resolution magnetic spectrograph PA of CNS was also presented. Collaboration possibilities for nuclear astrophysics in the RIKEN campus are also touched.

  9. Laser tumor thermotherapy: Is there a clinically relevant effect on the immune system?

    NASA Astrophysics Data System (ADS)

    Tranberg, Karl-G.

    2006-02-01

    Laser thermotherapy is interesting from an immunological point of view since it can reduce tumor volume without causing immunosuppression at the same time as it may induce and/or enhance tumor immunity. In a rat liver tumor model, we have demonstrated that laser thermotherapy 1) is superior to surgical resection, 2) gives a strong rejection immunity associated with an immune cellular response of tumor-infiltrating macrophages and CD8 lymphocytes, 3) results in pronounced suppression of the growth of a simultaneous untreated tumor (distant bystander effect), 4) produces an increased anti-tumor lymphocyte proliferative response in tumor-draining and systemic lymph nodes and spleen, and 5) results in increased HSP70 immunoreactivity in tumors and tumor-infiltrating macrophages. Thus, the evidence for a laser-induced immunologic effect in tumor-bearing rats is strong. Some observations suggest that laser thermotherapy may be used for inducing favorable immunologic effects also in patients. Thus, we have shown a laser-induced bystander effect in a patient with malignant melanoma. In patients with breast cancer we have shown that laser thermotherapy induces intratumoral infiltration of immunocompetent cells like CD68 macrophages and CD8 lymphocytes. Laser thermotherapy is likely to be beneficial mainly when tumor burden is small, that is, when treatment is performed with curative intent, either with laser alone or together with surgical resection. For optimal effect, it appears likely that thermotherapy should be combined with other therapies. Most likely, a clinically meaningful effect can only be proven in prospective randomized studies comparing thermotherapy with other methods, particularly surgical resection.

  10. Antiretroviral therapy CNS penetration and HIV-1–associated CNS disease

    PubMed Central

    Winston, A.; Walsh, J.; Post, F.; Porter, K.; Gazzard, B.; Fisher, M.; Leen, C.; Pillay, D.; Hill, T.; Johnson, M.; Gilson, R.; Anderson, J.; Easterbrook, P.; Bansi, L.; Orkin, C.; Ainsworth, J.; Palfreeman, A.; Gompels, M.; Phillips, A.N.; Sabin, C.A.

    2011-01-01

    Objective: The impact of different antiretroviral agents on the risk of developing or surviving CNS disease remains unknown. The aim of this study was to investigate whether using antiretroviral regimens with higher CNS penetration effectiveness (CPE) scores was associated with reduced incidence of CNS disease and improved survival in the UK Collaborative HIV Cohort (CHIC) Study. Methods: Adults without previous CNS disease, who commenced combination antiretroviral therapy (cART) between 1996 and 2008, were included (n = 22,356). Initial and most recent cART CPE scores were calculated. CNS diseases were HIV encephalopathy (HIVe), progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis (TOXO), and cryptococcal meningitis (CRYPTO). Incidence rates and overall survival were stratified by CPE score. A multivariable Poisson regression model was used to identify independent associations. Results: The median (interquartile range) CPE score for initial cART regimen increased from 7 (5–8) in 1996–1997 to 9 (8–10) in 2000–2001 and subsequently declined to 6 (7–8) in 2006–2008. Differences in gender, HIV acquisition risk group, and ethnicity existed between CPE score strata. A total of 251 subjects were diagnosed with a CNS disease (HIVe 80; TOXO 59; CRYPTO 56; PML 54). CNS diseases occurred more frequently in subjects prescribed regimens with CPE scores ≤4, and less frequently in those with scores ≥10; however, these differences were nonsignificant. Initial and most recent cART CPE scores ≤4 were independently associated with increased risk of death. Conclusion: Clinical status at time of commencing cART influences antiretroviral selection and CPE score. This information should be considered when utilizing CPE scores for retrospective analyses. PMID:21339496

  11. The Impact of Immune System in Regulating Bone Metastasis Formation by Osteotropic Tumors.

    PubMed

    D'Amico, Lucia; Roato, Ilaria

    2015-01-01

    Bone metastases are frequent and debilitating consequence for many tumors, such as breast, lung, prostate, and kidney cancer. Many studies report the importance of the immune system in the pathogenesis of bone metastasis. Indeed, bone and immune system are strictly linked to each other because bone regulates the hematopoietic stem cells from which all cells of the immune system derive, and many immunoregulatory cytokines influence the fate of bone cells. Furthermore, both cytokines and factors produced by immune and bone cells promote the growth of tumor cells in bone, contributing to supporting the vicious cycle of bone metastasis. This review summarizes the current knowledge on the interactions among bone, immune, and tumor cells aiming to provide an overview of the osteoimmunology field in bone metastasis from solid tumors.

  12. The effect of tumor location and respiratory function on tumor movement estimated by real-time tracking radiotherapy (RTRT) system

    SciTech Connect

    Onimaru, Rikiya; Shirato, Hiroki . E-mail: hshirato@radi.med.hokudai.ac.jp; Fujino, Masaharu; Suzuki, Keishiro; Yamazaki, Kouichi; Nishimura, Masaharu; Dosaka-Akita, Hirotoshi; Miyasaka, Kazuo

    2005-09-01

    Purpose: The effects of tumor location and pulmonary function on the motion of fiducial markers near lung tumors were evaluated to deduce simple guidelines for determining the internal margin in radiotherapy without fiducial markers. Methods and Materials: Pooled data collected by a real-time tumor-tracking radiotherapy system on 42 markers in 39 patients were analyzed. The pulmonary functions of all patients were assessed before radiotherapy. Using chest X-ray film, the position of the marker was expressed relative to the geometry of the unilateral lung. Posterior location meant the area of the posterior half of the lung in a lateral chest X-ray film, and caudal location meant the caudal half of the chest X-ray film; these categories were determined by measuring the distance between the marker and anatomic landmarks, including the apex, costophrenic angle, midline of spinal canal, lateral, anterior, and posterior boundary of the lung. Results: Before the radiotherapy, 18 patients had obstructive respiratory dysfunction (ratio of forced expiratory volume in 1 s to forced vital capacity [FEV{sub 1.0}/FVC] <70), 5 patients had constrictive dysfunction (percent vital capacity [%VC] <80), and 3 had mixed dysfunction. Means of FEV{sub 1.0}/FVC and %VC were 97.0% and 66.5%, respectively. Median tumor movements in the x (left-right), y (anteroposterior), and z (craniocaudal) directions were 1.1 mm, 2.3 mm, and 5.4 mm, respectively. There was no significant correlation between respiratory function and magnitude of marker movement in any direction. Median marker movement in the z direction was 2.6 mm for the cranial location and 11.8 mm for the caudal location, respectively (p < 0.001). Median movement in the z direction was 11.8 mm for posterior location and 3.4 mm for anterior location, respectively (p < 0.01). Conclusions: Simple measurement of the relative location on plain chest X-ray film was related, but respiratory function test was not related, to the craniocaudal

  13. Intranasal Administration of CNS Therapeutics to Awake Mice

    PubMed Central

    Hanson, Leah R.; Fine, Jared M.; Svitak, Aleta L.; Faltesek, Katherine A.

    2013-01-01

    Intranasal administration is a method of delivering therapeutic agents to the central nervous system (CNS). It is non-invasive and allows large molecules that do not cross the blood-brain barrier access to the CNS. Drugs are directly targeted to the CNS with intranasal delivery, reducing systemic exposure and thus unwanted systemic side effects1. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways via an extracellular route and does not require drug to bind to any receptor or axonal transport2. Intranasal delivery is a widely publicized method and is currently being used in human clinical trials3. Intranasal delivery of drugs in animal models allows for initial evaluation of pharmacokinetic distribution and efficacy. With mice, it is possible to administer drugs to awake (non-anesthetized) animals on a regular basis using a specialized intranasal grip. Awake delivery is beneficial because it allows for long-term chronic dosing without anesthesia, it takes less time than with anesthesia, and can be learned and done by many people so that teams of technicians can dose large numbers of mice in short periods. Efficacy of therapeutics administered intranasally in this way to mice has been demonstrated in a number of studies including insulin in diabetic mouse models 4-6 and deferoxamine in Alzheimer's mouse models. 7,8 The intranasal grip for mice can be learned, but is not easy and requires practice, skill, and a precise grip to effectively deliver drug to the brain and avoid drainage to the lung and stomach. Mice are restrained by hand using a modified scruff in the non-dominant hand with the neck held parallel to the floor, while drug is delivered with a pipettor using the dominant hand. It usually takes 3-4 weeks of acclimating to handling before mice can be held with this grip without a stress response. We have prepared this JoVE video to make this intranasal delivery technique more accessible. PMID

  14. 3D cell culture systems modeling tumor growth determinants in cancer target discovery.

    PubMed

    Thoma, Claudio R; Zimmermann, Miriam; Agarkova, Irina; Kelm, Jens M; Krek, Wilhelm

    2014-04-01

    Phenotypic heterogeneity of cancer cells, cell biological context, heterotypic crosstalk and the microenvironment are key determinants of the multistep process of tumor development. They sign responsible, to a significant extent, for the limited response and resistance of cancer cells to molecular-targeted therapies. Better functional knowledge of the complex intra- and intercellular signaling circuits underlying communication between the different cell types populating a tumor tissue and of the systemic and local factors that shape the tumor microenvironment is therefore imperative. Sophisticated 3D multicellular tumor spheroid (MCTS) systems provide an emerging tool to model the phenotypic and cellular heterogeneity as well as microenvironmental aspects of in vivo tumor growth. In this review we discuss the cellular, chemical and physical factors contributing to zonation and cellular crosstalk within tumor masses. On this basis, we further describe 3D cell culture technologies for growth of MCTS as advanced tools for exploring molecular tumor growth determinants and facilitating drug discovery efforts. We conclude with a synopsis on technological aspects for on-line analysis and post-processing of 3D MCTS models.

  15. Potential central nervous system antitumor agents. Hydantoin derivatives.

    PubMed

    Peng, G W; Marquez, V E; Driscoll, J S

    1975-08-01

    Hydantoin derivatives of varying lipophilic character were prepared as nitrogen mustard carriers for CNS antitumor evaluation. Activity was studied in the murine ependymoblastoma brain tumor system. Multiple cures were observed for three of the four analogs examined. The compounds were also active in the intraperitoneal leukemia L1210 and P388 systems as well as in B16 melanoma and Lewis lung carcinoma.

  16. Cooperative Nanoparticle System for Photothermal Tumor Treatment without Skin Damage.

    PubMed

    Piao, Ji-Gang; Liu, Dong; Hu, Kan; Wang, Limin; Gao, Feng; Xiong, Yujie; Yang, Lihua

    2016-02-01

    How to ablate tumors without using skin-harmful high laser irradiance remains an ongoing challenge for photothermal therapy. Here, we achieve this with a cooperative nanosystem consisting of gold nanocage (AuNC) "activator" and a cationic mammalian-membrane-disruptive peptide, cTL, as photothermal antenna and anticancer agent, respectively. Specifically, this nanosystem is prepared by grafting cTL onto AuNC via a Au-S bond, followed by attachment of thiolated polyethylene glycol (PEG) for stealth effects. Upon NIR irradiation at skin-permissible dosage, the resulting cTL/PEG-AuNC nanoparticle effectively ablates both irradiated and nonirradiated cancer cells, likely owing to cTL being responsively unleashed by intracellular thiols exposed to cTL/PEG-AuNC via membrane damage initiated by AuNC's photothermal effects and deteriorated by the as-released cTL. When administered systematically in a mouse model, cTL/PEG-AuNC populates tumors through their porous vessels and effectively destroys them without damaging skin. PMID:26794418

  17. IDS crossing of the blood-brain barrier corrects CNS defects in MPSII mice.

    PubMed

    Polito, Vinicia Assunta; Cosma, Maria Pia

    2009-08-01

    Mucopolysaccharidosis type II (MPSII), or Hunter syndrome, arises from a deficiency in iduronate 2-sulfatase (IDS), and it is characterized by progressive somatic and neurological involvement. The MPSII mouse model reproduces the features of MPSII patients. Systemic administration of the AAV2/5CMV-hIDS vector in MPSII mouse pups results in the full correction of glycosaminoglycan (GAG) accumulation in visceral organs and in the rescue of the defects and GAG accumulation in the central nervous system (CNS). Remarkably, in treated MPSII animals, this CNS correction arises from the crossing of the blood-brain barrier by the IDS enzyme itself, not from the brain transduction. Thus, we show here that early treatment of MPSII mice with one systemic injection of AAV2/5CMV-hIDS results in prolonged and high levels of circulating IDS that can efficiently and simultaneously rescue both visceral and CNS defects for up to 18 months after therapy.

  18. TACE/ADAM17 is essential for oligodendrocyte development and CNS myelination.

    PubMed

    Palazuelos, Javier; Crawford, Howard C; Klingener, Michael; Sun, Bingru; Karelis, Jason; Raines, Elaine W; Aguirre, Adan

    2014-09-01

    Several studies have elucidated the significance of a disintegrin and metalloproteinase proteins (ADAMs) in PNS myelination, but there is no evidence if they also play a role in oligodendrogenesis and CNS myelination. Our study identifies ADAM17, also called tumor necrosis factor-α converting enzyme (TACE), as a novel key modulator of oligodendrocyte (OL) development and CNS myelination. Genetic deletion of TACE in oligodendrocyte progenitor cells (OPs) induces premature cell cycle exit and reduces OL cell survival during postnatal myelination of the subcortical white matter (SCWM). These cellular and molecular changes lead to deficits in SCWM myelination and motor behavior. Mechanistically, TACE regulates oligodendrogenesis by modulating the shedding of EGFR ligands TGFα and HB-EGF and, consequently, EGFR signaling activation in OL lineage cells. Constitutive TACE depletion in OPs in vivo leads to similar alterations in CNS myelination and motor behavior as to what is observed in the EGFR hypofunctional mouse line EgfrWa2. EGFR overexpression in TACE-deficient OPs restores OL survival and development. Our study reveals an essential function of TACE in oligodendrogenesis, and demonstrates how this molecule modulates EGFR signaling activation to regulate postnatal CNS myelination.

  19. TACE/ADAM17 Is Essential for Oligodendrocyte Development and CNS Myelination

    PubMed Central

    Palazuelos, Javier; Crawford, Howard C.; Klingener, Michael; Sun, Bingru; Karelis, Jason; Raines, Elaine W.

    2014-01-01

    Several studies have elucidated the significance of a disintegrin and metalloproteinase proteins (ADAMs) in PNS myelination, but there is no evidence if they also play a role in oligodendrogenesis and CNS myelination. Our study identifies ADAM17, also called tumor necrosis factor-α converting enzyme (TACE), as a novel key modulator of oligodendrocyte (OL) development and CNS myelination. Genetic deletion of TACE in oligodendrocyte progenitor cells (OPs) induces premature cell cycle exit and reduces OL cell survival during postnatal myelination of the subcortical white matter (SCWM). These cellular and molecular changes lead to deficits in SCWM myelination and motor behavior. Mechanistically, TACE regulates oligodendrogenesis by modulating the shedding of EGFR ligands TGFα and HB-EGF and, consequently, EGFR signaling activation in OL lineage cells. Constitutive TACE depletion in OPs in vivo leads to similar alterations in CNS myelination and motor behavior as to what is observed in the EGFR hypofunctional mouse line EgfrWa2. EGFR overexpression in TACE-deficient OPs restores OL survival and development. Our study reveals an essential function of TACE in oligodendrogenesis, and demonstrates how this molecule modulates EGFR signaling activation to regulate postnatal CNS myelination. PMID:25186737

  20. N-Acetylaspartate in the CNS: From Neurodiagnostics to Neurobiology

    PubMed Central

    Moffett, John R.; Ross, Brian; Arun, Peethambaran; Madhavarao, Chikkathur N.; Namboodiri, M. A. A.

    2007-01-01

    The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research

  1. Functional development of the CNS in pupils aged 7 to 19 years.

    PubMed

    Schalow, G

    2006-01-01

    In pupils aged 7 to 19 years, the functioning of the central nervous system (CNS) improved by a factor of 3 during their development. The CNS functioning was quantified in the framework of the dynamical system theory of pattern formation by the value of coordination dynamics. A transient increase in the optimal rate of arm and leg movements was observed in the pupils within 8 and 14 years of age. This high-speed moving is interpreted as a mean how the immature CNS tries to improve its functioning with respect to coordination and symmetry. Moreover, in very young pupils a lack of continuous drive of the CNS was observed; in other words, the concentration upon a certain task was not continuous. Some pupils were able to concentrate for only approximately 10 s. It was difficult for young pupils to simultaneously concentrate on two different tasks like moving and speaking or moving and thinking. It is concluded that concentration problems observed in young pupils are due to their immature CNS. PMID:16918200

  2. Selective vulnerability of mouse CNS neurons to latent infection with a neuroattenuated herpes simplex virus-1.

    PubMed

    Kesari, S; Lee, V M; Brown, S M; Trojanowski, J Q; Fraser, N W

    1996-09-15

    Herpes simplex viruses that lack ICP34.5 are neuroattenuated and are presently being considered for cancer and gene therapy in the nervous system. Previously, we documented the focal presence of the latency-associated transcripts (LATs) in the hippocampi of immunocompromised mice after intracranial (IC) inoculation of an ICP34.5-deficient virus called strain 1716. To characterize further the biological properties of strain 1716 in the CNS of immunocompetent mice, we determined the extent of viral gene expression in different cell types and regions of the CNS after stereotactic IC inoculation of this virus. At survival times of > 30 d after inoculation, we found that (1) infectious virus was not detectable by titration and immunohistochemical studies; (2) neurons harbored virus as demonstrated by the detection of the LATs by in situ hybridization (ISH); (3) transcripts expressed during the lytic cycle of infection were not detected by ISH; and (4) subsets of neurons were selectively vulnerable to latent infection, depending on the site of inoculation. These results suggest that the absence of ICP34.5 does not abrogate latent infection of the CNS by strain 1716. Additional studies of strain 1716 in the model system described here will facilitate the elucidation of the mechanisms that regulate the selective vulnerability of CNS cells to latent viral infection and lead to the development of ICP34.5 mutant viruses as therapeutic vectors for CNS diseases.

  3. Immune privilege of the CNS is not the consequence of limited antigen sampling

    NASA Astrophysics Data System (ADS)

    Harris, Melissa G.; Hulseberg, Paul; Ling, Changying; Karman, Jozsef; Clarkson, Benjamin D.; Harding, Jeffrey S.; Zhang, Mengxue; Sandor, Adam; Christensen, Kelsey; Nagy, Andras; Sandor, Matyas; Fabry, Zsuzsanna

    2014-03-01

    Central nervous system (CNS) immune privilege is complex, and it is still not understood how CNS antigens are sampled by the peripheral immune system under steady state conditions. To compare antigen sampling from immune-privileged or nonprivileged tissues, we created transgenic mice with oligodendrocyte or gut epithelial cell expression of an EGFP-tagged fusion protein containing ovalbumin (OVA) antigenic peptides and tested peripheral anti-OVA peptide-specific sentinel OT-I and OT-II T cell activation. We report that oligodendrocyte or gut antigens are sampled similarly, as determined by comparable levels of OT-I T cell activation. However, activated T cells do not access the CNS under steady state conditions. These data show that afferent immunity is normally intact as there is no barrier at the antigen sampling level, but that efferent immunity is restricted. To understand how this one-sided surveillance contributes to CNS immune privilege will help us define mechanisms of CNS autoimmune disease initiation.

  4. Influenza Vaccine-Induced CNS Demyelination in a 50-Year-Old Male

    PubMed Central

    Sacheli, Aaron; Bauer, Raymond

    2014-01-01

    Patient: Male, 50 Final Diagnosis: Acute post-vaccination CNS demyelinating disorder Symptoms: Blurred vision • hemiparesis • hemiplegia • hypertonia • itching • paresthesia Medication: — Clinical Procedure: MRI Specialty: Neurology Objective: Rare disease Background: There are several categories of primary inflammatory demyelinating disorders, which comprise clinically similar neurologic sequelae. Of interest, clinically isolated syndrome (CIS) and acute disseminated encephalomyelitis (ADEM) are 2 demyelinating conditions of the central nervous system (CNS), whose clinical similarity pose a significant challenge to definitive diagnosis. Yet, both remain important clinical considerations in patients with neurologic signs and symptoms in the context of recent vaccination. Case Report: We report a case of a 50-year-old Caucasian male with a course of progressive, focal, neurologic deficits within 24 h after receiving the influenza vaccine. Subsequent work-up revealed the possibility of an acute central nervous system (CNS) demyelinating episode secondary to the influenza vaccine, best described as either CIS or ADEM. Conclusions: Case reports of CNS demyelination following vaccinations have been previously noted, most often occurring in the context of recent influenza vaccination. This report serves to document a case of CNS demyelination occurring 24 h after influenza vaccination in a middle-aged patient, and will describe some salient features regarding the differential diagnosis of CIS and ADEM, as well as their potential management. PMID:25175754

  5. Electromagnetic thermotherapy system with needle arrays: a practical tool for the removal of cancerous tumors.

    PubMed

    Huang, Sheng-Chieh; Kang, Jui-Wen; Tsai, Hung-Wen; Shan, Yan-Shen; Lin, Xi-Zhang; Lee, Gwo-Bin

    2014-02-01

    Thermotherapy has been a promising method to treat tumor. In recent years, electromagnetic thermotherapy (EMT) has been extensively investigated and holds the potential for a variety of medical applications including for cancer treatment when combined with minimally invasive surgery approach. In this study, an alternating electromagnetic frequency was provided by an EMT system to heat up stainless steel needle arrays which were inserted into the target tumor to a high temperature, therefore leading to local ablation of the tumor. A new two-section needle-array apparatus was further demonstrated to encompass the tumor to prevent the tumor cells to spread after the treatment process. By using the needle-array insertion apparatus, there is no limitation of the treatment area; this method could, therefore, be applied for tumors that are larger than 6 cm. It was first successfully demonstrated in the in vitro experiments on porcine livers. Then an in vivo experiment was directly conducted on pigs. The two-section needle array incorporated with the needle-array apparatus and EMT was demonstrated to be promising for no-touch isolation treatment of cancerous tumors.

  6. Central nervous system tumors and related intracranial pathologies in radium dial workers

    SciTech Connect

    Stebbings, J.H.; Semkiw, W.

    1988-01-01

    Among the female radiation workers in the radium dial industry there is no overall excess of brain or central nervous system tumors. A significant excess did appear, however, in one of three major cohorts; the excess was not due to an excess of gliomas and cannot be ascribed with certainty to radium or external radiation. A significant proportional excess of tumors outside the brain was observed, and is consistent with irradiation of nervous system tissue from adjacent bone. Early deaths from brain abscess or mastoiditis, which are coded as diseases of the nervous system and sense organs, were observed. 12 refs., 11 tabs.

  7. Differences in Redox Regulatory Systems in Human Lung and Liver Tumors Suggest Different Avenues for Therapy

    PubMed Central

    Tobe, Ryuta; Carlson, Bradley A.; Tsuji, Petra A.; Lee, Byeong Jae; Gladyshev, Vadim N.; Hatfield, Dolph L.

    2015-01-01

    A common characteristic of many cancer cells is that they suffer from oxidative stress. They, therefore, require effective redox regulatory systems to combat the higher levels of reactive oxygen species that accompany accelerated growth compared to the normal cells of origin. An elevated dependence on these systems in cancers suggests that targeting these systems may provide an avenue for retarding the malignancy process. Herein, we examined the redox regulatory systems in human liver and lung cancers by comparing human lung adenocarcinoma and liver carcinoma to their respective surrounding normal tissues. Significant differences were found in the two major redox systems, the thioredoxin and glutathione systems. Thioredoxin reductase 1 levels were elevated in both malignancies, but thioredoxin was highly upregulated in lung tumor and only slightly upregulated in liver tumor, while peroxiredoxin 1 was highly elevated in lung tumor, but downregulated in liver tumor. There were also major differences within the glutathione system between the malignancies and their normal tissues. The data suggest a greater dependence of liver on either the thioredoxin or glutathione system to drive the malignancy, while lung cancer appeared to depend primarily on the thioredoxin system. PMID:26569310

  8. [Experiences with intra-arterial tumor chemotherapy of malignant liver tumors via totally implantable catheter systems].

    PubMed

    Matthias, M; Ridwelski, K; Wolff, H; Preiss, R; Sperling, P; Lüning, M

    1989-01-01

    Locoregional chemotherapy was applied to 30 patients for isolated, surgically not removable liver tumours (13 colorectal carcinomas, 17 carcinomas on different sites). Ten patients were in Stage I, 16 in Stage II, and four in Stage III. Cytostatics were administered through totally implantable catheter systems. The following therapeutic protocol was mainly used: 5-flourouracil 800-1,000 mg/m2/3hr/die X 5 in 22 days, adriamycin 30 mg/m2/3 hr/die X 2 in 22 days. The average time of treatment amounted to ten months. Cytotoxis side effects were of minor importance. Hepatic side effects, such as chemical hepatitis or sclerosing cholangitis, were not recordable. Reduction of tumour size by 50 percent or more was recorded by computed tomography from 14 cases (46.6 percent). The objectivated rate of responsiveness in patients with colorectal carcinoma was 61.5 percent. The average period up to progression amounted to 12.1 months. Premortal spreading of the disease beyond the liver was recorded from six patients. PMID:2750352

  9. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor.

    PubMed

    Li, Xiaoyu; Wu, Meiying; Pan, Limin; Shi, Jianlin

    2016-01-01

    To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors.

  10. Systemic Administration of Interleukin 2 Enhances the Therapeutic Efficacy of Dendritic Cell-Based Tumor Vaccines

    NASA Astrophysics Data System (ADS)

    Shimizu, K.; Fields, R. C.; Giedlin, M.; Mule, J. J.

    1999-03-01

    We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of non-toxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-γ production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.

  11. Alectinib's activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series.

    PubMed

    Metro, Giulio; Lunardi, Gianluigi; Bennati, Chiara; Chiarini, Pietro; Sperduti, Isabella; Ricciuti, Biagio; Marcomigni, Luca; Costa, Cinzia; Crinò, Lucio; Floridi, Piero; Gori, Stefania; Chiari, Rita

    2016-09-01

    In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS. PMID:27324494

  12. A Model of Tight Junction Function In CNS Myelinated Axons

    PubMed Central

    Gow, Alexander; Devaux, Jerome

    2010-01-01

    The insulative properties of myelin sheaths in the central and peripheral nervous systems (CNS and PNS) are widely thought to derive from the high resistance and low capacitance of the constituent membranes. Although this view adequately accounts for myelin function in large diameter PNS fibers, it poorly reflects the behavior of small fibers that are prominent in many regions of the CNS. Herein, we develop a computational model to more accurately represent conduction in small fibers. By incorporating structural features that, hitherto, have not been simulated, we demonstrate that myelin tight junctions improve saltatory conduction by reducing current flow through the myelin, limiting axonal membrane depolarization and restraining the activation of ion channels beneath the myelin sheath. Accordingly, our simulations provide a novel view of myelin by which tight junctions minimize charging of the membrane capacitance and lower the membrane time constant to improve the speed and accuracy of transmission in small diameter fibers. This study establishes possible mechanisms whereby TJs affect conduction in the absence of overt perturbations to myelin architecture and may in part explain the tremor and gait abnormalities observed in Claudin 11-null mice. PMID:20102674

  13. Phytocannabinoids as novel therapeutic agents in CNS disorders.

    PubMed

    Hill, Andrew J; Williams, Claire M; Whalley, Benjamin J; Stephens, Gary J

    2012-01-01

    The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1) receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ(9)-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ(9)-THC pCB-based medicines. PMID:21924288

  14. Nicotinic ACh receptors as therapeutic targets in CNS disorders.

    PubMed

    Dineley, Kelly T; Pandya, Anshul A; Yakel, Jerrel L

    2015-02-01

    The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels. These receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however, the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer's disease, AD), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain.

  15. Multiple hypertrophic relapsing remitting cranial neuropathies as an initial presentation of primary CNS lymphoma without any brain or spinal cord lesion

    PubMed Central

    Watane, Gaurav V; Pandya, Saumil P; Atre, Isha D; Kothari, Foram N

    2016-01-01

    Cranial nerve thickening as an initial isolated presentation of CNS lymphoma is rare. Once an extremely rare neoplasm, primary lymphoma of the central nervous system (CNS) now ranks only next to meningiomas and low-grade astrocytomas in prevalence. Multiple cranial nerve thickening can be a feature of primary CNS lymphoma. Here we report a case of a 45-year-old immunocompetent female who presented with relapsing remitting multiple cranial nerve thickening as an initial feature of primary CNS lymphoma without any other brain or spinal cord lesions. PMID:27081238

  16. Multifocal CNS demyelination following peripheral inoculation with herpes simplex virus type 1.

    PubMed

    Kastrukoff, L F; Lau, A S; Kim, S U

    1987-07-01

    The peripheral inoculation of herpes simplex virus type 1 (HSV 1) in experimental animals induces central nervous system (CNS) demyelinating lesions, but the potential relevance of this model to multiple sclerosis is lessened by the unifocal nature of the lesion. In this study, inbred strains of mice were selected on the basis of varying resistance to mortality following lip inoculation with virus. A spectrum of CNS pathology was observed, ranging from focal collections of inflammatory cells at the trigeminal root entry zone in resistant strains (C57BL/6J), to unifocal demyelinating lesions in moderately resistant strains (BALB/cByJ), to multifocal demyelinating lesions throughout the brain in susceptible strains (A/J). Findings from viral titration studies of the CNS support a direct cytolytic effect of virus in the development of demyelinating lesions at the trigeminal root entry zone but cannot exclude an immune-mediated component. Furthermore, 50% tissue-culture-infective doses, immunofluorescence, and electron microscopic studies of primary cultures of oligodendrocytes, derived from the three strains of adult mice, identify differences in resistance to HSV 1 infection in vitro, suggesting that differences at this level may also contribute to the pathological appearance. Multifocal lesions in A/J mice were first observed when the infectious virus could no longer be isolated from the CNS and may be the result of an immune-mediated process "triggered" by the acute CNS infection in susceptible strains of mice.

  17. Matrine protects neuro-axon from CNS inflammation-induced injury.

    PubMed

    Kan, Quan-Cheng; Lv, Peng; Zhang, Xiao-Jian; Xu, Yu-Ming; Zhang, Guang-Xian; Zhu, Lin

    2015-02-01

    Neuro-axonal injury in the central nervous system (CNS) is one of the major pathological hallmarks of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has recently been shown to effectively suppress EAE through an anti-inflammatory mechanism. However, whether MAT can also protect myelin/axons from damage is not known. In the present study we show that, while untreated rats developed severe clinical disease, CNS inflammatory demyelination, and axonal damage, these clinical and pathological signs were significantly reduced by MAT treatment. Consistently, MAT treatment reduced the concentration of myelin basic protein in serum and downregulated expression of β-amyloid (Aβ) and B-site APP cleaving enzyme 1 (BACE-1) in the CNS. Further, the CNS of MAT-treated rats exhibited increased expression of brain-derived neurotrophic factor (BDNF), an important factor for neuronal survival and axonal growth. Together, these results demonstrate that MAT effectively prevented neuro-axonal injury, which can likely be attributed to inhibiting risk factors such as BACE-1 and upregulating neuroprotective factors such as BDNF. We conclude that this novel natural reagent, MAT, which effectively protects neuro-axons from CNS inflammation-induced damage, could be a potential candidate for the treatment of neurodegenerative diseases such as MS.

  18. Aberrant dendritic excitability: a common pathophysiology in CNS disorders affecting memory?

    PubMed Central

    Nestor, Michael W.; Hoffman, Dax A.

    2012-01-01

    Discovering the etiology of pathophysiologies and aberrant behavior in many central nervous system (CNS) disorders has proven elusive because susceptibility to these diseases can be a product of multiple factors such as genetics, epigenetics, and environment. Advances in molecular biology and wide-scale genomics have shown that a large heterogeneity of genetic mutations are potentially responsible for the neuronal pathologies and dysfunctional behaviors seen in CNS disorders. (Need to distinguish between pure genetic forms which are rare, and what most people get which is probable combination of genetic susceptibility and environmental insults). Despite this seemingly complex array of genetic and physiological factors, many disorders of the CNS converge on common dysfunctions in memory. In this review, we propose that mechanisms underlying the development of many CNS diseases may share an underlying cause involving abnormal dendritic integration of synaptic signals. Through understanding the relationship between molecular genetics and dendritic computation, future research may uncover important links between neuronal physiology at the cellular level and higher-order circuit and network abnormalities observed in CNS diseases, and their subsequent affect on memory. PMID:22528602

  19. Global stability and tumor clearance conditions for a cancer chemotherapy system

    NASA Astrophysics Data System (ADS)

    Valle, Paul A.; Starkov, Konstantin E.; Coria, Luis N.

    2016-11-01

    In this paper we study the global dynamics of a cancer chemotherapy system presented by de Pillis et al. (2007). This mathematical model describes the interaction between tumor cells, effector-immune cells, circulating lymphocytes and chemotherapy treatment. By applying the localization method of compact invariant sets, we find lower and upper bounds for these three cells populations. Further, we define a bounded domain in R+,04 where all compact invariant sets of the system are located and provide conditions under which this domain is positively invariant. We apply LaSalle's invariance principle and one result concerning two-dimensional competitive systems in order to derive sufficient conditions for tumor clearance and global asymptotic stability of the tumor-free equilibrium point. These conditions are computed by using bounds of the localization domain and they are given in terms of the chemotherapy treatment. Finally, we perform numerical simulations in order to illustrate our results.

  20. Multicolor detection of rare tumor cells in blood using a novel flow cytometry-based system.

    PubMed

    Watanabe, Masaru; Uehara, Yuri; Yamashita, Namiko; Fujimura, Yuu; Nishio, Kaori; Sawada, Takeshi; Takeda, Kazuo; Koizumi, Fumiaki; Koh, Yasuhiro

    2014-03-01

    The presence and number of circulating tumor cells (CTCs) in the blood of patients with solid tumors are predictive of their clinical outcomes. To date, the CellSearch system is the only US Food and Drug Administration-approved CTC enumeration system for advanced breast, prostate, and colon cancers. However, sensitivity issues due to epithelial cellular adhesion molecule (EpCAM)-based enrichment and limited capability for subsequent molecular analysis must be addressed before CTCs can be used as predictive markers in the clinical setting. We have developed a multicolor CTC detection system using cross-contamination-free flow cytometry, which permits the enumeration and characterization of CTCs for multiple molecular analyses. Tumor cell lines with different expression levels of EpCAM were spiked into peripheral blood obtained from healthy donors. Spike-in samples were negatively enriched using anti-CD45-coated magnetic beads to remove white blood cells, and this was followed by fixation and labeling with CD45-Alexa Fluor 700, EpCAM-phycoerythrin, cytokeratin (CK)-fluorescein isothiocyanate antibodies, and/or 7-aminoactinomycin D for nuclei staining. Excellent detection (slope = 0.760-0.888) and a linear performance (R(2) = 0.994-0.998) were noted between the observed and expected numbers of tumor cells, independent of EpCAM expression. The detection rate was markedly higher than that obtained using the CellSearch system, suggesting the superior sensitivity of our system in detecting EpCAM- tumor cells. Additionally, the incorporation of an epithelial-mesenchymal transition (EMT) marker allowed us to detect EpCAM-/CK- cells and EMT-induced tumor cells. Taken together, our multicolor CTC detection system may be highly efficient in detecting previously unrecognized populations of CTCs.

  1. Tumor Endothelial Cell-Specific Drug Delivery System Using Apelin-Conjugated Liposomes

    PubMed Central

    Kawahara, Hiroki; Naito, Hisamichi; Takara, Kazuhiro; Wakabayashi, Taku; Kidoya, Hiroyasu; Takakura, Nobuyuki

    2013-01-01

    Background A drug delivery system specifically targeting endothelial cells (ECs) in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors. Methods and Results Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs. Conclusions ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors. PMID:23799018

  2. Stochastic resonance in a tumor-immune system subject to bounded noises and time delay

    NASA Astrophysics Data System (ADS)

    Guo, Wei; Mei, Dong-Cheng

    2014-12-01

    Immunotherapy is one of the most recent approaches in cancer therapy. A mathematical model of tumor-immune interaction, subject to a periodic immunotherapy treatment (imitated by a periodic signal), correlative and bounded stochastic fluctuations and time delays, is investigated by numerical simulations for its signal power amplification (SPA). Within the tailored parameter regime, the synchronous response of tumor growth to the immunotherapy, stochastic resonance (SR), versus both the noises and delays is obtained. The details are as follows (i) the peak values of SPA versus the noise intensity (A) in the proliferation term of tumor cells decrease as the frequency of periodic signal increases, i.e. an increase of the frequency restrains the SR; (ii) an increase of the amplitude of periodic signal restrains the SR versus A, but boosts up the SR versus the noise intensity B in the immune term; (iii) there is an optimum cross-correlated degree between the two bounded noises, at which the system exhibits the strongest SR versus the delay time τα(the reaction time of tumor cell population to their surrounding environment constraints); (iv) upon increasing the delay time τα, double SR versus the delay time τβ (the time taken by both the tumor antigen identification and tumor-stimulated proliferation of effectors) emerges. These results may be helpful for an immunotherapy treatment for the sufferer.

  3. A review of gene therapy for the treatment of central nervous system tumors.

    PubMed

    Qureshi, N H; Chiocca, E A

    1999-01-01

    The transfer of genes into tumors of the central nervous system has been touted as a novel treatment. However, several scientific and technological hurdles will have to be resolved before such strategies become useful clinical tools. This review summarizes the current knowledge in the field. Some of the gene delivery vectors employed both preclinically and clinically are those based on retroviruses, herpes simplex viruses, adenoviruses, adeno-associated viruses, and reoviruses. Cells such as fibroblasts and neural progenitor cells may also provide therapeutic value. These vectors are used to deliver into the tumor cell a variety of anticancer genes, such as those that activate chemotherapy agents, increase tumor immunogenicity, modulate tumor apoptosis and/or angiogenesis. One of the issues confronting such therapeutic strategies revolves around the blood-brain-barrier that may limit the penetration of vectors and genes form the circulation into the tumor. Results from a variety of clinical trials are becoming available. While the safety of this treatment strategy appears to have been established, therapeutic efficacy has been lacking. Additional refinements in the basic technology of vector construction and further understanding of the basic biology of gene transfer and expression will help in establishing gene therapy as clinically useful against brain tumors.

  4. Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery

    PubMed Central

    Stewart, Adam Michael; Gerlai, Robert; Kalueff, Allan V.

    2015-01-01

    The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery. PMID:25729356

  5. Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery.

    PubMed

    Stewart, Adam Michael; Gerlai, Robert; Kalueff, Allan V

    2015-01-01

    The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery. PMID:25729356

  6. Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery.

    PubMed

    Stewart, Adam Michael; Gerlai, Robert; Kalueff, Allan V

    2015-01-01

    The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery.

  7. Preparation of embryonic retinal explants to study CNS neurite growth.

    PubMed

    Hanea, Sonia T; Shanmugalingam, Ushananthini; Fournier, Alyson E; Smith, Patrice D

    2016-05-01

    This protocol outlines the preparation of embryonic mouse retinal explants, which provides an effective technique to analyze neurite outgrowth in central nervous system (CNS) neurons. This validated ex vivo system, which displays limited neuronal death, is highly reproducible and particularly amenable to manipulation. Our previously published studies involving embryonic chick or adult mouse retinal explants were instrumental in the preparation of this protocol; aspects of these previous techniques were combined, adopted and optimized. This protocol thus permits more efficient analysis of neurite growth. Briefly, the retina is dissected from the embryonic mouse eye using precise techniques that take into account the small size of the embryonic eye. The approach applied ensures that the retinal ganglion cell (RGC) layer faces the adhesion substrate on coated cover slips. Neurite growth is clear, well-delineated and readily quantifiable. These retinal explants can therefore be used to examine the neurite growth effects elicited by potential therapeutic agents. PMID:27072342

  8. Autoimmune control of lesion growth in CNS with minimal damage

    NASA Astrophysics Data System (ADS)

    Mathankumar, R.; Mohan, T. R. Krishna

    2013-07-01

    Lesions in central nervous system (CNS) and their growth leads to debilitating diseases like Multiple Sclerosis (MS), Alzheimer's etc. We developed a model earlier [1, 2] which shows how the lesion growth can be arrested through a beneficial auto-immune mechanism. We compared some of the dynamical patterns in the model with different facets of MS. The success of the approach depends on a set of control parameters and their phase space was shown to have a smooth manifold separating the uncontrolled lesion growth region from the controlled. Here we show that an optimal set of parameter values exist in the model which minimizes system damage while, at once, achieving control of lesion growth.

  9. Oncogenic extracellular vesicles in brain tumor progression.

    PubMed

    D'Asti, Esterina; Garnier, Delphine; Lee, Tae H; Montermini, Laura; Meehan, Brian; Rak, Janusz

    2012-01-01

    The brain is a frequent site of neoplastic growth, including both primary and metastatic tumors. The clinical intractability of many brain tumors and their distinct biology are implicitly linked to the unique microenvironment of the central nervous system (CNS) and cellular interactions within. Among the most intriguing forms of cellular interactions is that mediated by membrane-derived extracellular vesicles (EVs). Their biogenesis (vesiculation) and uptake by recipient cells serves as a unique mechanism of intercellular trafficking of complex biological messages including the exchange of molecules that cannot be released through classical secretory pathways, or that are prone to extracellular degradation. Tumor cells produce EVs containing molecular effectors of several cancer-related processes such as growth, invasion, drug resistance, angiogenesis, and coagulopathy. Notably, tumor-derived EVs (oncosomes) also contain oncogenic proteins, transcripts, DNA, and microRNA (miR). Uptake of this material may change properties of the recipient cells and impact the tumor microenvironment. Examples of transformation-related molecules found in the cargo of tumor-derived EVs include the oncogenic epidermal growth factor receptor (EGFRvIII), tumor suppressors (PTEN), and oncomirs (miR-520g). It is postulated that EVs circulating in blood or cerebrospinal fluid (CSF) of brain tumor patients may be used to decipher molecular features (mutations) of the underlying malignancy, reflect responses to therapy, or molecular subtypes of primary brain tumors [e.g., glioma or medulloblastoma (MB)]. It is possible that metastases to the brain may also emit EVs with clinically relevant oncogenic signatures. Thus, EVs emerge as a novel and functionally important vehicle of intercellular communication that can mediate multiple biological effects. In addition, they provide a unique platform to develop molecular biomarkers in brain malignancies. PMID:22934045

  10. Immunotherapy for cancer in the central nervous system: Current and future directions

    PubMed Central

    Binder, David C.; Davis, Andrew A.; Wainwright, Derek A.

    2016-01-01

    ABSTRACT Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and still remains incurable. Although immunotherapeutic vaccination against GBM has demonstrated immune-stimulating activity with some promising survival benefits, tumor relapse is common, highlighting the need for additional and/or combinatorial approaches. Recently, antibodies targeting immune checkpoints were demonstrated to generate impressive clinical responses against advanced melanoma and other malignancies, in addition to showing potential for enhancing vaccination and radiotherapy (RT). Here, we summarize the current knowledge of central nervous system (CNS) immunosuppression, evaluate past and current immunotherapeutic trials and discuss promising future immunotherapeutic directions to treat CNS-localized malignancies. PMID:27057463

  11. Improved local and systemic anti-tumor efficacy for irreversible electroporation in immunocompetent versus immunodeficient mice.

    PubMed

    Neal, Robert E; Rossmeisl, John H; Robertson, John L; Arena, Christopher B; Davis, Erica M; Singh, Ravi N; Stallings, Jonathan; Davalos, Rafael V

    2013-01-01

    Irreversible electroporation (IRE) is a non-thermal focal ablation technique that uses a series of brief but intense electric pulses delivered into a targeted region of tissue, killing the cells by irrecoverably disrupting cellular membrane integrity. This study investigates if there is an improved local anti-tumor response in immunocompetent (IC) BALB/c versus immunodeficient (ID) nude mice, including the potential for a systemic protective effect against rechallenge. Subcutaneous murine renal carcinoma tumors were treated with an IRE pulsing protocol that used 60% of the predicted voltage required to invoke complete regressions in the ID mice. Tumors were followed for 34 days following treatment for 11 treated mice from each strain, and 7 controls from each strain. Mouse survival based on tumor burden and the progression-free disease period was substantially longer in the treated IC mice relative to the treated ID mice and sham controls for both strains. Treated IC mice were rechallenged with the same cell line 18 days after treatment, where growth of the second tumors was shown to be significantly reduced or prevented entirely. There was robust CD3+ cell infiltration in some treated BALB/C mice, with immunocytes focused at the transition between viable and dead tumor. There was no difference in the low immunocyte presence for untreated tumors, nude mice, and matrigel-only injections in both strains. These findings suggest IRE therapy may have greater therapeutic efficacy in immunocompetent patients than what has been suggested by immunodeficient models, and that IRE may invoke a systemic response beyond the targeted ablation region. PMID:23717630

  12. Improved Local and Systemic Anti-Tumor Efficacy for Irreversible Electroporation in Immunocompetent versus Immunodeficient Mice

    PubMed Central

    Neal, Robert E.; Rossmeisl, John H.; Robertson, John L.; Arena, Christopher B.; Davis, Erica M.; Singh, Ravi N.; Stallings, Jonathan; Davalos, Rafael V.

    2013-01-01

    Irreversible electroporation (IRE) is a non-thermal focal ablation technique that uses a series of brief but intense electric pulses delivered into a targeted region of tissue, killing the cells by irrecoverably disrupting cellular membrane integrity. This study investigates if there is an improved local anti-tumor response in immunocompetent (IC) BALB/c versus immunodeficient (ID) nude mice, including the potential for a systemic protective effect against rechallenge. Subcutaneous murine renal carcinoma tumors were treated with an IRE pulsing protocol that used 60% of the predicted voltage required to invoke complete regressions in the ID mice. Tumors were followed for 34 days following treatment for 11 treated mice from each strain, and 7 controls from each strain. Mouse survival based on tumor burden and the progression-free disease period was substantially longer in the treated IC mice relative to the treated ID mice and sham controls for both strains. Treated IC mice were rechallenged with the same cell line 18 days after treatment, where growth of the second tumors was shown to be significantly reduced or prevented entirely. There was robust CD3+ cell infiltration in some treated BALB/C mice, with immunocytes focused at the transition between viable and dead tumor. There was no difference in the low immunocyte presence for untreated tumors, nude mice, and matrigel-only injections in both strains. These findings suggest IRE therapy may have greater therapeutic efficacy in immunocompetent patients than what has been suggested by immunodeficient models, and that IRE may invoke a systemic response beyond the targeted ablation region. PMID:23717630

  13. Grading of complications of transurethral resection of bladder tumor using Clavien–Dindo classification system

    PubMed Central

    Bansal, Ankur; Sankhwar, Satyanarayan; Goel, Apul; Kumar, Manoj; Purkait, Bimalesh; Aeron, Ruchir

    2016-01-01

    Introduction: Clavien–Dindo classification system is used for grading complications of various oncological, renal, and endourological procedures. We applied this system for grading the severity of perioperative complications in patients undergoing transurethral resection of bladder tumor (TURBT) and identify parameters predicting these complications. Materials and Methods: Data of 984 patients who underwent TURBT from 2006 to 2014 were included in this study. All data was retrospectively collected and analyzed for complications occurring within the first postoperative month. All complications were classified according to the five grades of modified CCS (.Clavien classification system). Results: A total of 172 complications were observed in 138 patients. Majority were low grade complications (Grade 1 [77.3%] and Grade 2 [12.7%]). Higher grade complications were rare (Grade 3 [6.4%] and Grade 4 [3.0%]). There was one death (Grade 5 0.6%), with an overall mortality rate of 0.1%. The incidence of complications was significantly greater for age >60 years, baseline serum creatinine >1.4 mg/dl, size of tumor >4 cm, tumor located at dome, resection time >60 min, incomplete resection and if surgery performed by a resident urologist. Conclusions: Clavien–Dindo classification system can be easily applied to grade the complications of TURBT, and it is easily reproducible. We observed that TURBT was a safe procedure. Majority of complications were Grade 1–2 (90%) and Grade 3–5 were rare (10%). Postoperative bleeding is the most common complication. A greater rate of complications of TURBT was associated with patient age, size of tumor, location of tumor, surgeon experience, resection time, and completion of tumor resection. PMID:27555684

  14. Molecular determinants of lung cancer metastasis to the central nervous system

    PubMed Central

    Whitsett, Timothy G.; Inge, Landon J.; Dhruv, Harshil D.; Cheung, Philip Y.; Weiss, Glen J.; Bremner, Ross M.; Winkles, Jeffrey A.

    2013-01-01

    Lung cancer remains the leading cause of cancer-related mortality worldwide. The propensity for metastasis to the central nervous system (CNS) is a major clinical hurdle contributing to the low five-year survival rate of advanced disease. CNS metastases significantly outnumber primary brain tumors and carry a dismal prognosis in part due to the inability of therapeutic agents to cross the blood brain barrier. Standard treatment using radiation has been largely ineffective in improving mortality, suggesting the need for new agents targeting the critical metastatic drivers. The genetic and molecular events governing CNS metastasis from the lung are poorly understood at this time. This review highlights genetic events associated with CNS dissemination from the lung and molecular mechanisms associated with CNS metastasis. In vivo model systems that faithfully recapitulate escape from the lung and colonization of the CNS are described as tools for understanding the metastatic phenotype and for testing new therapeutic agents. A deeper understanding of the mechanisms of lung cancer metastasis to the CNS is needed to elucidate novel therapeutic avenues towards the improvement of the mortality associated with advanced stage lung cancer. PMID:25806243

  15. Clinical outcomes of systemic therapy for patients with deep fibromatoses (desmoid tumors)

    PubMed Central

    de Camargo, Veridiana Pires; Keohan, Mary L.; D’Adamo, David R.; Antonescu, Cristina R.; Brennan, Murray F.; Singer, Samuel; Ahn, Linda S.; Maki, Robert G.

    2010-01-01

    Objectives We examined outcomes of patients with desmoid tumors receiving systemic therapy at a single institution to provide a basis for examination of newer agents. Methods We reviewed records of patients with desmoid tumors treated with chemotherapy at our institution. The activity of NSAIDs was not addressed. Patients without measurable disease, those receiving therapy we could not document, and those receiving prophylactic therapy were excluded. Results Sixty-eight patients received 157 lines of therapy. Nine patients died, 7 of progressive disease. The cohort was 62% female with median age 32.5, 32% with Gardner syndrome, median follow-up 63 months, and median of 2 lines of therapy. Intra-abdominal primary location was most common (44%). The greatest RECIST response rate was observed with anthracyclines and hormonal therapy and lowest with single agent dacarbazine/temozolomide or tyrosine kinase inhibitors, principally imatinib. In a multivariate analysis, only nodular gross morphology and presence of Gardner syndrome were the only tumor factors associated with greater time to progression. Conclusions Anti-estrogens and anthracycline-containing regimens are associated with a higher radiological response rate against desmoid tumors than other agents. Systemic therapy for desmoid tumors can be successful in patients with desmoids, and is a viable option in lieu of morbid or disabling surgery. PMID:20187095

  16. Split immunity: immune inhibition of rat gliomas by subcutaneous exposure to unmodified live tumor cells.

    PubMed

    Volovitz, Ilan; Marmor, Yotvat; Azulay, Meir; Machlenkin, Arthur; Goldberger, Ofir; Mor, Felix; Slavin, Shimon; Ram, Zvi; Cohen, Irun R; Eisenbach, Lea

    2011-11-15

    Gliomas that grow uninhibited in the brain almost never metastasize outside the CNS. The rare occurrences of extracranial metastasis are usually associated with a suppressed immune system. This observation raises the possibility that some gliomas might not grow outside the CNS due to an inherent immune response, We report in this study that the highly malignant F98 Fischer rat undifferentiated glioma, which grows aggressively in the brain, spontaneously regresses when injected live s.c. We found that this regression is immune-mediated and that it markedly enhances the survival or cures rats challenged with the same tumor intracranially either before or after the s.c. live-cell treatment. Adoptive transfer experiments showed the effect was immune-mediated and that the CD8 T cell fraction, which exhibited direct tumor cytotoxicity, was more effective than the CD4 T cell fraction in mediating resistance to intracranial challenge of naive rats. Brain tumors from treated rats exhibited enhanced CD3(+)CD8(+)CD4(-) and CD3(+)CD4(+)CD8(-) T cell infiltration and IFN-γ secretion. The results in the F98 glioma were corroborated in the Lewis rat CNS-1 astrocytoma. In both tumor models, s.c. treatment with live cells was significantly better than immunization with irradiated cells. We propose in this study a location-based immunotherapeutic phenomenon we term "split immunity": a tumor that thrives in an immune-privileged site may be inhibited by injecting live, unmodified tumor cells into a site that is not privileged, generating protective immunity that spreads back to the privileged site. Split immunity could explain several long-standing paradoxes regarding the lack of overt extracranial metastasis in patients with primary brain tumors.

  17. Asymptotic profile of a parabolic-hyperbolic system with boundary effect arising from tumor angiogenesis

    NASA Astrophysics Data System (ADS)

    Mei, Ming; Peng, Hongyun; Wang, Zhi-An

    2015-11-01

    This paper concerns a parabolic-hyperbolic system on the half space R+ with boundary effect. The system is derived from a singular chemotaxis model describing the initiation of tumor angiogenesis. We show that the solution of the system subject to appropriate boundary conditions converges to a traveling wave profile as time tends to infinity if the initial data is a small perturbation around the wave which is shifted far away from the boundary but its amplitude can be arbitrarily large.

  18. CNS activity of Calotropis gigantea roots.

    PubMed

    Argal, Ameeta; Pathak, Anupam Kumar

    2006-06-15

    Alcoholic extract of peeled roots of Calotropis gigantea R.Br. (Asclepiadaceae) was tested orally in albino rats at the dose level of 250 and 500 mg/kg bodyweight for CNS activity. Prominent analgesic activity was observed in Eddy's hot plate method and acetic acid induced writhings. The paw licking time was delayed and the numbers of writhings were greatly reduced. Significant anticonvulsant activity was seen as there was a delay in the onset of pentylenetetrazole induced convulsions as well as decrease in its severity. The extract treated rats spent more time in the open arm of EPM showing its antianxiety activity. There was a decrease in the locomotor activity. The fall off time (motor coordination) was also decreased. A potentiation in the pentobarbitone-induced sleep due to the sedative effect of the extract was observed. No mortality was seen upto the dose of 1 g/kg. These results show the analgesic, anticonvulsant, anxiolytic and sedative effect of the extract.

  19. p28 in Treating Younger Patients With Recurrent or Progressive Central Nervous System Tumors

    ClinicalTrials.gov

    2016-10-21

    Teratoid Tumor, Atypical; Choroid Plexus Neoplasms; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Brainstem Tumors; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Medulloblastoma; Neuroectodermal Tumor, Primitive

  20. Precise Scheduling of Chemotherapy Primes VEGF-producing Tumors for Successful Systemic Oncolytic Virotherapy

    PubMed Central

    Kottke, Timothy; Chester, John; Ilett, Elizabeth; Thompson, Jill; Diaz, Rosa; Coffey, Matt; Selby, Peter; Nuovo, Gerard; Pulido, Jose; Mukhopadhyay, Debabrata; Pandha, Hardev; Harrington, Kevin; Melcher, Alan; Vile, Richard

    2011-01-01

    We have previously reported that a burst of vascular endothelial growth factor (VEGF) signaling to tumor-associated endothelium induces a proviral state, during which systemically delivered oncolytic reovirus can replicate in endothelium, thereby inducing immune-mediated vascular collapse and significant antitumor therapy. Using chimeric receptors, we show here that induction of the proviral state proceeds through VEGFR2, but not VEGFR1, signaling in endothelial cells. In contrast, innate immune activation by reovirus-exposed endothelial cells was predominantly through VEGFR1. By screening conventional chemotherapies for their ability to induce similar effects in combination with reovirus both in vitro and in vivo, we observed that the proviral state could also be induced in endothelial cells exposed to VEGF during rebound from paclitaxel-mediated inhibition of VEGF signaling. We translated these in vitro findings in vivo by careful scheduling of paclitaxel chemotherapy with systemic virotherapy, neither of which alone had therapeutic effects against B16 tumors. Systemic availability of reovirus during endothelial cell recovery from paclitaxel treatment allowed for endothelial replication of the virus, immune-mediated therapy, and tumor cures. Therefore, careful scheduling of combination viro- and chemotherapies, which preclinical testing suggests are individually ineffective against tumor cells, can lead to rational new clinical protocols for systemic treatments with oncolytic viruses. PMID:21792179

  1. Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy.

    PubMed

    Kottke, Timothy; Chester, John; Ilett, Elizabeth; Thompson, Jill; Diaz, Rosa; Coffey, Matt; Selby, Peter; Nuovo, Gerard; Pulido, Jose; Mukhopadhyay, Debabrata; Pandha, Hardev; Harrington, Kevin; Melcher, Alan; Vile, Richard

    2011-10-01

    We have previously reported that a burst of vascular endothelial growth factor (VEGF) signaling to tumor-associated endothelium induces a proviral state, during which systemically delivered oncolytic reovirus can replicate in endothelium, thereby inducing immune-mediated vascular collapse and significant antitumor therapy. Using chimeric receptors, we show here that induction of the proviral state proceeds through VEGFR2, but not VEGFR1, signaling in endothelial cells. In contrast, innate immune activation by reovirus-exposed endothelial cells was predominantly through VEGFR1. By screening conventional chemotherapies for their ability to induce similar effects in combination with reovirus both in vitro and in vivo, we observed that the proviral state could also be induced in endothelial cells exposed to VEGF during rebound from paclitaxel-mediated inhibition of VEGF signaling. We translated these in vitro findings in vivo by careful scheduling of paclitaxel chemotherapy with systemic virotherapy, neither of which alone had therapeutic effects against B16 tumors. Systemic availability of reovirus during endothelial cell recovery from paclitaxel treatment allowed for endothelial replication of the virus, immune-mediated therapy, and tumor cures. Therefore, careful scheduling of combination viro- and chemotherapies, which preclinical testing suggests are individually ineffective against tumor cells, can lead to rational new clinical protocols for systemic treatments with oncolytic viruses. PMID:21792179

  2. 21 CFR 866.6010 - Tumor-associated antigen immunological test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Tumor-associated antigen immunological test system. 866.6010 Section 866.6010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN..., plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for...

  3. 21 CFR 866.6010 - Tumor-associated antigen immunological test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Tumor-associated antigen immunological test system. 866.6010 Section 866.6010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN..., plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for...

  4. [Suspicion of anorexia nervosa as a cause of delayed diagnosis of brain tumor. A case report].

    PubMed

    Niedzielska, Ewa; Węcławek-Tompol, Jadwiga; Kazanowska, Bernarda; Barg, Ewa

    2015-01-01

    Tumors of the central nervous system (CNS) are the most common solid tumors diagnosed in children. The most frequent symptoms of brain tumors in this age group are headaches and vomiting, regardless of the location of the lesions. These symptoms are non-specific, and in each case require differential diagnosis, especially if there is no gradual improvement in the patient's condition or progression. The most common signs of anorexia nervosa are chronic vomiting, weakness of the body, pain and in extreme cases cachexia. These symptoms are similar to the clinical image of CNS tumor. Teenager, described in our case report presented the following signs for several weeks prior to the diagnosis of a brain tumor: vomiting (especially after meals), non-specific headache and epigastric pain. No significant progression in the patient's condition oriented the diagnostic process towards anorexia nervosa. Although anorexia in this age group is much more common disease, compared to a brain tumor, it is vital to ruled out/ exclude organic disorders prior to diagnosis of psychogenic disorder. At the same time the waiting for the specialist consultations (ophthalmologist, neurologist) and test results (head CT, head NMR) should not prolong the patients referral to a specialist center. PMID:26615049

  5. Biocompatability of carbon nanotubes with stem cells to treat CNS injuries

    PubMed Central

    Bokara, Kiran Kumar; Kim, Jong Youl; Lee, Young Il; Yun, Kyungeun; Webster, Tom J

    2013-01-01

    Cases reporting traumatic injuries to the brain and spinal cord are extended range of disorders that affect a large percentage of the world's population. But, there are only few effective treatments available for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. The use of stem cell therapy in regenerative medicine has been extensively examined to replace lost cells during CNS injuries. But, given the complexity of CNS injuries oxidative stress, toxic byproducts, which prevails in the microenvironment during the diseased condition, may limit the survival of the transplanted stem cells affecting tissue regeneration and even longevity. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine for the prevention, diagnosis and therapy of certain diseases, including CNS diseases. In particular, the use of CNTs as substrates/scaffolds for supporting the stem cell differentiation has been an area of active research. Single-walled and multi-walled CNT's have been increasingly used as scaffolds for neuronal growth and more recently for neural stem cell growth and differentiation. This review summarizes recent research on the application of CNT-based materials to direct the differentiation of progenitor and stem cells toward specific neurons and to enhance axon regeneration and synaptogenesis for the effective treatment of CNS injuries. Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in neurological research. PMID:23869255

  6. [Metastasis tumors of the central nervous system: molecular biology].

    PubMed

    Bello, M Josefa; González-Gómez, P; Rey, J A

    2004-12-01

    Metastases in the nervous system represent an important and growing problem in the clinical practice, being the cause of a great mortality in the developed countries. This article reviews the few data available on the molecular mechanisms involved in the pathogenesis of these tumours, leading to oncogene activation, inactivation of tumour suppressor genes, not only by the classical mechanisms, but also by the tumour cell epigenetic balance alteration. We conclude that all this knowledge will lead in the future to a better diagnosis, treatment and clinic evolution of these patients.

  7. The electromagnetic-trait imaging computation of traveling wave method in breast tumor microwave sensor system.

    PubMed

    Tao, Zhi-Fu; Han, Zhong-Ling; Yao, Meng

    2011-01-01

    Using the difference of dielectric constant between malignant tumor tissue and normal breast tissue, breast tumor microwave sensor system (BRATUMASS) determines the detected target of imaging electromagnetic trait by analyzing the properties of target tissue back wave obtained after near-field microwave radicalization (conelrad). The key of obtained target properties relationship and reconstructed detected space is to analyze the characteristics of the whole process from microwave transmission to back wave reception. Using traveling wave method, we derive spatial transmission properties and the relationship of the relation detected points distances, and valuate the properties of each unit by statistical valuation theory. This chapter gives the experimental data analysis results.

  8. Application of a spring-dashpot system to clinical lung tumor motion data

    SciTech Connect

    Ackerley, E. J.; Wilson, P. L.; Cavan, A. E.; Berbeco, R. I.; Meyer, J.

    2013-02-15

    Purpose: The treatment efficacy of radiation therapy for lung tumors can be increased by compensating for breath-induced tumor motion. In this study, we quantitatively examine a mathematical model of pseudomechanical linkages between an external surrogate signal and lung tumor motion. Methods: A spring-dashpot system based on the Voigt model was developed to model the correlation between abdominal respiratory motion and tumor motion during lung radiotherapy. The model was applied to clinical data obtained from 52 treatments ('beams') from 10 patients, treated on the Mitsubishi Real-Time Radiation Therapy system, Sapporo, Japan. In Stage 1, model parameters were optimized for individual patients and beams to determine reference values and to investigate how well the model can describe the data. In Stage 2, for each patient the optimal parameters determined for a single beam were applied to data from other beams to investigate whether a beam-specific set of model parameters is sufficient to model tumor motion over a course of treatment. Results: In Stage 1, the baseline root mean square (RMS) residual error for all individually optimized beam data was 0.90 {+-} 0.40 mm (mean {+-} 1 standard deviation). In Stage 2, patient-specific model parameters based on a single beam were found to model the tumor position closely, even for irregular beam data, with a mean increase with respect to Stage 1 values in RMS error of 0.37 mm. On average, the obtained model output for the tumor position was 95% of the time within an absolute bound of 2.0 and 2.6 mm in Stages 1 and 2, respectively. The model was capable of dealing with baseline, amplitude and frequency variations of the input data, as well as phase shifts between the input abdominal and output tumor signals. Conclusions: These results indicate that it may be feasible to collect patient-specific model parameters during or prior to the first treatment, and then retain these for the rest of the treatment period. The model has

  9. Gene therapy for CNS diseases – Krabbe disease

    PubMed Central

    Rafi, Mohammad A.

    2016-01-01

    Summary This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS) Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV) alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases. PMID:27525222

  10. Periodic and chaotic oscillations in a tumor and immune system interaction model with three delays

    SciTech Connect

    Bi, Ping; Ruan, Shigui; Zhang, Xinan

    2014-06-15

    In this paper, a tumor and immune system interaction model consisted of two differential equations with three time delays is considered in which the delays describe the proliferation of tumor cells, the process of effector cells growth stimulated by tumor cells, and the differentiation of immune effector cells, respectively. Conditions for the asymptotic stability of equilibria and existence of Hopf bifurcations are obtained by analyzing the roots of a second degree exponential polynomial characteristic equation with delay dependent coefficients. It is shown that the positive equilibrium is asymptotically stable if all three delays are less than their corresponding critical values and Hopf bifurcations occur if any one of these delays passes through its critical value. Numerical simulations are carried out to illustrate the rich dynamical behavior of the model with different delay values including the existence of regular and irregular long periodic oscillations.

  11. Synoptic reporting in tumor pathology: advantages of a web-based system.

    PubMed

    Qu, Zhenhong; Ninan, Shibu; Almosa, Ahmed; Chang, K G; Kuruvilla, Supriya; Nguyen, Nghia

    2007-06-01

    The American College of Surgeons Commission on Cancer (ACS-CoC) mandates that pathology reports at ACS-CoC-approved cancer programs include all scientifically validated data elements for each site and tumor specimen. The College of American Pathologists (CAP) has produced cancer checklists in static text formats to assist reporting. To be inclusive, the CAP checklists are pages long, requiring extensive text editing and multiple intermediate steps. We created a set of dynamic tumor-reporting templates, using Microsoft Active Server Page (ASP.NET), with drop-down list and data-compile features, and added a reminder function to indicate missing information. Users can access this system on the Internet, prepare the tumor report by selecting relevant data from drop-down lists with an embedded tumor staging scheme, and directly transfer the final report into a laboratory information system by using the copy-and-paste function. By minimizing extensive text editing and eliminating intermediate steps, this system can reduce reporting errors, improve work efficiency, and increase compliance.

  12. A Type-2 Fuzzy Image Processing Expert System for Diagnosing Brain Tumors.

    PubMed

    Zarinbal, M; Fazel Zarandi, M H; Turksen, I B; Izadi, M

    2015-10-01

    The focus of this paper is diagnosing and differentiating Astrocytomas in MRI scans by developing an interval Type-2 fuzzy automated tumor detection system. This system consists of three modules: working memory, knowledge base, and inference engine. An image processing method with three steps of preprocessing, segmentation and feature extraction, and approximate reasoning is used in inference engine module to enhance the quality of MRI scans, segment them into desired regions, extract the required features, and finally diagnose and differentiate Astrocytomas. However, brain tumors have different characteristics in different planes, so considering one plane of patient's MRI scan may cause inaccurate results. Therefore, in the developed system, several consecutive planes are processed. The performance of this system is evaluated using 95 MRI scans and the results show good improvement in diagnosing and differentiating Astrocytomas.

  13. Systemic DNA Damage Accumulation Under in Vivo Tumor Growth can be Inhibited by the Antioxidant Tempol

    PubMed Central

    Georgakilas, Alexandros G.; Redon, Christophe E.; Ferguson, Nicholas F.; Kryston, Thomas B.; Parekh, Palak; Dickey, Jennifer S.; Nakamura, Asako J.; Mitchell, James B.; Bonner, William M.; Martin, Olga A.

    2014-01-01

    Aims Recently we found that mice bearing subcutaneous non-metastatic tumors exhibited elevated levels of two types of complex DNA damage, i.e., double-strand breaks and oxidatively-induced clustered DNA lesions in various tissues throughout the body, both adjacent to and distant from the tumor site. This DNA damage was dependent on CCL2, a cytokine involved in the recruitment and activation of macrophages, suggesting that this systemic DNA damage was mediated via tumor-induced chronic inflammatory responses involving cytokines, activation of macrophages, and consequent free radical production. If free radicals are involved, then a diet containing an antioxidant may decrease the distant DNA damage. Results Here we repeated our standard protocol in cohorts of two syngeneic tumor-bearing C57BL/6NCr mice that were on a Tempol-supplemented diet. We show that double-strand break and oxidatively-induced clustered DNA lesion levels were considerably decreased, about 2-3 fold, in the majority of tissues studied from the tumor-bearing mice fed the antioxidant Tempol compared to the control tumor-bearing mice. Similar results were also observed in nude mice suggesting that the Tempol effects are independent of functioning adaptive immunity. Conclusions This is the first in vivo study demonstrating the effect of a dietary antioxidant on abscopal DNA damage in tissues distant from a localized source of genotoxic stress. These findings may be important for understanding the mechanisms of genomic instability and carcinogenesis caused by chronic stress-induced systemic DNA damage and for developing preventative strategies. PMID:25069035

  14. SU-E-J-182: Reproducibility of Tumor Motion Probability Distribution Function in Stereotactic Body Radiation Therapy of Lung Using Real-Time Tumor-Tracking Radiotherapy System

    SciTech Connect

    Shiinoki, T; Hanazawa, H; Park, S; Takahashi, T; Shibuya, K; Kawamura, S; Uehara, T; Yuasa, Y; Koike, M

    2015-06-15

    Purpose: We aim to achieve new four-dimensional radiotherapy (4DRT) using the next generation real-time tumor-tracking (RTRT) system and flattening-filter-free techniques. To achieve new 4DRT, it is necessary to understand the respiratory motion of tumor. The purposes of this study were: 1.To develop the respiratory motion analysis tool using log files. 2.To evaluate the reproducibility of tumor motion probability distribution function (PDF) during stereotactic body RT (SBRT) of lung tumor. Methods: Seven patients having fiducial markers closely implanted to the lung tumor were enrolled in this study. The positions of fiducial markers were measured using the RTRT system (Mitsubishi Electronics Co., JP) and recorded as two types of log files during the course of SBRT. For each patients, tumor motion range and tumor motion PDFs in left-right (LR), anterior-posterior (AP) and superior-inferior (SI) directions were calculated using log files of all beams per fraction (PDFn). Fractional PDF reproducibility (Rn) was calculated as Kullback-Leibler (KL) divergence between PDF1 and PDFn of tumor motion. The mean of Rn (Rm) was calculated for each patient and correlated to the patient’s mean tumor motion range (Am). The change of Rm during the course of SBRT was also evluated. These analyses were performed using in-house developed software. Results: The Rm were 0.19 (0.07–0.30), 0.14 (0.07–0.32) and 0.16 (0.09–0.28) in LR, AP and SI directions, respectively. The Am were 5.11 mm (2.58–9.99 mm), 7.81 mm (2.87–15.57 mm) and 11.26 mm (3.80–21.27 mm) in LR, AP and SI directions, respectively. The PDF reproducibility decreased as the tumor motion range increased in AP and SI direction. That decreased slightly through the course of RT in SI direction. Conclusion: We developed the respiratory motion analysis tool for 4DRT using log files and quantified the range and reproducibility of respiratory motion for lung tumors.

  15. Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

    PubMed

    Marques, Andrea Horvath; Bjørke-Monsen, Anne-Lise; Teixeira, Antônio L; Silverman, Marni N

    2015-08-18

    Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying

  16. The blood-brain barrier in primary CNS lymphomas: ultrastructural evidence of endothelial cell death.

    PubMed Central

    Molnár, P. P.; O'Neill, B. P.; Scheithauer, B. W.; Groothuis, D. R.

    1999-01-01

    The vasculature of 24 primary CNS B-cell lymphomas that were not related to acquired immunodeficiency syndrome was systematically studied by electron microscopy. Seven low-grade astrocytic tumors were included for comparison. Classical electron microscopy features of apoptosis were found in lymphoma cells of 21 of 22 subjects. Capillaries of gliomas and lymphomas showed changes reported previously: variability of endothelial cell (EC)-thickness and number, basal lamina thickness and duplication, and fenestrations. Primary CNS B-cell lymphoma ECs showed two distinctive populations of electron-dense and electron-lucent cells. The electron-dense ECs occurred in 38% of all capillaries, with changes consisting of chromatin condensation in bizarre and contracted nuclei, cytoplasmic shrinkage with markedly increased electron density, and dilatation of the endoplasmic reticulum. We interpreted these changes as indicative of apoptosis. Cell death eventually resulted in complete disintegration of the endothelium with frank discontinuities of the EC component of the blood-tumor barrier in capillaries and postcapillary venules. Another population of ECs had increased cell volume, conspicuous cytoplasmic electron lucency, dispersed organelles, scattered vesicles, and apical stress fibers. We interpreted these changes as indicative of cellular regeneration. Individual apoptotic ECs often lay next to normal or regenerating ECs. Neither type of EC change was observed in gliomas, which also lacked perivascular neoplastic lymphocytic cuffing. We believe that these populations of ECs, which have not been described in other disorders affecting the blood-brain barrier, may be induced by cytokines released from necrotic and/or apoptotic tumor lymphocytes and may explain the unusual imaging characteristics of primary CNS B-cell lymphomas treated with corticosteroids. PMID:11550310

  17. The efficiency of tumor cell purging using immunomagnetic CD34+ cell separation systems.

    PubMed

    Roots-Weiss, A; Papadimitriou, C; Serve, H; Hoppe, B; Koenigsmann, M; Reufi, B; Oberberg, D; Thiel, E; Berdel, W E

    1997-06-01

    Immunomagnetic separation with anti-CD34 monoclonal antibodies and paramagnetic microbeads has been used to enrich hematopoietic stem cells from human bone marrow (BM) or mobilized peripheral blood mononuclear cells (PBMNC). The introduction of this technique also constitutes a new principle of tumor cell purging. The efficiency in terms of purging tumor cells from PBMNC was evaluated in seven different experiments. Mobilized (chemotherapy and G-CSF) PBMNC were collected from patients with solid tumors (n = 6) and multiple myeloma (n = 1) by leukapheresis using an automated MNC separation system and contaminated with 1% (n = 5) or 10% (n = 2) tumor cells from different epithelial cell lines being CD34-negative. The cell mixture was sensitized with anti-CD34 (9C5) antibodies and sheep anti-mouse IgG1 paramagnetic microspheres and enriched for CD34+ cells using an Isolex 50 magnetic separator. Purify of CD34+ cells was studied by flow cytometry (FACScan) and tumor cell depletion was evaluated by comparative human tumor cloning assays (HTCA) containing methylcellulose and agar. We achieved a median purity of CD34+ cells of 85.9% (range 69.8-92.9%) and a median yield of 48.1% (range 21.0-85.2%). From these data in each case the estimated log depletion of tumor cells was calculated and compared with the experimentally achieved (HTCA) log depletion (log delta depletion = log experimental depletion--log calculated depletion). In our experiments we achieved a median depletion of 2.75 log (range 1.55-3.69 log). When corrected for CD34+ cell yield of each experiment we observed a median 'yield corrected depletion' of 2.38 log (range 1.48-3.15 log). The following delta depletion values were obtained: +0.32 log (HTB 129, breast), +0.21 log (HTB 26, breast), +0.04 log (HTB 26) for experiments with higher experimental depletion, and -0.23 log (HTB 26), -0.9 log (HTB 26, PBMNC from patient with multiple myeloma), -0.82 log (HTB 131, breast) and -1.66 log (HTB 131) for lower

  18. Improvement of tumor response to photodynamic therapy by manipulation of tumor oxygenation in an in-vivo model system

    NASA Astrophysics Data System (ADS)

    Chen, Qun; Huang, Zheng; Chen, Hua; Shapiro, Howard; Beckers, Jill; Hetzel, Fred W.

    2002-09-01

    Photodynamic therapy (PDT) requires molecular oxygen during light irradiation in order to generate reactive oxygen species. Tumor hypoxia, either pre-existing or induced by PDT, can severely hamper the effectiveness of PDT treatment. Lowering the light irradiation dose rate or fractionating a light dose may improve cell kill of PDT induced hypoxic cells, but will have no effect on pre-existing hypoxic cells. In this study, hyper-oxygenation technique was used during PDT to overcome hypoxia. C3H mice with transplanted mammary carcinoma tumors were injected with 12.5 mg/kg Photofrin and irradiated with 630 nm laser light 24 hours later. Tumor oxygenation was manipulated by subjecting the animals to 3 atp hyperbaric oxygen or normobaric oxygen during PDT light irradiation. The results show a significant improvement in tumor response when PDT was delivered during hyper-oxygenation. With hyper-oxygenation, up to 80% of treated tumors showed no re-growth after 60 days. In comparison, only 20% of tumors treated while animals breathed room air did not re-grow. To explore the effect of hyper-oxygenation on tumor oxygenation, tumor pO2 was measured with microelectrodes positioned in pre-existing hypoxic regions before and during the PDT. The results show that hyper-oxygenation may oxygenate pre-existing hypoxic cells and compensate for oxygen depletion induced by PDT light irradiation. In conclusion, hyper-oxygenation may provide effective ways to improve PDT treatment efficiency by oxygenating both pre-existing and treatment induced cell hypoxia.

  19. BBB-targeting, protein-based nanomedicines for drug and nucleic acid delivery to the CNS.

    PubMed

    Peluffo, Hugo; Unzueta, Ugutz; Negro-Demontel, María Luciana; Xu, Zhikun; Váquez, Esther; Ferrer-Miralles, Neus; Villaverde, Antonio

    2015-01-01

    The increasing incidence of diseases affecting the central nervous system (CNS) demands the urgent development of efficient drugs. While many of these medicines are already available, the Blood Brain Barrier and to a lesser extent, the Blood Spinal Cord Barrier pose physical and biological limitations to their diffusion to reach target tissues. Therefore, efforts are needed not only to address drug development but specially to design suitable vehicles for delivery into the CNS through systemic administration. In the context of the functional and structural versatility of proteins, recent advances in their biological fabrication and a better comprehension of the physiology of the CNS offer a plethora of opportunities for the construction and tailoring of plain nanoconjugates and of more complex nanosized vehicles able to cross these barriers. We revise here how the engineering of functional proteins offers drug delivery tools for specific CNS diseases and more transversally, how proteins can be engineered into smart nanoparticles or 'artificial viruses' to afford therapeutic requirements through alternative administration routes.

  20. CSF as a surrogate for assessing CNS exposure: an industrial perspective.

    PubMed

    Lin, Jiunn H

    2008-01-01

    For drugs that directly act on targets in the central nervous system (CNS), sufficient drug delivery into the brain is a prerequisite for drug action. Systemically administered drugs can reach CNS by passage across the endothelium of capillary vasculatures, the so-called blood-brain barrier (BBB). Literature data suggest that most marketed CNS drugs have good membrane permeability and relatively high plasma unbound fraction, but are not good P-glycoprotein (P-gp) substrates. Therefore, it is important to use the in vitro parameters of P-gp function activity, membrane permeability and plasma unbound fraction as key criteria for lead optimization during the early stage of drug discovery. Evidence from preclinical and clinical studies suggests that drug concentration in cerebrospinal fluid (CSF) appears to be reasonably accurate in predicting unbound drug concentration in the brain. Therefore, CSF can be used as a useful surrogate for in vivo assessment of CNS exposure and provides an important basis for the selection of drug candidates for entry into development. However, it is important to point out that CSF drug concentration is not always an accurate surrogate for predicting unbound drug concentration in the brain. Depending on the physicochemical properties of drugs and the site/timing of CSF sampling, the unbound drug concentration at the biophase within the brain could differ significantly from the corresponding CSF drug concentration.

  1. Novel approaches and challenges to treatment of CNS viral infections

    PubMed Central

    Nath, Avindra; Tyler, Kenneth L.

    2014-01-01

    Existing and emerging viral CNS infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus. Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available including candidate thiazolide and purazinecarboxamide derivatives with potential broad-spectrum antiviral efficacy. New herpesvirus drugs include viral helicase-primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antivirals and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll-like receptor agonists, and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus-specific cytotoxic T-lymphocytes have been used in humans and may provide an effective therapies for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre-exposure prophylaxis for rabies. PMID:23913580

  2. Evolution of the CNS myelin gene regulatory program.

    PubMed

    Li, Huiliang; Richardson, William D

    2016-06-15

    Myelin is a specialized subcellular structure that evolved uniquely in vertebrates. A myelinated axon conducts action potentials many times faster than an unmyelinated axon of the same diameter; for the same conduction speed, the unmyelinated axon would need a much larger diameter and volume than its myelinated counterpart. Hence myelin speeds information transfer and saves space, allowing the evolution of a powerful yet portable brain. Myelination in the central nervous system (CNS) is controlled by a gene regulatory program that features a number of master transcriptional regulators including Olig1, Olig2 and Myrf. Olig family genes evolved from a single ancestral gene in non-chordates. Olig2, which executes multiple functions with regard to oligodendrocyte identity and development in vertebrates, might have evolved functional versatility through post-translational modification, especially phosphorylation, as illustrated by its evolutionarily conserved serine/threonine phospho-acceptor sites and its accumulation of serine residues during more recent stages of vertebrate evolution. Olig1, derived from a duplicated copy of Olig2 in early bony fish, is involved in oligodendrocyte development and is critical to remyelination in bony vertebrates, but is lost in birds. The origin of Myrf orthologs might be the result of DNA integration between an invading phage or bacterium and an early protist, producing a fusion protein capable of self-cleavage and DNA binding. Myrf seems to have adopted new functions in early vertebrates - initiation of the CNS myelination program as well as the maintenance of mature oligodendrocyte identity and myelin structure - by developing new ways to interact with DNA motifs specific to myelin genes. This article is part of a Special Issue entitled SI: Myelin Evolution.

  3. Acceptable Toxicity After Stereotactic Body Radiation Therapy for Liver Tumors Adjacent to the Central Biliary System

    SciTech Connect

    Eriguchi, Takahisa; Takeda, Atsuya; Sanuki, Naoko; Oku, Yohei; Aoki, Yousuke; Shigematsu, Naoyuki; Kunieda, Etsuo

    2013-03-15

    Purpose: To evaluate biliary toxicity after stereotactic body radiation therapy (SBRT) for liver tumors. Methods and Materials: Among 297 consecutive patients with liver tumors treated with SBRT of 35 to 50 Gy in 5 fractions, patients who were irradiated with >20 Gy to the central biliary system (CBS), including the gallbladder, and had follow-up times >6 months were retrospectively analyzed. Toxicity profiles, such as clinical symptoms and laboratory and radiologic data especially for obstructive jaundice and biliary infection, were investigated in relation to the dose volume and length relationship for each biliary organ. Results: Fifty patients with 55 tumors were irradiated with >20 Gy to the CBS. The median follow-up period was 18.2 months (range, 6.0-80.5 months). In the dose length analysis, 39, 34, 14, and 2 patients were irradiated with >20 Gy, >30 Gy, >40 Gy, and >50 Gy, respectively, to >1 cm of the biliary tract. Seven patients were irradiated with >20 Gy to >20% of the gallbladder. Only 2 patients experienced asymptomatic bile duct stenosis. One patient, metachronously treated twice with SBRT for tumors adjacent to each other, had a transient increase in hepatic and biliary enzymes 12 months after the second treatment. The high-dose area >80 Gy corresponded to the biliary stenosis region. The other patient experienced biliary stenosis 5 months after SBRT and had no laboratory changes. The biliary tract irradiated with >20 Gy was 7 mm and did not correspond to the bile duct stenosis region. No obstructive jaundice or biliary infection was found in any patient. Conclusions: SBRT for liver tumors adjacent to the CBS was feasible with minimal biliary toxicity. Only 1 patient had exceptional radiation-induced bile duct stenosis. For liver tumors adjacent to the CBS without other effective treatment options, SBRT at a dose of 40 Gy in 5 fractions is a safe treatment with regard to biliary toxicity.

  4. Asymptotic dynamics on a singular chemotaxis system modeling onset of tumor angiogenesis

    NASA Astrophysics Data System (ADS)

    Wang, Zhi-An; Xiang, Zhaoyin; Yu, Pei

    2016-02-01

    The asymptotic behavior of solutions to a singular chemotaxis system modeling the onset of tumor angiogenesis in two and three dimensional whole spaces is investigated in the paper. By a Cole-Hopf type transformation, the singular chemotaxis is converted into a non-singular hyperbolic system. Then we study the transformed system and establish the global existence, asymptotic decay rates and diffusion convergence rate of solutions by the method of energy estimates. The main novelty of our results is the finding of a hidden interactive dissipation structure in the system by which the energy dissipation is established.

  5. Papillary Tumor of the Pineal Region: A Distinct Molecular Entity.

    PubMed

    Heim, Stephanie; Sill, Martin; Jones, David T W; Vasiljevic, Alexandre; Jouvet, Anne; Fèvre-Montange, Michelle; Wesseling, Pieter; Beschorner, Rudi; Mittelbronn, Michel; Kohlhof, Patricia; Hovestadt, Volker; Johann, Pascal; Kool, Marcel; Pajtler, Kristian W; Korshunov, Andrey; Ruland, Vincent; Sperveslage, Jan; Thomas, Christian; Witt, Hendrik; von Deimling, Andreas; Paulus, Werner; Pfister, Stefan M; Capper, David; Hasselblatt, Martin

    2016-03-01

    Papillary tumor of the pineal region (PTPR) is a neuroepithelial brain tumor, which might pose diagnostic difficulties and recurs often. Little is known about underlying molecular alterations. We therefore investigated chromosomal copy number alterations, DNA methylation patterns and mRNA expression profiles in a series of 24 PTPRs. Losses of chromosome 10 were identified in all 13 PTPRs examined. Losses of chromosomes 3 and 22q (54%) as well as gains of chromosomes 8p (62%) and 12 (46%) were also common. DNA methylation profiling using Illumina 450k arrays reliably distinguished PTPR from ependymomas and pineal parenchymal tumors of intermediate differentiation. PTPR could be divided into two subgroups based on methylation pattern, PTPR group 2 showing higher global methylation and a tendency toward shorter progression-free survival (P = 0.06). Genes overexpressed in PTPR as compared with ependymal tumors included SPDEF, known to be expressed in the rodent subcommissural organ. Notable SPDEF protein expression was encountered in 15/19 PTPRs as compared with only 2/36 ependymal tumors, 2/19 choroid plexus tumors and 0/23 samples of other central nervous system (CNS) tumor entities. In conclusion, PTPRs show typical chromosomal alterations as well as distinct DNA methylation and expression profiles, which might serve as useful diagnostic tools.

  6. Validation of tumor markers in central nervous system germ cell tumors by real-time reverse transcriptase polymerase chain reaction using formalin-fixed paraffin-embedded tissues.

    PubMed

    Kim, Dowhan; Lee, Da Hye; Choi, Junjeong; Shim, Kyu Won; Kim, Se Hoon

    2013-01-01

    The therapeutic protocols for treatment of germinomas and non-germinomatous germ cell tumors (NGGCTs) are completely different, so it is important to distinguish pure germinomas from NGGCTs. As it can be difficult to diagnose by morphology alone, immunohisto-chemistry (IHC) has been widely used as an ancillary test to improve diagnostic accuracy. However, IHC has limitations due to the misinterpretation of results or the aberrant loss of immunoreactivity. However, real-time RT-PCR has certain advantages over IHC, including its quantitative nature. The aim of our study was to evaluate the usefulness of real-time RT-PCR on formalin-fixed paraffin-embedded (FFPE) tissue blocks for the diagnosis of germ cell tumors of the central nervous system. We selected eight markers of germ cell tumors using a literature search, and validated them using real-time RT-PCR. Among them, POU5F1, NANOG and TGFB2 were statistically significant (P=0.05) in multiple comparisons (MANOVA) of three groups (pure germinomas, mature teratomas and malignant germ cell tumors). Two-group (pure germinomas and NGGCTs) discriminant analysis achieved a 70.0% success rate in cross-validation. We concluded that real-time RT-PCR using FFPE tissue has adequate validating power comparable to IHC in the diagnosis of central nervous system germ cell tumors; therefore, when IHC is not available, not conclusive or not informative, RT-PCR is a potential alternative to a repeat biopsy.

  7. Validation of tumor markers in central nervous system germ cell tumors by real-time reverse transcriptase polymerase chain reaction using formalin-fixed paraffin-embedded tissues.

    PubMed

    Kim, Dowhan; Lee, Da Hye; Choi, Junjeong; Shim, Kyu Won; Kim, Se Hoon

    2013-01-01

    The therapeutic protocols for treatment of germinomas and non-germinomatous germ cell tumors (NGGCTs) are completely different, so it is important to distinguish pure germinomas from NGGCTs. As it can be difficult to diagnose by morphology alone, immunohisto-chemistry (IHC) has been widely used as an ancillary test to improve diagnostic accuracy. However, IHC has limitations due to the misinterpretation of results or the aberrant loss of immunoreactivity. However, real-time RT-PCR has certain advantages over IHC, including its quantitative nature. The aim of our study was to evaluate the usefulness of real-time RT-PCR on formalin-fixed paraffin-embedded (FFPE) tissue blocks for the diagnosis of germ cell tumors of the central nervous system. We selected eight markers of germ cell tumors using a literature search, and validated them using real-time RT-PCR. Among them, POU5F1, NANOG and TGFB2 were statistically significant (P=0.05) in multiple comparisons (MANOVA) of three groups (pure germinomas, mature teratomas and malignant germ cell tumors). Two-group (pure germinomas and NGGCTs) discriminant analysis achieved a 70.0% success rate in cross-validation. We concluded that real-time RT-PCR using FFPE tissue has adequate validating power comparable to IHC in the diagnosis of central nervous system germ cell tumors; therefore, when IHC is not available, not conclusive or not informative, RT-PCR is a potential alternative to a repeat biopsy. PMID:23124437

  8. A Phase l Study of a Tumor-targeted Systemic Nanodelivery System, SGT-94, in Genitourinary Cancers.

    PubMed

    Siefker-Radtke, Arlene; Zhang, Xin-Qiao; Guo, Charles C; Shen, Yu; Pirollo, Kathleen F; Sabir, Sharjeel; Leung, Chris; Leong-Wu, Cindy; Ling, Chi-Ming; Chang, Esther H; Millikan, Randall E; Benedict, William F

    2016-08-01

    Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy.

  9. A new scoring system using multiple immunohistochemical markers for diagnosis of uterine smooth muscle tumors

    PubMed Central

    Rath-Wolfson, Lea; Rosenblat, Yevgenia; Halpern, Marisa; Herbert, M; Hammel, I; Gal, Rivka; Leabu, M; Koren, Rumelia

    2006-01-01

    The diagnosis of uterine smooth muscle neoplasms by light microscopy is difficult. Multiple classification schemes have been proposed based on mitotic rate, nuclear atypia, and the presence or absence of necrosis. None of these classification systems has been entirely successful. This study was undertaken to evaluate the use of selected immunohistochemical and histochemical markers in differentiating these tumors, in addition to accepted morphologic criteria. Ten cases of each of the following: leiomyosarcomas (LMS), atypical leiomyomas (AL), cellular leiomyomas (CL) and usual leiomyomas (UL), were classically evaluated for histological diagnosis and were stained for Ki-67 (MIB-1), bcl-2 and p53 using monoclonal antibodies and the avidin-biotin peroxidase method, and argyrophilic nucleolar organizer region (AgNORs). The number of stained cells was counted in the most positively stained region in a 4 mm2 square cover glass mounted on each slide. The mean value was calculated for each group of tumors. The data for Ki-67 (MIB-1), bcl-2, p53 and AgNOR staining respectively, were significantly higher in LMS by comparison to UL, CL or AL. Because many singular cases had superimposed data being difficult to diagnose, a new scoring system for pathological evaluation was created. The results obtained by this scoring system suggest that immunohistochemical markers Ki-67 (MIB-1), bcl-2, p53 together with the AgNOR staining could be useful, by the scoring system, as an adjunct to the current accepted morphologic criteria in differentiating smooth muscle tumors of the uterus. PMID:16563231

  10. Effects of diabetes mellitus on astrocyte GFAP and glutamate transporters in the CNS.

    PubMed

    Coleman, Elaine; Judd, Robert; Hoe, Lori; Dennis, John; Posner, Philip

    2004-11-01

    Diabetes mellitus increases the risk of central nervous system (CNS) disorders such as stroke, seizures, dementia, and cognitive impairment. The cellular mechanisms responsible for the increased risk of these disorders are incompletely understood. Astrocytes are proving critical for normal CNS function, and alterations in their activity could contribute to diabetes-related disturbances in the brain. We examined the effects of streptozotocin (STZ)-induced diabetes in rats on the level of the astrocyte intermediate filament protein, glial fibrillary acidic protein (GFAP), number of astrocytes, and levels of the astrocyte glutamate transporters, glutamate transporter-1 (GLT-1) and glutamate/aspartate transporter (GLAST), in the cerebral cortex, hippocampus, and cerebellum by Western blotting (WB) and immunohistochemistry (IH). Studies were carried out at 4 and 8 weeks of diabetes duration. Diabetes resulted in a significant decrease in GFAP protein levels (WB) in the hippocampus and cerebellum at 4 weeks and in the cerebral cortex, hippocampus and cerebellum by 8 weeks. Attenuated GFAP immunoreactivity (IH) was evident in the hippocampus, cerebellum and white matter regions such as the corpus callosum and external capsule at both 4 and 8 weeks of diabetes. Astrocyte cell counts of adjacent sections immunoreactive for S-100B were not different between control and diabetic animals. No significant differences were noted in astrocyte glutamate transporter levels in the cerebral cortex, hippocampus, or cerebellum at either time period (WB, IH). With the expanding list of astrocyte functions in the CNS, the role of astrocytes in diabetes-induced CNS disorders clearly warrants further investigation.

  11. Mapping the prion protein distribution in marsupials: insights from comparing opossum with mouse CNS.

    PubMed

    Poggiolini, Ilaria; Legname, Giuseppe

    2012-01-01

    The cellular form of the prion protein (PrP(C)) is a sialoglycoprotein widely expressed in the central nervous system (CNS) of mammalian species during neurodevelopment and in adulthood. The location of the protein in the CNS may play a role in the susceptibility of a species to fatal prion diseases, which are also known as the transmissible spongiform encephalopathies (TSEs). To date, little is known about PrP(C) distribution in marsupial mammals, for which no naturally occurring prion diseases have been reported. To extend our understanding of varying PrP(C) expression profiles in different mammals we carried out a detailed expression analysis of PrP(C) distribution along the neurodevelopment of the metatherian South American short-tailed opossum (Monodelphis domestica). We detected lower levels of PrP(C) in white matter fiber bundles of opossum CNS compared to mouse CNS. This result is consistent with a possible role for PrP(C) in the distinct neurodevelopment and neurocircuitry found in marsupials compared to other mammalian species.

  12. Flipping the transcriptional switch from myelin inhibition to axon growth in the CNS

    PubMed Central

    Carmel, Jason B.; Young, Wise; Hart, Ronald P.

    2015-01-01

    Poor regeneration of severed axons in the central nervous system (CNS) limits functional recovery. Regeneration failure involves interplay of inhibitory environmental elements and the growth state of the neuron. To find internal changes in gene expression that might overcome inhibitory environmental cues, we compared several paradigms that allow growth in the inhibitory environment. Conditions that allow axon growth by axotomized and cultured dorsal root ganglion (DRG) neurons on CNS myelin include immaturity (the first few postnatal days), high levels of cyclic adenosine mono phosphate (cAMP), and conditioning with a peripheral nerve lesion before explant. This shift from inhibition to growth depends on transcription. Seeking to understand the transcriptome changes that allow axon growth in the CNS, we collaborated with the Marie Filbin laboratory to identify several mRNAs that are functionally relevant, as determined by gain- and loss-of-function studies. In this Perspective, we review evidence from these experiments and discuss the merits of comparing multiple regenerative paradigms to identify a core transcriptional program for CNS axon regeneration. PMID:26236189

  13. Histoplasmosis with Deep CNS Involvement: Case Presentation with Discussion and Literature Review

    PubMed Central

    Hariri, Omid R.; Minasian, Tanya; Quadri, Syed A.; Dyurgerova, Anya; Farr, Saman; Miulli, Dan E.; Siddiqi, Javed

    2015-01-01

    Central nervous system (CNS) histoplasmosis is rare and difficult to diagnose because it is often overlooked or mistaken for other pathologies due to its nonspecific symptoms. A 32-year-old Hispanic man with advanced acquired immunodeficiency virus presented with altered mental status and reported confusion for the past 3 months. He had a Glasgow Coma Scale of 12, repetitive nonfluent speech, and a disconjugate gaze with a right gaze preference. Lung computed tomography (CT) findings indicated a pulmonary histoplasmosis infection. Magnetic resonance imaging of the brain revealed a ring-enhancing lesion in the left caudate nucleus. A CT-guided left retroperitoneal node biopsy was performed and indicated a benign inflammatory process with organisms compatible with fungal yeast. Treatment with amphotericin B followed by itraconazole was initiated in spite of negative cerebrospinal fluid (CSF) cultures and proved effective in mitigating associated CNS lesions and resolving neurologic deficits. The patient was discharged 3 weeks later in stable condition. Six weeks later, his left basal ganglia mass decreased. Early recognition of symptoms and proper steps is key in improving outcomes of CNS histoplasmosis. Aggressive medical management is possible in the treatment of intracranial deep mass lesions, and disseminated histoplasmosis with CNS involvement can be appropriately diagnosed and treated, despite negative CSF and serology studies. PMID:26251798

  14. Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

    PubMed Central

    Williams, Jessica L.; Holman, David W.; Klein, Robyn S.

    2014-01-01

    In the adult central nervous system (CNS), chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier (BBB) including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease. PMID:24920943

  15. The choroid plexus—a multi-role player during infectious diseases of the CNS

    PubMed Central

    Schwerk, Christian; Tenenbaum, Tobias; Kim, Kwang Sik; Schroten, Horst

    2015-01-01

    The choroid plexus (CP) is the source of cerebrospinal fluid (CSF) production and location of the blood-CSF barrier (BCSFB), which is constituted by the epithelial cells of the CP. Several infectious pathogens including viruses, bacteria, fungi and parasites cross the BCSFB to enter the central nervous system (CNS), ultimately leading to inflammatory infectious diseases like meningitis and meningoencephalitis. The CP responds to this challenge by the production of chemokines and cytokines as well as alterations of the barrier function of the BCSFB. During the course of CNS infectious disease host immune cells enter the CNS, eventually contributing to the cellular damage caused by the disease. Additional complications, which are in certain cases caused by choroid plexitis, can arise due to the response of the CP to the pathogens. In this review we will give an overview on the multiple functions of the CP during brain infections highlighting the CP as a multi-role player during infectious diseases of the CNS. In this context the importance of tools for investigation of these CP functions and a possible suitability of the CP as therapeutic target will be discussed. PMID:25814932

  16. The allometry of CNS size and consequences of miniaturization in orb-weaving and cleptoparasitic spiders.

    PubMed

    Quesada, Rosannette; Triana, Emilia; Vargas, Gloria; Douglass, John K; Seid, Marc A; Niven, Jeremy E; Eberhard, William G; Wcislo, William T

    2011-11-01

    Allometric studies of the gross neuroanatomy of adults from nine species of spiders from six web-weaving families (Orbicularia), and nymphs from six of these species, show that very small spiders resemble other small animals in having disproportionately larger central nervous systems (CNSs) relative to body mass when compared with large-bodied forms. Small spiderlings and minute adult spiders have similar relative CNS volumes. The relatively large CNS of a very small spider occupies up to 78% of the cephalothorax volume. The CNSs of very small spiders extend into their coxae, occupying as much as 26% of the profile area of the coxae of an Anapisona simoni spiderling (body mass < 0.005 mg). Such modifications occur both in species with minute adults, and in tiny spiderlings of species with large-bodied adults. In at least one such species, Leucauge mariana, the CNS of the spiderling extends into a prominent ventral bulge of the sternum. Tiny spiders also have reduced neuronal cell body diameters. The adults of nearly all orbicularian spiders weave prey capture webs, as do the spiderlings, beginning with second instar nymphs. Comparable allometric relations occur in adults of both orb-weaving and cleptoparasitic species, indicating that this behavioral difference is not reflected in differences in gross CNS allometry. PMID:22036838

  17. The choroid plexus-a multi-role player during infectious diseases of the CNS.

    PubMed

    Schwerk, Christian; Tenenbaum, Tobias; Kim, Kwang Sik; Schroten, Horst

    2015-01-01

    The choroid plexus (CP) is the source of cerebrospinal fluid (CSF) production and location of the blood-CSF barrier (BCSFB), which is constituted by the epithelial cells of the CP. Several infectious pathogens including viruses, bacteria, fungi and parasites cross the BCSFB to enter the central nervous system (CNS), ultimately leading to inflammatory infectious diseases like meningitis and meningoencephalitis. The CP responds to this challenge by the production of chemokines and cytokines as well as alterations of the barrier function of the BCSFB. During the course of CNS infectious disease host immune cells enter the CNS, eventually contributing to the cellular damage caused by the disease. Additional complications, which are in certain cases caused by choroid plexitis, can arise due to the response of the CP to the pathogens. In this review we will give an overview on the multiple functions of the CP during brain infections highlighting the CP as a multi-role player during infectious diseases of the CNS. In this context the importance of tools for investigation of these CP functions and a possible suitability of the CP as therapeutic target will be discussed. PMID:25814932

  18. Comparative value of bone scintigraphy and radiography in monitoring tumor response in systemically treated prostatic carcinoma

    SciTech Connect

    Levenson, R.M.; Sauerbrunn, B.J.; Bates, H.R.; Newman, R.D.; Eddy, J.L.; Ihde, DC

    1983-02-01

    Radionuclide bone scans and skeletal radiographs were obtained before and during combination chemotherapy or initial hormonal treatment in 46 patients with disseminated adenocarcinoma of the prostate. The purpose of the study was to determine the usefulness of these two modalities in evaluating tumor response to therapy. Prior to treatment, bone scans were positive in 44 patients (96%). In all but one patient either bone radiographs or bone marrow biopsy revealed evidence of osseous metastases. In 22 patients partial response to therapy was documented by a variety of other staging tests. Eleven of these patients showed concurrent or later improvement on bone scans; one showed improvement on a radiograph. Flare phenomena were observed relatively frequently since 23% of the scans and 50% of the radiographs showed worsening at the time of response. Bone scans revealed worsening in 79% of 33 patients with disease progression of extraosseous tumor; radiographs were equally sensitive (82% worsening). It is concluded that bone scans in particular are useful for monitoring tumor status in systemically treated patients with prostate cancer. However, because of the lack of sensitivity for response and paradoxical worsening with tumor regression in some patients, scans are not accurate enough to be employed as the sole test in following these patients.

  19. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    SciTech Connect

    Ratikan, Josephine Anna; Sayre, James William

    2013-11-15

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy.

  20. A diffuse reflectance spectral imaging system for tumor margin assessment using custom annular photodiode arrays

    PubMed Central

    Dhar, Sulochana; Lo, Justin Y.; Palmer, Gregory M.; Brooke, Martin A.; Nichols, Brandon S.; Yu, Bing; Ramanujam, Nirmala; Jokerst, Nan M.

    2012-01-01

    Diffuse reflectance spectroscopy (DRS) is a well-established method to quantitatively distinguish between benign and cancerous tissue for tumor margin assessment. Current multipixel DRS margin assessment tools are bulky fiber-based probes that have limited scalability. Reported herein is a new approach to multipixel DRS probe design, which utilizes direct detection of the DRS signal by using optimized custom photodetectors in direct contact with the tissue. This first fiberless DRS imaging system for tumor margin assessment consists of a 4 × 4 array of annular silicon photodetectors and a constrained free-space light delivery tube optimized to deliver light across a 256 mm2 imaging area. This system has 4.5 mm spatial resolution. The signal-to-noise ratio measured for normal and malignant breast tissue-mimicking phantoms was 35 dB to 45 dB for λ = 470 nm to 600 nm. PMID:23243571

  1. Cancer Screening by Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression

    PubMed Central

    Browne, Andrew W.; Leddon, Jennifer L.; Currier, Mark A.; Williams, Jon P.; Frischer, Jason S.; Collins, Margaret H.; Ahn, Chong H.; Cripe, Timothy P.

    2011-01-01

    Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor-selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a “theragnostic” agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world. PMID:21589655

  2. Personalized Medicine for Nervous System Manifestations of von Hippel–Lindau Disease

    PubMed Central

    Schunemann, Victoria; Huntoon, Kristin; Lonser, Russell R.

    2016-01-01

    von Hippel–Lindau disease (VHL) is a familial neoplasia syndrome associated with multisystem tumor development. Depending on tumor type and location, current treatments for VHL-associated tumors can include a combination of chemotherapy, radiation therapy, and/or surgery. Central nervous system (CNS) manifestations of VHL include craniospinal hemangioblastomas and endolymphatic sac tumors (ELSTs). While the first-line treatment for both types of VHL-associated CNS tumors is surgery, the indications for treatment are patient specific and different for each tumor type. Although early sign/symptom formation is the primary indication for resection of craniospinal hemangioblastomas, radiographic discovery (asymptomatic and symptomatic) of ELSTs can be an indication for resection of ELSTs in VHL patients. Recently, research has revealed that specific VHL germline mutations may permit targeted medical treatments of not only CNS manifestations of VHL-associated tumors but also visceral tumors. Specifically, missense mutations can result in the translation of functional VHL protein (pVHL) that is rapidly degraded resulting in functional loss of the pVHL, and inhibitors of pVHL degradation may slow protein degradation and restore pVHL function. Emerging research will investigate the safety and practicality of using potential targeted therapies. PMID:27446927

  3. Hematopoietic tumors of the female genital system: imaging features with pathologic correlation.

    PubMed

    Salem, Usama; Menias, Christine O; Shaaban, Akram; Bhosale, Priya R; Youssef, Ayda; Elsayes, Khaled M

    2014-08-01

    Various hematopoietic neoplasms can involve the female genital system. The most common hematological malignancy that involves the female genital system is lymphoma and secondary involvement is more common than primary genital lymphoma. Rarely, leukemic infiltration and extramedullary plasmacytomas of the female genital tract may also occur. Being infrequent, these lesions are commonly misdiagnosed radiologically. Therefore, understanding these malignancies of the female genital system and recognizing their imaging features are of utmost clinical importance. Although definitive diagnosis can be made only by histological analysis, imaging of these tumors plays an important role in detecting lesion extensions, guiding biopsies, staging disease, planning therapy, and detecting recurrence.

  4. Development of a Patient-Derived Xenograft Model Using Brain Tumor Stem Cell Systems to Study Cancer.

    PubMed

    Chokshi, Chirayu; Dhillon, Manvir; McFarlane, Nicole; Venugopal, Chitra; Singh, Sheila K

    2016-01-01

    Patient-derived xenograft (PDX) models provide an excellent platform to understand cancer initiation and development in vivo. In the context of brain tumor initiating cells (BTICs), PDX models allow for characterization of tumor formation, growth, and recurrence, in a clinically relevant in vivo system. Here, we detail procedures to harvest, culture, characterize, and orthotopically inject human BTICs derived from patient samples.

  5. Enrichment of circulating tumor cells using a centrifugal affinity plate system.

    PubMed

    Lee, Sung-Woo; Hyun, Kyung-A; Kim, Seung-Il; Kang, Ji-Yoon; Jung, Hyo-Il

    2014-12-19

    Circulating tumor cells (CTCs) are defined as cells that have detached from a primary tumor and are circulating in the bloodstream. Their isolation and quantification is of great value for cancer prognoses and drug testing. Here, the development of a centrifugal affinity plate (CAP) system is described, in which centrifugal force and antibody-based capture are exploited to enrich CTCs on one plate and hematological cells on the other. The CAP is rotated to exert centrifugal force on the cells in a blood sample, quickly transporting them to the anti-epithelial adhesion molecule (EpCAM)-coated and anti-CD45-coated surface of the CAP to shorten the reaction time and increase the adhesion force between the tumor and blood cells and each antibody. The effect of a rotating process on cell capture was investigated, and the capture efficiency was demonstrated using blood samples from healthy donors spiked with human non-small cell lung cancer (NCI-H1650) and breast cancer (MCF-7) cells. The CAP system was capable of rapid isolation and identification of CTCs without the requirement for pretreatment of blood samples. Finally, the CAP system was tested to evaluate the detection efficiency of CTCs in the blood samples of breast cancer patients. The number of captured CTCs in only 1ml of blood varied from 6 to 10.

  6. CpG expedites regression of local and systemic tumors when combined with activatable nanodelivery.

    PubMed

    Kheirolomoom, Azadeh; Ingham, Elizabeth S; Mahakian, Lisa M; Tam, Sarah M; Silvestrini, Matthew T; Tumbale, Spencer K; Foiret, Josquin; Hubbard, Neil E; Borowsky, Alexander D; Murphy, William J; Ferrara, Katherine W

    2015-12-28

    Ultrasonic activation of nanoparticles provides the opportunity to deliver a large fraction of the injected dose to insonified tumors and produce a complete local response. Here, we evaluate whether the local and systemic response to chemotherapy can be enhanced by combining such a therapy with locally-administered CpG as an immune adjuvant. In order to create stable, activatable particles, a complex between copper and doxorubicin (CuDox) was created within temperature-sensitive liposomes. Whereas insonation of the CuDox liposomes alone has been shown to produce a complete response in murine breast cancer after 8 treatments of 6 mg/kg delivered over 4 weeks, combining this treatment with CpG resolved local cancers within 3 treatments delivered over 7 days. Further, contralateral tumors regressed as a result of the combined treatment, and survival was extended in systemic disease. In both the treated and contralateral tumor site, the combined treatment increased leukocytes and CD4+ and CD8+ T-effector cells and reduced myeloid-derived suppressor cells (MDSCs). Taken together, the results suggest that this combinatorial treatment significantly enhances the systemic efficacy of locally-activated nanotherapy. PMID:26471394

  7. Immunotherapy in Cancer: A Combat between Tumors and the Immune System; You Win Some, You Lose Some

    PubMed Central

    Madorsky Rowdo, Florencia Paula; Baron, Antonela; Urrutia, Mariela; Mordoh, José

    2015-01-01

    Cancer immunotherapy has emerged as a treatment modality, mainly as the result of discoveries in the immune response regulation, including mechanisms that turn off immune responses. Immunogenic cutaneous melanoma is a canonical model for therapeutic immunotherapy studies. “Passive” immunotherapy with monoclonal antibodies (mAbs) has outpaced “active” immunotherapy with anti-tumor vaccines, and mAbs that antagonize the off responses have been recently introduced in clinical practice. Despite these recent successes, many unresolved practical and theoretical questions remain. Notably unknown are the identity of the lymphocytes that eliminate tumor cells, which white cells enter into tumors, through which endothelium, in what order, and how they perform their task. The parameters of size and location that could be used to determine in which tumors the immune response may be sufficient to eradicate the tumor are yet unknown. Immunotherapy has been so far more efficient to treat solid and hematologic tumors located outside the central nervous system, than primary brain tumors and brain metastases. In contrast to recent advances with mAbs, anti-tumor vaccine development has been lagging behind. The multiplicity of antigens that must be targeted to achieve significant clinical response is partially responsible for this lag, especially in melanoma, one of the most mutated tumors. Further hampering vaccination results is the fact that tumor elimination by the immune system is the result of a race between tumors with different growth rates and the relatively slow development of the adaptive immune response. The enhancement of the native arm of the immune response or the administration of targeted chemotherapy to slow tumor development, are approaches that should be studied. Finally, criteria used to analyze patient response to immunotherapeutic treatments must be perfected, and the patient populations that could benefit the most from this approach must be better

  8. Tumor Vascular Permeability Pattern Is Associated With Complete Response in Immunocompetent Patients With Newly Diagnosed Primary Central Nervous System Lymphoma

    PubMed Central

    Chung, Sae Rom; Choi, Young Jun; Kim, Ho Sung; Park, Ji Eun; Shim, Woo Hyun; Kim, Sang Joon

    2016-01-01

    Abstract A dynamic contrast-enhanced MR imaging (DCE-MRI) could provide the information about tumor drug delivery efficacy. We investigated the potential utility of the permeability pattern of DCE-MRI for predicting tumor response to high dose-methotrexate treatment and progression-free survival (PFS) in patients with primary CNS lymphoma (PCNSL). Clinical and conventional imaging parameters were assessed as potential predictors of tumor response in 48 immunocompetent PCNSL patients in a preliminary study. Fifty additional immunocompetent patients (27 men and 23 women; mean age, 60.6 years) with PCNSL underwent DCE-MRI before starting first-line treatment with high dose-methotrexate. The DCE-MRI pattern was categorized as diffuse or nondiffuse. After 4 courses of high dose methotrexate, patients underwent follow-up brain MR imaging to identify their complete response (CR). Predictors of CR and PFS were analyzed using clinical parameters, conventional MRI, and DCE-MRI. CR was noted in 20 (74.1%) of 27 patients with diffuse DCE-MRI pattern and in 4 (17.4%) of 23 patients with nondiffuse DCE-MRI pattern. The diffuse DCE-MRI pattern showed a significantly higher association with CR than the nondiffuse pattern (P < 0.001). Multivariate Cox proportional hazards model revealed that the DCE-MRI pattern (hazard ratio = 0.70; P = 0.045), age (hazard ratio = 1.47; P = 0.041), and adjuvant autologous stem-cell transplantation (hazard ratio = 6.97; P = 0.003) tended to be associated with a PFS. The pretreatment diffuse DCE-MRI pattern can be used as a potential imaging biomarker for predicting CR and a longer PFS in patients with newly diagnosed PCNSLs. PMID:26871782

  9. CNS Dopamine Transmission Mediated by Noradrenergic Innervation

    PubMed Central

    Smith, Caroline C.; Greene, Robert W.

    2012-01-01

    The pre-synaptic source of dopamine in the CA1 field of dorsal hippocampus is uncertain due to an anatomical mismatch between dopaminergic terminals and receptors. We show, in an in vitro slice preparation from C57BL6 male mice, that a dopamine (DA) D1 receptor (D1R) mediated enhancement in glutamate synaptic transmission occurs following release of endogenous DA with amphetamine exposure. It is assumed DA is released from terminals innervating from the ventral tegmental area (VTA) even though DA transporter (DAT) positive fibers are absent in hippocampus, a region with abundant D1Rs. It has been suggested this results from a lack of DAT expression on VTA terminals rather than a lack of these terminals per se. Neither a knockdown of tyrosine hydroxylase (TH) expression in the VTA by THsiRNA, delivered locally, by adeno-associated viral vector, nor localized pharmacological blockade of DAT to prevent amphetamine uptake into DA terminals, has any effect on the D1R synaptic, enhancement response to amphetamine. However, either a decrease in TH expression in the locus coeruleus (LC) or a blockade of the norepinephrine (NE) transporter prevents the DA mediated response, indicating LC terminals can release both NE and DA. These findings suggest noradrenergic fibers may be the primary source of DA release in hippocampus and corresponding DA mediated increase in synaptic transmission. Accordingly, these data imply the LC may have a role in DA transmission in the CNS in response to drugs of abuse, and potentially, under physiological conditions. PMID:22553014

  10. Generation of spike trains in CNS neurons.

    PubMed

    Calvin, W H

    1975-01-24

    The membrane potential waveforms to be expected from many asynchronous inputs to CNS neurons are described, along with modes for repetitive firing through which the input waveforms are converted into spike trains. Area beneath a postsynaptic potential (PSP), rather than PSP peak height, is shown to be an important parameter susceptible to modification. Occasional crossings of threshold produce occasional spikes, but a sustained depolarizing waveform which attempts to hold the membrane potential above threshold elicits rhythmic firing. Firing rate is graded with the amount by which the synaptic depolarizing currents exceed the minimum current for rhythmic firing (approximately rheobase). A systematic sequence of alterations in the membrane potential trajectory between spikes, quite different from those of receptors and invertebrate neurons, may control the firing rate and give rise to sudden changes in the "gain" of this conversion of depolarizing current into firing rate. The different implications of synaptic location during the occasional spike mode and the rhythmic firing mode are discussed, as is the role of the antidromic invasion of the soma-dendritic region during rhythmic firing. Less frequently an"extra spike mode" is seen where depolarizing afterpotentials following a spike themselves cross threshold to elicit an extra spike, which may similarly elicit another extra spike, etc., in a regenerative cycle. The character of the underlying depolarizing afterpotentials (or "delayed depolarizations") is reviewed, along with theories for their origin from the antidromic invasion of the dendritic tree. The stereotyped burst firing patterns characteristic of the extra spike mode can also be seen in deafferented neurons and neurons studied in chronic syndromes such as epilepsy and central pain. This raises the question as to whether some disease states may augment extra spike firing, thus multiplying many-fold the response to a normal input. PMID:163121

  11. Accuracy of tumor motion compensation algorithm from a robotic respiratory tracking system: A simulation study

    SciTech Connect

    Seppenwoolde, Yvette; Berbeco, Ross I.; Nishioka, Seiko; Shirato, Hiroki; Heijmen, Ben

    2007-07-15

    The Synchrony{sup TM} Respiratory Tracking System (RTS) is a treatment option of the CyberKnife robotic treatment device to irradiate extra-cranial tumors that move due to respiration. Advantages of RTS are that patients can breath normally and that there is no loss of linac duty cycle such as with gated therapy. Tracking is based on a measured correspondence model (linear or polynomial) between internal tumor motion and external (chest/abdominal) marker motion. The radiation beam follows the tumor movement via the continuously measured external marker motion. To establish the correspondence model at the start of treatment, the 3D internal tumor position is determined at 15 discrete time points by automatic detection of implanted gold fiducials in two orthogonal x-ray images; simultaneously, the positions of the external markers are measured. During the treatment, the relationship between internal and external marker positions is continuously accounted for and is regularly checked and updated. Here we use computer simulations based on continuously and simultaneously recorded internal and external marker positions to investigate the effectiveness of tumor tracking by the RTS. The Cyberknife does not allow continuous acquisition of x-ray images to follow the moving internal markers (typical imaging frequency is once per minute). Therefore, for the simulations, we have used data for eight lung cancer patients treated with respiratory gating. All of these patients had simultaneous and continuous recordings of both internal tumor motion and external abdominal motion. The available continuous relationship between internal and external markers for these patients allowed investigation of the consequences of the lower acquisition frequency of the RTS. With the use of the RTS, simulated treatment errors due to breathing motion were reduced largely and consistently over treatment time for all studied patients. A considerable part of the maximum reduction in treatment error

  12. Influence of internal fixation systems on radiation therapy for spinal tumor.

    PubMed

    Li, Jingfeng; Yan, Lei; Wang, Jianping; Cai, Lin; Hu, Dongcai

    2015-07-08

    In this study, the influence of internal fixation systems on radiation therapy for spinal tumor was investigated in order to derive a theoretical basis for adjustment of radiation dose for patients with spinal tumor and internal fixation. Based on a common method of internal fixation after resection of spinal tumor, different models of spinal internal fixation were constructed using the lumbar vertebra of fresh domestic pigs and titanium alloy as the internal fixation system. Variations in radiation dose in the vertebral body and partial spinal cord in different types of internal fixation were studied under the same radiation condition (6 MV and 600 mGy) in different fixation models and compared with those irradiated based on the treatment planning system (TPS). Our results showed that spinal internal fixation materials have great impact on the radiation dose absorbed by spinal tumors. Under the same radiation condition, the influence of anterior internal fixation material or combined anterior and posterior approach on radiation dose at the anterior border of the vertebral body was the greatest. Regardless of the kinds of internal fixation method employed, radiation dose at the anterior border of the vertebral body was significantly different from that at other positions. Notably, the influence of posterior internal fixation material on the anterior wall of the vertebral canal was the greatest. X-ray attenuation and scattering should be taken into consideration for most patients with bone metastasis that receive fixation of metal implants. Further evaluation should then be conducted with modified TPS in order to minimize the potentially harmful effects of inappropriate radiation dose.

  13. Alcohol intake alters immune responses and promotes CNS viral persistence in mice.

    PubMed

    Loftis, Jennifer M; Taylor, Jonathan; Raué, Hans-Peter; Slifka, Mark K; Huang, Elaine

    2016-10-01

    Chronic hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. This study investigated the role of alcohol in regulating viral persistence and CNS immunopathology in mice infected with lymphocytic choriomeningitis virus (LCMV), a model for HCV infections in humans. Female and male BALB/c mice (n=94) were exposed to alcohol (ethanol; EtOH) and water (or water only) using a two-bottle choice paradigm, followed one week later by infection with either LCMV clone 13 (causes chronic infection similar to chronic HCV), LCMV Armstrong (causes acute infection), or vehicle. Mice were monitored for 60days post-infection and continued to receive 24-h access to EtOH and water. Animals infected with LCMV clone 13 drank more EtOH, as compared to those with an acute or no viral infection. Six weeks after infection with LCMV clone 13, mice with EtOH exposure evidenced higher serum viral titers, as compared to mice without EtOH exposure. EtOH intake was also associated with reductions in virus-specific CD8(+) T cell frequencies (particularly CD11a(hi) subsets) and evidence of persistent CNS viremia in chronically infected mice. These findings support the hypothesis that EtOH use and chronic viral infection can result in combined tox