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Sample records for system cns tumors

  1. CNS and spinal tumors.

    PubMed

    Furtado, Andre D; Panigrahy, Ashok; Fitz, Charles R

    2016-01-01

    Primary CNS tumors consist of a diverse group of neoplasms originating from various cell types in the CNS. Brain tumors are the most common solid malignancy in children under the age of 15 years and the second leading cause of cancer death after leukemia. The most common brain neoplasms in children differ consistently from those in older age groups. Pediatric brain tumors demonstrate distinct patterns of occurrence and biologic behavior according to sex, age, and race. This chapter highlights the imaging features of the most common tumors that affect the child's CNS (brain and spinal cord).

  2. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in the tumors of central nervous system (CNS).

    PubMed

    Lukaszewicz-Zając, Marta; Mroczko, Barbara; Kornhuber, Johannes; Lewczuk, Piotr

    2014-05-01

    Malignant neoplasms of the central nervous system (CNS) account for about 1.3 % of all tumors and 2.2 % of all cancer-related deaths. CNS tumors consist of heterogeneous group of neoplasms, including different variants of primary brain tumors and metastatic neoplasms. Advanced imaging techniques improved the neuroradiological diagnostic accuracy, although these methods are not specific enough for differentiation of CNS tumors, thus new approaches of patients' diagnosis are critically needed. The best solution for the diagnosis of patients with CNS tumors could be easily available biomarkers, which could be useful for the management of CNS neoplasms. Biomarkers should facilitate the diagnosis, monitor of treatment response and assess the prognosis of patients' survival. Currently, except for rare germ cell tumors, there is a lack of knowledge on biochemical markers for CNS neoplasms. Therefore, in this paper we summarized and referred a number of comprehensive reviews concerning the role of matrix metalloproteinases (MMPs) and their tissue inhibitors in tumor progression, including CNS neoplasms as well as described the general biochemistry of MMPs and their tissue inhibitors. Moreover, we presented the wide variety of previous findings, where authors suggested the significance of selected MMPs and their tissue inhibitors as potential biomarkers of human tumors, including CNS tumors. However, future investigations are needed to be performed before some of these enzymes could finally be used as biomarkers of specific types of CNS neoplasms.

  3. Incidence of CNS tumors in Appalachian children.

    PubMed

    Huang, Bin; Luo, Alice; Durbin, Eric B; Lycan, Ellen; Tucker, Thomas; Chen, Quan; Horbinski, Craig; Villano, John L

    2017-03-11

    Determine whether the risk of astrocytomas in Appalachian children is higher than the national average. We compared the incidence of pediatric brain tumors in Appalachia versus non-Appalachia regions, covering years 2000-2011. The North American Association of Central Cancer Registries (NAACCR) collects population-based data from 55 cancer registries throughout U.S. and Canada. All invasive primary (i.e. non-metastatic tumors), with age at diagnosis 0-19 years old, were included. Nearly 27,000 and 2200 central nervous system (CNS) tumors from non-Appalachia and Appalachia, respectively comprise the cohorts. Age-adjusted incidence rates of each main brain tumor subtype were compared. The incidence rate of pediatric CNS tumors was 8% higher in Appalachia, 3.31 [95% CI 3.17-3.45] versus non-Appalachia, 3.06, [95% CI 3.02-3.09] for the years 2001-2011, all rates are per 100,000 population. Astrocytomas accounted for the majority of this difference, with the rate being 16% higher in Appalachian children, 1.77, [95% CI 1.67-1.87] versus non-Appalachian children, 1.52, [95% CI 1.50-1.55]. Among astrocytomas, World Health Organization (WHO) grade I astrocytomas were 41% higher in Appalachia, 0.63 [95% CI 0.56-0.70] versus non-Appalachia 0.44 [95% CI 0.43-0.46] for the years 2004-2011. This is the first study to demonstrate that Appalachian children are at greater risk of CNS neoplasms, and that much of this difference is in WHO grade I astrocytomas, 41% more common. The cause of this increased incidence is unknown and we discuss the importance of this in relation to genetic and environmental findings in Appalachia.

  4. 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.

  5. Risk of subsequent cancer following a primary CNS tumor.

    PubMed

    Strodtbeck, Kyle; Sloan, Andrew; Rogers, Lisa; Fisher, Paul Graham; Stearns, Duncan; Campbell, Laura; Barnholtz-Sloan, Jill

    2013-04-01

    Improvements in survival among central nervous system (CNS) tumor patients has made the risk of developing a subsequent cancer an important survivorship issue. Such a risk is likely influenced by histological and treatment differences between CNS tumors. De-identified data for 41,159 patients with a primary CNS tumor diagnosis from 9 Surveillance, Epidemiology and End Results (SEER) registries were used to calculate potential risk for subsequent cancer development. Relative risk (RR) and 95 % confidence interval (CI) of subsequent cancer was calculated using SEER*Stat 7.0.9, comparing observed number of subsequent cancers versus expected in the general United States population. For all CNS tumors studied, there were 830 subsequent cancers with a RR of 1.26 (95 % CI, 1.18-1.35). Subsequent cancers were observed in the CNS, digestive system, bones/joints, soft tissue, thyroid and leukemia. Radiotherapy was associated with an elevated risk, particularly in patients diagnosed with a medulloblastoma/primitive neuroectodermal tumor (MPNET). MPNET patients who received radiotherapy were at a significant risk for development of cancers of the digestive system, leukemia, bone/joint and cranial nerves. Glioblastoma multiforme patients who received radiotherapy were at lower risks for female breast and prostate cancers, though at an elevated risk for cancers of the thyroid and brain. Radiotherapy is associated with subsequent cancer development, particularly for sites within the field of radiation, though host susceptibility and post-treatment status underlie this risk. Variation in subsequent cancer risk among different CNS tumor histological subtypes indicate a complex interplay between risk factors in subsequent cancer development.

  6. 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.

  7. 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.

  8. Imaging of CNS Tumors in Children: Advances and Limitations

    PubMed Central

    Vézina, Louis-Gilbert

    2009-01-01

    MR technology is constantly improving. Functional imaging techniques such as MR spectroscopy, perfusion imaging, diffusion imaging and diffusion tensor imaging are increasingly utilized in the pediatric patient with a brain tumor. However estimate of tumor size remains the primary imaging endpoint in the evaluation of response to treatment; validation across institutions and vendor platforms of MRI functional parameters is necessary given the relative uncommon occurrence of brain tumors in children. Pediatric neuroimaging can be challenging, and the optimal way to image children with CNS tumors is not uniformly applied across all centers. Application of proper scanning techniques and validation of functional imaging techniques should lead to improved care of children with CNS tumors PMID:18952579

  9. Overcoming the challenges in the effective delivery of chemotherapies to CNS solid tumors

    PubMed Central

    Sarin, Hemant

    2011-01-01

    Locoregional therapies, such as surgery and intratumoral chemotherapy, do not effectively treat infiltrative primary CNS solid tumors and multifocal metastatic solid tumor disease of the CNS. It also remains a challenge to treat such CNS malignant solid tumor disease with systemic chemotherapies, although these lipid-soluble small-molecule drugs demonstrate potent cytotoxicity in vitro. Even in the setting of a ‘normalized’ tumor microenvironment, small-molecule drugs do not accumulate to effective concentrations in the vast majority of tumor cells, which is due to the fact that small-molecule drugs have short blood half-lives. It has been recently shown that drug-conjugated spherical lipid-insoluble nanoparticles within the 7–10 nm size range can deliver therapeutic concentrations of drug fraction directly into individual tumor cells following systemic administration, since these functionalized particles maintain peak blood concentrations for several hours and are smaller than the physiologic upper limit of pore size in the VEGF-derived blood capillaries of solid tumors, which is approximately 12 nm. In this article, the physiologic and ultrastructural basis of this novel translational approach for the treatment of CNS, as well as non-CNS, solid cancers is reviewed. PMID:22163071

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

    ClinicalTrials.gov

    2017-02-17

    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. C.N.S. tumors in eastern Saudi Arabia.

    PubMed

    Ibrahim, A W

    1992-01-01

    In Saudi Arabia, there were no attempts previously to describe a population based frequency or incidence, particularly so the age adjusted incidence of various CNS tumors. This paper presents the primary CNS tumors from a population based tumor registry over two years period, from January 1987 till December 1988. There was a total of 85 cases representing 5.4% of the total captured cases (1,568 cases of malignant tumors at all sites). The population of the Eastern Province is estimated to be 1.37 million, the Saudis forming 80% of the total population. Out of the 85 cases captured over two years, there were 64 cases diagnosed in indigenous Saudi population forming 75%. The remaining occurred in non-Saudi residents. The male/female ratio in Saudis was 1:1.1 with a slight predominance of the female, while the reverse is true in the non-Saudis (2:1). The total captured cases per annum is 43, making the incidence of primary CNS neoplasms in the Eastern Province of Saudi Arabia 3.1/100,000 of all the population and 2.9/100,000 in Saudi nationals. Comparing this incidence to the international figure, it was clear that it is far less than the incidence reported from North America and Europe, particularly in the Caucasian population, but similar to incidences reported in the Chinese, black Americans, Romanians and Yugoslavians, but certainly less than the Ashkenazi or Safari Jews, and slightly higher than the incidence reported in Japan and Southeast Asia. Malignant brain tumors of various types dominated the primary CNS neoplasms reported over these two years forming 69% of the cases and 52% of the primary brain tumors.

  12. 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

  13. 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

  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

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

    2016-09-16

    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.

  15. 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

  16. 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.

  17. Deriving therapies for children with primary CNS tumors using pharmacokinetic modeling and simulation of cerebral microdialysis data.

    PubMed

    Jacus, M O; Throm, S L; Turner, D C; Patel, Y T; Freeman, B B; Morfouace, M; Boulos, N; Stewart, C F

    2014-06-16

    The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to

  18. Deriving Therapies for Children with Primary CNS Tumors Using Pharmacokinetic Modeling and Simulation of Cerebral Microdialysis Data

    PubMed Central

    Jacus, M.O.; Throm, S.L.; Turner, D.C.; Patel, Y.T.; Freeman, B.B.; Morfouace, M.; Boulos, N.; Stewart, C. F.

    2014-01-01

    The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. Pharmacokinetic Properties of Anticancer Agents for the Treatment of CNS Tumors: Update of the Literature

    PubMed Central

    Jacus, Megan O.; Daryani, Vinay M.; Harstead, K. Elaine; Patel, Yogesh T.; Throm, Stacy L.; Stewart, Clinton F.

    2015-01-01

    Despite significant improvement in outcomes for patients with hematological malignancies and solid tumors over the past 10 years, patients with primary or metastatic brain tumors continue to have a poor prognosis. A primary reason for this is the inability of many chemotherapeutic drugs to penetrate into the brain and brain tumors at concentrations high enough to exert an antitumor effect due to unique barriers and efflux transporters. Several studies have been published recently examining the CNS pharmacokinetics of various anticancer drugs in patients with primary and metastatic brain tumors. To summarize recent advances in the field, this review will critically present studies published within the last 9 years examining brain and cerebrospinal fluid penetration of clinically available anticancer agents for patients with CNS tumors. PMID:26293618

  10. Profiling pathway-specific novel therapeutics in preclinical assessment for central nervous system atypical teratoid rhabdoid tumors (CNS ATRT): favorable activity of targeting EGFR- ErbB2 signaling with lapatinib.

    PubMed

    Singh, Anjali; Lun, Xueqing; Jayanthan, Aarthi; Obaid, Halah; Ruan, Yibing; Strother, Douglas; Chi, Susan N; Smith, Amy; Forsyth, Peter; Narendran, Aru

    2013-06-01

    Despite intensifying multimodal treatments, children with central nervous system atypical teratoid/rhabdoid tumor (CNS ATRT) continue to endure unacceptably high mortality rates. At present, concerted efforts are focusing on understanding the characteristic INI1 mutation and its implications for the growth and survival of these tumors. Additionally, pharmaceutical pipeline libraries constitute a significant source of potential agents that can be taken to clinical trials in a timely manner. However, this process requires efficient target validation and relevant preclinical studies. As an initial screening approach, a panel of 129 small molecule inhibitors from multiple pharmaceutical pipeline libraries was tested against three ATRT cell lines by in vitro cytotoxicity assays. Based on these data, agents that have strong activity and corresponding susceptible cellular pathways were identified. Target modulation, antibody array analysis, drug combination and in vivo xenograft studies were performed on one of the pathway inhibitors found in this screening. Approximately 20% of agents in the library showed activity with IC(50) values of 1 μM or less and many showed IC(50) values less than 0.05 μM. Intra cell line variability was also noted among some of the drugs. However, it was determined that agents capable of affecting pathways constituting ErbB2, mTOR, proteasomes, Hsp90, Polo like kinases and Aurora kinases were universally effective against the three ATRT cell lines. The first target selected for further analysis, the inhibition of ErbB2-EGFR pathway by the small molecule inhibitor lapatinib, indicated inhibition of cell migration properties and the initiation of apoptosis. Synergy between lapatinib and IGF-IR inhibition was also demonstrated by combination index (CI) values. Xenograft studies showed effective antitumor activity of lapatinib in vivo. We present an experimental approach to identifying agents and drug combinations for future clinical trials and

  11. 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

  12. Adults with CNS primitive neuroectodermal tumors/pineoblastomas: results of multimodal treatment according to the pediatric HIT 2000 protocol.

    PubMed

    Friedrich, Carsten; Müller, Klaus; von Hoff, Katja; Kwiecien, Robert; Pietsch, Torsten; Warmuth-Metz, Monika; Gerber, Nicolas U; Hau, Peter; Kuehl, Joachim; Kortmann, Rolf D; von Bueren, André O; Rutkowski, Stefan

    2014-02-01

    Central nervous system primitive neuroectodermal tumors (CNS-PNET) and pineoblastomas (PBL) are rare in adulthood. Knowledge on clinical outcome and the efficacy and toxicities of chemotherapy in addition to radiotherapy is limited. Patients older than 21 years at diagnosis were followed in the observational arm of the prospective pediatric multicenter trial HIT 2000. After surgery, craniospinal irradiation and maintenance or sandwich chemotherapy were recommended. Radiotherapy was normo- (35.2 Gy; tumor region, 55.0 Gy; metastasis, 49.6 Gy) or hyperfractionated (40.0 Gy; tumor bed, 68.0 Gy; metastasis, 50-60 Gy). Maintenance chemotherapy consisted of eight courses (vincristine, lomustine, cisplatin). Sandwich chemotherapy included two cycles of postoperative chemotherapy followed by radiotherapy, and four courses of maintenance chemotherapy. Seventeen patients (CNS-PNET, n = 7; PBL, n = 10), median age 30 years, were included. Eight patients had a postoperative residual tumor and four patients metastatic disease. The median follow-up of ten surviving patients was 41 months. The estimated rates for 3-year progression-free survival (PFS) and overall survival were 68 ± 12 and 66 ± 13%, respectively. PBL compared to CNS-PNET tended towards a better PFS, although the difference was not clear (p = 0.101). Both chemotherapeutic (maintenance, n = 6; sandwich, n = 8) protocols did not differ in their PFS and were feasible with acceptable toxicities. Intensified regimens of combined chemo- and radiotherapy are generally feasible in adults with CNS-PNET/PBL. The impact of intensified chemotherapy on survival should be further assessed.

  13. 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

  14. The role of astrocytes in CNS tumors: pre-clinical models and novel imaging approaches

    PubMed Central

    O'Brien, Emma R.; Howarth, Clare; Sibson, Nicola R.

    2013-01-01

    Brain metastasis is a significant clinical problem, yet the mechanisms governing tumor cell extravasation across the blood-brain barrier (BBB) and CNS colonization are unclear. Astrocytes are increasingly implicated in the pathogenesis of brain metastasis but in vitro work suggests both tumoricidal and tumor-promoting roles for astrocyte-derived molecules. Also, the involvement of astrogliosis in primary brain tumor progression is under much investigation. However, translation of in vitro findings into in vivo and clinical settings has not been realized. Increasingly sophisticated resources, such as transgenic models and imaging technologies aimed at astrocyte-specific markers, will enable better characterization of astrocyte function in CNS tumors. Techniques such as bioluminescence and in vivo fluorescent cell labeling have potential for understanding the real-time responses of astrocytes to tumor burden. Transgenic models targeting signaling pathways involved in the astrocytic response also hold great promise, allowing translation of in vitro mechanistic findings into pre-clinical models. The challenging nature of in vivo CNS work has slowed progress in this area. Nonetheless, there has been a surge of interest in generating pre-clinical models, yielding insights into cell extravasation across the BBB, as well as immune cell recruitment to the parenchyma. While the function of astrocytes in the tumor microenvironment is still unknown, the relationship between astrogliosis and tumor growth is evident. Here, we review the role of astrogliosis in both primary and secondary brain tumors and outline the potential for the use of novel imaging modalities in research and clinical settings. These imaging approaches have the potential to enhance our understanding of the local host response to tumor progression in the brain, as well as providing new, more sensitive diagnostic imaging methods. PMID:23596394

  15. Years of potential life lost for brain and CNS tumors relative to other cancers in adults in the United States, 2010

    PubMed Central

    Rouse, Chaturia; Gittleman, Haley; Ostrom, Quinn T.; Kruchko, Carol; Barnholtz-Sloan, Jill S.

    2016-01-01

    Background Years of potential life lost (YPLL) complement incidence and survival rates by measuring how much a patient's life is likely to be shortened by his or her cancer. In this study, we examine the impact of death due to brain and other central nervous system (CNS) tumors compared to other common cancers in adults by investigating the YPLL of adults in the United States. Methods Mortality and life table data were obtained from the Centers for Disease Control and Prevention's National Center for Health Statistics Vital Statistics Data for 2010. The study population included individuals aged 20 years or older at death who died from one of the selected cancers. YPLL was calculated by taking an individual's age at death and finding the corresponding expected remaining years of life using life table data. Results The cancers with the greatest mean YPLL were other malignant CNS tumors (20.65), malignant brain tumors (19.93), and pancreatic cancer (15.13) for males and malignant brain tumors (20.31), breast cancer (18.78), and other malignant CNS tumors (18.36) for females. For both sexes, non-Hispanic whites had the lowest YPLL, followed by non-Hispanic blacks, and Hispanics. Conclusion Malignant brain and other CNS tumors have the greatest mean YPLL, thereby reflecting their short survival time post diagnosis. These findings will hopefully motivate more research into mitigating the impact of these debilitating tumors. PMID:26459813

  16. Chemotherapy-induced neurotoxicity in pediatric solid non-CNS tumor patients: An update on current state of research and recommended future directions.

    PubMed

    Sleurs, Charlotte; Deprez, Sabine; Emsell, Louise; Lemiere, Jurgen; Uyttebroeck, Anne

    2016-07-01

    Neurocognitive sequelae are known to be induced by cranial radiotherapy and central-nervous-system-directed chemotherapy in childhood Acute Lymphoblastic Leukemia (ALL) and brain tumor patients. However, less evidence exists for solid non-CNS-tumor patients. To get a better understanding of the potential neurotoxic mechanisms of non-CNS-directed chemotherapy during childhood, we performed a comprehensive literature review of this topic. Here, we provide an overview of preclinical and clinical studies investigating neurotoxicity associated with chemotherapy in the treatment of pediatric solid non-CNS tumors. Research to date suggests that chemotherapy has deleterious biological and psychological effects, with animal studies demonstrating histological evidence for neurotoxic effects of specific agents and human studies demonstrating acute neurotoxicity. Although the existing literature suggests potential neurotoxicity throughout neurodevelopment, research into the long-term neurocognitive sequelae in survivors of non-CNS cancers remains limited. Therefore, we stress the critical need for neurodevelopmental focused research in children who are treated for solid non-CNS tumors, since they are at risk for potential neurocognitive impairment.

  17. Pomalidomide shows significant therapeutic activity against CNS lymphoma with a major impact on the tumor microenvironment in murine models.

    PubMed

    Li, Zhimin; Qiu, Yushi; Personett, David; Huang, Peng; Edenfield, Brandy; Katz, Jason; Babusis, Darius; Tang, Yang; Shirely, Michael A; Moghaddam, Mehran F; Copland, John A; Tun, Han W

    2013-01-01

    Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS

  18. 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

  19. CNS tumor induction by radiotherapy: A report of four new cases and estimate of dose required

    SciTech Connect

    Cavin, L.W.; Dalrymple, G.V.; McGuire, E.L.; Maners, A.W.; Broadwater, J.R. )

    1990-02-01

    We have analyzed 60 cases of intra-axial brain tumors associated with antecedent radiation therapy. These include four new cases. The patients had originally received radiation therapy for three reasons: (a) cranial irradiation for acute lymphoblastic leukemia (ALL), (b) definitive treatment of CNS neoplasia, and (c) treatment of benign disease (mostly cutaneous infections). The number of cases reported during the past decade has greatly increased as compared to previous years. Forty-six of the 60 intra-axial tumors have been reported since 1978. The relative risk of induction of an intra-axial brain tumor by radiation therapy is estimated to be more than 100, as compared to individuals who have not had head irradiation.

  20. 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.

  1. Tumor necrosis factor-alpha regulation of the Id gene family in astrocytes and microglia during CNS inflammatory injury.

    PubMed

    Tzeng, S F; Kahn, M; Liva, S; De Vellis, J

    1999-04-01

    The inhibitors of DNA binding (Id) gene family is highly expressed during embryogenesis and throughout adulthood in the rat central nervous system (CNS). In vitro studies suggest that the Id gene family is involved in the regulation of cell proliferation and differentiation. Recently, Id gene expression was shown to be expressed in immature and mature astrocytes during development and upregulated in reactive astrocytes after spinal cord injury. These results suggest that the Id gene family may play an important role in regulating astrocyte development and reactivity; however, the factors regulating Id expression in astrocytes remain undefined. Tumor necrosis factor-alpha (TNF alpha), a proinflammatory cytokine, is thought to play a crucial role in astrocyte/microglia activation after injury to the CNS. To determine if TNF alpha plays a role in Id gene expression, we exogenously administered TNF alpha into developing postnatal rats. We report that TNF alpha injections resulted in a rapid and transient increase in both cell number and mRNA expression for Id2 and Id3 when compared to levels observed in noninjected or control-injected animals. Id1 mRNA levels were also upregulated after TNF alpha treatment, but to a lesser degree. Significant increases in TNF alpha-induced Id2 and Id3 mRNA were observed in the ventricular/subventricular zone, cingulum and corpus callosum. TNF alpha also increased Id2 mRNA expression in the caudate putamen and hippocampus at the injection site. Id2 and Id3 mRNA+ cells were identified as GFAP+ and S100 alpha + astrocytes as well as ED1+ microglia. This is the first report to show TNF-alpha-induced modulation of the Id gene family and suggests that Id may be involved in the formation of reactive astrocytes and activated microglia in the rodent brain. These results suggest a putative role for the Id family in the molecular mechanisms regulating cellular responsiveness to TNF alpha and CNS inflammation.

  2. 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

  3. 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.

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

    ClinicalTrials.gov

    2016-11-07

    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

  5. 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

  6. Nanomedicines for the Treatment of CNS Diseases.

    PubMed

    Reynolds, Jessica L; Mahato, Ram I

    2017-03-01

    Targeting and delivering macromolecular therapeutics to the central nervous system (CNS) has been a major challenge. The blood-brain barrier (BBB) is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Therefore, much effort has been channelled into improving transport of therapeutics across the BBB and into the CNS including the use of nanoparticles. In this thematic issue, several reviews and original research are presented that address "Nanomedicines for CNS Diseases." The articles in this issue are concentrated on either CNS-HIV disease or CNS tumors. In regards to CNS-HIV disease, there are two reviews that discuss the role of nanoparticles for improving the delivery of HIV therapeutics to the CNS. In addition, there are two original articles focusing on therapies for CNS-HIV, one of them uses nanoparticles for delivery of siRNA specific to a key protein in autophagy to microglia, and another discusses nanoparticle delivery of a soluble mediator to suppress neuroinflammation. Furthermore, a comprehensive review about gene therapy for CNS neurological diseases is also included. Finally, this issue also includes review articles on enhanced drug targeting to CNS tumors. These articles include a review on the use of nanoparticles for CNS tumors, a review on functionalization (ligands) of nanoparticles for drug targeting to the brain tumor by overcoming BBB, and the final review discusses the use of macrophages as a delivery vehicle to CNS tumors. This thematic issue provides a wealth of knowledge on using nanomedicines for CNS diseases.

  7. 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

  8. Rumor management in nursing systems: role of the psychiatric CNS.

    PubMed

    Chase, P; Stuart, G W

    1995-11-01

    RUMOR MANAGEMENT AND control is particularly important in nursing systems during times of change. In this article, a brief history of the study of rumor and the rumor process is given and applied to nursing, systems thinking and the CNS, and three types of rumor are described. Examples are given and strategies and approaches for managing rumor are prescribed. The first approach, used when a final decision about a planned change has not been made, helps avoid "trickle down" and builds trust and empowerment by soliciting and using input from those who will be affected by the proposed change. The intent of the second approach, used when a decision has been finalized or an event has occurred and rumor has preceded an official announcement, is to debrief from the occurrence or transform the decision. The last approach is used to interrupt a pattern of misinformation and to clarify or inform. The nurse leader or manager must stay in the communication loop and refrain from blaming a speculated source in order to correct information.

  9. 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.

  10. 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

    2016-09-12

    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.

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

    PubMed Central

    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

  12. Congenital tumors of the central nervous system.

    PubMed

    Severino, Mariasavina; Schwartz, Erin S; Thurnher, Majda M; Rydland, Jana; Nikas, Ioannis; Rossi, Andrea

    2010-06-01

    Congenital tumors of the central nervous system (CNS) are often arbitrarily divided into "definitely congenital" (present or producing symptoms at birth), "probably congenital" (present or producing symptoms within the first week of life), and "possibly congenital" (present or producing symptoms within the first 6 months of life). They represent less than 2% of all childhood brain tumors. The clinical features of newborns include an enlarged head circumference, associated hydrocephalus, and asymmetric skull growth. At birth, a large head or a tense fontanel is the presenting sign in up to 85% of patients. Neurological symptoms as initial symptoms are comparatively rare. The prenatal diagnosis of congenital CNS tumors, while based on ultrasonography, has significantly benefited from the introduction of prenatal magnetic resonance imaging studies. Teratomas constitute about one third to one half of these tumors and are the most common neonatal brain tumor. They are often immature because of primitive neural elements and, rarely, a component of mixed malignant germ cell tumors. Other tumors include astrocytomas, choroid plexus papilloma, primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, and medulloblastomas. Less common histologies include craniopharyngiomas and ependymomas. There is a strong predilection for supratentorial locations, different from tumors of infants and children. Differential diagnoses include spontaneous intracranial hemorrhage that can occur in the presence of coagulation factor deficiency or underlying vascular malformations, and congenital brain malformations, especially giant heterotopia. The prognosis for patients with congenital tumors is generally poor, usually because of the massive size of the tumor. However, tumors can be resected successfully if they are small and favorably located. The most favorable outcomes are achieved with choroid plexus tumors, where aggressive surgical treatment leads to disease-free survival.

  13. 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

  14. Non Hodgkin's lymphoma involving the adrenal glands and the central nervous system (CNS): a particular evolution after chemotherapy.

    PubMed

    Vélayoudom, F-L; Cardot-Bauters, C; Decouvelaere, A-V; Vlaeminck, V; Bauters, F; Wémeau, J-L

    2005-12-01

    Adrenal lymphoma is extremely rare. The prognostic depends on involvement of other organs (such as the central nervous system) responsible for lower median survival. We report the case of a 51-year-old man with non Hodgkin's Diffuse Large B Cell Lymphoma (DLBCL) involving the central nervous system (CNS) and the adrenal glands simultaneously. The endocrine exploration revealed a partial adrenal insufficiency and ruled out a pheochromocytoma. Computerized tomographic (CT) scan directed needle biopsy of the adrenal gland allowed the diagnostic of non-Hodgkin lymphoma (NHL). CNS biopsies showed similar histopathologic lesions. After aggressive polychemotherapy and methotrexate intrathecal injection, a dissociated therapeutic response was observed with a decrease of the cerebral lesion and an increase of the adrenal mass. This result may be explained by the efficacy of corticosteroid therapy on cerebral edema. The prognosis was poor with tumor infiltration of the leptomeninges and death 16 months after diagnosis.

  15. Advising potential recipients on the use of organs from donors with primary central nervous system tumors.

    PubMed

    Warrens, Anthony N; Birch, Rhiannon; Collett, David; Daraktchiev, Maren; Dark, John H; Galea, George; Gronow, Katie; Neuberger, James; Hilton, David; Whittle, Ian R; Watson, Christopher J E

    2012-02-27

    Deciding to use an organ from a donor with a primary central nervous system (CNS) tumor necessitates offsetting the risk of tumor transmission with the chances of survival if the patient waits for another offer of a transplant. Published data vary in the quoted risk of tumor transmission. We used data obtained by reviewing 246 UK recipients of organs taken from donors with CNS tumors and found no evidence of a difference in overall patient mortality for recipients of a kidney, liver, or cardiothoracic organ, compared with recipients of organs from donors without a CNS tumor. Recent publication of the UK experience of transplanting organs from CNS tumor donors found no transmission in 448 recipients of organs from 177 donors with a primary CNS tumor (Watson et al., Am J Transplant 2010; 10: 1437). This 0% transmission rate is associated with an upper 95% confidence interval limit of 1.5%. Using a series of assumptions of risk, we compared the risks of dying as a result of the transmission of a primary brain tumor with the risks of dying if not transplanted. On this basis, the use of kidneys from a donor with a primary CNS tumor provides a further 8 years of life over someone who waited for a donor who did not have a primary CNS tumor, in addition to the life years gained by the transplant itself. The benefits for the recipients of livers and cardiothoracic organs were less, but there was no disadvantage in the impact on life expectancy.

  16. 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.

  17. Prophylactic CNS directed therapy in systemic diffuse large B cell lymphoma.

    PubMed

    Ghose, Abhimanyu; Kundu, Ria; Latif, Tahir

    2014-09-01

    Overall survival in diffuse large B-cell lymphoma (DLBCL) has significantly improved in the last decade, especially after the incorporation of rituximab. Involvement of the central nervous system (CNS) at presentation or at recurrence is an uncommon event, but carries a dismal prognosis with median survival of less than 6 months. Although prophylactic CNS directed therapy is a widely used approach to prevent this complication, randomized clinical trials have been very limited. CNS prophylaxis has inherent toxicities; therefore, identifying the population of patients who would receive most benefit is of utmost importance. From an extensive review of current literature, we report the incidence of CNS relapse in DLBCL and describe the role of CNS prophylaxis in the post-rituximab compared to the pre-rituximab era. We also review the current modalities of CNS prophylaxis and attempt to identify the high-risk patients who would benefit. Lastly, we present a treatment algorithm that defines the role of CNS prophylaxis in the management of patients with DLBCL.

  18. Changes with age in leucocyte counts, protein and IgG content of lumbar cerebrospinal fluid (CSF) of patients with inflammatory, ischemic, and hemorrhagic diseases or tumors of the central nervous system (CNS).

    PubMed

    Kleine, T O; Weber, L; Zöfel, P

    1988-01-01

    Parameters of blood-brain barrier (BBB) function and of humoral and cellular immune response were determined in lumbar CSF and blood serum samples from 717 patients and statistically compared to "healthy" controls (n = 190). Leucocyte counts (mainly mononuclear cells), total protein and IgG levels in CSF were significantly higher, and prealbumin fraction mostly lower in patients, besides other alterations of protein electrophoresis. Serum fractions (median) of protein electrophoresis were within the reference range. When parameters were correlated with age, a significant increase of total protein of 1.62 mg/dl and of IgG of 0.13 mg/dl per 10 years of age was found in lumbar CSF of controls. Elevated leucocyte counts did not correlate with age of patients, but they increased significantly with age, with respect to controls, to a higher extent in patients with polyneuritis, ischemia and injury; they decreased in patients with brain tumors and polyneuropathy. When compared to controls, elevated total protein levels significantly increased with age only with tumors and injury patients. In multiple sclerosis, IgG increased and beta-globulin fraction decreased significantly in CSF with age. The findings point to age-dependent alterations of BBB and immune response only in some patients groups which were different from those of controls.

  19. [Immune system and tumors].

    PubMed

    Terme, Magali; Tanchot, Corinne

    2017-02-01

    Despite having been much debated, it is now well established that the immune system plays an essential role in the fight against cancer. In this article, we will highlight the implication of the immune system in the control of tumor growth and describe the major components of the immune system involved in the antitumoral immune response. The immune system, while exerting pressure on tumor cells, also will play a pro-tumoral role by sculpting the immunogenicity of tumors cells as they develop. Finally, we will illustrate the numerous mechanisms of immune suppression that take place within the tumoral microenvironment which allow tumor cells to escape control from the immune system. The increasingly precise knowledge of the brakes to an effective antitumor immune response allows the development of immunotherapy strategies more and more innovating and promising of hope.

  20. 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.

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

    PubMed

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

    2015-07-01

    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.

  2. The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity

    PubMed Central

    Thompson, Kaitlyn K.; Tsirka, Stella E.

    2017-01-01

    Autoimmune diseases of the central nervous system (CNS) involve inflammatory components and result in neurodegenerative processes. Microglia, the resident macrophages of the CNS, are the first responders after insults to the CNS and comprise a major link between the inflammation and neurodegeneration. Here, we will focus on the roles of microglia in two autoimmune diseases: the prevalent condition of multiple sclerosis (MS) and the much rarer Rasmussen’s encephalitis (RE). Although there is an abundance of evidence that microglia actively contribute to neuronal damage in pathological states such as MS and RE, there is also evidence of important reparative functions. As current research supports a more complex and diverse array of functions and phenotypes that microglia can assume, it is an especially interesting time to examine what is known about both the damaging and restorative roles that microglia can play in the inflammatory CNS setting. We will also discuss the pharmacological approaches to modulating microglia towards a more neuroprotective state. PMID:28245617

  3. Emerging roles of system [Formula: see text] antiporter and its inhibition in CNS disorders.

    PubMed

    Patel, Dhaval; Kharkar, Prashant S; Nandave, Mukesh

    2015-01-01

    System [Formula: see text] is an antiporter belonging to the hetero(di)meric amino acid transporter family. It is located on astrocytes as well as on blood-brain barrier within the CNS. It plays a pivotal role in free radical neutralization as well as neuronal signalling by regulating the glutathione production which occurs via the exchange of intracellular glutamate with extracellular cystine at 1:1 molar ratio. Understandably, it is a vital component responsible for the maintenance of neuronal homeostasis (e.g. redox state). Hence, it could be postulated that any perturbation in system [Formula: see text] function may contribute, directly or indirectly, to the pathophysiology of a variety of CNS disorders like Alzheimer's disease, schizophrenia, drug addiction, depression, multiple sclerosis, hypoglycemic neuronal cell death, glioma, and excitotoxicity, making system [Formula: see text] a promising target for treating CNS disorders. In recent times, recognizing the potential of this target, variety of inhibitors has been synthesized by modifying commercially available potent inhibitors including sulfasalazine, erastin, and sorafenib. Although, they have demonstrated efficacy, the in-depth data is still lacking to warrant their use for the treatment of aforementioned CNS disorders. In this review, we discuss the in-depth role of system [Formula: see text] transporter in maintaining normal physiology as well as in the pathophysiology of CNS diseases. Additionally, we have also listed some of the potent inhibitors of system [Formula: see text]. In conclusion, the critical role of system [Formula: see text] in multiple CNS disorders and advanced research on its inhibitors have promising future prospects for better management of the CNS ailments.

  4. 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.

  5. Cytogenetic characterizations of central nervous system tumors: the first comprehensive report from a single institution in Korea.

    PubMed

    Kim, Kyung-Eun; Kim, Ki-Uk; Kim, Dae-Cheol; Park, Joo-In; Han, Jin-Yeong

    2009-06-01

    The World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporates morphology, cytogenetics, molecular genetics, and immunologic markers. Despite the relatively large number of CNS tumors with clonal chromosome abnormalities, only few studies have investigated cytogenetic abnormalities for CNS tumors in Korea. Thus, we investigated 119 CNS tumors by conventional G-banded karyotypes to characterize patterns of chromosomal abnormalities involving various CNS tumors, and 92.4% of them were cultured and karyotyped successfully. Totally, 51.8% of karyotypable CNS tumors showed abnormal cytogenetic results, including neuroepithelial tumors (75.0%), meningeal tumors (71.1%), pituitary adenomas (4.2%), schwannomas (44.4%), and metastatic tumors (100.0%). Glioblastomas had hyperdiploid, complex karyotypes, mainly involving chromosomes Y, 1, 2, 6, 7, 10, 12, 13, and 14. Monosomy 22 was observed in 56.4% of meningiomas. There was a significant increase in the frequencies of karyotypic complexity according to the increase of WHO grade between grades I and II (P=0.0422) or IV (P=0.0101). Abnormal karyotypes were more complex at high-grade tumors, suggesting that the karyotype reflects the biologic nature of the tumor. More detailed cytogenetic and molecular characterizations of CNS tumors contribute to better diagnostic criteria and deeper insights of tumorigenesis, eventually resulting in development of novel therapeutic strategies.

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

    ClinicalTrials.gov

    2017-02-21

    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.

  9. Disability, body image and sports/physical activity in adult survivors of childhood CNS tumors: population-based outcomes from a cohort study.

    PubMed

    Boman, Krister K; Hörnquist, Lina; De Graaff, Lisanne; Rickardsson, Jenny; Lannering, Birgitta; Gustafsson, Göran

    2013-03-01

    Childhood CNS tumor survivors risk health and functional impairments that threaten normal psychological development and self-perception. This study investigated the extent to which health and functional ability predict adult survivors' body image (BI) and self-confidence regarding sports and physical activity. The study cohort covered 708 eligible ≥ 18 year old CNS tumor survivors, and data from 528 (75 %) were analyzed. Disability was estimated using the Health Utilities Index™ Mark2/3, a multidimensional self-report instrument. Physical self-confidence in terms of BI and sports/physical activity-related self-confidence (SPAS) were assessed using the BI and the Sports/Athletics modules of a standardized self-report assessment scale. In adjusted regression models, global health and functional status (GHFS) predicted BI (B = 0.94, 95 % CI 0.69-1.19) and SPAS (B = 0.79, 95 % CI 0.55-1.04). Emotion and pain, and to a lesser degree cognition, speech and vision disability, were associated with poorer BI and SPAS. Gender, sub-diagnosis, and time since diagnosis influenced the relationship between health status and physical self-confidence outcomes. Females had poorer GHFS, BI and SPAS than males. Decreased health and functional ability following childhood CNS cancer intrudes on physical self-confidence, with females being at heightened risk for both disability and negative self-confidence. Identified disability and gender-related risk calls for a follow-up plan that integrates treatment of psychological sequelae in lifetime monitoring of childhood CNS tumor survivors to restore and protect self-image and self-confidence, essential mental health correlates. An expanded plan should recognize the need for such services, optimizing life-long quality of survival for CNS tumor survivors.

  10. 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

  11. 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.

  12. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.

    PubMed

    Torchia, Jonathon; Golbourn, Brian; Feng, Shengrui; Ho, King Ching; Sin-Chan, Patrick; Vasiljevic, Alexandre; Norman, Joseph D; Guilhamon, Paul; Garzia, Livia; Agamez, Natalia R; Lu, Mei; Chan, Tiffany S; Picard, Daniel; de Antonellis, Pasqualino; Khuong-Quang, Dong-Anh; Planello, Aline C; Zeller, Constanze; Barsyte-Lovejoy, Dalia; Lafay-Cousin, Lucie; Letourneau, Louis; Bourgey, Mathieu; Yu, Man; Gendoo, Deena M A; Dzamba, Misko; Barszczyk, Mark; Medina, Tiago; Riemenschneider, Alexandra N; Morrissy, A Sorana; Ra, Young-Shin; Ramaswamy, Vijay; Remke, Marc; Dunham, Christopher P; Yip, Stephen; Ng, Ho-Keung; Lu, Jian-Qiang; Mehta, Vivek; Albrecht, Steffen; Pimentel, Jose; Chan, Jennifer A; Somers, Gino R; Faria, Claudia C; Roque, Lucia; Fouladi, Maryam; Hoffman, Lindsey M; Moore, Andrew S; Wang, Yin; Choi, Seung Ah; Hansford, Jordan R; Catchpoole, Daniel; Birks, Diane K; Foreman, Nicholas K; Strother, Doug; Klekner, Almos; Bognár, Laszló; Garami, Miklós; Hauser, Péter; Hortobágyi, Tibor; Wilson, Beverly; Hukin, Juliette; Carret, Anne-Sophie; Van Meter, Timothy E; Hwang, Eugene I; Gajjar, Amar; Chiou, Shih-Hwa; Nakamura, Hideo; Toledano, Helen; Fried, Iris; Fults, Daniel; Wataya, Takafumi; Fryer, Chris; Eisenstat, David D; Scheinemann, Katrin; Fleming, Adam J; Johnston, Donna L; Michaud, Jean; Zelcer, Shayna; Hammond, Robert; Afzal, Samina; Ramsay, David A; Sirachainan, Nongnuch; Hongeng, Suradej; Larbcharoensub, Noppadol; Grundy, Richard G; Lulla, Rishi R; Fangusaro, Jason R; Druker, Harriet; Bartels, Ute; Grant, Ronald; Malkin, David; McGlade, C Jane; Nicolaides, Theodore; Tihan, Tarik; Phillips, Joanna; Majewski, Jacek; Montpetit, Alexandre; Bourque, Guillaume; Bader, Gary D; Reddy, Alyssa T; Gillespie, G Yancey; Warmuth-Metz, Monika; Rutkowski, Stefan; Tabori, Uri; Lupien, Mathieu; Brudno, Michael; Schüller, Ulrich; Pietsch, Torsten; Judkins, Alexander R; Hawkins, Cynthia E; Bouffet, Eric; Kim, Seung-Ki; Dirks, Peter B; Taylor, Michael D; Erdreich-Epstein, Anat; Arrowsmith, Cheryl H; De Carvalho, Daniel D; Rutka, James T; Jabado, Nada; Huang, Annie

    2016-12-12

    We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

  13. 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

  14. The "Liquid Biopsy": the Role of Circulating DNA and RNA in Central Nervous System Tumors.

    PubMed

    Connolly, Ian D; Li, Yingmei; Gephart, Melanie Hayden; Nagpal, Seema

    2016-03-01

    The detection of tumor-derived circulating nucleic acids in patients with cancer, known as the "liquid biopsy," has expanded from use in plasma to other bodily fluids in an increasing number of malignancies. Circulating nucleic acids could be of particular use in central nervous system tumors as biopsy carries a 5-7 % risk of major morbidity. This application presents unique challenges that have limited the use of cell-free DNA and RNA in the diagnosis and monitoring of CNS tumors. Recent work suggests that cerebrospinal fluid may be a useful source of CNS tumor-derived circulating nucleic acids. In this review, we discuss the available data and future outlook on the use of the liquid biopsy for CNS tumors.

  15. 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.

  16. A review of multifunctional nanoemulsion systems to overcome oral and CNS drug delivery barriers.

    PubMed

    Ganta, Srinivas; Deshpande, Dipti; Korde, Anisha; Amiji, Mansoor

    2010-10-01

    The oral and central nervous systems (CNS) present a unique set of barriers to the delivery of important diagnostic and therapeutic agents. Extensive research over the past few years has enabled a better understanding of these physical and biological barriers based on tight cellular junctions and expression of active transporters and metabolizing enzymes at the luminal surfaces of the gastrointestinal (GI) tract and the blood-brain barrier (BBB). This review focuses on the recent understanding of transport across the GI tract and BBB and the development of nanotechnology-based delivery strategies that can enhance bioavailability of drugs. Multifunctional lipid nanosystems, such as oil-in-water nanoemulsions, that integrate enhancement in permeability, tissue and cell targeting, imaging, and therapeutic functions are especially promising. Based on strategic choice of edible oils, surfactants and additional surface modifiers, and different types of payloads, rationale design of multifunctional nanoemulsions can serve as a safe and effective delivery vehicle across oral and CNS barriers.

  17. 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

  18. Research on the airborne SINS/CNS integrated navigation system assisted by BD navigation system

    NASA Astrophysics Data System (ADS)

    Xie, Mei-lin; Yang, Xiao-xu; Han, Jun-feng; Wei, Yu; Yue, Peng; Deng, Xiao-guo; Huang, Wei

    2016-01-01

    When the star navigation system working during the day, the strong sky background radiation lead to a result that the detect target light is too weak, in the field of view, because of the limitation on the number of the navigation star, usually choose the single star navigation work mode. In order to improve the reliability of the airborne SINS/CNS integrated navigation system, meet the demand of the long-endurance and high precision navigation, use the tight combination way, single star patrol algorithm to get the position and attitude. There exists filtering divergence problem because of the model error and the system measurement noise is uncertain, put forward a new fuzzy adaptive kalman filtering algorithm. Adjust the size of measurement noise to prevent the filter divergence; the positioning accuracy of integrated navigation system can be improved through BeiDou satellite. Without the information of BeiDou satellite, based on the level of the virtual reference, the navigation precision of integrated navigation system can be ensured over a period of time.

  19. 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

  20. 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.

  1. The CNS in the ICU: A Bedside Notation System for Nurses

    PubMed Central

    Mertz, Susan L.; Ash, Stephen R.; Farrell, Joan

    1982-01-01

    An extended trial of two months was instituted utilizing the CNS as a bedside nursing notation system in an intensive care unit. Analysis of data was based on content analysis of the notes, training time, subjective data and quantitative content of the notes. It is possible to totally replace other written forms of notation in the paper record with a computer printed note. Such a system is well accepted by staff, easy to implement, and results in timely notes of better organization and content without increase in time involved.

  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.

  3. Central Nervous System (CNS) Delivery of Glucocorticoids Is Fine-Tuned by Saturable Transporters at the Blood-CNS Barriers and Nonbarrier Regions

    PubMed Central

    Pariante, Carmine M.; Jamel, Sara; Thomas, Sarah A.

    2010-01-01

    Proper functioning of the hypothalamic-pituitary-adrenal axis depends on the ability of glucocorticoids (GCs), mainly cortisol in humans and corticosterone in rodents, to access brain targets and regulate their own secretion. Being highly lipophilic, GCs have been assumed to passively diffuse through the cell membrane. However, the access of these GCs to the brain may be a more complicated process, because the free movement of molecules into the central nervous system (CNS) is restricted by the presence of the blood-brain and blood-cerebrospinal fluid barriers. GCs do interact with some transporter systems, including the efflux transporter, P-glycoprotein, and members of the organic anion transporter polypeptide (oatp) family, both of which have been found at the blood-CNS barriers. Using an in situ brain/choroid plexus perfusion, P-glycoprotein was shown to not majorly regulate the access of [3H]cortisol and [3H]corticosterone to the choroid plexus or pituitary gland. Interactions of [3H]cortisol and [3H]corticosterone with saturable influx transporters were detected at the hypothalamus, cerebellum, choroid plexus, and pituitary gland. Oatp2 seems to have some role in the influx of [3H]cortisol and [3H]corticosterone to the choroid plexus and the pituitary gland and other transporters, unlikely to be oatp2, may play a very minor role in the access of [3H]cortisol and [3H]corticosterone to the brain, as well as having a significant effect on [3H]glucocorticoid receptor accumulation in the pituitary gland. Overall, these data suggest that the majority of cortisol and corticosterone present in the plasma diffuse into the CNS and that transporters do not play a major role in the accumulation of these GCs in the brain. PMID:20881247

  4. Central nervous system tumors with ependymal features: a broadened spectrum of primarily ependymal differentiation?

    PubMed

    Lehman, Norman L

    2008-03-01

    Ependymomas are well-characterized central nervous system (CNS) tumors that occur most often in children and young adults. Several other CNS tumor entities, including astroblastoma, chordoid glioma, papillary tumor of the pineal region, angiocentric glioma, and pilomyxoid astrocytoma, variably display histopathologic features of ependymal differentiation. The ependymal differentiation in some of these tumors is generally accepted, whereas in others, it is controversial. This article briefly reviews ependymal cell development and conventional ependymomas, the pathologic findings and clinical behavior of tumors with variable ependymal features, and the rationales for their inclusion with ependymomas or exclusion from a larger family of ependymal tumors. These issues are addressed in the context of early morphologic insights of Bailey and Cushing, Friede, and others; contemporary oncologic concepts; and recent relevant molecular and tumor stem cell studies.

  5. Immunosuppressive Mechanisms of Malignant Gliomas: Parallels at Non-CNS Sites

    PubMed Central

    Perng, Powell; Lim, Michael

    2015-01-01

    The central nervous system (CNS) possesses powerful local and global immunosuppressive capabilities that modulate unwanted inflammatory reactions in nervous tissue. These same immune-modulatory mechanisms are also co-opted by malignant brain tumors and pose a formidable challenge to brain tumor immunotherapy. Routes by which malignant gliomas coordinate immunosuppression include the mechanical and functional barriers of the CNS; immunosuppressive cytokines and catabolites; immune checkpoint molecules; tumor-infiltrating immune cells; and suppressor immune cells. The challenges to overcoming tumor-induced immunosuppression, however, are not unique to the brain, and several analogous immunosuppressive mechanisms also exist for primary tumors outside of the CNS. Ultimately, the immune responses in the CNS are linked and complementary to immune processes in the periphery, and advances in tumor immunotherapy in peripheral sites may therefore illuminate novel approaches to brain tumor immunotherapy, and vice versa. PMID:26217588

  6. 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.

  7. The role of glutamate and the immune system in organophosphate-induced CNS damage.

    PubMed

    Eisenkraft, Arik; Falk, Avshalom; Finkelstein, Arseny

    2013-08-01

    Organophosphate (OP) poisoning is associated with long-lasting neurological damage, which is attributed mainly to the excessive levels of glutamate caused by the intoxication. Glutamate toxicity, however, is not specific to OP poisoning, and is linked to propagation of damage in both acute and chronic neurodegenerative conditions in the central nervous system (CNS). In addition to acute excitotoxic effects of glutamate, there is now a growing amount of evidence of its intricate immunomodulatory effects in the brain, involving both the innate and the adaptive immune systems. Moreover, it was demonstrated that immunomodulatory treatments, aimed at regulating the interaction between the resident immune cells of the brain (microglia) and the peripheral immune system, can support buffering of excessive levels of glutamate and restoration of the homeostasis. In this review, we will discuss the role of glutamate as an excitotoxic agent in the acute phase of OP poisoning, and the possible functions it may have as both a neuroprotectant and an immunomodulator in the sub-acute and chronic phases of OP poisoning. In addition, we will describe the novel immune-based neuroprotective strategies aimed at counteracting the long-term neurodegenerative effects of glutamate in the CNS.

  8. 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.

  9. Systemic Tolerance Mediated by Melanoma Brain Tumors is Reversible by Radiotherapy and Vaccination

    PubMed Central

    Jackson, Christopher M.; Kochel, Christina M.; Nirschl, Christopher J.; Durham, Nicholas M.; Ruzevick, Jacob; Alme, Angela; Francica, Brian J.; Elias, Jimmy; Daniels, Andrew; Dubensky, Thomas W.; Lauer, Peter; Brockstedt, Dirk G.; Baxi, Emily G.; Calabresi, Peter A.; Taube, Janis M.; Pardo, Carlos A.; Brem, Henry; Pardoll, Drew M.; Lim, Michael; Drake, Charles G.

    2016-01-01

    Purpose Immune responses to antigens originating in the CNS are generally attenuated, since collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. Experimental Design The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGF-β secretion from microglia and in the serum and TGF-β signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. Additionally, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. Results CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGF-β; however, blocking TGF-β signaling with a small molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios and decreased TGF-β secretion from microglia. Conclusions These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS while antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in more contemporary melanoma models as well as human trials. PMID:26490306

  10. 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

  11. Tumor immunity within the central nervous system stimulated by recombinant Listeria monocytogenes vaccination.

    PubMed

    Liau, Linda M; Jensen, Eric R; Kremen, Thomas J; Odesa, Sylvia K; Sykes, Steven N; Soung, Michael C; Miller, Jeff F; Bronstein, Jeff M

    2002-04-15

    Tumors arising within the central nervous system (CNS) present the immune system with a challenging target, given the heterogeneous nature of these neoplasms and their location within an "immunologically privileged" site. We used the lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a pseudotumor antigen to investigate recombinant Listeria monocytogenes as a tumor vaccine against s.c. and intracerebral challenges with a NP-expressing glioma, 9L-NP. Using Fischer 344 rats, we demonstrate that vaccination with recombinant L. monocytogenes-NP stimulates protection against s.c., but not intracerebral, 9L-NP tumor challenge in an antigen-specific, CD8(+) T-cell-dependent manner. After s.c. tumor rejection, enhanced antitumor immunity is achieved via epitope spreading that permits complete resistance against lethal intracerebral challenge with 9L-NP and with the untransfected parental 9L tumor. Unlike the CD8(+)-dependent immune responses against s.c. 9L-NP tumors, this expanded intracerebral immunity against endogenous tumor-associated antigens is dependent on both CD4(+) and CD8(+) T cells. Taken together, these results demonstrate that the mechanisms of tumor immunity within the brain are different from those elicited against non-CNS tumors. Furthermore, vaccination approaches exploiting the concept of epitope spreading may enhance the efficacy of antitumor immune responses within the immunologically privileged CNS, potentially mediating tumor cell killing through both CD4(+)- and CD8(+)-dependent effector pathways.

  12. Evidence toward an expanded international civil aviation organization (ICAO) concept of a single unified global communication navigation surveillance air traffic management (CNS/ATM) system: A quantitative analysis of ADS-B technology within a CNS/ATM system

    NASA Astrophysics Data System (ADS)

    Gardner, Gregory S.

    This research dissertation summarizes research done on the topic of global air traffic control, to include technology, controlling world organizations and economic considerations. The International Civil Aviation Organization (ICAO) proposed communication, navigation, surveillance, air traffic management system (CNS/ATM) plan is the basis for the development of a single global CNS/ATM system concept as it is discussed within this study. Research will be evaluated on the efficacy of a single technology, Automatic Dependent Surveillance-Broadcast (ADS-B) within the scope of a single global CNS/ATM system concept. ADS-B has been used within the Federal Aviation Administration's (FAA) Capstone program for evaluation since the year 2000. The efficacy of ADS-B was measured solely by using National Transportation Safety Board (NTSB) data relating to accident and incident rates within the Alaskan airspace (AK) and that of the national airspace system (NAS).

  13. Efficiency of Crizotinib on an ALK-Positive Inflammatory Myofibroblastic Tumor of the Central Nervous System: A Case Report

    PubMed Central

    Chennouf, Anas; Arslanian, Elizabeth; Roberge, David; Berthelet, France; Bojanowski, Michel; Bahary, Jean-Paul; Masucci, Laura; Belanger, Karl; Florescu, Marie

    2017-01-01

    Inflammatory myofibroblastic tumors (IMT) of the central nervous system (CNS) are rare entities that have a predilection for local recurrences. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in the over-expression of the anaplastic lymphoma kinase (ALK) gene. We hereby present the case of a patient diagnosed with a left parieto-occipital IMT that recurred after multiple surgeries and radiotherapy. Immuno-histochemical examination of the tumor demonstrated ALK overexpression and the presence of an ALK rearrangement observed in lung cancers. The patient was subsequently started on an ALK inhibitor. A response evaluation criteria in solid tumors (RECIST) partial response was observed by the seventh month of ALK inhibition and the tumor remained in control for 14 months. The current case reiterates the activity of ALK inhibitors within the CNS and suggests that radiotherapy may potentiate the permeability of ALK inhibitors in CNS tumors addicted to ALK signalling.

  14. Quantitative systems pharmacology as an extension of PK/PD modeling in CNS research and development.

    PubMed

    Geerts, Hugo; Spiros, Athan; Roberts, Patrick; Carr, Robert

    2013-06-01

    Quantitative systems pharmacology (QSP) is a recent addition to the modeling and simulation toolbox for drug discovery and development and is based upon mathematical modeling of biophysical realistic biological processes in the disease area of interest. The combination of preclinical neurophysiology information with clinical data on pathology, imaging and clinical scales makes it a real translational tool. We will discuss the specific characteristics of QSP and where it differs from PK/PD modeling, such as the ability to provide support in target validation, clinical candidate selection and multi-target MedChem projects. In clinical development the approach can provide additional and unique evaluation of the effect of comedications, genotypes and disease states (patient populations) even before the initiation of actual trials. A powerful property is the ability to perform failure analysis. By giving examples from the CNS R&D field in schizophrenia and Alzheimer's disease, we will illustrate how this approach can make a difference for CNS R&D projects.

  15. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature

    PubMed Central

    Warnatz, K; Peter, H; Schumacher, M; Wiese, L; Prasse, A; Petschner, F; Vaith, P; Volk, B; Weiner, S

    2003-01-01

    Background: Immunosuppressive treatment of rheumatic diseases may be associated with several opportunistic infections of the brain. The differentiation between primary central nervous system (CNS) involvement and CNS infection may be difficult, leading to delayed diagnosis. Objective: To differentiate between CNS involvement and CNS infection in systemic rheumatic diseases. Methods and results: Three patients with either longstanding or suspected systemic rheumatic diseases (systemic lupus erythematodes, Wegener's granulomatosis, and cerebral vasculitis) who presented with various neuropsychiatric symptoms are described. All three patients were pretreated with different immunosuppressive drugs (leflunomide, methotrexate, cyclophosphamide) in combination with corticosteroids. Magnetic resonance imaging of the brain was suggestive of infectious disease, which was confirmed by cerebrospinal fluid analysis or stereotactic brain biopsy (progressive multifocal leucoencephalopathy (PML) in two and nocardiosis in one patient). Discussion: More than 20 cases of PML or cerebral nocardiosis in patients receiving corticosteroids and cytotoxic drugs for rheumatic disease have been reported. The clinical aspects of opportunistic CNS infections and the role of brain imaging, cerebrospinal fluid analysis and stereotactic brain biopsy in the differential diagnosis are reviewed. PMID:12480669

  16. 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.

  17. 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.

  18. Shedding Light on the 2016 World Health Organization Classification of Tumors of the Central Nervous System in the Era of Radiomics and Radiogenomics.

    PubMed

    Colen, Rivka R; Hassan, Islam; Elshafeey, Nabil; Zinn, Pascal O

    2016-11-01

    The new World Health Organization classification of brain tumors depends on combining the histologic light microscopy features of central nervous system (CNS) tumors with canonical genetic alterations. This integrated diagnosis is redrawing the pedigree chart of brain tumors with rearrangement of tumor groups on the basis of geno-phenotypical behaviors into meaningful groups. Multiple radiogenomic studies provide a bridge between imaging features and tumor microenvironment. An overlap that can be integrated within the genophenotypical classification of CNS tumors for a better understanding of different clinically relevant entities.

  19. Genomic deletions in cell lines derived from primitive neuroectodermal tumors of the central nervous system.

    PubMed

    Dallas, Peter B; Terry, Philippa A; Kees, Ursula R

    2005-06-01

    Extensive genomic deletions affecting a variety of chromosomes are a common finding in primitive neuroectodermal tumors of the central nervous system (CNS-PNETs), implicating the loss of multiple tumor suppressor genes in the pathogenesis of these tumors. We have used representational difference analysis, microsatellite mapping, and quantitative polymerase chain reaction to identify and verify the presence of genomic deletions on a number of chromosomes in CNS-PNET cell lines. This systematic approach has confirmed the importance of deletions at 10q, 16q, and 17p in PNET pathology and has revealed other regions of deletion not commonly described (e.g., Xq, 1p, 7p, and 13q). These data highlight the prevalence of hemizygous loss in CNS-PNET cells, suggesting that haploinsufficiency affecting multiple tumor suppressor genes may play a fundamental role in CNS-PNET pathogenesis. The identification of specific genes and signaling pathways that are compromised in CNS-PNET cells is crucial for development of more efficacious and less invasive treatments, as are urgently needed.

  20. Clinicopathologic Features of the Non-CNS Primary Ewing Sarcoma Family of Tumors in the Head and Neck Region.

    PubMed

    Woo, Chang Gok; Lee, Bora; Song, Joon Seon; Cho, Kyung-Ja

    2017-02-28

    Ewing sarcoma family of tumor (ESFT) is a group of malignant neoplasms that affect children and young adults. Primary ESFT does not commonly arise from the head and neck region. This study aimed to elucidate the clinicopathologic characteristics of ESFT of the head and neck region except for central nervous system primitive neuroectodermal tumors. Among the 207 cases of ESFT of the bone and soft tissue, diagnosed at Asan Medical Center during a 20-year period, 25 (12.1%) involved the head and neck region. Of those, 21 were available for histologic, immunohistochemical, and molecular studies. EWSR1 rearrangement was detected in 19 cases by reverse transcriptase-polymerase chain reaction and/or fluorescence in situ hybridization. Primary sites included the cranial area (6 cases, 31.6%), sinonasal tract (6 cases, 31.6%), paraspinal space (4 cases, 21.0%), and other spaces (3 cases, 15.8%). The 5-year overall survival and disease-free survival rates for all cases were 69.7% and 33.6%, respectively. A large tumor size (>5 cm) correlated significantly with overall survival (P=0.009), but not with disease-free survival (P=0.210). Microscopically, 8 cases (42.1%) showed nested growth pattern. Clear and/or eosinophilic cytoplasm was observed in 68.4% cases. Immunopositivity for CD99, Friend leukaemia integration-1 (FLI-1), CD57, and caveloin-1 were detected in 100%, 88.9%, 83.3%, and 50% cases, respectively. ESFT in the head and neck region had a favorable prognosis and frequent atypical and epithelioid features. An awareness of these histologic and immunophenotypic characteristics will improve the diagnostic accuracy for head and neck round cell malignancies.

  1. Transcript Diversification in the Nervous System: A to I RNA Editing in CNS Function and Disease Development

    PubMed Central

    Tariq, Aamira; Jantsch, Michael F.

    2012-01-01

    RNA editing by adenosine deaminases that act on RNA converts adenosines to inosines in coding and non-coding regions of mRNAs. Inosines are interpreted as guanosines and hence, this type of editing can change codons, alter splice patterns, or influence the fate of an RNA. A to I editing is most abundant in the central nervous system (CNS). Here, targets for this type of nucleotide modification frequently encode receptors and channels. In many cases, the editing-induced amino acid exchanges alter the properties of the receptors and channels. Consistently, changes in editing patterns are frequently found associated with diseases of the CNS. In this review we describe the mechanisms of RNA editing and focus on target mRNAs of editing that are functionally relevant to normal and aberrant CNS activity. PMID:22787438

  2. Immunohistological localization of serotonin in the CNS and feeding system of the stable fly stomoxys calcitrans L. (Diptera: muscidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Serotonin, or 5-hydroxytryptamine (5-HT), plays critical roles as a neurotransmitter and neuromodulator that control or modulate many behaviors in insects, such as feeding. Neurons immunoreactive (IR)to 5-HT were detected in the central nervous system (CNS) of the larval and adult stages of the stab...

  3. Risk factors for central nervous system tumors in children: New findings from a case-control study

    PubMed Central

    Tamayo-Uria, Ibon; Gómez-Barroso, Diana; López-Abente, Gonzalo; Morales-Piga, Antonio; Pardo Romaguera, Elena; Aragonés, Nuria; García-Pérez, Javier

    2017-01-01

    Background Central nervous system tumors (CNS) are the most frequent solid tumor in children. Causes of CNS tumors are mainly unknown and only 5% of the cases can be explained by genetic predisposition. We studied the effects of environmental exposure on the incidence of CNS tumors in children by subtype, according to exposure to industrial and/or urban environment, exposure to crops and according to socio-economic status of the child. Methods We carried out a population-based case-control study of CNS tumors in Spain, covering 714 incident cases collected from the Spanish Registry of Childhood Tumors (period 1996–2011) and 4284 controls, individually matched by year of birth, sex, and autonomous region of residence. We built a covariate to approximate the exposure to industrial and/or urban environment and a covariate for the exposure to crops (GCI) using the coordinates of the home addresses of the children. We used the 2001 Census to obtain information about socio-economic status (SES). We fitted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs). Results The results for all CNS tumors showed an excess risk (OR = 1.37; 95%CI = 1.09–1.73) for SES, i.e., children living in the least deprived areas had 37% more risk of CNS tumor than children living in the most deprived areas. For GCI, an increase of 10% in crop surface in the 1-km buffer around the residence implied an increase of 22% in the OR (OR = 1.22; 95%CI = 1.15–1.29). Children living in the intersection of industrial and urban areas could have a greater risk of CNS tumors than children who live outside these areas (OR = 1.20; 95%CI = 0.82–1.77). Living in urban areas (OR = 0.90; 95%CI = 0.65–1.24) or industrial areas (OR = 0.96; 95%CI = 0.81–1.77) did not seem to increase the risk for all CNS tumors together. By subtype, Astrocytomas, Intracranial and intraspinal embryonal tumors, and other gliomas showed similar results. Conclusion Our results

  4. Long-Term Neurocognitive Functioning and Social Attainment in Adult Survivors of Pediatric CNS Tumors: Results From the St Jude Lifetime Cohort Study

    PubMed Central

    Krasin, Matthew J.; Liu, Wei; Armstrong, Gregory T.; Ojha, Rohit P.; Sadighi, Zsila S.; Gupta, Pankaj; Kimberg, Cara; Srivastava, Deokumar; Merchant, Thomas E.; Gajjar, Amar; Robison, Leslie L.; Hudson, Melissa M.; Krull, Kevin R.

    2016-01-01

    Purpose To assess the prevalence and severity of neurocognitive impairment in adult survivors of pediatric CNS tumors and to examine associated treatment exposures. Patients and Methods Participants included 224 survivors of CNS tumors who were treated at St Jude Children's Research Hospital (current median age [range], 26 years [19 to 53 years]; time from diagnosis, 18 years [11 to 42 years]) and completed neurocognitive testing. Information on cranial radiation therapy (CRT) doses and parameters of delivery were abstracted from medical records. The prevalence of severe impairment (ie, at least two standard deviations below normative mean) was compared across radiation treatment groups (no CRT, focal irradiation, craniospinal irradiation) using the χ2 test. Log-binomial models were used to estimate risk ratios (RRs) and corresponding 95% CIs for severe impairment. Results In multivariable models, craniospinal irradiation was associated with a 1.5- to threefold increased risk of severe impairment compared with no CRT (eg, intelligence: RR = 2.70; 95% CI, 1.37 to 5.34; memory: RR = 2.93; 95% CI, 1.69 to 5.08; executive function: RR = 1.74; 95% CI, 1.24 to 2.45). Seizures were associated with impaired academic performance (RR = 1.48; 95% CI, 1.02 to 2.14), attention (RR = 1.54; 95% CI, 1.12 to 2.13), and memory (RR = 1.44; 95% CI, 1.04 to 1.99). Hydrocephalus with shunt placement was associated with impaired intelligence (RR = 1.78; 95% CI, 1.12 to 2.82) and memory (RR = 1.42; 95% CI, 1.03 to 1.95). Differential follow-up time contributed to variability in prevalence estimates between survivors treated with older nonconformal and those treated with more contemporary conformal radiation therapy methods. Neurocognitive impairment was significantly associated with lower educational attainment, unemployment, and nonindependent living. Conclusion Survivors of pediatric CNS tumors are at risk of severe neurocognitive impairment in adulthood. The prevalence of severe

  5. 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.

  6. Childhood Central Nervous System Germ Cell Tumors Treatment

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood CNS germ cell tumors may ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. Some cancer ...

  7. An octopaminergic system in the CNS of the snails, Lymnaea stagnalis and Helix pomatia

    PubMed Central

    Hiripi, L.

    1998-01-01

    Octopamine (OA) levels in each ganglion of the terrestrial snail, Helix pomatia, and the pond snail, Lymnaea stagnalis, were measured by using the HPLC technique. In both species an inhomogeneous distribution of OA was found in the central nervous system. The buccal ganglia contained a concentration of OA (12.6 pmol mg-1 and 18.8 pmol mg-1) that was two to three times higher than the pedal (4.93 pmol mg-1 and 9.2 pmol mg-1) or cerebral (4.46 pmol mg-1 and 4.9 pmol mg-1) ganglia of Helix and Lymnaea, respectively, whereas no detectable amount of OA could be assayed in the visceroparietal complex. In Lymnaea ganglia, the OA uptake into the synaptosomal fraction had a high (Km1 = 4.07 ± 0.51 μM, Vmax1 = 0.56 ± 0.11 pmol mg-1 per 20 min), and a low (Km2 = 47.6 ± 5.2 μM, Vmax2 = 4.2 ± 0.27 pmol mg-1 per 20 min), affinity component. A specific and dissociable 3H-OA binding to the membrane pellet prepared from the CNS of both Helix and Lymnaea was demonstrated. The Scatchard analysis of the ligand binding data showed a one-binding site, representing a single receptor site. The Kd and Bmax values were found to be 33.7 ± 5.95 nM and 1678 ± 179 fmol g-1 tissue in Helix and 84.9 ± 17.4 nM and 3803 ± 515 fmol g-1 tissue in Lymnaea preparation. The pharmacological properties of the putative molluscan OA receptor were characterized in both species and it was demonstrated that the receptor resembled the insect OA2 rather than to the cloned Lymnaea OA receptor. Immunocytochemical labelling demonstrated the presence of OA-immunoreactive neurons and fibres in the buccal, cerebral and pedal ganglia in the central nervous system of both species investigated. Electrophysiological experiments also suggested that the Lymnaea brain possessed specific receptors for OA. Local application of OA onto the identified buccal B2 neuron evoked a hyperpolarization which could selectively be inhibited by the OAergic agents phentolamine, demethylchlordimeform and 2-chloro-4-methyl-2

  8. Medicinal chemistry based approaches and nanotechnology-based systems to improve CNS drug targeting and delivery.

    PubMed

    Vlieghe, Patrick; Khrestchatisky, Michel

    2013-05-01

    The central nervous system (CNS) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood-brain barrier (BBB), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug-targeting approaches and targeted nanotechnology-based systems, two promising strategies for BBB targeting and delivery of drugs to the brain.

  9. 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...

  10. Utility of squash smear cytology in intraoperative diagnosis of central nervous system tumors

    PubMed Central

    Patil, Savita S; Kudrimoti, Jyoti K; Agarwal, Rachana D; Jadhav, Meenal V; Chuge, Ashish

    2016-01-01

    Background: Central nervous system (CNS) squash cytology (CSC) has established itself as a technically simple, rapid, inexpensive, fairly accurate, and dependable intraoperative diagnostic tool. It helps neurosurgeons immensely when management is dependent on it. Aims: This study aimed at finding out the utility of CSC as an intraoperative diagnostic tool from a neurosurgeon's perspective. Materials and Methods: Fifty prospectively registered patients with clinical diagnosis of CNS tumors were enrolled in the study. All the patients were subjected to magnetic resonance imaging (MRI). Intraoperative CSC was performed and smears were stained with Leishman and rapid Hematoxylin and Eosin (H and E) stain. The diagnosis of CSC was compared with MRI diagnosis and histopathological diagnosis. The CNS tumors were categorized based on clinical and therapeutic implications. Diagnostic accuracy, sensitivity, specificity, and positive and negative predictive value of MRI and CSC were calculated by using appropriate formulae. Results and Conclusions: The age range of the CNS tumors included in the study was 2 to 68 years. There was a slight female preponderance. Sensitivity, specificity, positive predictive value, and negative predictive value of preoperative MRI were 90.47%, 82.76%, 79.17%, and 92.31% respectively. These values of utility parameters for CSC were 100% for each of the clinical and therapeutic implications. It helped neurosurgeons in optimizing surgical procedure in 12 cases of meningioma. It influenced surgical management in 1 case of infratentorial pilocytic astrocytoma, and helped in the diagnosis and management of 9 unexpected tumors missed on MRI. PMID:28028335

  11. Nanomaterial-mediated CNS Delivery of Diagnostic and Therapeutic Agents

    PubMed Central

    Biddlestone-Thorpe, Laura; Marchi, Nicola; Guo, Kathy; Ghosh, Chaitali; Janigro, Damir; Valerie, Kristoffer; Yang, Hu

    2011-01-01

    Research into the diagnosis and treatment of central nervous system (CNS) diseases has been enhanced by rapid advances in nanotechnology and an expansion in the library of nanostructured carriers. This review discusses the latest applications of nanomaterials in the CNS with an emphasis on brain tumors. Novel administration routes and transport mechanisms for nanomaterial-mediated CNS delivery of diagnostic and therapeutic agents to bypass or cross the blood brain barrier (BBB) are also discussed. These include temporary disruption of the BBB, use of impregnated polymers (polymer wafers), convection-enhanced delivery (CED), and intranasal delivery. Moreover, an in vitro BBB model capable of mimicking geometrical, cellular and rheological features of the human cerebrovasculature has been developed. This is a useful tool that can be used for screening CNS nanoparticles or therapeutics prior to in vivo and clinical investigation. A discussion of this novel model is included. PMID:22178615

  12. 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.

  13. Completeness of required site-specific factors for brain and CNS tumors in the Surveillance, Epidemiology and End Results (SEER) 18 database (2004-2012, varying).

    PubMed

    Ostrom, Quinn T; Gittleman, Haley; Kruchko, Carol; Louis, David N; Brat, Daniel J; Gilbert, Mark R; Petkov, Valentina I; Barnholtz-Sloan, Jill S

    2016-10-01

    Cancer registries are an important source of population-level information on brain tumor incidence and survival. Surveillance, Epidemiology, and End Results (SEER) registries currently collect data on specific required factors related to brain tumors as defined by the American Joint Commission on Cancer, including World Health Organization (WHO) grade, MGMT methylation and 1p/19q codeletion status. We assessed 'completeness', defined as having valid values over the time periods that they have been collected, overall, by year, histology, and registry. Data were obtained through a SEER custom data request for four factors related to brain tumors for the years 2004-2012 (3/4 factors were collected only from 2010 to 2012). SEER*Stat was used to generate frequencies of 'completeness' for each factor overall, and by year, histology and registry. The four factors varied in completeness, but increased over time. WHO grade has been collected the longest, and showed significant increases in completeness. Completeness of MGMT and 1p/19q codeletion was highest for glioma subtypes for which testing is recommended by clinical practice guidelines. Completeness of all factors varied by histology and cancer registry. Overall, several of the factors had high completeness, and all increased in completeness over time. With increasing focus on 'precision medicine' and the incorporation of molecular parameters into the 2016 WHO CNS tumor classification, it is critical that the data are complete, and factors collected at the population level are fully integrated into cancer reporting. It is critical that cancer registries continue to collect established and emerging prognostic and predictive factors.

  14. Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties

    PubMed Central

    2010-01-01

    The interplay among commonly used physicochemical properties in drug design was examined and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochemical parameters ((a) lipophilicity, calculated partition coefficient (ClogP); (b) calculated distribution coefficient at pH = 7.4 (ClogD); (c) molecular weight (MW); (d) topological polar surface area (TPSA); (e) number of hydrogen bond donors (HBD); (f) most basic center (pKa)), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compounds (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0−6), in comparison to 60% of the Pfizer CNS candidates. This analysis suggests that this algorithm could potentially be used to identify compounds with a higher probability of successfully testing hypotheses in the clinic. In addition, a relationship between an increasing CNS MPO score and alignment of key in vitro attributes of drug discovery (favorable permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and safety) was seen in the marketed CNS drug set, the Pfizer candidate set, and the Pfizer proprietary diversity set. The CNS MPO scoring function offers advantages over hard cutoffs or utilization of single parameters to optimize structure−activity relationships (SAR) by expanding medicinal chemistry design space through a holistic assessment approach. Based on six physicochemical properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compounds with increased probability of success. PMID:22778837

  15. Performance Enhancement of a USV INS/CNS/DVL Integration Navigation System Based on an Adaptive Information Sharing Factor Federated Filter.

    PubMed

    Wang, Qiuying; Cui, Xufei; Li, Yibing; Ye, Fang

    2017-02-03

    To improve the ability of autonomous navigation for Unmanned Surface Vehicles (USVs), multi-sensor integrated navigation based on Inertial Navigation System (INS), Celestial Navigation System (CNS) and Doppler Velocity Log (DVL) is proposed. The CNS position and the DVL velocity are introduced as the reference information to correct the INS divergence error. The autonomy of the integrated system based on INS/CNS/DVL is much better compared with the integration based on INS/GNSS alone. However, the accuracy of DVL velocity and CNS position are decreased by the measurement noise of DVL and bad weather, respectively. Hence, the INS divergence error cannot be estimated and corrected by the reference information. To resolve the problem, the Adaptive Information Sharing Factor Federated Filter (AISFF) is introduced to fuse data. The information sharing factor of the Federated Filter is adaptively adjusted to maintaining multiple component solutions usable as back-ups, which can improve the reliability of overall system. The effectiveness of this approach is demonstrated by simulation and experiment, the results show that for the INS/CNS/DVL integrated system, when the DVL velocity accuracy is decreased and the CNS cannot work under bad weather conditions, the INS/CNS/DVL integrated system can operate stably based on the AISFF method.

  16. Performance Enhancement of a USV INS/CNS/DVL Integration Navigation System Based on an Adaptive Information Sharing Factor Federated Filter

    PubMed Central

    Wang, Qiuying; Cui, Xufei; Li, Yibing; Ye, Fang

    2017-01-01

    To improve the ability of autonomous navigation for Unmanned Surface Vehicles (USVs), multi-sensor integrated navigation based on Inertial Navigation System (INS), Celestial Navigation System (CNS) and Doppler Velocity Log (DVL) is proposed. The CNS position and the DVL velocity are introduced as the reference information to correct the INS divergence error. The autonomy of the integrated system based on INS/CNS/DVL is much better compared with the integration based on INS/GNSS alone. However, the accuracy of DVL velocity and CNS position are decreased by the measurement noise of DVL and bad weather, respectively. Hence, the INS divergence error cannot be estimated and corrected by the reference information. To resolve the problem, the Adaptive Information Sharing Factor Federated Filter (AISFF) is introduced to fuse data. The information sharing factor of the Federated Filter is adaptively adjusted to maintaining multiple component solutions usable as back-ups, which can improve the reliability of overall system. The effectiveness of this approach is demonstrated by simulation and experiment, the results show that for the INS/CNS/DVL integrated system, when the DVL velocity accuracy is decreased and the CNS cannot work under bad weather conditions, the INS/CNS/DVL integrated system can operate stably based on the AISFF method. PMID:28165369

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

    PubMed Central

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

    2015-01-01

    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 × 1011 or 3 × 1011 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 × 1011 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 × 1011 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. PMID:25964428

  18. 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.

  19. 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.

  20. Increased fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) uptake in childhood CNS tumors is correlated with malignancy grade: a study with FDG positron emission tomography/magnetic resonance imaging coregistration and image fusion.

    PubMed

    Borgwardt, Lise; Højgaard, Liselotte; Carstensen, Henrik; Laursen, Henning; Nowak, Markus; Thomsen, Carsten; Schmiegelow, Kjeld

    2005-05-01

    PURPOSE Positron emission tomography (PET) has been used in grading of CNS tumors in adults, whereas studies of children have been limited. PATIENTS AND METHODS Nineteen boys and 19 girls (median age, 8 years) with primary CNS tumors were studied prospectively by fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) PET with (n = 16) or without (n = 22) H(2)(15)O-PET before therapy. Image processing included coregistration to magnetic resonance imaging (MRI) in all patients. The FDG uptake in tumors was semiquantitatively calculated by a region-of-interest-based tumor hotspot/brain index. Eight tumors without histologic confirmation were classified as WHO grade 1 based on location, MRI, and clinical course (22 to 42 months). Results Four grade 4 tumors had a mean index of 4.27 +/- 0.5, four grade 3 tumors had a mean index of 2.47 +/- 1.07, 10 grade 2 tumors had a mean index of 1.34 +/- 0.73, and eight of 12 grade 1 tumors had a mean index of -0.31 +/- 0.59. Eight patients with no histologic confirmation had a mean index of 1.04. For these 34 tumors, FDG uptake was positively correlated with malignancy grading (n = 34; r = 0.72; P < .01), as for the 26 histologically classified tumors (n = 26; r = 0.89; P < .01). The choroid plexus papilloma (n = 1) and the pilocytic astrocytomas (n = 3) had a mean index of 3.26 (n = 38; r = 0.57; P < .01). H(2)(15)O-uptake showed no correlation with malignancy. Digitally performed PET/MRI coregistration increased information on tumor characterization in 90% of cases. CONCLUSION FDG PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Improved PET/MRI imaging of the benign hypermetabolic tumors is needed to optimize clinical use.

  1. 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

  2. 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.

  3. Pilot study of systemic and intrathecal mafosfamide followed by conformal radiation for infants with intracranial central nervous system tumors: a pediatric brain tumor consortium study (PBTC-001).

    PubMed

    Blaney, Susan M; Kocak, Mehmet; Gajjar, Amar; Chintagumpala, Murali; Merchant, Thomas; Kieran, Mark; Pollack, Ian F; Gururangan, Sri; Geyer, Russ; Phillips, Peter; McLendon, Roger E; Packer, Roger; Goldman, Stewart; Banerjee, Anu; Heideman, Richard; Boyett, James M; Kun, Larry

    2012-09-01

    A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n = 71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M(0)) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis. 71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M + disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52 ± 6.5 % and 33 ± 13 %, and 67 ± 6.2 % and 51 ± 11 %, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive neuroectodermal tumor (PNET, n = 9), and atypical teratoid rhabdoid tumor (ATRT, n = 12) was 80 ± 7 %, 67 ± 15 % and 27 ± 13 % and 5-year PFS was 65 ± 19 %, 37 ± 29 %, and 0 ± 0 %, respectively. The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.

  4. Ionizing radiation increases systemic nanoparticle tumor accumulation

    PubMed Central

    Giustini, A.J.; Petryk, A.A.; Hoopes, P.J.

    2012-01-01

    Nanoparticle-based therapies are currently being explored for both the imaging and treatment of primary and metastatic cancers. Effective nanoparticle cancer therapy requires significant accumulations of nanoparticles within the tumor environment. Various techniques have been used to improve tumor nanoparticle uptake and biodistribution. Most notable of these techniques are the use of tumor-specific-peptide-conjugated nanoparticles and chemical modification of the nanoparticles with immune-evading polymers. Another strategy for improving the tumor uptake of the nanoparticles is modification of the tumor microenvironment with a goal of enhancing the enhanced permeability and retention effect inherent to solid tumors. We demonstrate a two-fold increase in the tumor accumulation of systemically delivered iron oxide nanoparticles following a single, 15 Gy radiation dose in a syngeneic mouse breast tumor model. This increase in nanoparticle tumor accumulation correlates with a radiation-induced decrease in tumor interstitial pressure and a subsequent increase in vascular permeability. PMID:22633900

  5. Morphological alterations of central nervous system (CNS) myelin in vanadium (V)-exposed adult rats.

    PubMed

    García, Graciela B; Quiroga, Ariel D; Stürtz, Nelson; Martinez, Alejandra I; Biancardi, María E

    2004-08-01

    In the present work we show morphological data of the in vivo susceptibility of CNS myelin to sodium metavanadate [V(+5)] in adult rats. The possible role of vanadium in behavioral alterations and in brain lipid peroxidation was also investigated. Animals were injected intraperitoneally (i.p.) with 3 mg/kg body weight (bw) of sodium metavanadate [1.25 V/kg bw/day] for 5 consecutive days. Open field and rotarod tests were performed the day after the last dose had been administered and then animals were sacrificed by different methods for histological and lipid peroxidation studies. The present results show that intraperitoneal administration of V(+5) to adult rats resulted in changes in locomotor activity, specific myelin stainings and lipid peroxidation in some brain areas. They support the notion that CNS myelin could be a preferential target of V(+5)-mediated lipid peroxidation in adult rats. The mechanisms underlying this action could affect the myelin sheath leading to behavioral perturbations.

  6. 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.

  7. Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity.

    PubMed

    Nogueiras, Ruben; Pérez-Tilve, Diego; Veyrat-Durebex, Christelle; Morgan, Donald A; Varela, Luis; Haynes, William G; Patterson, James T; Disse, Emmanuel; Pfluger, Paul T; López, Miguel; Woods, Stephen C; DiMarchi, Richard; Diéguez, Carlos; Rahmouni, Kamal; Rohner-Jeanrenaud, Françoise; Tschöp, Matthias H

    2009-05-06

    We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

  8. Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies.

    PubMed

    Khambhla, Ekta; Shah, Viral; Baviskar, Kalpesh

    2016-01-01

    The current epoch has witnessed a lifestyle impregnated with stress, which is a major cause of several neurological disorders. High morbidity and mortality rate due to neurological diseases and disorders have generated a huge social impact. Despite voluminous research, patients suffering from fatal and/or debilitating CNS diseases such as brain tumors, HIV, encephalopathy, Alzheimer's, epilepsy, Parkinson's, migraine and multiple sclerosis outnumbered those suffering from systemic cancer or heart diseases. The brain being a highly sensitive neuronal organ, has evolved with vasculature barriers, which regulates the efflux and influx of substances to CNS. Treatment of CNS diseases/disorders is challenging because of physiologic, metabolic and biochemical obstacles created by these barriers which comprise mainly of BBB and BCFB. The inability of achieving therapeutically active concentration has become the bottleneck level difficulty, hampering the therapeutic efficiency of several promising drug candidates for CNS related disorders. Parallel maturation of an effective CNS drug delivery strategy with CNS drug discovery is the need of the hour. Recently, the focus of the pharmaceutical community has aggravated in the direction of developing novel and more efficient drug delivery systems, giving the potential of more effective and safer CNS therapies. The present review outlines several hurdles in drug delivery to the CNS along with ideal physicochemical properties desired in drug substance/formulation for CNS delivery. The review also focuses on different conventional and novel strategies for drug delivery to the CNS. The article also assesses and emphasizes on possible benefits of biomaterial based formulations for drug delivery to the CNS.

  9. Prediction of CNS occupancy of dopamine D2 receptor based on systemic exposure and in vitro experiments.

    PubMed

    Kanamitsu, Kayoko; Arakawa, Ryosuke; Sugiyama, Yuichi; Suhara, Tetsuya; Kusuhara, Hiroyuki

    2016-12-01

    The effect of drugs in the central nervous system (CNS) is closely related to occupancy of their target receptor. In this study, we integrated plasma concentrations, in vitro/in vivo data for receptor or protein binding, and in silico data, using a physiologically based pharmacokinetic model, to examine the predictability of receptor occupancy in humans. The occupancy of the dopamine D2 receptor and the plasma concentrations of the antipsychotic drugs quetiapine and perospirone in humans were collected from the literature or produced experimentally. Association and dissociation rate constants and unbound fractions in the serum and brain were determined in vitro/in vivo using human D2 receptor-expressing membrane fractions, human serum and mouse brain. The permeability of drugs across the blood-brain barrier was estimated based on their physicochemical properties. The effect of a metabolite of perospirone, ID-15036, was also considered. The time profiles of D2 receptor occupancy following oral dose of quetiapine and perospirone predicted were similar to the observed values. This approach could assist in the design of clinical studies for drug development and the prediction of the impact of drug-drug interactions on CNS function in clinical settings.

  10. 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.

  11. 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

  12. X-ray microbeams: Tumor therapy and central nervous system research

    NASA Astrophysics Data System (ADS)

    Dilmanian, F. A.; Qu, Y.; Liu, S.; Cool, C. D.; Gilbert, J.; Hainfeld, J. F.; Kruse, C. A.; Laterra, J.; Lenihan, D.; Nawrocky, M. M.; Pappas, G.; Sze, C.-I.; Yuasa, T.; Zhong, N.; Zhong, Z.; McDonald, J. W.

    2005-08-01

    Irradiation with parallel arrays of thin, planar slices of X-ray beams (microplanar beams, or microbeams) spares normal tissue, including the central nervous system (CNS), and preferentially damages tumors. The effects are mediated, at least in part, by the tissue's microvasculature that seems to effectively repair itself in normal tissue but fails to do so in tumors. Consequently, the therapeutic index of single-fraction unidirectional microbeam irradiations has been shown to be larger than that of single-fraction unidirectional unsegmented beams in treating the intracranial rat 9L gliosarcoma tumor model (9LGS) and the subcutaneous murine mammary carcinoma EMT-6. This paper presents results demonstrating that individual microbeams, or arrays of parallel ones, can also be used for targeted, selective cell ablation in the CNS, and also to induce demyelination. The results highlight the value of the method as a powerful tool for studying the CNS through selective cell ablation, besides its potential as a treatment modality in clinical oncology.

  13. CNS reservoirs for HIV: implications for eradication.

    PubMed

    Hellmuth, Joanna; Valcour, Victor; Spudich, Serena

    2015-04-01

    Controversy exists as to whether the central nervous system (CNS) serves as a reservoir site for HIV, in part reflecting the varying perspectives on what constitutes a 'reservoir' versus a mere site of latent viral integration. However, if the CNS proves to be a site of HIV persistence capable of replicating and reseeding the periphery, leading to failure of virological control, this privileged anatomical site would need dedicated consideration during the development of HIV cure strategies. In this review we discuss the current literature focused on the question of the CNS as a reservoir for HIV, covering the clinical evidence for continued CNS involvement despite suppressive therapy, the theorised dynamics of HIV integration into the CNS, as well as studies indicating that HIV can replicate independently and compartmentalise in the CNS. The unique cellular and anatomical sites of HIV integration in the CNS are also reviewed, as are the potential implications for HIV cure strategies.

  14. The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons

    PubMed Central

    Simpson, Matthew T; Venkatesh, Ishwariya; Callif, Ben L; Thiel, Laura K; Coley, Denise M; Winsor, Kristen N; Wang, Zimei; Kramer, Audra A; Lerch, Jessica K; Blackmore, Murray G

    2015-01-01

    Neurons in the embryonic and peripheral nervous system respond to injury by activating transcriptional programs supportive of axon growth, ultimately resulting in functional recovery. In contrast, neurons in the adult central nervous system (CNS) possess a limited capacity to regenerate axons after injury, fundamentally constraining repair. Activating pro-regenerative gene expression in CNS neurons is a promising therapeutic approach, but progress is hampered by incomplete knowledge of the relevant transcription factors. An emerging hypothesis is that factors implicated in cellular growth and motility outside the nervous system may also control axon growth in neurons. We therefore tested sixty-nine transcription factors, previously identified as possessing tumor suppressive or oncogenic properties in non-neuronal cells, in assays of neurite outgrowth. This screen identified YAP1 and E2F1 as enhancers of neurite outgrowth, and PITX1, RBM14, ZBTB16, and HHEX as inhibitors. Follow-up experiments focused on the tumor suppressor HHEX, one of the strongest growth inhibitors. HHEX is widely expressed in adult CNS neurons, including corticospinal tract neurons after spinal injury, but is present in only trace amounts in immature cortical neurons and adult peripheral neurons. HHEX overexpression in early postnatal cortical neurons reduced both initial axonogenesis and the rate of axon elongation, and domain deletion analysis strongly implicated transcriptional repression as the underlying mechanism. These findings suggest a role for HHEX in restricting axon growth in the developing CNS, and substantiate the hypothesis that previously identified oncogenes and tumor suppressors can play conserved roles in axon extension. PMID:26306672

  15. Cancer stem cells in nervous system tumors.

    PubMed

    Singh, Sheila K; Clarke, Ian D; Hide, Takuichiro; Dirks, Peter B

    2004-09-20

    Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and more recently in solid tumors such as breast cancer suggests that the tumor cell population is heterogeneous with respect to proliferation and differentiation. Recently, several groups have described the existence of a cancer stem cell population in human brain tumors of different phenotypes from both children and adults. The finding of brain tumor stem cells (BTSCs) has been made by applying the principles for cell culture and analysis of normal neural stem cells (NSCs) to brain tumor cell populations and by identification of cell surface markers that allow for isolation of distinct tumor cell populations that can then be studied in vitro and in vivo. A population of brain tumor cells can be enriched for BTSCs by cell sorting of dissociated suspensions of tumor cells for the NSC marker CD133. These CD133+ cells, which also expressed the NSC marker nestin, but not differentiated neural lineage markers, represent a minority fraction of the entire brain tumor cell population, and exclusively generate clonal tumor spheres in suspension culture and exhibit increased self-renewal capacity. BTSCs can be induced to differentiate in vitro into tumor cells that phenotypically resembled the tumor from the patient. Here, we discuss the evidence for and implications of the discovery of a cancer stem cell in human brain tumors. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC. Specific genetic and molecular analyses of the BTSC will further our understanding of the mechanisms of brain tumor growth, reinforcing parallels between normal neurogenesis and brain tumorigenesis.

  16. Clinical outcomes of children and adults with central nervous system primitive neuroectodermal tumor.

    PubMed

    Lester, Rachael A; Brown, Lindsay C; Eckel, Laurence J; Foote, Robert T; NageswaraRao, Amulya A; Buckner, Jan C; Parney, Ian F; Wetjen, Nicholas M; Laack, Nadia N

    2014-11-01

    Central nervous system primitive neuroectodermal tumors (CNS PNETs) predominantly occur in children and rarely in adults. Because of the rarity of this tumor, its outcomes and prognostic variables are not well characterized. The purpose of this study was to evaluate clinical outcomes and prognostic factors for children and adults with CNS PNET. The records of 26 patients (11 children and 15 adults) with CNS PNET from 1991 to 2011 were reviewed retrospectively. Disease-free survival (DFS) and overall survival (OS) were estimated with the Kaplan-Meier method, and relevant prognostic factors were analyzed. For the cohort, both the 5-year DFS and the OS were 46 %. For pediatric patients, the 5-year DFS was 78 %; for adult patients, it was 22 % (P = 0.004). Five-year OS for the pediatric and adult patients was 67 and 33 %, respectively (P = 0.07). With bivariate analysis including chemotherapy regimen (high dose vs. standard vs. nonstandard) or risk stratification (standard vs. high) and age, the increased risk of disease recurrence in adults persisted. A nonsignificant tendency toward poorer OS in adult patients relative to pediatric patients also persisted. High-dose chemotherapy with stem cell rescue was associated with a statistically significant improvement in OS and a tendency toward improved DFS, although the findings were mitigated when the effect of age was considered. Local recurrence was the primary pattern of treatment failure in both adults and children. Our results suggest that adult patients with CNS PNETs have inferior outcomes relative to the pediatric cohort. Further research is needed to improve outcomes for CNS PNET in populations of all ages.

  17. 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

  18. Screening for ALK abnormalities in central nervous system metastases of non-small-cell lung cancer: ALK abnormalities in CNS metastases of NSCLC.

    PubMed

    Nicoś, Marcin; Jarosz, Bożena; Krawczyk, Paweł; Wojas-Krawczyk, Kamila; Kucharczyk, Tomasz; Sawicki, Marek; Pankowski, Juliusz; Trojanowski, Tomasz; Milanowski, Janusz

    2016-11-23

    Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. However, there are no reports concerning the frequency of ALK rearrangement in CNS metastases. We assessed the frequency of ALK abnormalities in 145 formalin fixed paraffin embedded (FFPE) tissue samples from CNS metastases of NSCLC using immunohistochemical (IHC) automated staining (BenchMark GX, Ventana, USA) and fluorescence in situ hybridization (FISH) technique (Abbot Molecular, USA). The studied group was heterogeneous in terms of histopathology and smoking status. ALK abnormalities were detected in 4.8% (7/145) of CNS metastases. ALK abnormalities were observed in six AD (7.5%; 6/80) and in single patients with adenosuqamous lung carcinoma. Analysis of clinical and demographic factors indicated that expression of abnormal ALK was significantly more frequently observed (p=0.0002; χ(2) =16.783) in former-smokers. Comparison of IHC and FISH results showed some discrepancies, which were caused by unspecific staining of macrophages and glial/nerve cells, which constitute the background of CNS tissues. Our results indicate high frequency of ALK gene rearrangement in CNS metastatic sites of NSCLC that are in line with prior studies concerning evaluation of the presence of ALK abnormalities in such patients. However, we showed that assessment of ALK by IHC and FISH methods in CNS tissues require additional standardizations. This article is protected by copyright. All rights reserved.

  19. 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

  20. 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.

  1. 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

  2. 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 Central

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

    2016-01-01

    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. PMID:26620558

  3. 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.

  4. Systemic Therapies for Advanced Pancreatic Neuroendocrine Tumors

    PubMed Central

    Raj, Nitya; Reidy-Lagunes, Diane

    2016-01-01

    SYNOPSIS Pancreatic neuroendocrine tumors are a rare tumor type, and comprise 1-2% of all pancreatic neoplasms. When nonfunctional (i.e. nonhormone secreting), these tumors generally cause few symptoms and often go unnoticed for several years; for this reason, they are rarely localized at presentation, and are typically diagnosed in the presence of metastatic disease, most commonly to the liver. Although pancreatic neuroendocrine tumors can be less aggressive than other tumor types, the management poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The therapy of pancreatic neuroendocrine tumors includes a multimodality approach and can often include surgery, liver-directed therapies (i.e. embolization), as well as targeted and cytotoxic systemic treatments. A variety of systemic therapies have been developed for the management of pancreatic neuroendocrine tumors. These therapies include somatostatin analogs (octreotide or lanreotide), a select group of cytotoxic chemotherapy agents (alkylating, fluorouracil and platinum drugs), as well as targeted or biologic agents (everolimus and sunitinib). This chapter will review the available systemic therapy options for advanced pancreatic neuroendocrine tumors. PMID:26614372

  5. 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.

  6. Serial EM analysis of a copepod larval nervous system: Naupliar eye, optic circuitry, and prospects for full CNS reconstruction.

    PubMed

    Lacalli, Thurston C

    2009-09-01

    The medial eye and optic center of the first nauplius of Dactylopusia (=Dactylopodia) tisboides, a harpacticoid copepod, were reconstructed from serial EM micrographs. Axons from the eye project to a set of matching cartridges defined by glial cells processes, and input is then processed in sequence through two synaptic fields. A single class of local relay neurons provides the main pathway between these, subject to modulatory input from a class of densely stained neurons with distinctive dense terminals. The importance of other outside sources of synaptic input to the second synaptic field indicates that the latter is a major site for integrating the optic input with signals originating elsewhere in the CNS. This accords with physiological data on the shadow response in barnacles, whose visual system is also derived from a naupliar eye. With a body length of ca. 80microns, copepod larvae like that of Dactylopusia are arguably among the smallest functional metazoans with a complex nervous system. Hence they are promising subjects for full reconstruction of neural circuitry at the EM level that could, in principle, reveal where key decision-making functions are localized.

  7. Rhabdoid tumors of the central nervous system.

    PubMed

    Reinhardt, D; Behnke-Mursch, J; Weiss, E; Christen, H J; Kühl, J; Lakomek, M; Pekrun, A

    2000-04-01

    Rhabdoid tumors of the central nervous system are rare malignancies with a still almost uniformly fatal outcome. There is still no proven curative therapy available. We report our experience with nine patients with central nervous system rhabdoid tumors. Gross complete surgical removal of the tumor was achieved in six patients. Seven patients received intensive chemotherapy. Four of these were treated in addition with both neuroaxis radiotherapy and a local boost directed to the tumor region, while two patients received local radiotherapy only. The therapy was reasonably well tolerated in most cases. Despite the aggressive therapy, eight of the nine patients died from progressive tumor disease, and one patient died from hemorrhagic brain stem lesions of unknown etiology. The mean survival time was 10 months after diagnosis. Conventional treatment, although aggressive, cannot change the fatal prognosis of central nervous system rhabdoid tumors. As these neoplasms are so rare, a coordinated register would probably be a good idea, offering a means of learning more about the tumor's biology and possible strategies of treatment.

  8. 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.

  9. Revisiting the concept of CNS immune privilege

    PubMed Central

    Louveau, Antoine; Harris, Tajie H.; Kipnis, Jonathan

    2015-01-01

    Whereas the study of the interactions between the immune system and the central nervous system (CNS) has often focused on pathological conditions, the importance of neuroimmune communication in CNS homeostasis and function has become clear over that last two decades. Here we discuss the progression of our understanding of the interaction between the peripheral immune system and the CNS. We examine the notion of immune privilege of the CNS in light of both earlier findings and recent studies revealing a functional meningeal lymphatic system that drains cerebrospinal fluid (CSF) to the deep cervical lymph nodes, and consider the implications of a revised perspective on the immune privilege of the CNS on the etiology and pathology of different neurological disorders. PMID:26431936

  10. Molecular Imaging System for Monitoring Tumor Angiogenesis

    NASA Astrophysics Data System (ADS)

    Aytac, Esra; Burcin Unlu, Mehmet

    2012-02-01

    In cancer, non-invasive imaging techniques that monitor molecular processes associated with the tumor angiogenesis could have a central role in the evaluation of novel antiangiogenic and proangiogenic therapies as well as early detection of the disease. Matrix metalloproteinases (MMP) can serve as specific biological targets for imaging of angiogenesis since expression of MMPs is required for angiogenesis and has been found to be upregulated in every type of human cancer and correlates with stage, invasive, metastatic properties and poor prognosis. However, for most cancers it is still unknown when, where and how MMPs are involved in the tumor angiogenesis [1]. Development of high-resolution, high sensitivity imaging techniques in parallel with the tumor models could prove invaluable for assessing the physical location and the time frame of MMP enzymatic acitivity. The goal of this study is to understand where, when and how MMPs are involved in the tumor angiogenesis. We will accomplish this goal by following two objectives: to develop a high sensitivity, high resolution molecular imaging system, to develop a virtual tumor simulator that can predict the physical location and the time frame of the MMP activity. In order to achieve our objectives, we will first develop a PAM system and develop a mathematical tumor model in which the quantitative data obtained from the PAM can be integrated. So, this work will develop a virtual tumor simulator and a molecular imaging system for monitoring tumor angiogenesis. 1.Kessenbrock, K., V. Plaks, and Z. Werb, MMP:regulators of the tumor microenvironment. Cell, 2010. 141(1)

  11. Methyl methacrylate-induced changes in CNS (central nervous system) activity. 1 March 1978-28 February 1980

    SciTech Connect

    Innes, D.L.

    1980-01-01

    Experiments were performed to determine if methyl-methacrylate (MMA) monomer vapor in air caused central nervous system (CNS) changes in exposed rats. Rats were exposed to 400 parts per million (ppm) MMA vapor for 60 minutes. The only significant changes occurred in the lateral hypothalamic and ventral hippocampal nuclei. Several substudies suggested that the changes in the hippocampal neuronal firing rates were related to the perception of the MMA odor and dependent on an intact nervous connection to the receptors in the nose. In a subchronic study no consistent long term changes in neuronal activity were detected. However, a decrease in neuronal activity was detected during the first week of exposure. In another study, the exposure levels of MMA ranged from 50 to 800 ppm. The lateral hypothalamic and ventral hippocampal nuclei responded as before, but not at the 50 ppm level. The author concludes that the threshold exposure concentration for the observed effects are the same as or slightly less than the current threshold limit value for MMA vapor in the workplace.

  12. Expression of CD150 in tumors of the central nervous system: identification of a novel isoform.

    PubMed

    Romanets-Korbut, Olga; Najakshin, Alexander M; Yurchenko, Mariya; Malysheva, Tatyana A; Kovalevska, Larysa; Shlapatska, Larysa M; Zozulya, Yuriy A; Taranin, Alexander V; Horvat, Branka; Sidorenko, Svetlana P

    2015-01-01

    CD150 (IPO3/SLAM) belongs to the SLAM family of receptors and serves as a major entry receptor for measles virus. CD150 is expressed on normal and malignant cells of the immune system. However, little is known about its expression outside the hematopoietic system, especially tumors of the central nervous system (CNS). Although CD150 was not found in different regions of normal brain tissues, our immunohistochemical study revealed its expression in 77.6% of human CNS tumors, including glioblastoma, anaplastic astrocytoma, diffuse astrocytoma, ependymoma, and others. CD150 was detected in the cytoplasm, but not on the cell surface of glioma cell lines, and it was colocalized with the endoplasmic reticulum and Golgi complex markers. In addition to the full length mRNA of the mCD150 splice isoform, in glioma cells we found a highly expressed novel CD150 transcript (nCD150), containing an 83 bp insert. The insert is derived from a previously unrecognized exon designated Cyt-new, which is located 510 bp downstream of the transmembrane region exon, and is a specific feature of primate SLAMF1. Both mCD150 and nCD150 cDNA variants did not contain any mutations and had the leader sequence. The nCD150 transcript was also detected in normal and malignant B lymphocytes, primary T cells, dendritic cells and macrophages; however, in glioma cells nCD150 was found to be the predominant CD150 isoform. Similarly to mCD150, cell surface expression of nCD150 allows wild type measles virus entry to the cell. Our data indicate that CD150 expression in CNS tumors can be considered a new diagnostic marker and potential target for novel therapeutic approaches.

  13. The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases.

    PubMed

    Wright, John W; Harding, Joseph W

    2013-01-01

    The classic renin-angiotensin system (RAS) was initially described as a hormone system designed to mediate cardiovascular and body water regulation, with angiotensin II as its major effector. The discovery of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT(1), AT(2), and AT(4) receptor subtypes. Next, we discuss the classic physiologies and behaviors controlled by the RAS including cardiovascular, thirst, and sodium appetite. A final section summarizes non-classic functions and clinical conditions mediated by the brain RAS with focus on memory and Alzheimer's disease. There is no doubt that the brain RAS is an important component in the development of dementia. It also appears to play a role in normal memory consolidation and retrieval. The presently available anti-dementia drugs are proving to be reasonably ineffective, thus alternative treatment approaches must be developed. At the same time, presently available drugs must be tested for their efficacy to treat newly identified syndromes and diseases connected with the RAS. The list of non-classic physiologies and behaviors is ever increasing in both number and scope, attesting to the multidimensional influences of the RAS. Such diversity in function presents a dilemma for both researchers and clinicians. Namely, the blunting of RAS subsystems in the hopes of combating one constellation of underlying causes and disease symptoms may be counter-balanced by unanticipated and unwanted consequences to another RAS subsystem. For example, the use of angiotensin-converting enzyme inhibitors and AT(1) and/or AT(2) receptor blockers have shown great promise in the treatment of cardiovascular related

  14. 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…

  15. CNS regulation of appetite.

    PubMed

    Harrold, Joanne A; Dovey, Terry M; Blundell, John E; Halford, Jason C G

    2012-07-01

    This article reviews the regulation of appetite from a biopsychological perspective. It considers psychological experiences and peripheral nutritional systems (both episodic and tonic) and addresses their relationship with the CNS networks that process and integrate their input. Whilst such regulatory aspects of obesity focus on homeostatic control mechanisms, in the modern environment hedonic aspects of appetite are also critical. Enhanced knowledge of the complexity of appetite regulation and the mechanisms that sustain obesity indicate the challenge presented by management of the obesity epidemic. Nonetheless, effective control of appetite expression remains a critical therapeutic target for weight management. Currently, strategies which utilise a combination of agents to target both homeostatic and hedonic control mechanisms represent the most promising approaches. This article is part of a Special Issue entitled 'Central Control of Food Intake'.

  16. Exposure setup to test effects of wireless communications systems on the CNS.

    PubMed

    Burkhardt, M; Spinelli, Y; Kuster, N

    1997-11-01

    This paper presents an exposure setup designed for in vivo studies of possible effects on the central nervous system due to the electromagnetic exposure from handheld mobile communications equipment. The setup consists of a carousel on which 10 rats, each restrained in a radially positioned tube, are exposed to the electromagnetic field emanating from a dipole antenna at the center. The rats are positioned with their snouts at a distance of 35 mm from the dipole antenna. The tubes restrain the movement of the animals to such an extent as to allow for well defined exposure conditions, yet without totally immobilizing them. Numerical and experimental dosimetric analysis of the setup was conducted using rats weighing 250-300 g at a frequency of 900 MHz. A detailed rat phantom derived from MRI scans was developed for the numerical assessment with a commercially available code based on the finite integration technique. The results were validated by measurements of the temperature rise in selected points of a rat cadaver. The dosimetric analysis shows that the setup is eminently suitable for central nervous system studies. It enables well defined field strengths to be induced in the brain tissue, whereby the variations in the specific absorption rate averaged over the brain tissue caused by movement and varying animal sizes was shown to be less than +/-16%. The specific absorption rate distribution in the brain is nonhomogeneous but comparable to that induced in the brain of a human using a handheld wireless phone. The efficiency of the exposure is about 0.20+/-0.05 mW g(-1) for the brain average value per 100 mA feedpoint current. The whole-body average specific absorption rate is considerably lower, i.e., about half of that of the brain averaged value. In addition, the setup has been proven to be practical in use, and the stress levels caused by restraining the animals in this setup are deemed by neurologists and veterinary scientists to be very low.

  17. TSC1/TSC2 Signaling in the CNS

    PubMed Central

    Han, Juliette M.; Sahin, Mustafa

    2011-01-01

    Over the past several years, the study of a hereditary tumor syndrome, tuberous sclerosis complex (TSC), has shed light on the regulation of cellular proliferation and growth. TSC is an autosomal dominant disorder that is due to inactivating mutations in TSC1 or TSC2 and characterized by benign tumors (hamartomas) involving multiple organ systems. The TSC1/2 complex has been found to play a crucial role in an evolutionarily-conserved signaling pathway that regulates cell growth: the mTORC1 pathway. This pathway promotes anabolic processes and inhibits catabolic processes in response to extracellular and intracellular factors. Findings in cancer biology have reinforced the critical role for TSC1/2 in cell growth and proliferation. In contrast to cancer cells, in the CNS, the TSC1/2 complex not only regulates cell growth/proliferation, but also orchestrates an intricate and finely tuned system that has distinctive roles under different conditions, depending on cell type, stage of development, and subcellular localization. Overall, TSC1/2 signaling in the CNS, via its multi-faceted roles, contributes to proper neural connectivity. Here, we will review the TSC signaling in the CNS. PMID:21329690

  18. Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011.

    PubMed

    Ostrom, Quinn T; de Blank, Peter M; Kruchko, Carol; Petersen, Claire M; Liao, Peter; Finlay, Jonathan L; Stearns, Duncan S; Wolff, Johannes E; Wolinsky, Yingli; Letterio, John J; Barnholtz-Sloan, Jill S

    2015-01-01

    The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0–14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0–14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

  19. High-Dose Methotrexate and Cytarabine-Based Multi-Agent Chemotherapy (Modified Bonn Protocol) for Systemic Lymphoma with CNS Involvement.

    PubMed

    Umino, Kento; Fujiwara, Shin-Ichiro; Sato, Kazuya; Minakata, Daisuke; Nakano, Hirofumi; Yamasaki, Ryoko; Kawasaki, Yasufumi; Sugimoto, Miyuki; Yamamoto, Chihiro; Hatano, Kaoru; Okazuka, Kiyoshi; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Muroi, Kazuo; Kanda, Yoshinobu

    2017-01-01

    The prognosis of patients with systemic lymphoma with central nervous system (CNS) involvement is very poor and there is no established standard therapy. We retrospectively analyzed 18 patients (4 untreated and 14 relapsed) with systemic lymphoma with CNS involvement who received methotrexate and cytarabine-based multiagent chemotherapy (modified Bonn protocol). Complete and partial responses were achieved in 56 and 22% of the patients, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) was 81.0 and 39.2%, respectively. Patients with parenchymal involvement showed a better 1-year PFS than those with either leptomeningeal involvement or both. In a multivariate analysis, poor performance status (PS) was the only independent prognostic factor for the 1-year OS and PFS (HR 10.8, 95% CI 1.09-108, p = 0.042; HR 20.8, 95% CI 2.39-181, p = 0.006, respectively). Grade 4 neutropenia and thrombocytopenia occurred in 17 patients each (94%), but there were no grade 4 nonhematopoietic adverse events. The modified Bonn protocol resulted in relatively favorable response and survival, and provided clinical benefits to patients with good PS, in particular. This study demonstrated that the modified Bonn protocol could be a feasible and encouraging treatment approach for lymphoma with CNS and systemic involvement.

  20. SYNTHESIS OF AMINO AND HYDRAZINO DERIVATIVES OF ALICYCLIC AND HETEROCYCLIC SYSTEMS WITH POTENTIAL PHARMACOLOGICAL ACTIVITY ON C.N.S.

    DTIC Science & Technology

    probable formula I) was prepared, from 6-methyl- and 6-chloro- 3 -hydroxymethylene- 4 - chromanones by reaction with various dialkylaminoalkylhydrazines. A...In fulfillment of the research project directed toward the preparation of compounds with potential activity on C.N.S., a group of 10 pyrazoles

  1. Completeness and concordancy of WHO grade assignment for brain and central nervous system tumors in the United States, 2004-2011.

    PubMed

    Lym, Ryan L; Ostrom, Quinn T; Kruchko, Carol; Couce, Marta; Brat, Daniel J; Louis, David N; Barnholtz-Sloan, Jill S

    2015-05-01

    Central nervous system (CNS) tumors are categorized and graded for clinical and research purposes according to the World Health Organization (WHO) scheme which segregates tumors by histological type and predicted biological behavior. However, reporting of WHO grade in pathological reports is inconsistent despite its collection in cancer registration. We studied the completeness, concordancy, and yearly trends in the collection of WHO grade for primary CNS tumors between 2004 and 2011. Data from the Surveillance, Epidemiology and End Results program were analyzed for the percentage of histologically diagnosed primary CNS tumor cases with concordantly documented WHO grades between 2004 and 2011. Yearly trends were calculated with annual percentage changes (APC) and 95% confidence intervals (95% CI). Completeness and concordancy of the collection of WHO grade varied significantly by histological type and year. The percentage of cases with documented WHO grade increased significantly from 2004 to 2011: 39.0% of cases in 2004 had documented WHO grade, while 77.5% of cases had documented grade in 2011 (APC, 10.3; 95% CI: 9.0, 11.5). Among cases with documented WHO grade, the percentage graded concordantly increased significantly from 89.1% in 2004 to 93.7% in 2007 (APC, 1.8; 95% CI: 1.0, 2.6) and these values varied over time by histological type. One common trend among all histologies was a significant increase in the percentage of cases with documented WHO grade. A sizeable proportion of reported CNS tumors collected by cancer registrars have undocumented WHO grade, while a much smaller proportion are graded discordantly. Data collection on grade has improved in completeness and concordancy over time. Efforts to further improve collection of this variable are essential for clinical care and the epidemiological surveillance of CNS tumors.

  2. Spontaneous and nitrosourea-induced primary tumors of the central nervous system in Fischer 344 rats chronically exposed to 836 MHz modulated microwaves.

    PubMed

    Adey, W R; Byus, C V; Cain, C D; Higgins, R J; Jones, R A; Kean, C J; Kuster, N; MacMurray, A; Stagg, R B; Zimmerman, G; Phillips, J L; Haggren, W

    1999-09-01

    We have tested an 836.55 MHz field with North American Digital Cellular (NADC) modulation in a 2-year animal bioassay that included fetal exposure. In offspring of pregnant Fischer 344 rats, we tested both spontaneous tumorigenicity and the incidence of induced central nervous system (CNS) tumors after a single dose of the carcinogen ethylnitrosourea (ENU) in utero, followed by intermittent digital-phone field exposure for 24 months. Far-field exposures began on gestational day 19 and continued until weaning at age 21 days. Near-field exposures began at 35 days and continued for the next 22 months, 4 consecutive days weekly, 2 h/day. SAR levels simulated localized peak brain exposures of a cell phone user. Of the 236 original rats, 182 (77%) survived to the termination of the whole experiment and were sacrificed at age 709-712 days. The 54 rats (23%) that died during the study ("preterm rats") formed a separate group for some statistical analyses. There was no evidence of tumorigenic effects in the CNS from exposure to the TDMA field. However, some evidence of tumor-inhibiting effects of TDMA exposure was apparent. Overall, the TDMA field-exposed animals exhibited trends toward a reduced incidence of spontaneous CNS tumors (P < 0. 16, two-tailed) and ENU-induced CNS tumors (P < 0.16, two-tailed). In preterm rats, where primary neural tumors were determined to be the cause of death, fields decreased the incidence of ENU-induced tumors (P < 0.03, two-tailed). We discuss a possible approach to evaluating with greater certainty the possible inhibitory effects of TDMA-field exposure on tumorigenesis in the CNS.

  3. 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

  4. A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702)

    PubMed Central

    Stokland, Tore; Liu, Jo-Fen; Ironside, James W.; Ellison, David W.; Taylor, Roger; Robinson, Kathryn J.; Picton, Susan V.; Walker, David A.

    2010-01-01

    The purpose of this study was to identify risk factors for the progression of low-grade glioma in children from a large population-based cohort. Patient and tumor details of a national cohort of children with low-grade glioma, recruited into an international multidisciplinary clinical strategy, were subjected to univariate and multivariate analyses of progression-free survival and overall survival. From the cohort of 798 patients, 639 patients were eligible, with a median age 6.71 years (0.26–16.75 years); 49% were males; 15.9% had neurofibromatosis type 1, 63.7% pilocytic astrocytoma, 5.9% fibrillary astrocytoma, 4.2% mixed neuronal-glial tumors, and 3.6% others; 21.1% were diagnosed clinically. Anatomically implicated were 31.6% cerebellum, 24.6% chiasma/hypothalamus, 16.0% cerebral hemispheres, 9.9% brain stem, 6.1% other supratentorial midline structures, 5.9% optic nerve only, 4.5% spinal cord, and 1.4% others. The 5-year overall survival and progression-free survival in the whole cohort were 94.6% and 69.4%, respectively. There was a significant association between age and site (P < .001) and extent of tumor resection and site (P < .001). Multivariate analysis identified young age, fibrillary astrocytoma, and extent of surgical resection as significant independent risk factors for progression. Hypothalamic/chiasmatic tumors demonstrated the most sustained tendency to progress. In conclusion, the influence of age and anatomical site upon the risk of tumor progression suggests that these factors strongly influence tumor behavior for the majority of pilocytic tumors. Age <1 year and 1–5 years, fibrillary histology, completeness of resection, and chiasmatic location are candidates for stratification in future studies. PMID:20861086

  5. Prodrug approaches for CNS delivery.

    PubMed

    Rautio, Jarkko; Laine, Krista; Gynther, Mikko; Savolainen, Jouko

    2008-01-01

    Central nervous system (CNS) drug delivery remains a major challenge, despite extensive efforts that have been made to develop novel strategies to overcome obstacles. Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which subsequently exerts the desired pharmacological effect. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that overcome barriers to a drug's usefulness. This review provides insight into various prodrug strategies explored to date for CNS drug delivery, including lipophilic prodrugs, carrier- and receptor-mediated prodrug delivery systems, and gene-directed enzyme prodrug therapy.

  6. 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

  7. 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

  8. 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

  9. The movers and shapers in immune privilege of the CNS.

    PubMed

    Engelhardt, Britta; Vajkoczy, Peter; Weller, Roy O

    2017-02-01

    Discoveries leading to an improved understanding of immune surveillance of the central nervous system (CNS) have repeatedly provoked dismissal of the existence of immune privilege of the CNS. Recent rediscoveries of lymphatic vessels within the dura mater surrounding the brain, made possible by modern live-cell imaging technologies, have revived this discussion. This review emphasizes the fact that understanding immune privilege of the CNS requires intimate knowledge of its unique anatomy. Endothelial, epithelial and glial brain barriers establish compartments in the CNS that differ strikingly with regard to their accessibility to immune-cell subsets. There is a unique system of lymphatic drainage from the CNS to the peripheral lymph nodes. We summarize current knowledge on the cellular and molecular mechanisms involved in immune-cell trafficking and lymphatic drainage from the CNS, and we take into account differences in rodent and human CNS anatomy.

  10. The rare malignancy of the hepatobiliary system: ampullary carcinoid tumor.

    PubMed

    Ozsoy, Mustafa; Ozsoy, Yucel; Canda, Aras Emre; Nalbant, Olcay Ak; Haskaraca, Fatih

    2011-01-01

    Introduction. Carcinoid tumors are low-grade tumors originating from endoderm and mostly involving the gastrointestinal system. However; they may be seen in any site within the gastrointestinal system. Case Presentation. A 69-year-old female patient. The results of blood tests were observed to be consistent with obstructive jaundice. A mass appearance was not encountered on tomographic examination. Papilla that was tumor-like macroscopically was seen in the second part of the duodenum in diagnostic endoscopy. Pylorus-preserving pancreaticoduodenectomy surgical procedure was applied. On pathological examination of the mass, a tumoral mass was detected in ampulla vateri localization, 1.5 × 1 × 0.8 cm in size, which, in immunohistochemical staining, was evaluated as a neuroendocrine tumor. Also, Metastasis was observed. Conclusion. The rarest type of carcinoid tumor is ampullary located carcinoid tumor, and tumor size is not a reliable indicator for tumor aggressivity in ampullary carcinoid tumors.

  11. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects.

    PubMed

    Probert, L

    2015-08-27

    Tumor necrosis factor (TNF) is the prototypic pro-inflammatory cytokine. It is central to host defense and inflammatory responses but under certain circumstances also triggers cell death and tissue degeneration. Its pleiotropic effects often lead to opposing outcomes during the development of immune-mediated diseases, particularly those affecting the central nervous system (CNS). The reported contradictions may result from lack of precision in discussing TNF. TNF signaling comprises at minimum a two-ligand (soluble and transmembrane TNF) and two-receptor (TNFR1 and TNFR2) system, with ligands and receptors both differentially expressed and regulated on different cell types. The "functional multiplicity" this engenders is the focus of much research, but there is still no general consensus on functional outcomes of TNF signaling in general, let alone in the CNS. In this review, evidence showing the effects of TNF in the CNS under physiological and pathophysiological conditions is placed in the context of major advances in understanding of the cellular and molecular mechanisms that govern TNF function in general. Thus the roles of TNF signaling in the CNS shift from the conventional dichotomy of beneficial and deleterious, that mainly explain effects under pathological conditions, to incorporate a growing number of "essential" and "desirable" roles for TNF and its main cellular source in the CNS, microglia, under physiological conditions including regulation of neuronal activity and maintenance of myelin. An improved holistic view of TNF function in the CNS might better reconcile the expansive experimental data with stark clinical evidence that reduced functioning of TNF and its dominant pro-inflammatory receptor, TNFR1, are risk factors for the development of multiple sclerosis. It will also facilitate the safe translation of basic research findings from animal models to humans and propel the development of more selective anti-TNF therapies aimed at selectively

  12. Nanotechnology-novel therapeutics for CNS disorders.

    PubMed

    Srikanth, Maya; Kessler, John A

    2012-04-24

    Research into treatments for diseases of the CNS has made impressive strides in the past few decades, but therapeutic options are limited for many patients with CNS disorders. Nanotechnology has emerged as an exciting and promising new means of treating neurological disease, with the potential to fundamentally change the way we approach CNS-targeted therapeutics. Molecules can be nanoengineered to cross the blood-brain barrier, target specific cell or signalling systems, respond to endogenous stimuli, or act as vehicles for gene delivery, or as a matrix to promote axon elongation and support cell survival. The wide variety of available nanotechnologies allows the selection of a nanoscale material with the characteristics best suited to the therapeutic challenges posed by an individual CNS disorder. In this Review, we describe recent advances in the development of nanotechnology for the treatment of neurological disorders-in particular, neurodegenerative disease and malignant brain tumours-and for the promotion of neuroregeneration.

  13. ABC transporters in the CNS - an inventory.

    PubMed

    Hartz, A M S; Bauer, B

    2011-04-01

    In the present review we provide a summary of ATP-binding cassette (ABC) transporters in the central nervous system (CNS). Our review is focused on transporters of the ABC A, B, C, D, and G families that have been detected in the cells of the neurovascular unit/blood-brain barrier including brain capillary endothelial cells, pericytes, astrocytes, and neurons, as well as in other brain cells, such as microglia, oligodendrocytes, and choroid plexus epithelial cells. In this review, we provide an overview, organized by ABC family, of transporter expression, localization, and function. We summarize recent findings on ABC transporter regulation in the CNS and address the role of ABC transporters in CNS diseases including brain cancer, seizures/epilepsy, and Alzheimer's disease. Finally, we discuss new therapeutic strategies focused on ABC transporters in CNS disease.

  14. Expression of LFA-1/ICAM-1 in CNS lymphomas: possible mechanism for lymphoma homing into the brain.

    PubMed

    Bashir, R; Coakham, H; Hochberg, F

    1992-02-01

    We examined a possible role for the adhesion molecules LFA-1 and ICAM-1 in localizing central nervous system non-Hodgkin's lymphomas (CNS-NHLs) to the brain. Fresh frozen sections from 12 monoclonal CNS NHLs (11 primary, one secondary) were stained with monoclonal antibodies to LFA-1 alpha chain (CD11a), beta chain (CD18) and, ICAM-1 (CD54). Additional staining made use of rat monoclonal antibodies to the human and mouse high endothelial venule antigens HECA 452 and MECA 79 and mouse ICAM-1. The expression of these same molecules was also studied in mice with severe combined immunodeficiency (SCID) mice, bearing intracranial human lymphoblastoid cells. Eleven of the CNS-NHL tumors expressed LFA-1 alpha (one strongly, one intermediate, nine weakly). Nine of the tumors weakly expressed LFA-1 beta.. Nine of twelve tumors weakly expressed ICAM-1. In six of seven tumors definite blood vessels stained for ICAM-1. Non-tumor brain from two patients and non-tumor cerebral blood vessels showed no staining with CD11a, CD18 or CD54 antibodies. Strong expression of LFA-alpha and LFA-beta as well as ICAM-1 was noted in human lymphoblastoid cells (LCLs)/SCID mouse CNS lymphomas. Tumor blood vessels in these mice stained for mouse ICAM-1. Normal SCID mouse brains showed no staining with CD11a, CD18, CD54 or mouse ICAM-1 antibodies. Human, human/mouse CNS lymphomas, normal human, and mouse brains showed no staining with either HECA 452 or MECA 79.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. 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.

  16. 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.

  17. 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

  18. Local Observability Analysis of Star Sensor Installation Errors in a SINS/CNS Integration System for Near-Earth Flight Vehicles

    PubMed Central

    Yang, Yanqiang; Zhang, Chunxi; Lu, Jiazhen

    2017-01-01

    Strapdown inertial navigation system/celestial navigation system (SINS/CNS) integrated navigation is a fully autonomous and high precision method, which has been widely used to improve the hitting accuracy and quick reaction capability of near-Earth flight vehicles. The installation errors between SINS and star sensors have been one of the main factors that restrict the actual accuracy of SINS/CNS. In this paper, an integration algorithm based on the star vector observations is derived considering the star sensor installation error. Then, the star sensor installation error is accurately estimated based on Kalman Filtering (KF). Meanwhile, a local observability analysis is performed on the rank of observability matrix obtained via linearization observation equation, and the observable conditions are presented and validated. The number of star vectors should be greater than or equal to 2, and the times of posture adjustment also should be greater than or equal to 2. Simulations indicate that the star sensor installation error could be readily observable based on the maneuvering condition; moreover, the attitude errors of SINS are less than 7 arc-seconds. This analysis method and conclusion are useful in the ballistic trajectory design of near-Earth flight vehicles. PMID:28275211

  19. Local Observability Analysis of Star Sensor Installation Errors in a SINS/CNS Integration System for Near-Earth Flight Vehicles.

    PubMed

    Yang, Yanqiang; Zhang, Chunxi; Lu, Jiazhen

    2017-01-16

    Strapdown inertial navigation system/celestial navigation system (SINS/CNS) integrated navigation is a fully autonomous and high precision method, which has been widely used to improve the hitting accuracy and quick reaction capability of near-Earth flight vehicles. The installation errors between SINS and star sensors have been one of the main factors that restrict the actual accuracy of SINS/CNS. In this paper, an integration algorithm based on the star vector observations is derived considering the star sensor installation error. Then, the star sensor installation error is accurately estimated based on Kalman Filtering (KF). Meanwhile, a local observability analysis is performed on the rank of observability matrix obtained via linearization observation equation, and the observable conditions are presented and validated. The number of star vectors should be greater than or equal to 2, and the times of posture adjustment also should be greater than or equal to 2. Simulations indicate that the star sensor installation error could be readily observable based on the maneuvering condition; moreover, the attitude errors of SINS are less than 7 arc-seconds. This analysis method and conclusion are useful in the ballistic trajectory design of near-Earth flight vehicles.

  20. Long-term fate of neural precursor cells following transplantation into developing and adult CNS.

    PubMed

    Lepore, A C; Neuhuber, B; Connors, T M; Han, S S W; Liu, Y; Daniels, M P; Rao, M S; Fischer, I

    2006-05-12

    Successful strategies for transplantation of neural precursor cells for replacement of lost or dysfunctional CNS cells require long-term survival of grafted cells and integration with the host system, potentially for the life of the recipient. It is also important to demonstrate that transplants do not result in adverse outcomes. Few studies have examined the long-term properties of transplanted neural precursor cells in the CNS, particularly in non-neurogenic regions of the adult. The aim of the present study was to extensively characterize the fate of defined populations of neural precursor cells following transplantation into the developing and adult CNS (brain and spinal cord) for up to 15 months, including integration of graft-derived neurons with the host. Specifically, we employed neuronal-restricted precursors and glial-restricted precursors, which represent neural precursor cells with lineage restrictions for neuronal and glial fate, respectively. Transplanted cells were prepared from embryonic day-13.5 fetal spinal cord of transgenic donor rats that express the marker gene human placental alkaline phosphatase to achieve stable and reliable graft tracking. We found that in both developing and adult CNS grafted cells showed long-term survival, morphological maturation, extensive distribution and differentiation into all mature CNS cell types (neurons, astrocytes and oligodendrocytes). Graft-derived neurons also formed synapses, as identified by electron microscopy, suggesting that transplanted neural precursor cells integrated with adult CNS. Furthermore, grafts did not result in any apparent deleterious outcomes. We did not detect tumor formation, cells did not localize to unwanted locations and no pronounced immune response was present at the graft sites. The long-term stability of neuronal-restricted precursors and glial-restricted precursors and the lack of adverse effects suggest that transplantation of lineage-restricted neural precursor cells can

  1. Reassembly of Excitable Domains after CNS Axon Regeneration

    PubMed Central

    Marin, Miguel A.; de Lima, Silmara; Gilbert, Hui-Ya; Giger, Roman J.; Benowitz, Larry

    2016-01-01

    Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown. Using mouse optic nerve crush as a model for CNS traumatic injury, we performed a detailed analysis of AIS and node disruption after nerve crush. We found significant disruption of AIS and loss of nodes within days of the crush, and complete loss of nodes 1 week after injury. Genetic deletion of the tumor suppressor phosphatase and tensin homolog (Pten) in retinal ganglion cells (RGCs), coupled with stimulation of RGCs by inflammation and cAMP, dramatically enhanced regeneration. With this treatment, we found significant reestablishment of RGC AIS, remyelination, and even reassembly of nodes in regions proximal, within, and distal to the crush site. Remyelination began near the retina, progressed distally, and was confirmed by electron microscopy. Although axons grew rapidly, remyelination and nodal ion channel clustering was much slower. Finally, genetic deletion of ankyrinG from RGCs to block AIS reassembly did not affect axon regeneration, indicating that preservation of neuronal polarity is not required for axon regeneration. Together, our results demonstrate, for the first time, that regenerating CNS axons can be remyelinated and reassemble new AIS and nodes of Ranvier. SIGNIFICANCE STATEMENT We show, for the first time, that regenerated CNS axons have the capacity to both remyelinate and reassemble the axon initial segments and nodes of Ranvier necessary for rapid and efficient action potential propagation. PMID:27581456

  2. Neural Stem Cell Transplantation and CNS Diseases.

    PubMed

    Gonzalez, Rodolfo; Hamblin, Milton H; Lee, Jean-Pyo

    2016-01-01

    In neurological disorders, pathological lesions in the central nervous system (CNS) may be globally dispersed throughout the brain or localized to specific regions. Although native neural stem cells (NSCs) are present in the adult mammalian brain, intrinsic self-repair of injured adult CNS tissue is inadequate or ineffective. The brain's poor regenerative ability may be due to the fact that NSCs are restricted to discrete locations, are few in number, or are surrounded by a microenvironment that does not support neuronal differentiation. Therapeutic potential of NSC transplantation in CNS diseases characterized by global degeneration requires that gene products and/or replaced cells be widely distributed. Global degenerative CNS diseases include inherited pediatric neurodegenerative diseases (inborn errors of metabolism, including lysosomal storage disorders (LSDs), such as Tay-Sachs-related Sandhoff disease), hypoxic or ischemic encephalopathy, and some adult CNS diseases (such as multiple sclerosis). Both mouse and human NSCs express many chemokines and chemokine receptors (including CXCR4 and adhesion molecules, such as integrins, selectins, and immunoglobulins) that mediate homing to sources of inflammatory chemokines, such as SDF-1α. In mammalian brains of all ages, NSCs may be attracted even at a great distance to regions of neurodegeneration. Consequently, NSC transplantation presents a promising strategy for treating many CNS diseases.

  3. 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.

  4. Flow cytometry of cerebrospinal fluid (CSF) lymphocytes: alterations of blood/CSF ratios of lymphocyte subsets in inflammation disorders of human central nervous system (CNS).

    PubMed

    Kleine, T O; Albrecht, J; Zöfel, P

    1999-03-01

    Flow cytometry was adapted to measure lymphocytes in human cerebrospinal fluid (CSF). The method was sufficiently precise, reproducible and accurate despite low cell counts. In lumbar CSF of controls with 500 to 3500 (10(3)/l) leukocytes, lymphocyte counts correlated with those in corresponding venous blood: blood/CSF ratios of approximately 2000 : 1 were found for total T cells (CD3+) and CD3+ HLA-DR-, CD3+4+, CD3+8+ subsets, ratios were increased for the lymphocyte subsets CD3+ HLA-DR+ < or = CD3+16+56+ < CD16+56+3- < CD8+3- < CD19+; CD8+4+ ratio was half of CD3+ ratio. Data indicate selective barriers (blood-brain and blood-CSF barriers) to blood lymphocyte subsets which favor the transfer of T subsets. Correlation of the subset ratios to the CD3+ ratio indicates distinct barrier properties which changed differently with acute and subacute inflammations and neuroimmunological diseases of central nervous system (CNS) in lumbar or ventricular CSF, but not with simple protein barrier disturbance. HLA DR+ T ratios were higher than HLA DR- T ratios only with controls and some neuroimmunological diseases. Lymphocyte barrier characteristics were related to protein leakage situated at the same barriers, indicating for the lymphocyte subsets selective transfer routes in control subjects and non-selective routes in patients with CNS inflammation where altered ratios revealed a mixture of both routes.

  5. Models of CNS radiation damage during space flight

    NASA Astrophysics Data System (ADS)

    Hopewell, J. W.

    1994-10-01

    The primary structural and functional arrangement of the different cell types within the CNS are reviewed. This was undertaken with a view to providing a better understanding of the complex interrelationships that may contribute to the pathogenesis of lesions in this tissue after exposure to ionizing radiation. The spectrum of possible CNS radiation-induced syndromes are discussed although not all have an immediate relevance to exposure during space flight. The specific characteristics of the lesions observed would appear to be dose related. Very high doses may produce an acute CNS syndrome that can cause death. Of the delayed lesions, selective coagulation necrosis of white matter and a later appearing vascular microangiopathy, have been reported in patients after cancer therapy doses. Lower doses, perhaps very low doses, may produce a delayed generalised CNS atrophy; this effect and the probability of the induction of CNS tumors could potentially have the greatest significance for space flight.

  6. Hypothalamic-Pituitary Axis Dysfunction in Survivors of Childhood CNS Tumors: Importance of Systematic Follow-Up and Early Endocrine Consultation.

    PubMed

    Chemaitilly, Wassim; Armstrong, Gregory T; Gajjar, Amar; Hudson, Melissa M

    2016-12-20

    The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. An 11-year-old male with a history of metastatic tectal plate low-grade glioma who was diagnosed at age 2.8 years transferred his care to the long-term follow-up clinic. He completed treatment with multiagent chemotherapy-carboplatin, vincristine, temozolomide, procarbazine, lomustine, and thioguanine-at age 4.5 years and did not require radiotherapy. At primary diagnosis, he presented with hydrocephalus that required ventriculoperitoneal shunt placement, with a subsequent shunt revision at age 6 years. Residual metastatic tumors in the third and fourth ventricles and in the suprasellar region remained stable for more than 5 years. The patient achieved normal developmental milestones and was not taking medications. He was offered screening for hypothalamic-pituitary axis (HPA) dysfunction because of his suprasellar lesion. His height was at the 25th percentile for chronological age, with decline from the 50th percentile noted during the preceding 18 months ( Fig 1 , point c). Pubertal stage was Tanner 4 for pubic hair and penile size, which contrasted with small testes (4.5 mL). Pubic hair and voice changes were noticed 2 to 3 years before this visit. Plasma testosterone level was consistent with Tanner 4 (255 ng/dL = 8.9 nmol/L). An x-ray of the left hand revealed a notably advanced bone age of 15.5 years. Plasma free T4, thyroid-stimulating hormone (TSH), and 8 am cortisol levels were normal. The patient was referred to the endocrinology clinic where he

  7. Perspectives on Dual Targeting Delivery Systems for Brain Tumors.

    PubMed

    Gao, Huile

    2017-03-01

    Brain tumor remains one of the most serious threats to human beings. Different from peripheral tumors, drug delivery to brain tumor is largely restricted by the blood brain barrier (BBB). To fully conquer this barrier and specifically deliver drugs to brain tumor, dual targeting delivery systems were explored, which are functionalized with two active targeting ligands: one to the BBB and the other to the brain tumor. The development of dual targeting delivery system is still in its early stage, and attentions need to be paid to issues and concerns that remain unresolved in future studies.

  8. HIV-1 target cells in the CNS.

    PubMed

    Joseph, Sarah B; Arrildt, Kathryn T; Sturdevant, Christa B; Swanstrom, Ronald

    2015-06-01

    HIV-1 replication in the central nervous system (CNS) is typically limited by the availability of target cells. HIV-1 variants that are transmitted and dominate the early stages of infection almost exclusively use the CCR5 coreceptor and are well adapted to entering, and thus infecting, cells expressing high CD4 densities similar to those found on CD4+ T cells. While the "immune privileged" CNS is largely devoid of CD4+ T cells, macrophage and microglia are abundant throughout the CNS. These cells likely express CD4 densities that are too low to facilitate efficient entry or allow sustained replication by most HIV-1 isolates. Examination of CNS viral populations reveals that late in disease the CNS of some individuals contains HIV-1 lineages that have evolved the ability to enter cells expressing low levels of CD4 and are well-adapted to entering macrophages. These macrophage-tropic (M-tropic) viruses are able to maintain sustained replication in the CNS for many generations, and their presence is associated with severe neurocognitive impairment. Whether conditions such as pleocytosis are necessary for macrophage-tropic viruses to emerge in the CNS is unknown, and extensive examinations of macrophage-tropic variants have not revealed a genetic signature of this phenotype. It is clear, however, that macrophage tropism is rare among HIV-1 isolates and is not transmitted, but is important due to its pathogenic effects on hosts. Prior to the evolution of macrophage-tropic variants, the viruses that are predominately infecting T cells (R5 T cell-tropic) may infect macrophages at a low level and inefficiently, but this could contribute to the reservoir.

  9. HIV-1 target cells in the CNS

    PubMed Central

    Joseph, Sarah B.; Arrildt, Kathryn T.; Sturdevant, Christa B.; Swanstrom, Ronald

    2014-01-01

    HIV-1 replication in the central nervous system (CNS) is typically limited by the availability of target cells. HIV-1 variants that are transmitted and dominate the early stages of infection almost exclusively use the CCR5 coreceptor and are well adapted to entering, and thus infecting, cells expressing high CD4 densities similar to those found on CD4+ T cells. While the “immune privileged” CNS is largely devoid of CD4+ T cells, macrophage and microglia are abundant throughout the CNS. These cells likely express CD4 densities that are too low to facilitate efficient entry or allow sustained replication by most HIV-1 isolates. Examination of CNS viral populations reveals that late in disease the CNS of some individuals contains HIV-1 lineages that have evolved the ability to enter cells expressing low levels of CD4 and are well-adapted to entering macrophages. These macrophage-tropic (M-tropic) viruses are able to maintain sustained replication in the CNS for many generations, and their presence is associated with severe neurocognitive impairment. Whether conditions such as pleocytosis are necessary for macrophage-tropic viruses to emerge in the CNS is unknown, and extensive examinations of macrophage-tropic variants have not revealed a genetic signature of this phenotype. It is clear, however, that macrophage tropism is rare among HIV-1 isolates and is not transmitted, but is important due to its pathogenic effects on hosts. Prior to the evolution of macrophage-tropic variants, the viruses that are predominately infecting T cells (R5 T cell-tropic) may infect macrophages at a low level and inefficiently, but this could contribute to the reservoir. PMID:25236812

  10. Conditional survival after diagnosis with malignant brain and central nervous system tumor in the United States, 1995-2012.

    PubMed

    Farah, Paul; Blanda, Rachel; Kromer, Courtney; Ostrom, Quinn T; Kruchko, Carol; Barnholtz-Sloan, Jill S

    2016-07-01

    General population-based survival statistics for primary malignant brain or other central nervous system (CNS) tumors do not provide accurate estimations of prognosis for individuals who have survived for a significant period of time. For these persons, the use of conditional survival percentages provides more accurate information to estimate potential outcomes. Using information from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program from 1995 to 2012, conditional survival percentages were calculated for 1 or 5 years of additional survival for all primary malignant brain and CNS tumors overall and by gender, race, ethnicity and age. Rates were calculated to include 1, 2, 3, 4, 5, 10 and 15 years post diagnosis. Conditional survival was also calculated in intervals from 1995-2004 to 2005-2012, to examine the potential effect that the introduction of new treatment protocols may have had on survival rates. The percentage of patients surviving one or five additional years varied by histology, age at diagnosis, gender, race and ethnicity. Younger persons (age <15 years at diagnosis) had higher conditional survival percentages for all histologies as compared to all histologies in older patients (age ≥15 years at diagnosis). The longer the amount of time post-diagnosis of a malignant brain or other CNS tumor, the higher the conditional survival. Younger persons at diagnosis had the highest conditional survival irrespective of histology. Use of conditional survival rates provides relevant additional information for patients and their families, as well as for clinicians and researchers, and helps with understanding prognosis.

  11. 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.

  12. Correlation of Intraoperative Frozen Section Report and Histopathological Diagnosis of 
Central Nervous System Tumors – A Six-Year Retrospective Study

    PubMed Central

    Al-Ajmi, Radiya; Al-Kindi, Hunaina; George, Mina; Thomas, Kurien

    2016-01-01

    Objectives To evaluate the degree of agreement between the intraoperative frozen section (FS) reporting of central nervous system (CNS) tumors and final histopathological diagnosis based on permanent paraffin section. Methods All CNS tumor cases with a diagnosis at FS and subsequent permanent section (n = 261) taken from 2007 to 2012 were retrospectively reviewed. Twenty percent of FS were double-checked by a senior pathologist as part of the study and the intraobserver agreement between the pathologist and the agreement between final report, and initial FS report was estimated by the intraclass correlation coefficient (ICC). Results A total of 261 cases were reviewed. The most common diagnosis was glioblastoma (grade IV) and meningioma (grade I–II) forming 45.6% of cases. Fifty-three cases were subjected to intraobserver agreement of histological diagnosis. There was nearly perfect intraobserver agreement on histopathology (ICC = 0.9). Out of 261 cases, 224 cases showed a strong agreement between the FS diagnosis and final histological diagnosis (ICC = 0.747). A discrepancy between the FS and final diagnosis were found in eight cases. The disagreement did not relate to any specific tumor type. However, in three cases, the discrepancy was in the grading of the glioma. In 29 cases, a definite opinion could not be given on FS as the samples examined were nonrepresentative. Conclusions Histopathological slides classified by World Health Organization criteria of CNS tumors had excellent intraobserver agreement. Our results show a moderate to high degree of agreement in the intraoperative diagnosis of CNS lesions using FS. However, there are limitations, and some lesions are a diagnostic challenge. There is a need to improve our diagnostic skills and knowledge of possible errors and establish better communication with neurosurgeons. PMID:27974956

  13. Population-based survival analyses of central nervous system tumors from 1994 to 2008. An up-dated study in the temozolomide-era.

    PubMed

    Fuentes-Raspall, Rafael; Puig-Vives, Montserrat; Guerra-Prio, Silvia; Perez-Bueno, Ferran; Marcos-Gragera, Rafael

    2014-06-01

    The present population-based study describes the survival of malignant central nervous system (CNS) tumors diagnosed during 15 years. Also, we obtained individual data regarding the use of temozolomide to analyze the impact of this drug on the survival of patients diagnosed with glioblastoma. From 1994 to 2008, a total of 679 incident cases of primary CNS tumors were reported by the Girona Cancer Registry after excluding 39 cases diagnosed by death certificate only. Number of cases and the corresponding proportion for each CNS histological subtype in the study population were: 25 oligodendroglial and oligoastrocytics (3.7%), 22 ependymal tumors (3.2%), 24 embryonal (3.5%), 372 astrocytic (54.8%), 1 choroid plexus (0.1%) and 235 without histological confirmation (34.6%). Observed survival after 5 years since diagnosis for the histological subtype were: 58.8%; 47.5%; 37.0%; 14.5% and 6.5%, respectively (p<0.001). Survival of patients diagnosed with glioblastoma according to temozolomide treatment (yes/no) was 60.8% vs. 13.6% and 5.9% vs. 2.5% after 1 and 5 years since diagnosis, respectively. Short-term survival was higher for patients diagnosed with glioblastoma and treated with temozolomide than patients not treated with temozolomide.

  14. Differences in environmental exposure assignment due to residential mobility among children with a central nervous system tumor: Texas, 1995-2009.

    PubMed

    Danysh, Heather E; Mitchell, Laura E; Zhang, Kai; Scheurer, Michael E; Lupo, Philip J

    2017-01-01

    In epidemiologic studies of childhood cancer, environmental exposures are often assigned based on either residence at birth or diagnosis without considering the impact of residential mobility. Therefore, we evaluated residential mobility and exposure assignment differences to hazardous air pollutants between birth and diagnosis in children with a central nervous system (CNS) tumor. Children diagnosed with CNS tumors during 1995-2009 (N=1,196) were identified from the Texas Cancer Registry. Census tract-level estimates of 1,3-butadiene and benzene were used to assign quartiles of exposure based on the maternal residence at birth and the child's residence at diagnosis. Overall, 64% of younger (0-4 years) children and 79% of older (5-14 years) children moved between birth and diagnosis. Using mixed-effects ordinal logistic regression, residence at diagnosis compared to birth did not result in a significant change in exposure assignment for younger children; however, older children were more likely to be placed in a lower 1,3-butadiene or benzene exposure quartile based on residence at diagnosis compared to birth (odds ratio (OR)=0.58, 95% confidence interval (CI)=0.45-0.76; OR=0.57, 95% CI=0.44-0.75, respectively). In conclusion, while the majority of children moved between birth and CNS tumor diagnosis, mobility did not significantly impact 1,3-butadiene and benzene exposure assessment in younger children.

  15. Biologic scaffold for CNS repair.

    PubMed

    Meng, Fanwei; Modo, Michel; Badylak, Stephen F

    2014-05-01

    Injury to the CNS typically results in significant morbidity and endogenous repair mechanisms are limited in their ability to restore fully functional CNS tissue. Biologic scaffolds composed of individual purified components have been shown to facilitate functional tissue reconstruction following CNS injury. Extracellular matrix scaffolds derived from mammalian tissues retain a number of bioactive molecules and their ability for CNS repair has recently been recognized. In addition, novel biomaterials for dural mater repairs are of clinical interest as the dura provides barrier function and maintains homeostasis to CNS. The present article describes the application of regenerative medicine principles to the CNS tissues and dural mater repair. While many approaches have been exploring the use of cells and/or therapeutic molecules, the strategies described herein focus upon the use of extracellular matrix scaffolds derived from mammalian tissues that are free of cells and exogenous factors.

  16. 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

  17. Drug delivery systems for brain tumor therapy.

    PubMed

    Rautioa, Jarkko; Chikhale, Prashant J

    2004-01-01

    Brain tumors are one of the most lethal forms of cancer. They are extremely difficult to treat. Although, the rate of brain tumor incidence is relatively low, the field clearly lacks therapeutic strategies capable of overcoming barriers for effective delivery of drugs to brain tumors. Clinical failure of many potentially effective therapeutics for the treatment of brain tumors is usually not due to a lack of drug potency, but rather can be attributed to shortcomings in the methods by which a drug is delivered to the brain and into brain tumors. In response to the lack of efficacy of conventional drug delivery methods, extensive efforts have been made to develop novel strategies to overcome the obstacles for brain tumor drug delivery. The challenge is to design therapeutic strategies that deliver drugs to brain tumors in a safe and effective manner. This review provides some insight into several potential techniques that have been developed to improve drug delivery to brain tumors, and it should be helpful to clinicians and research scientists as well.

  18. ED-26ATYPICAL TERATOID/RHABDOID TUMOR OF THE CENTRAL NERVOUS SYSTEM IN A 27-YEARS OLD PATIENT

    PubMed Central

    Rivas, Rodrigo; Carrasco, Paula; Ayach, Freddy

    2014-01-01

    INTRODUCTION: Atypical Teratoid/Rhabdoid Tumor (ATRT), according to the World Health Organization (WHO) Classification of Tumors, is a highly malignant neoplasm (grade IV) of the Central Nervous System (CNS) that preferentially manifests in children less than three years of age. These tumors are mainly composed of rhabdoid cells, with the addition or not of areas demonstrating characteristics of primitive neuroectodermal tumor. Less than 40 cases were published in the literature about this neoplasm. OBJECTIVE: In this context our aim is to present an unusual case of ATRT. MATERIAL AND METHOD: A 27-year old male, with intellectual disability. He referred headache, nausea and vomiting and was associated with progressive left femoral brachial paresis, so he consulted in the clinic in March 2013. Brain CT and magnetic resonance (MRI) spectroscopy revealed a solid cystic mass in the right temporal medial lobe of 65x57 mm, with an intense contrast (gadolinium) enhancement, the tumor compressed the third ventricles, displacing the midline and deforming the ventricles. RESULTS: The neoplasm was totally excised, histological and immunohistochemical analysis demonstrated atypical rhabdoid cells strongly and diffusely positive for EMA and Vimentin as well as focally immunoreactive for GFAP. The patient was treated with chemotherapy (vincristine) and radiotherapy. The patient finally died in Abril 2014. CONCLUSIONS: Few previous case of ATRT have been reported in adults, thus far. This unusual presentation underlines the necessity of considering this devastating neoplasm in the differential diagnosis of malignant brain tumor of young adults.

  19. Plant sterols: Friend or foe in CNS disorders?

    PubMed

    Vanmierlo, Tim; Bogie, Jeroen F J; Mailleux, Jo; Vanmol, Jasmine; Lütjohann, Dieter; Mulder, Monique; Hendriks, Jerome J A

    2015-04-01

    In mammals, the central nervous system (CNS) is the most cholesterol rich organ by weight. Cholesterol metabolism is tightly regulated in the CNS and all cholesterol available is synthesized in situ. Deficits in cholesterol homeostasis at the level of synthesis, transport, or catabolism result in severe disorders featured by neurological disability. Recent studies indicate that a disturbed cholesterol metabolism is involved in CNS disorders, such as Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In contrast to circulating cholesterol, dietary plant sterols, can cross the blood-brain barrier and accumulate in the membranes of CNS cells. Plant sterols are well-known for their ability to lower circulating cholesterol levels. The finding that they gain access to the CNS has fueled research focusing on the physiological roles of plant sterols in the healthy and diseased CNS. To date, both beneficial and detrimental effects of plant sterols on CNS disorders are defined. In this review, we discuss recent findings regarding the impact of plant sterols on homeostatic and pathogenic processes in the CNS, and elaborate on the therapeutic potential of plant sterols in CNS disorders.

  20. Dual systemic tumor targeting with ligand-directed phage and Grp78 promoter induces tumor regression.

    PubMed

    Kia, Azadeh; Przystal, Justyna M; Nianiaris, Nastasia; Mazarakis, Nicholas D; Mintz, Paul J; Hajitou, Amin

    2012-12-01

    The tumor-specific Grp78 promoter is overexpressed in aggressive tumors. Cancer patients would benefit greatly from application of this promoter in gene therapy and molecular imaging; however, clinical benefit is limited by lack of strategies to target the systemic delivery of Grp78-driven transgenes to tumors. This study aims to assess the systemic efficacy of Grp78-guided expression of therapeutic and imaging transgenes relative to the standard cytomegalovirus (CMV) promoter. Combination of ligand and Grp78 transcriptional targeting into a single vector would facilitate systemic applications of the Grp78 promoter. We generated a dual tumor-targeted phage containing the arginine-glycine-aspartic acid tumor homing ligand and Grp78 promoter. Next, we combined flow cytometry, Western blot analysis, bioluminescence imaging of luciferase, and HSVtk/ganciclovir gene therapy and compared efficacy to conventional phage carrying the CMV promoter in vitro and in vivo in subcutaneous models of rat and human glioblastoma. We show that double-targeted phage provides persistent transgene expression in vitro and in tumors in vivo after systemic administration compared with conventional phage. Next, we showed significant tumor killing in vivo using the HSVtk/ganciclovir gene therapy and found a systemic antitumor effect of Grp78-driven HSVtk against therapy-resistant tumors. Finally, we uncovered a novel mechanism of Grp78 promoter activation whereby HSVtk/ganciclovir therapy upregulates Grp78 and transgene expression via the conserved unfolded protein response signaling cascade. These data validate the potential of Grp78 promoter in systemic cancer gene therapy and report the efficacy of a dual tumor targeting phage that may prove useful for translation into gene therapy and molecular imaging applications.

  1. CNS Regulation of Energy Metabolism: Ghrelin versus Leptin

    PubMed Central

    Nogueiras, Ruben; Tschöp, Matthias H.; Zigman, Jeffrey M.

    2010-01-01

    In this brief review, we introduce some major themes in the regulation of energy, lipid and glucose metabolism by the central nervous system (CNS). Rather than comprehensively discussing the field, we instead will discuss some of the key findings made regarding the interaction of the hormones ghrelin and leptin with the CNS. PMID:18448790

  2. 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...

  3. The risk of CNS involvement in aggressive lymphomas in the rituximab era.

    PubMed

    Benevolo, Giulia; Chiappella, Annalisa; Vitolo, Umberto

    2013-12-01

    The risk of CNS dissemination and CNS prophylaxis strategies in aggressive non-Hodgkin lymphoma (NHL) is still debated. CNS dissemination is a rare but fatal event. A CNS prophylaxis is common for Burkitt and B-cell lymphoblastic lymphoma; however, in other NHLs, prophylactic treatments are not systematically warranted. Current risk models showed low sensitivity in predicting CNS involvement, implying overtreatment in roughly 70% of high-risk patients. Risk models in the rituximab era were modulated for the detection of occult CNS disease at diagnosis using flow cytometry. The optimal regimen for CNS prophylaxis in aggressive lymphoma patients has not been established thus far and should be modulated at different levels of 'intensity' such as standard intrathecal chemotherapy, 'active' intrathecal chemotherapy with liposomal cytarabine or more aggressive systemic treatment with high doses of drugs having good CNS bioavailability reserved for patients who are truly at high risk of CNS dissemination.

  4. [Imaging features of CNS tuberculosis].

    PubMed

    Semlali, S; El Kharras, A; Mahi, M; Hsaini, Y; Benameur, M; Aziz, N; Chaouir, S; Akjouj, S

    2008-02-01

    CNS tuberculosis remains relatively frequent in endemic regions. Both CT and MRI are valuable for diagnosis. Even though non-specific, MRI including diffusion-weighted imaging and proton spectroscopy is more sensitive than CT for detection of some lesions. The purpose of this paper is to illustrate the imaging features of CNS tuberculosis.

  5. Current Multistage Drug Delivery Systems Based on the Tumor Microenvironment

    PubMed Central

    Chen, Binlong; Dai, Wenbing; He, Bing; Zhang, Hua; Wang, Xueqing; Wang, Yiguang; Zhang, Qiang

    2017-01-01

    The development of traditional tumor-targeted drug delivery systems based on EPR effect and receptor-mediated endocytosis is very challenging probably because of the biological complexity of tumors as well as the limitations in the design of the functional nano-sized delivery systems. Recently, multistage drug delivery systems (Ms-DDS) triggered by various specific tumor microenvironment stimuli have emerged for tumor therapy and imaging. In response to the differences in the physiological blood circulation, tumor microenvironment, and intracellular environment, Ms-DDS can change their physicochemical properties (such as size, hydrophobicity, or zeta potential) to achieve deeper tumor penetration, enhanced cellular uptake, timely drug release, as well as effective endosomal escape. Based on these mechanisms, Ms-DDS could deliver maximum quantity of drugs to the therapeutic targets including tumor tissues, cells, and subcellular organelles and eventually exhibit the highest therapeutic efficacy. In this review, we expatiate on various responsive modes triggered by the tumor microenvironment stimuli, introduce recent advances in multistage nanoparticle systems, especially the multi-stimuli responsive delivery systems, and discuss their functions, effects, and prospects. PMID:28255348

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

    PubMed

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

    2008-09-01

    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/s2 in the lateral direction, and 9.5 mm/s and 29.5 mm/s2 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.

  7. 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

  8. 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.

  9. A high-throughput multicomponent screening method for diuretics, masking agents, central nervous system (CNS) stimulants and opiates in human urine by UPLC-MS/MS.

    PubMed

    Thörngren, John-Olof; Ostervall, Fredrik; Garle, Mats

    2008-07-01

    A simple and rapid multicomponent screening method of 130 substances for direct injections of urine samples has been developed. The fully automated method based on ultra-performance liquid chromatography (UPLC) and tandem mass spectrometry (MS/MS) is used for three different classes of doping agents: diuretics, central nervous system stimulants (CNS stimulants) and opiates. The samples are diluted with buffer containing internal standards (IS) by a pipetting robot system into 96-well plates. Samples are injected on a reversed phase sub 2-microm particle column connected to a fast polarity switching and rapid scanning tandem mass spectrometer with an electrospray interface. The software used to evaluate the results produced reports containing a small-sized window for each component and a data table list with flags to indicate any adverse analytical findings in the sample. The report can also be processed automatically using an application software, which interpret the data and indicate if there is a suspicious sample. One 96-well plate can be analyzed within 16 h.

  10. Cerebellar metastases of recurrent phyllodes tumor breast; a rare phenomenon reflecting the unpredictable outcome.

    PubMed

    Singh, Jyotsna; Majumdar, Kaushik; Gupta, Rahul; Batra, Vineeta Vijay

    2015-01-01

    Carcinomas of lung, breast, colon, kidney, and malignant melanomas are the most common malignancies that metastasize to the central nervous system (CNS). Phyllodes tumor is a rare fibroepithelial tumor of the breast, often having unpredictable recurrences, with increasing histological grade and distant metastasis. Malignant forms exist, which may develop distant metastases usually to the lung, pleura, bone, and liver. CNS metastasis of phyllodes tumor is rare and associated with a poor prognosis, with resistance to chemotherapy and radiation. We present a rare case of cerebellar metastasis in recurrent phyllodes tumor breast with subsequent rapid downhill course.

  11. Spontaneous and nitrosourea-induced primary tumors of the central nervous system in Fischer 344 rats exposed to frequency-modulated microwave fields.

    PubMed

    Adey, W R; Byus, C V; Cain, C D; Higgins, R J; Jones, R A; Kean, C J; Kuster, N; MacMurray, A; Stagg, R B; Zimmerman, G

    2000-04-01

    In a 2-year bioassay, we exposed Fischer 344 rats to a frequency-modulated (FM) signal (836.55 MHz +/- 12.5 KHz deviation) simulating radiofrequency exposures in the head of users of hand-held mobile phones. We tested for effects on spontaneous tumorigenicity of central nervous system (CNS) tumors in the offspring of pregnant rats and also for modified incidence of primary CNS tumors in rats treated with a single dose of the neurocarcinogen ethylnitrosourea (ENU) in utero. ENU dosage (4 mg/kg) was selected to give an expected brain tumor incidence of 10-15% over the mean life span of 26 months. Pregnant dams (n = 102) were randomly assigned to six groups. Their offspring were treated as cohorts in each of the six groups (n = 90 per group; total, n = 540): Sham ENU/Sham Field, Sham ENU/Field Exposed, ENU/Sham Field, ENU/Field Exposed, ENU/Cage Control, and Sham ENU/Cage Control. Intermittent field exposures began on gestation day 19 and continued until weaning at 21 days, resuming thereafter at 31 days and continuing until experiment termination at 731-734 days. Energy absorption rates (SARs) in the rats' brains were similar to localized peak brain exposures of a phone user (female, 236 g, 1.0 W/kg; male, 450 g, 1.2 W/kg). Of the original 540 rats, 168 died before the termination of the experiment. In these rats, ENU significantly reduced survival from a mean of 708 days in three groups without ENU treatment to 645 days in three groups treated with ENU (P < 0.0005). There were no effects on survival attributable to FM field exposure in either ENU-treated or in sham-treated groups. Spontaneous CNS tumor incidence in control groups was 1.1-4.4% but sharply higher in rats receiving ENU (14.4-22.2%; P < 0.0001). No FM field-mediated changes were observed in number, incidence, or histological type of either spontaneous or ENU-induced brain tumors, nor were gender differences detected in tumor numbers. These negative findings with FM fields contrast with our study using

  12. A comparison of the fluorescence spectra of murine and bovine central nervous system (CNS) and other tissues

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Here we describe a comparison of the fluorescence spectra of bovine tissues with murine tissues in order to determine whether spectral features are conserved and whether an appropriate and practical laboratory small animal model system could be identified to be used for investigation of tissue and a...

  13. [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.

  14. Cognitive Impairment and Persistent CNS Injury in Treated HIV.

    PubMed

    Chan, Phillip; Hellmuth, Joanna; Spudich, Serena; Valcour, Victor

    2016-08-01

    The implementation of combination antiretroviral therapy (cART) has changed HIV infection into a chronic illness, conveying extensive benefits, including greater longevity and advantages for the central nervous system (CNS). However, studies increasingly confirm that the CNS gains are incomplete, with reports of persistent immune activation affecting the CNS despite suppression of plasma HIV RNA. The rate of cognitive impairment is unchanged, although severity is generally milder than in the pre-cART era. In this review, we discuss cognitive outcomes from recently published clinical HIV studies, review observations on HIV biomarkers for cognitive change, and emphasize longitudinal imaging findings. Additionally, we summarize recent studies on CNS viral invasion, CD8 encephalitis, and how CNS involvement during the earliest stages of infection may set the stage for later cognitive manifestations.

  15. Generation of a mouse model of atypical teratoid/rhabdoid tumor of the central nervous system through combined deletion of Snf5 and p53.

    PubMed

    Ng, Jessica M Y; Martinez, Daniel; Marsh, Eric D; Zhang, Zhe; Rappaport, Eric; Santi, Mariarita; Curran, Tom

    2015-11-01

    Malignant rhabdoid tumors arise in several anatomic locations and are associated with poor outcomes. In the brain, these tumors are known as atypical teratoid/rhabdoid tumors (AT/RT). While genetically engineered models for malignant rhabdoid tumors exist, none of them recapitulate AT/RT, for which preclinical models remain lacking. In the majority of AT/RT, LOH occurs at the genetic locus SNF5 (Ini1/BAF47/Smarcb1), which functions as a subunit of the SWI/SNF chromatin-remodeling complex and a tumor suppressor in familial and sporadic malignant rhabdoid tumors. Therefore, we generated mice in which Snf5 was ablated specifically in nestin-positive and/or glial fibrillary acid protein (GFAP)-positive progenitor cells of the developing central nervous system (CNS). Snf5 ablation in nestin-positive cells resulted in early lethality that could not be rescued by loss of p53. However, Snf5 ablation in GFAP-positive cells caused a neurodegenerative phenotype exacerbated by p53 loss. Notably, these double mutants exhibited AT/RT development, associated with an earlier failure in granule neuron migration in the cerebellum, reduced neuronal projections in the hippocampus, degeneration of the corpus callosum, and ataxia and seizures. Gene expression analysis confirmed that the tumors that arose in Snf5/p53 mutant mice were distinct from other neural tumors and most closely resembled human AT/RT. Our findings uncover a novel role for Snf5 in oligodendrocyte generation and survival, and they offer evidence of the first genetically engineered mouse model for AT/RT in the CNS.

  16. 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.

  17. The role of dendritic cells in CNS autoimmunity

    PubMed Central

    Zozulya, Alla L.; Clarkson, Benjamin D.; Ortler, Sonja; Fabry, Zsuzsanna

    2010-01-01

    Multiple sclerosis (MS) is a chronic immune-mediated, central nervous system (CNS) demyelinating disease. Clinical and histopathological features suggest an inflammatory etiology involving resident CNS innate cells as well as invading adaptive immune cells. Encephalitogenic myelin-reactive T cells have been implicated in the initiation of an inflammatory cascade, eventually resulting in demyelination and axonal damage (the histological hallmarks of MS). Dendritic cells (DC) have recently emerged as key modulators of this immunopathological cascade, as supported by studies in humans and experimental disease models. In one such model, experimental autoimmune encephalomyelitis (EAE), CNS microvessel-associated DC have been shown to be essential for local antigen recognition by myelin-reactive T cells. Moreover, the functional state and compartmental distribution of DC derived from CNS and associated lymphatics seem to be limiting factors in both the induction and effector phases of EAE. Moreover, DC modulate and balance the recruitment of encephalitogenic and regulatory T cells into CNS tissue. This capacity is critically influenced by DC surface expression of co-stimulatory or co-inhibitory molecules. The fact that DC accumulate in the CNS before T cells and can direct T-cell responses suggests that they are key determinants of CNS autoimmune outcomes. Here we provide a comprehensive review of recent advances in our understanding of CNS-derived DC and their relevance to neuroinflammation. PMID:20217033

  18. 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.

  19. 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

  20. 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.

  1. [Radiation-induced tumors of the nervous system in man].

    PubMed

    Hubert, D; Bertin, M

    1993-11-01

    The risk of developing a tumor of the nervous system in humans is analysed in several studies of populations, exposed to ionising radiation for medical reasons, or exposed to military or occupational radiation. The main data come from series of patients who underwent radiotherapy during childhood: a high incidence of tumors of the nervous system is found after irradiation of one to a few grays as treatment of a benign disease (especially tinea capitis), as well as after irradiation at higher doses of a few tens of grays for the treatment of cancer (in particular cerebral irradiation in acute lymphoblastic leukaemia). The type of radiation-induced tumors is variable, but meningioma is more frequent after low doses and glioma and sarcoma after higher doses used in the treatment of neoplastic diseases. A dose-effect relationship appeared between the risk of tumor of the nervous system and the radiation dose. The risk was higher when radiation was delivered at a younger age. Much less data are available after radiotherapy in the adulthood, but an increased risk of cerebral tumor appears in the series of ankylosing spondylitis patients. As for the exposures to radiodiagnosis exams, the main problem is the risk of cerebral tumor in children whose mother has undergone abdominal or pelvic X-rays during pregnancy. No risk of neurologic tumor was found in the A-bomb survivors irradiated at Hiroshima and Nagasaki. Occupational exposure to ionising radiation has been incriminated in the first radiologists exposed to high doses. In nuclear industry workers, the results of epidemiological studies are contradictory and at the present time it is not possible to link their radiologic exposure with a risk of tumor of the nervous system. In populations living near nuclear plants, mortality due to tumors of the nervous system was not increased.

  2. Alpha-mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function.

    PubMed

    Borgwardt, L; Danielsen, E R; Thomsen, C; Månsson, J E; Taouatas, N; Thuesen, A M; Olsen, K J; Fogh, J; Dali, C I; Lund, A M

    2015-07-23

    Alpha-mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty-four patients, aged 6-35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF-oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age-inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau-protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF-biomarkers and CSF-oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.

  3. Impact of epidemiological characteristics of supratentorial gliomas in adults brought about by the 2016 world health organization classification of tumors of the central nervous system.

    PubMed

    Jiang, Haihui; Cui, Yong; Wang, Junmei; Lin, Song

    2016-11-24

    The latest World Health Organization (WHO) classification of tumors of the central nervous system (CNS) integrates both histological and molecular features in the definition of diagnostic entities. This new approach enrolls novel entities of gliomas. In this study, we aimed to reveal the epidemiological characteristics, including age at diagnosis, gender ratio, tumor distribution and survival, of these new entities. We retrospectively reclassified 1210 glioma samples according to the 2016 CNS WHO diagnostic criteria. In our cohort, glioblastoma multiforme (GBM) with wildtype isocitrate dehydrogenase (IDH) was the most common malignant tumor in the brain. Almost all gliomas were more prevalent in males, especially in the cluster of WHO grade III gliomas and IDH-wildtype GBM. Age at diagnosis was directly proportional to tumor grade. With respect to the distribution by histology, we found that gliomas concurrent with IDH-mutant and 1p/19q-codeleted or with single IDH-mutant were mainly distributed in frontal lobe, while those with IDH-wildtype were dominant in temporal lobe. Lesions located in insular lobe were more likely to be IDH-mutant astrocytoma. In summary, our results elucidated the epidemiological characteristics as well as the regional constituents of these new gliomas entities, which could bring insights into tumorigenesis and personalized treatment of Chinese glioma population.

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

    PubMed

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

    2010-01-01

    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.

  5. Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer.

    PubMed

    Gadgeel, Shirish M; Shaw, Alice T; Govindan, Ramaswamy; Gandhi, Leena; Socinski, Mark A; Camidge, D Ross; De Petris, Luigi; Kim, Dong-Wan; Chiappori, Alberto; Moro-Sibilot, Denis L; Duruisseaux, Michael; Crino, Lucio; De Pas, Tommaso; Dansin, Eric; Tessmer, Antje; Yang, James Chih-Hsin; Han, Ji-Youn; Bordogna, Walter; Golding, Sophie; Zeaiter, Ali; Ou, Sai-Hong Ignatius

    2016-12-01

    Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. CNS Anticancer Drug Discovery and Development Conference White Paper

    PubMed Central

    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.

    2015-01-01

    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. PMID:26403167

  12. 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.

  13. Primary lymphomas of the central nervous system: patterns of failure and factors that influence survival

    SciTech Connect

    Loeffler, J.S.; Ervin, T.J.; Mauch, P.; Skarin, A.; Weinstein, H.J.; Canellos, G.; Cassady, J.R.

    1985-04-01

    Primary lymphomas of the CNS are rare tumors accounting for less than 2% of all extranodal non-Hodgkin's lymphomas. The treatment for this disease has been disappointing. Radiation therapy and surgery have produced consistently poor control of this disease, with a median survival of 15 months. A review of ten cases of primary lymphoma of the CNS treated at the Joint Center for Radiation Therapy or Dana-Farber Cancer Institute (Boston) from 1968 to 1981 is presented. All patients had biopsy- proven CNS lymphomas without systemic disease at presentation. In this series, control of CNS lymphoma was seen only in patients receiving craniospinal radiation or CNS-penetrating chemotherapy.

  14. 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

  15. 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.

  16. CNS Vasculitis Associated with Waldenström Macroglobulinemia.

    PubMed

    Riangwiwat, Tanawan; Wu, Chris Y; Santos-Ocampo, Alberto S; Liu, Randal J; McMurtray, Aaron M; Nakamoto, Beau K

    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.

  17. 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. PMID:27818812

  18. Contribution of CNS cells in NeuroAIDS

    PubMed Central

    Verma, Ashish Swarup; Singh, Udai Pratap; Dwivedi, Premendra Dhar; Singh, Anchal

    2010-01-01

    NeuroAIDS is becoming a major health problem among AIDS patients and long-term HIV survivors. As per 2009 estimates of UNAIDS report, more than 34 million people have been infected with HIV out of which ≥ 50% show signs and symptoms of neuropsychiatric disorders. These disorders affect central nervous system (CNS) and peripheral nervous systems (PNS). CNS is one of the most protected organ systems in body which is protected by blood-brain barrier (BBB). Not only this, most of the cells of CNS are negative for receptors and co-receptors for HIV infections. Neurons have been found to be completely nonpermissive for HIV infection. These facts suggest that neurotoxicity could be an indirect mechanism responsible for neuropsychiatric complications. In this review, we will discuss the importance of different cell types of CNS and their contribution toward neurotoxicity. PMID:21180461

  19. 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.

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

    PubMed Central

    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.

    2015-01-01

    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. PMID:26575352

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations.

    PubMed

    Abrams, Charles K; Goman, Mikhail; Wong, Sarah; Scherer, Steven S; Kleopa, Kleopas A; Peinado, Alejandro; Freidin, Mona M

    2017-01-10

    CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short-duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. What distinguishes mutations with and without CNS manifestations has been unclear. Here we studied a total of 14 Cx32 mutations, 10 of which are associated with florid episodic CNS clinical syndromes in addition to peripheral neuropathy. The other 4 mutations exhibit neuropathy without clinical or subclinical CNS abnormalities. These "PNS-only" mutations (Y151C, V181M, R183C and L239I) form gap junction plaques and produce levels of junctional coupling similar to those for wild-type Cx32. In contrast, mutants with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W T55I, R164Q and C168Y) either form no morphological gap junction plaques or, if they do, produce little or no detectable junctional coupling. Thus, PNS and CNS abnormalities may involve different aspects of connexin function.

  7. Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations

    PubMed Central

    Abrams, Charles K.; Goman, Mikhail; Wong, Sarah; Scherer, Steven S.; Kleopa, Kleopas A.; Peinado, Alejandro; Freidin, Mona M.

    2017-01-01

    CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short-duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. What distinguishes mutations with and without CNS manifestations has been unclear. Here we studied a total of 14 Cx32 mutations, 10 of which are associated with florid episodic CNS clinical syndromes in addition to peripheral neuropathy. The other 4 mutations exhibit neuropathy without clinical or subclinical CNS abnormalities. These “PNS-only” mutations (Y151C, V181M, R183C and L239I) form gap junction plaques and produce levels of junctional coupling similar to those for wild-type Cx32. In contrast, mutants with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W T55I, R164Q and C168Y) either form no morphological gap junction plaques or, if they do, produce little or no detectable junctional coupling. Thus, PNS and CNS abnormalities may involve different aspects of connexin function. PMID:28071741

  8. 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

  9. 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.

  10. Efficacy of cabazitaxel in mouse models of pediatric brain tumors

    PubMed Central

    Girard, Emily; Ditzler, Sally; Lee, Donghoon; Richards, Andrew; Yagle, Kevin; Park, Joshua; Eslamy, Hedieh; Bobilev, Dmitri; Vrignaud, Patricia; Olson, James

    2015-01-01

    Background There is an unmet need in the treatment of pediatric brain tumors for chemotherapy that is efficacious, avoids damage to the developing brain, and crosses the blood-brain barrier. These experiments evaluated the efficacy of cabazitaxel in mouse models of pediatric brain tumors. Methods The antitumor activity of cabazitaxel and docetaxel were compared in flank and orthotopic xenograft models of patient-derived atypical teratoid rhabdoid tumor (ATRT), medulloblastoma, and central nervous system primitive neuroectodermal tumor (CNS-PNET). Efficacy of cabazitaxel and docetaxel were also assessed in the Smo/Smo spontaneous mouse medulloblastoma tumor model. Results This study observed significant tumor growth inhibition in pediatric patient-derived flank xenograft tumor models of ATRT, medulloblastoma, and CNS-PNET after treatment with either cabazitaxel or docetaxel. Cabazitaxel, but not docetaxel, treatment resulted in sustained tumor growth inhibition in the ATRT and medulloblastoma flank xenograft models. Patient-derived orthotopic xenograft models of ATRT, medulloblastoma, and CNS-PNET showed significantly improved survival with treatment of cabazitaxel. Conclusion These data support further testing of cabazitaxel as a therapy for treating human pediatric brain tumors. PMID:25140037

  11. cJun promotes CNS axon growth

    PubMed Central

    Lerch, Jessica K; Martinez, Yania; Bixby, John L; Lemmon, Vance P

    2014-01-01

    A number of genes regulate regeneration of peripheral axons, but their ability to drive axon growth and regeneration in the central nervous system (CNS) remains largely untested. To address this question we overexpressed eight transcription factors and one small GTPase alone and in pairwise combinations to test whether combinatorial overexpression would have a synergistic impact on CNS neuron neurite growth. The Jun oncogene/signal transducer and activator of transcription 6 (JUN/STAT6) combination increased neurite growth in dissociated cortical neurons and in injured cortical slices. In injured cortical slices, JUN overexpression increased axon growth to a similar extent as JUN and STAT6 together. Interestingly, JUN overexpression was not associated with increased growth associated protein 43 (GAP43) or integrin alpha 7 (ITGA7) expression, though these are predicted transcriptional targets. This study demonstrates that JUN overexpression in cortical neurons stimulates axon growth, but does so independently of changes in expression of genes thought to be critical for JUN’s effects on axon growth. We conclude that JUN activity underlies this CNS axonal growth response, and that it is mechanistically distinct from peripheral regeneration responses, in which increases in JUN expression coincide with increases in GAP43 expression. PMID:24521823

  12. Medulloblastomas and central nervous system primitive neuroectodermal tumors.

    PubMed

    McLean, Thomas W

    2003-12-01

    Significant advances in the treatment of medulloblastoma and primitive neuroectodermal tumors have been made in the past three decades. Maximal surgical resection is a mainstay of therapy. However, unlike many other central nervous system neoplasms, medulloblastoma and primitive neuroectodermal tumors are radiation and chemotherapy responsive. Despite this response, the prognosis for patients with these tumors remains variable and is relatively poor in infants and patients with metastatic disease. These tumors most commonly arise in children, thus most clinical trials emphasize the reduction of long-term sequelae, in addition to improving survival. All newly diagnosed patients who are eligible should be offered participation in a clinical trial. If a patient is ineligible or declines consent/assent for a clinical trial, the best current treatment approach is surgical resection, followed by radiation therapy (except for children younger than 3 years) with weekly vincristine. For high-risk patients, 36 Gy of craniospinal irradiation should be delivered plus a boost of 19.8 Gy to the posterior fossa/primary tumor bed and sites of bulk metastatic disease. For average-risk patients, the craniospinal irradiation dose may be lowered to 23.4 Gy plus 32.4 Gy to the posterior fossa/tumor bed. After radiation therapy, intensive multimodal chemotherapy should be used for all patients.

  13. 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.

  14. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by or linked with viruses are: Cervical cancer (human papillomavirus) Most anal cancers (human papillomavirus) Some throat ...

  15. 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

  16. B cells and Autoantibodies: Complex Roles in CNS Injury

    PubMed Central

    Ankeny, Daniel P.; Popovich, Phillip G.

    2010-01-01

    Emerging data indicate that traumatic injury to the brain or spinal cord activates B lymphocytes, culminating in the production of antibodies specific for antigens found within and outside the central nervous system (CNS). In this article, we summarize what is known about the effects of CNS injury on B cells. We outline the potential mechanisms for CNS trauma-induced B cell activation and discuss the potential consequences of these injury-induced B cell responses. Based on recent data, we hypothesize that a subset of autoimmune B cell responses initiated by CNS injury are pathogenic and that targeted inhibition of B cells could improve recovery in brain and spinal cord injured patients. PMID:20691635

  17. 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.

  18. [Influence of a CNS pathology on the electrocochleography response].

    PubMed

    Arslan, E; Lupi, G; Rosignoli, M

    1994-01-01

    This study analyzed 73 electrocochleographic recordings made in children with a normal hearing threshold, selected retrospectively from 1563 recordings made between 1973 and 1990. The aim of the study was to check the original findings for any correlation between the various response parameters which might be indicative of a pathological condition. Compound action potential (AP) latency and amplitude, presynaptic summation potential (SP) and cochlear microphonic (CM) amplitudes and AP rapid adaptation behavior were calculated and recordings were associated with clinical information on aetiologic diagnosis, otoscopic examination, impedance measurement data and the finding of any central nervous system (CNS) pathology. The trend of the amplitudes as a function of the intensity of all three potentials (input-output functions), CM and SP in particular, demonstrated unexpected scattered values especially towards the high intensities. This was found correlated to the presence of CNS pathology. The comparison between the two groups (with vs without CNS pathology) with the aid of the Student's t-test proved statically significant, especially for CM and SP amplitudes while rather less so for AP amplitude. In particular, all CM and SP amplitude values outside the confidence intervals (calculated as 95% of normal cases) revealed CNS pathology. It has been suggested that the influence of the CNS on cochlear function is due to a disturbed function of the olicocochlear bundle, which is known to have an inhibitory effect on cochlear dynamics; furthermore, there is also proof that it can be activated regardless of any ipso-and/or contra-lateral acoustic stimulation. The effects observed on the electrocochleography in cases with CNS disorders would thus be explained by an interruption of the olivocochlear bundle at the CNS level or a disruption of the CNS mechanism capable of controlling its activation.

  19. The role of inflammation in CNS injury and disease.

    PubMed

    Lucas, Sian-Marie; Rothwell, Nancy J; Gibson, Rosemary M

    2006-01-01

    For many years, the central nervous system (CNS) was considered to be 'immune privileged', neither susceptible to nor contributing to inflammation. It is now appreciated that the CNS does exhibit features of inflammation, and in response to injury, infection or disease, resident CNS cells generate inflammatory mediators, including proinflammatory cytokines, prostaglandins, free radicals and complement, which in turn induce chemokines and adhesion molecules, recruit immune cells, and activate glial cells. Much of the key evidence demonstrating that inflammation and inflammatory mediators contribute to acute, chronic and psychiatric CNS disorders is summarised in this review. However, inflammatory mediators may have dual roles, with detrimental acute effects but beneficial effects in long-term repair and recovery, leading to complications in their application as novel therapies. These may be avoided in acute diseases in which treatment administration might be relatively short-term. Targeting interleukin (IL)-1 is a promising novel therapy for stroke and traumatic brain injury, the naturally occurring antagonist (IL-1ra) being well tolerated by rheumatoid arthritis patients. Chronic disorders represent a greater therapeutic challenge, a problem highlighted in Alzheimer's disease (AD); significant data suggested that anti-inflammatory agents might reduce the probability of developing AD, or slow its progression, but prospective clinical trials of nonsteroidal anti-inflammatory drugs or cyclooxygenase inhibitors have been disappointing. The complex interplay between inflammatory mediators, ageing, genetic background, and environmental factors may ultimately regulate the outcome of acute CNS injury and progression of chronic neurodegeneration, and be critical for development of effective therapies for CNS diseases.

  20. 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

  1. 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

  2. RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer.

    PubMed

    Ahlers, Katelin E; Chakravarti, Bandana; Fisher, Rory A

    2016-05-01

    Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gαi/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.

  3. Human African trypanosomiasis, chemotherapy and CNS disease.

    PubMed

    Rodgers, Jean

    2009-06-25

    Trypanosomes have been recognised as human pathogens for over a century. Human African trypanosomiasis is endemic in an area sustaining 60 million people and is fatal without chemotherapeutic intervention. Available trypanocidal drugs require parenteral administration and are associated with adverse reactions including the development of a severe post-treatment reactive encephalopathy (PTRE). Following infection the parasites proliferate in the systemic compartment before invading the CNS where a cascade of events results in neuroinflammation. This review summarises the clinical manifestations of the infection and chemotherapeutic regimens as well as the current research findings and hypotheses regarding the neuropathogenesis of the disease.

  4. Thalamic rosette-forming a glioneuronal tumor in an elderly patient: Case report and literature review.

    PubMed

    Cebula, H; Chibbaro, S; Santin, M N; Kremer, S; Chaussemy, D; Proust, F

    2016-02-01

    The rosette-forming glioneuronal tumor (RGNT) is a novel type of brain tumor recently listed in the WHO 2007 classification of central nervous system (CNS) tumors. We report the case of a 75-year-old woman harboring a thalamic RGNT with third ventricle dissemination. Age and location make the present case exceptional and which has never previously been reported. A review of the clinical, pathological and radiological features is presented along with the relevant literature.

  5. Scoring system for prediction of metastatic spine tumor prognosis

    PubMed Central

    Tokuhashi, Yasuaki; Uei, Hiroshi; Oshima, Masashi; Ajiro, Yasumitsu

    2014-01-01

    Assessing the prognosis before treatment for metastatic spine tumor is extremely important in therapy selection. Therefore, we review some prognostic scoring systems and their outcomes. Articles with combinations of two keywords among “metastatic spine tumor” and “prognosis”, “score”, “scoring system”, “predicting”, or “life expectancy” were searched for in PubMed. As a result, 236 articles were extracted. Those referring to representative scoring systems about predicting the survival of patients with metastatic spine tumors were used. The significance and limits of these scoring systems, and the future perspectives were described. Tokuhashi score, Tomita score, Baur score, Linden score, Rades score, and Katagiri score were introduced. They are all scoring systems prepared by combining factors that affect prognosis. The primary site of cancer and visceral metastasis were common factors in all of these scoring systems. Other factors selected to influence the prognosis varied. They were useful to roughly predict the survival period, such as, “more than one year or not” or “more than six months or not”. In particular, they were utilized for decision-making about operative indications and avoidance of excessive medical treatment. Because the function depended on the survival period in the patients with metastatic spine tumor, it was also utilized in assessing functional prognosis. However, no scoring system had more than 90% consistency between the predicted and actual survival periods. Future perspectives should adopt more oncological viewpoints with adjustment of the process of treatment for metastatic spine tumor. PMID:25035829

  6. The role of peripheral immune cells in the CNS in steady state and disease.

    PubMed

    Prinz, Marco; Priller, Josef

    2017-02-01

    The CNS is protected by the immune system, including cells that reside directly within the CNS and help to ensure proper neural function, as well as cells that traffic into the CNS with disease. The CNS-resident immune system is comprised mainly of innate immune cells and operates under homeostatic conditions. These myeloid cells in the CNS parenchyma and at CNS-periphery interfaces are highly specialized but also extremely plastic cells that immediately react to any changes in CNS homeostasis and become reactive in the context of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease. However, when the blood-brain barrier is impaired during CNS diseases such as multiple sclerosis or altered with cerebral ischemia, peripheral adaptive and innate immune cells, including monocytes, neutrophils, T cells and B cells, can enter the CNS, where they execute distinct cell-mediated effects. On the basis of these observations, we assess strategies for targeting peripheral immune cells to reduce CNS disease burden.

  7. 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.

  8. The exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

    PubMed Central

    Agrahari, Vivek

    2017-01-01

    Delivering therapeutics to the central nervous system (CNS) and brain-tumor has been a major challenge. The current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in providing significant benefits to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB). The BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nanotherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer significant advantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are briefly discussed. The drug transport mechanisms at the BBB are outlined. The approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic approaches for their enhanced clinical application in brain-tumor therapy are discussed.

  9. Modern cerebrospinal fluid analyses for the diagnosis of diffuse large B-cell lymphoma of the CNS.

    PubMed

    Baraniskin, Alexander; Schroers, Roland

    2014-01-01

    CNS lymphomas represent rare and aggressive variants of extranodal non-Hodgkin's lymphomas, which may present with diverse neurological symptoms and are often diagnostically challenging. Primary CNS lymphomas develop within the CNS and characteristically involve the brain, leptomeninges, eyes and, in rare cases, spinal cord. Secondary CNS lymphomas are characterized by expansion of systemic lymphomas to the CNS. Multimodal investigation of cerebrospinal fluid (CSF) comprises an important component of the diagnostic work-up for patients with suspected CNS lymphomas. Cytopathological examination of the CSF is still regarded as the 'gold standard' for the diagnosis of leptomeningeal malignant disease. However, cytopathology has only a low sensitivity in detecting leptomeningeal lymphoma involvement. Modern technologies including proteochemical and immunophenotypic studies by flow cytometry, and molecular genetic analyses of CSF may increase sensitivity and specificity, therefore, facilitating the diagnosis of CNS lymphomas. This review gives an overview and discussion of the current aspects of CSF analyses in CNS lymphomas.

  10. A systematic review of inhaled intranasal therapy for central nervous system neoplasms: an emerging therapeutic option.

    PubMed

    Peterson, Asa; Bansal, Amy; Hofman, Florence; Chen, Thomas C; Zada, Gabriel

    2014-02-01

    The intranasal route for drug delivery is rapidly evolving as a viable means for treating selected central nervous system (CNS) conditions. We aimed to identify studies pertaining to the application of intranasal drug administration for the treatment of primary CNS tumors. A systematic literature review was conducted to identify all studies published in the English language pertaining to intranasal therapy for CNS neoplasms, and/or general mechanisms and pharmacokinetics regarding targeted intranasal CNS drug delivery. A total of 194 abstracts were identified and screened. Thirty-seven studies met inclusion criteria. Of these, 21 focused on intranasal treatment of specific primary CNS tumors, including gliomas (11), meningiomas (1), and pituitary adenomas (4). An additional 16 studies focused on general mechanisms of intranasal therapy and drug delivery to the CNS using copolymer micelles, viral vectors, and nanoparticles. Inhaled compounds/substances investigated included perillyl alcohol, vesicular stomatitis virus, parvovirus, telomerase inhibitors, neural stem and progenitor cells, antimetabolites, somatostatin analogues, and dopamine agonists. Radiolabeling, CSF concentration measurement, imaging studies, and histological examination were utilized to clarify the mechanism and distribution by which drugs were delivered to the CNS. Successful drug delivery and tumor/symptom response was reported in all 21 tumor-specific studies. The intranasal route holds tremendous potential as a viable option for drug delivery for CNS neoplasms. A variety of antitumoral agents may be delivered via this route, thereby potentially offering a more direct delivery approach and ameliorating the adverse effects associated with systemic drug delivery.

  11. Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy

    PubMed Central

    Economopoulou, Panagiota

    2016-01-01

    Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM) represent a frequent complication of non-small cell lung cancer (NSCLC). Patients with BM comprise a heterogeneous group, with a median survival that ranges from 3 to 14 months. However, in the majority of patients, the occurrence of CNS metastases is usually accompanied by severe morbidity and substantial deterioration in quality of life. Local therapies, such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection, either alone or as part of a multimodality treatment are available treatment strategies for BM and the choice of therapy varies depending on patient group and prognosis. Meanwhile, introduction of tyrosine kinase inhibitors (TKIs) in clinical practice has led to individualization of therapy based upon the presence of the exact abnormality, resulting in a major therapeutic improvement in patients with NSCLC who harbor epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene rearrangements, respectively. Based on their clinical activity in systemic disease, such molecular agents could offer the promise of improved BM control without substantial toxicity; however, their role in combination with radiotherapy is controversial. In this review, we discuss the controversy regarding the use of TKIs in combination with radiotherapy and illustrate future perspectives in the treatment of BM in NSCLC. PMID:28149754

  12. 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....

  13. CNS Myelination Requires Cytoplasmic Dynein Function

    PubMed Central

    Yang, Michele L.; Shin, Jimann; Kearns, Christina A.; Langworthy, Melissa M.; Snell, Heather; Walker, Macie B.; Appel, Bruce

    2014-01-01

    Background Cytoplasmic dynein provides the main motor force for minus-end-directed transport of cargo on microtubules. Within the vertebrate central nervous system (CNS), proliferation, neuronal migration and retrograde axon transport are among the cellular functions known to require dynein. Accordingly, mutations of DYNC1H1, which encodes the heavy chain subunit of cytoplasmic dynein, have been linked to developmental brain malformations and axonal pathologies. Oligodendrocytes, the myelinating glial cell type of the CNS, migrate from their origins to their target axons and subsequently extend multiple long processes that ensheath axons with specialized insulating membrane. These processes are filled with microtubules, which facilitate molecular transport of myelin components. However, whether oligodendrocytes require cytoplasmic dynein to ensheath axons with myelin is not known. Results We identified a mutation of zebrafish dync1h1 in a forward genetic screen that caused a deficit of oligodendrocytes. Using in vivo imaging and gene expression analyses, we additionally found evidence that dync1h1 promotes axon ensheathment and myelin gene expression. Conclusions In addition to its well known roles in axon transport and neuronal migration, cytoplasmic dynein contributes to neural development by promoting myelination. PMID:25488883

  14. Astrocyte scar formation aids CNS axon regeneration

    PubMed Central

    Anderson, Mark A.; Burda, Joshua E.; Ren, Yilong; Ao, Yan; O’Shea, Timothy M.; Kawaguchi, Riki; Coppola, Giovanni; Khakh, Baljit S.; Deming, Timothy J.; Sofroniew, Michael V.

    2017-01-01

    Summary Transected axons fail to regrow in the mature central nervous system (CNS). Astrocyte scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or deleting chronic astrocyte scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. In striking contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocyte scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth supporting molecules. Our findings show that contrary to prevailing dogma, astrocyte scar formation aids rather than prevents CNS axon regeneration. PMID:27027288

  15. Activation of the basal cell carcinoma pathway in a patient with CNS HGNET-BCOR diagnosis: consequences for personalized targeted therapy

    PubMed Central

    Russo, Alexandra; Kron, Bettina; Malki, Khalifa El; Lehmann, Nadine; Wingerter, Arthur; Neu, Marie A.; Gerhold-Ay, Aslihan; Wagner, Wolfgang; Sommer, Clemens; Pietsch, Torsten; Seidmann, Larissa; Faber, Jörg

    2016-01-01

    High grade neuroepithelial tumor of the central nervous system with BCOR alteration (CNS HGNET-BCOR) is a recently described new tumor entity with a dismal prognosis. The objective of this study was to identify and validate pathways deregulated in CNS HGNET-BCOR as basis for targeted therapy approaches. We characterized the BCOR alteration in a pediatric patient with CNS HGNET-BCOR diagnosis by Sanger sequencing and demonstrated an elevated BCOR expression by qRT-PCR and western blot. By whole transcriptome sequencing and Ingenuity Pathway Analysis, we identified the activation of the Sonic Hedgehog (SHH) and of the WNT signaling pathway in two different regions of the primary tumor and of one inoculation metastasis compared to normal brain. We validated the activation of the SHH and of the WNT pathway by qRT-PCR analysis of GLI1 and AXIN2 respectively. GLI1 and AXIN2 were upregulated in the primary tumor and in two inoculation metastases compared to normal brain. Mutational analysis of SMO, PTCH1 and SUFU, three key components of the SHH pathway, revealed a Single Nucleotide Polymorphism (SNP) in PTCH1 (rs357564). We tested the effect of the GLI-inhibitor arsenic trioxide (ATO) on a short-term cell culture isolated from the metastasis. ATO was able to reduce the viability of the cells with an IC50 of 1.3 μM. In summary, these results provide functional evidence of altered BCOR expression and homogeneous coactivation of both the SHH and WNT signaling pathways, building the basis for potential novel therapeutic approaches for patients with a CNS HGNET-BCOR diagnosis. PMID:27825128

  16. Craniospinal irradiation using helical tomotherapy for central nervous system tumors.

    PubMed

    Schiopu, Sanziana R I; Habl, Gregor; Häfner, Matthias; Katayama, Sonja; Herfarth, Klaus; Debus, Juergen; Sterzing, Florian

    2017-01-17

    The aim of this study was to describe early and late toxicity, survival and local control in 45 patients with primary brain tumors treated with helical tomotherapy craniospinal irradiation (HT-CSI). From 2006 to 2014, 45 patients with central nervous system malignancies were treated with HT-CSI. The most common tumors were medulloblastoma in 20 patients, ependymoma in 10 patients, intracranial germinoma (ICG) in 7 patients, and primitive neuroectodermal tumor in 4 patients. Hematological toxicity during treatment included leukopenia Grades 1-4 (6.7%, 33.3%, 37.8% and 17.8%, respectively), anemia Grades 1-4 (44.4%, 22.2%, 22.2% and 0%, respectively) and thrombocytopenia Grades 1-4 (51.1%, 15.6%, 15.6% and 6.7%, respectively). The most common acute toxicities were nausea, vomiting, fatigue, loss of appetite, alopecia and neurotoxicity. No Grade 3 or higher late toxicity occurred. The overall 3- and 5-year survival rates were 80% and 70%, respectively. Survival for the main tumor entities included 3- and 5-year survival rates of 80% and 70%, respectively, for patients with medulloblastoma, 70% for both in patients with ependymoma, and 100% for both in patients with ICG. Relapse occurred in 11 patients (24.4%): 10 with local and 1 with multifocal relapse. One patient experienced a secondary cancer. M-status and the results of the re-evaluation at the end of treatment were significantly related to survival. Survival after HT-CSI was in line with the existing literature, and acute treatment-induced toxicity resolved quickly. Compared with conventional radiotherapy, HT offers benefits such as avoiding gaps and junctions, sparing organs, and better and more homogeneous dose distribution and coverage of the target volume.

  17. Mechanisms regulating regional localization of inflammation during CNS autoimmunity

    PubMed Central

    Pierson, Emily; Simmons, Sarah B.; Castelli, Luca; Goverman, Joan M.

    2013-01-01

    Summary Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by inflammatory, demyelinating lesions localized in the brain and spinal cord. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is induced by activating myelin-specific T cells and exhibits immune cell infiltrates in the CNS similar to those seen in MS. Both MS and EAE exhibit disease heterogeneity, reflecting variations in clinical course and localization of lesions within the CNS. Collectively, the differences seen in MS and EAE suggest that the brain and spinal cord function as unique microenvironments that respond differently to infiltrating immune cells. This review addresses the roles of the cytokines interferon-γ and interleukin-17 in determining the localization of inflammation to the brain or spinal cord in EAE. PMID:22725963

  18. 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.

  19. In vivo imaging of the neurovascular unit in CNS disease

    PubMed Central

    Merlini, Mario; Davalos, Dimitrios; Akassoglou, Katerina

    2014-01-01

    The neurovascular unit—comprised of glia, pericytes, neurons and cerebrovasculature—is a dynamic interface that ensures physiological central nervous system (CNS) functioning. In disease dynamic remodeling of the neurovascular interface triggers a cascade of responses that determine the extent of CNS degeneration and repair. The dynamics of these processes can be adequately captured by imaging in vivo, which allows the study of cellular responses to environmental stimuli and cell-cell interactions in the living brain in real time. This perspective focuses on intravital imaging studies of the neurovascular unit in stroke, multiple sclerosis (MS) and Alzheimer disease (AD) models and discusses their potential for identifying novel therapeutic targets. PMID:25197615

  20. 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.

  1. Lapatinib and Obatoclax Kill Tumor Cells through Blockade of ERBB1/3/4 and through Inhibition of BCL-xL and MCL-1

    PubMed Central

    Cruickshanks, Nichola; Hamed, Hossein A.; Bareford, M. Danielle; Poklepovic, Andrew; Fisher, Paul B.; Grant, Steven

    2012-01-01

    Prior studies in breast cancer cells have shown that lapatinib and obatoclax interact in a greater than additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses to the central nervous system (CNS) tumor cells and to further define mechanisms of drug action. Lapatinib and obatoclax killed multiple CNS tumor isolates. Cells lacking PTEN (phosphatase and tensin homolog on chromosome 10) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null cells restored drug sensitivity, and knockdown of PTEN promoted drug resistance. On the basis of knockdown of ERBB1-4 (erythroblastic leukemia viral oncogene homolog 1–4), we discovered that the inhibition of ERBB1/3/4 receptors were most important for enhancing obatoclax lethality rather than ERBB2. In parallel, we noted in CNS tumor cells that knockdown of BCL-xL (B-cell lymphoma-extra large)and MCL-1 (myeloid cell leukemia-1) interacted in an additive fashion to facilitate lapatinib lethality. Pretreatment of tumor cells with obatoclax enhanced the lethality of lapatinib to a greater extent than concomitant treatment. Treatment of animals carrying orthotopic CNS tumor isolates with lapatinib- and obatoclax-prolonged survival. Altogether, our data show that lapatinib and obatoclax therapy could be of use in the treatment of tumors located in the CNS. PMID:22357666

  2. Therapy of leptomeningeal metastasis in solid tumors.

    PubMed

    Mack, F; Baumert, B G; Schäfer, N; Hattingen, E; Scheffler, B; Herrlinger, U; Glas, M

    2016-02-01

    Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.

  3. RNAi therapeutics for CNS disorders.

    PubMed

    Boudreau, Ryan L; Davidson, Beverly L

    2010-06-18

    RNA interference (RNAi) is a process of sequence-specific gene silencing and serves as a powerful molecular tool to manipulate gene expression in vitro and in vivo. RNAi technologies have been applied to study gene function and validate drug targets. Researchers are investigating RNAi-based compounds as novel therapeutics to treat a variety of human diseases that are currently lacking sufficient treatment. To date, numerous studies support that RNAi therapeutics can improve disease phenotypes in various rodent models of human disease. Here, we focus on the development of RNAi-based therapies aimed at treating neurological disorders for which reduction of mutant or toxic gene expression may provide clinical benefit. We review RNAi-based gene-silencing strategies, proof-of-concept studies testing therapeutic RNAi for CNS disorders, and highlight the most recent research aimed at transitioning RNAi-based therapeutics toward clinical trials.

  4. 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.

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

    PubMed

    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

    2016-04-01

    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.

  6. Regulation of immune cell infiltration into the CNS by regional neural inputs explained by the gate theory.

    PubMed

    Arima, Yasunobu; Kamimura, Daisuke; Sabharwal, Lavannya; Yamada, Moe; Bando, Hidenori; Ogura, Hideki; Atsumi, Toru; Murakami, Masaaki

    2013-01-01

    The central nervous system (CNS) is an immune-privileged environment protected by the blood-brain barrier (BBB), which consists of specific endothelial cells that are brought together by tight junctions and tight liner sheets formed by pericytes and astrocytic end-feet. Despite the BBB, various immune and tumor cells can infiltrate the CNS parenchyma, as seen in several autoimmune diseases like multiple sclerosis (MS), cancer metastasis, and virus infections. Aside from a mechanical disruption of the BBB like trauma, how and where these cells enter and accumulate in the CNS from the blood is a matter of debate. Recently, using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found a "gateway" at the fifth lumber cord where pathogenic autoreactive CD4+ T cells can cross the BBB. Interestingly, this gateway is regulated by regional neural stimulations that can be mechanistically explained by the gate theory. In this review, we also discuss this theory and its potential for treating human diseases.

  7. CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.

    PubMed

    Spence, Tara; Sin-Chan, Patrick; Picard, Daniel; Barszczyk, Mark; Hoss, Katharina; Lu, Mei; Kim, Seung-Ki; Ra, Young-Shin; Nakamura, Hideo; Fangusaro, Jason; Hwang, Eugene; Kiehna, Erin; Toledano, Helen; Wang, Yin; Shi, Qing; Johnston, Donna; Michaud, Jean; La Spina, Milena; Buccoliero, Anna Maria; Adamek, Dariusz; Camelo-Piragua, Sandra; Peter Collins, V; Jones, Chris; Kabbara, Nabil; Jurdi, Nawaf; Varlet, Pascale; Perry, Arie; Scharnhorst, David; Fan, Xing; Muraszko, Karin M; Eberhart, Charles G; Ng, Ho-Keung; Gururangan, Sridharan; Van Meter, Timothy; Remke, Marc; Lafay-Cousin, Lucie; Chan, Jennifer A; Sirachainan, Nongnuch; Pomeroy, Scott L; Clifford, Steven C; Gajjar, Amar; Shago, Mary; Halliday, William; Taylor, Michael D; Grundy, Richard; Lau, Ching C; Phillips, Joanna; Bouffet, Eric; Dirks, Peter B; Hawkins, Cynthia E; Huang, Annie

    2014-08-01

    Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

  8. Cytogenetic diversity in primary human tumors.

    PubMed

    Wolman, S R; Camuto, P M; Perle, M A

    1988-02-01

    Cytogenetic patterns from primary short-term culture of breast cancer, renal carcinoma, and tumors of the central nervous system are presented to illustrate the range of karyotypic diversity of human solid tumors as well as their biologic differences in culture systems that support their growth. These studies have illustrated several major issues. 1) Results vary with the tissue of origin: primary cultures from breast are almost uniformly diploid, while renal tumors are near-diploid, mosaic, and show clonal aberrations; and CNS tumors are heterogeneous: some diploid, some near-diploid and some highly aneuploid. 2) Results after short-term culture are selective, representing subpopulations from the heterogeneous cells that are detected on direct analysis of fresh tumors by cytogenetics or flow cytometry (FCM). It is not yet clear whether prognosis depends on the dominant population of the primary tumor or alternatively should be influenced by detection of small aneuploid subpopulations. 3) Evidence from all three tumor types supports the interpretation that cytogenetically normal diploid cells constitute part of some tumor populations, and may be better adapted to routine growth in culture than aneuploid subpopulations from the same primary tumors. These cells may also compose a major portion of the viable population of tumors in vivo and, therefore, could represent a useful model for studies of tumorigenesis and therapeutic regimens.

  9. Viral nanoparticles associate with regions of inflammation and blood brain barrier disruption during CNS infection

    PubMed Central

    Shriver, Leah P.; Koudelka, Kristopher J.; Manchester, Marianne

    2010-01-01

    Targeted treatment of inflammatory diseases of the central nervous system (CNS) remains problematic due to the complex pathogenesis of these disorders and difficulty in drug delivery. The plant virus, cow pea mosaic virus (CPMV), has recently been explored as a nanoparticle delivery system for therapeutics targeting a number of diseases including cancer and neurodegeneration. To understand the biodistribution of CPMV in the CNS, we examined CPMV uptake during infection of mice with neurotropic mouse hepatitis virus (MHV). CPMV localized mainly to the CNS endothelium in areas that contained an intact blood brain barrier. However, in inflammatory lesions containing macrophage/microglial cell infiltration and IgG, CPMV could be detected in the brain parenchyma. Furthermore, CPMV showed rapid internalization in an in vitro model of the BBB. These results suggest that CPMV particles could be used to a vehicle to deliver therapeutics to the damaged CNS during neurodegenerative and infectious diseases of the CNS. PMID:19394707

  10. 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.

  11. Palmitoylethanolamide in CNS health and disease.

    PubMed

    Mattace Raso, Giuseppina; Russo, Roberto; Calignano, Antonio; Meli, Rosaria

    2014-08-01

    The existence of acylethanolamides (AEs) in the mammalian brain has been known for decades. Among AEs, palmitoylethanolamide (PEA) is abundant in the central nervous system (CNS) and conspicuously produced by neurons and glial cells. Antihyperalgesic and neuroprotective properties of PEA have been mainly related to the reduction of neuronal firing and to control of inflammation. Growing evidence suggest that PEA may be neuroprotective during CNS neurodegenerative diseases. Advances in the understanding of the physiology and pharmacology of PEA have potentiated its interest as useful biological tool for disease management. Several rapid non-genomic and delayed genomic mechanisms of action have been identified for PEA as peroxisome proliferator-activated receptor (PPAR)-α dependent. First, an early molecular control, through Ca(+2)-activated intermediate- and/or big-conductance K(+) channels opening, drives to rapid neuronal hyperpolarization. This is reinforced by the increase of the inward Cl(-) currents due to the modulation of the gamma aminobutyric acid A receptor and by the desensitization of the transient receptor potential channel type V1. Moreover, the gene transcription-mediated mechanism sustains the long-term anti-inflammatory effects, by reducing pro-inflammatory enzyme expression and increasing neurosteroid synthesis. Overall, the integration of these different modes of action allows PEA to exert an immediate and prolonged efficacious control in neuron signaling either on inflammatory process or neuronal excitability, maintaining cellular homeostasis. In this review, we will discuss the effect of PEA on metabolism, behavior, inflammation and pain perception, related to the control of central functions and the emerging evidence demonstrating its therapeutic efficacy in several neurodegenerative diseases.

  12. 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.

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

    PubMed Central

    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. PMID:26257732

  14. Embryonal Tumors With Abundant Neuropil and True Rosettes

    PubMed Central

    Gessi, Marco; Giangaspero, Felice; Lauriola, Libero; Gardiman, Marina; Scheithauer, Bernd W.; Halliday, William; Hawkins, Cynthia; Rosenblum, Marc K.; Burger, Peter C.; Eberhart, Charles G.

    2015-01-01

    Embryonal neoplasms of the central nervous system (CNS) generally arise in the early years of life and behave in a clinically aggressive manner, but vary somewhat in their microscopic appearance. Several groups have reported examples of an embryonal tumor with combined histologic features of ependymoblastoma and neuroblastoma, a lesion referred to as “embryonal tumor with abundant neuropil and true rosettes” (ETANTR). Herein, we present 22 new cases, and additional clinical follow-up on our 7 initially reported cases, to better define the histologic features and clinical behavior of this distinctive neoplasm. It affects infants and arises most often in cerebral cortex, the cerebellum and brainstem being less frequent sites. Unlike other embryonal tumors of the CNS, girls are more commonly affected than boys. On neuroimaging, the tumors appear as large, demarcated, solid masses featuring patchy or no contrast enhancement. Five of our cases (18%) were at least partly cystic. Distinctive microscopic features include a prominent background of mature neuropil punctuated by true rosettes formed of pseudo-stratified embryonal cells circumferentially disposed about a central lumen (true rosettes). Of the 25 cases with available follow-up, 19 patients have died, their median survival being 9 months. Performed on 2 cases, cytogenetic analysis revealed extra copies of chromosome 2 in both. We believe that the ETANTR represents a histologically distinctive form of CNS embryonal tumor. PMID:18987548

  15. 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.

  16. Epidemiology of central nervous system tumors in Karlovac area (Croatia), 1995-2010.

    PubMed

    Jancić, Ervin; Cvitanović, Hrvoje; Miholović, Vesna; Kralj, Diana; Hranilović, Biserka

    2011-09-01

    The aim of this study was to provide an overview of the central nervous system (CNS) tumours epidemiology in Karlovac region, over the 1995-2010 period. We analyzed data on 359 patients (194 men and 165 women), diagnosed with CNS tumours according to the World Health Organization's diagnostic criteria, in period 1995-2010. The data were obtained from the Neurology and Neurosurgery Department, including other medical records. The data were analysed with t-test and chi-square test. A total of 359 cases of tumours in CNS were recorded for the period of 1995-2010, with slight predominance of men (194;54.0%) over women (165;46.0%). Under the assumption of gender equality, we did not detect a significant gender difference in tumour diagnosis (p = 0.279). Mean age at the diagnosis was 64.1 +/- 12.6 years, with significant gender difference: mean age at diagnosis for men was 62.8 +/- 11.6 years, while for women it was 65.7 +/- 13.5 (p = 0.029). The commonest type of all tumours was metastases (144;40.1%). When only primary tumours were analysed, the commonest type was glioblastoma (125;58.15%), followed by meningeoma (44;20.5%). The remaining types were much less frequent, with i.e. 5 recorded cases of the following three types: astrocytoma, ependimoma and oligodendroglyoma (2.3%). These results suggest a commonly encountered epidemiological profile in the region, with commonest metastases, and glioblastoma as the most common primary tumour. Due to difficulties related to patient gravitating hospitals admittance and overall small sample size for more detailed analyses, it remains for future studies to determine potential association of the Homeland war (1991-1995) and the occurrence of CNS tumours.

  17. Immunochemotherapy with Intensive Consolidation for Primary CNS Lymphoma: A Pilot Study and Prognostic Assessment by Diffusion-Weighted MRI

    PubMed Central

    Wieduwilt, Matthew J.; Valles, Francisco; Issa, Samar; Behler, Caroline M.; Hwang, James; McDermott, Michael; Treseler, Patrick; O’Brien, Joan; Shuman, Marc A.; Cha, Soonmee; Damon, Lloyd E.; Rubenstein, James L.

    2012-01-01

    Purpose We evaluated a novel therapy for primary central nervous system (CNS) lymphoma (PCNSL) using induction immunochemotherapy with high-dose methotrexate, temozolomide and rituximab (MT-R) followed by intensive consolidation with infusional etoposide and high-dose cytarabine (EA). In addition, we evaluated the prognostic value of the minimum apparent diffusion coefficient (ADCmin) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in patients treated with this regimen. Experimental Design Thirty-one patients (median age, 61; median KPS, 60) received induction with methotrexate every 14 days for 8 planned cycles. Rituximab was administered the first 6 cycles and temozolomide administered on odd-numbered cycles. Patients with responsive or stable CNS disease received EA consolidation. Pretreatment DW-MRI was used to calculate the ADCmin of contrast-enhancing lesions. Results The complete response rate for MT-R induction was 52%. At a median follow-up of 79 months, the 2-year progression-free and overall survival were 45% and 58%, respectively. For patients receiving EA consolidation, the 2-year progression-free and overall survival were 78% and 93%, respectively. EA consolidation was also effective in an additional 3 patients who presented with synchronous CNS and systemic lymphoma. Tumor ADCmin <384 × 10−6 mm2/s was significantly associated with shorter progression-free and overall survival. Conclusions MT-R induction was effective and well-tolerated. MT-R followed by EA consolidation yielded progression-free and overall survival outcomes comparable to regimens using chemotherapy followed by whole-brain radiotherapy consolidation but without evidence of neurotoxicity. Tumor ADCmin derived from DW-MRI provided better prognostic information for PCNSL patients treated with the MTR-EA regimen than established clinical risk scores. PMID:22228634

  18. Discrimination of Different Brain Metastases and Primary CNS Lymphomas Using Morphologic Criteria and Diffusion Tensor Imaging.

    PubMed

    Bette, S; Wiestler, B; Delbridge, C; Huber, T; Boeckh-Behrens, T; Meyer, B; Zimmer, C; Gempt, J; Kirschke, J

    2016-12-01

    Purpose: Brain metastases are a common complication of cancer and occur in about 15 - 40 % of patients with malignancies. The aim of this retrospective study was to differentiate between metastases from different primary tumors/CNS lymphyomas using morphologic criteria, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Materials and Methods: Morphologic criteria such as hemorrhage, cysts, pattern of contrast enhancement and location were reported in 200 consecutive patients with brain metastases/primary CNS lymphomas. FA and ADC values were measured in regions of interest (ROIs) placed in the contrast-enhancing tumor part, the necrosis and the non-enhancing peritumoral region (NEPTR). Differences between histopathological subtypes of metastases were analyzed using non-parametric tests, decision trees and hierarchical clustering analysis. Results: Significant differences were found in morphologic criteria such as hemorrhage or pattern of contrast enhancement. In diffusion measurements, significant differences between the different tumor entities were only found in ADC analyzed in the contrast-enhancing tumor part. Among single tumor entities, primary CNS lymphomas showed significantly lower median ADC values in the contrast-enhancing tumor part (ADClymphoma 0.92 [0.83 - 1.07] vs. ADCno_lymphoma 1.35 [1.10 - 1.64] P = 0.001). Further differentiation between types of metastases was not possible using FA and ADC. Conclusion: There were morphologic differences among the main subtypes of brain metastases/CNS lymphomas. However, due to a high variability of common types of metastases and low specificity, prospective differentiation remained challenging. DTI including FA and ADC was not a reliable tool for differentiation between different histopathological subtypes of brain metastases except for CNS lymphomas showing lower ADC values. Biopsy, surgery and staging remain essential for diagnosis. Key Points:

  19. Delivery of therapeutic peptides and proteins to the CNS.

    PubMed

    Salameh, Therese S; Banks, William A

    2014-01-01

    Peptides and proteins have potent effects on the brain after their peripheral administration, suggesting that they may be good substrates for the development of CNS therapeutics. Major hurdles to such development include their relation to the blood-brain barrier (BBB) and poor pharmacokinetics. Some peptides cross the BBB by transendothelial diffusion and others cross in the blood-to-brain direction by saturable transporters. Some regulatory proteins are also transported across the BBB and antibodies can enter the CNS via the extracellular pathways. Glycoproteins and some antibody fragments can be taken up and cross the BBB by mechanisms related to adsorptive endocytosis/transcytosis. Many peptides and proteins are transported out of the CNS by saturable efflux systems and enzymatic activity in the blood, CNS, or BBB are substantial barriers to others. Both influx and efflux transporters are altered by various substances and in disease states. Strategies that manipulate these interactions between the BBB and peptides and proteins provide many opportunities for the development of therapeutics. Such strategies include increasing transendothelial diffusion of small peptides, upregulation of saturable influx transporters with allosteric regulators and other posttranslational means, use of vectors and other Trojan horse strategies, inhibition of efflux transporters including with antisense molecules, and improvement in pharmacokinetic parameters to overcome short half-lives, tissue sequestration, and enzymatic degradation.

  20. Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma.

    PubMed

    Maurice, Catherine; Schneider, Raphael; Kiehl, Tim-Rasmus; Bavi, Prashant; Roehrl, Michael H A; Mason, Warren P; Hogg, David

    2015-12-01

    Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell-rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors.

  1. Various Tumor-Mimicking Lesions in the Musculoskeletal System: Causes and Diagnostic Approach

    PubMed Central

    Kim, Sue Yon; Ryu, Kyung Nam; Jin, Wook; Park, So Young

    2011-01-01

    Tumor-mimicking lesions in the musculoskeletal system can be defined as lesions mistaken as tumors due to the presence of palpation upon physical examination or a tumor-like appearance upon radiological examination. Moreover, tumor-mimicking lesions show diverse etiologies and anatomic locations. We illustrated the various tumor-mimicking lesions involving bone and soft tissue. In this review, the tumor-mimicking lesions were classified into those based on clinical examination and those based on radiological examination in musculoskeletal radiology. Awareness of the various causes of tumor-mimicking lesions, correctly obtaining clinical information, and the proper selection of imaging modality are important for the differentiation of tumor-mimicking lesions from true neoplasms. PMID:21430940

  2. Mechanisms of tumor escape from immune system: role of mesenchymal stromal cells.

    PubMed

    Poggi, Alessandro; Musso, Alessandra; Dapino, Irene; Zocchi, Maria Raffaella

    2014-01-01

    Tumor microenvironment represents the site where the tumor tries to survive and escape from immune system-mediated recognition. Indeed, to proliferate tumor cells can divert the immune response inducing the generation of myeloid derived suppressor cells and regulatory T cells which can limit the efficiency of effector antitumor lymphocytes in eliminating neoplastic cells. Many components of the tumor microenvironment can serve as a double sword for the tumor and the host. Several types of fibroblast-like cells, which herein we define mesenchymal stromal cells (MSC), secrete extracellular matrix components and surrounding the tumor mass can limit the expansion of the tumor. On the other hand, MSC can interfere with the immune recognition of tumor cells producing immunoregulatory cytokines as transforming growth factor (TGF)ß, releasing soluble ligands of the activating receptors expressed on cytolytic effector cells as decoy molecules, affecting the correct interaction among lymphocytes and tumor cells. MSC can also serve as target for the same anti-tumor effector lymphocytes or simply impede the interaction between these lymphocytes and neoplastic cells. Thus, several evidences point out the role of MSC, both in epithelial solid tumors and hematological malignancies, in regulating tumor cell growth and immune response. Herein, we review these evidences and suggest that MSC can be a suitable target for a more efficient anti-tumor therapy.

  3. From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery.

    PubMed

    Banks, William A

    2016-04-01

    One of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders is achieving sufficient blood-brain barrier (BBB) penetration. Research in the past few decades has revealed that the BBB is not only a substantial barrier for drug delivery to the CNS but also a complex, dynamic interface that adapts to the needs of the CNS, responds to physiological changes, and is affected by and can even promote disease. This complexity confounds simple strategies for drug delivery to the CNS, but provides a wealth of opportunities and approaches for drug development. Here, I review some of the most important areas that have recently redefined the BBB and discuss how they can be applied to the development of CNS therapeutics.

  4. 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

  5. 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

  6. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4.

    PubMed

    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

    2015-02-01

    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.

  7. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy.

    PubMed

    Zamarin, Dmitriy; Holmgaard, Rikke B; Subudhi, Sumit K; Park, Joon Seok; Mansour, Mena; Palese, Peter; Merghoub, Taha; Wolchok, Jedd D; Allison, James P

    2014-03-05

    Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, we explored the immunotherapeutic potential of oncolytic Newcastle disease virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses, leading to lymphocytic infiltrates and antitumor effect in distant (nonvirally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4(+) and CD8(+) T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in the clinic.

  8. Electrophoretic deposition of cellulose nanocrystals (CNs) and CNs/alginate nanocomposite coatings and free standing membranes.

    PubMed

    Chen, Qiang; de Larraya, Uxua Pérez; Garmendia, Nere; Lasheras-Zubiate, María; Cordero-Arias, Luis; Virtanen, Sannakaisa; Boccaccini, Aldo R

    2014-06-01

    This study presents the electrophoretic deposition (EPD) of cellulose nanocrystals (CNs) and CNs-based alginate composite coatings for biomedical applications. The mechanism of anodic deposition of CNs and co-deposition of CNs/alginate composites was analyzed based on the results of zeta-potential, Fourier transform infrared spectroscopy and scanning electron microscopy (SEM) analyses. The capability of the EPD technique for manipulating the orientation of CNs and for the preparation of multilayer CNs coatings was demonstrated. The nanotopographic surface roughness and hydrophilicity of the deposited coatings were measured and discussed. Electrochemical testing demonstrated that a significant degree of corrosion protection of stainless steel could be achieved when CNs-containing coatings were present. Additionally, the one-step EPD-based processing of free-standing CNs/alginate membranes was demonstrated confirming the versatility of EPD to fabricate free-standing membrane structures compared to a layer-by-layer deposition technique. CNs and CNs/alginate nanocomposite coatings produced by EPD are potential candidates for biomedical, cell technology and drug delivery applications.

  9. 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....

  10. 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....

  11. Tumor Types: Understanding Brain Tumors

    MedlinePlus

    ... Resources Tools & Publications Tumor Types: Understanding Brain Tumors World Health Organization (WHO) Updates Official Classification of Tumors ... Central Nervous System On May 9, 2016, the World Health Organization (WHO) published an official reclassification of ...

  12. CNS Schwann cells display oligodendrocyte precursor-like potassium channel activation and antigenic expression in vitro.

    PubMed

    Kegler, Kristel; Imbschweiler, Ilka; Ulrich, Reiner; Kovermann, Peter; Fahlke, Christoph; Deschl, Ulrich; Kalkuhl, Arno; Baumgärnter, Wolfgang; Wewetzer, Konstantin

    2014-06-01

    Central nervous system (CNS) injury triggers production of myelinating Schwann cells from endogenous oligodendrocyte precursors (OLPs). These CNS Schwann cells may be attractive candidates for novel therapeutic strategies aiming to promote endogenous CNS repair. However, CNS Schwann cells have been so far mainly characterized in situ regarding morphology and marker expression, and it has remained enigmatic whether they display functional properties distinct from peripheral nervous system (PNS) Schwann cells. Potassium channels (K+) have been implicated in progenitor and glial cell proliferation after injury and may, therefore, represent a suitable pharmacological target. In the present study, we focused on the function and expression of voltage-gated K+ channels Kv(1-12) and accessory β-subunits in purified adult canine CNS and PNS Schwann cell cultures using electrophysiology and microarray analysis and characterized their antigenic phenotype. We show here that K+ channels differed significantly in both cell types. While CNS Schwann cells displayed prominent K D-mediated K+ currents, PNS Schwann cells elicited K(D-) and K(A-type) K+ currents. Inhibition of K+ currents by TEA and Ba2+ was more effective in CNS Schwann cells. These functional differences were not paralleled by differential mRNA expression of Kv(1-12) and accessory β-subunits. However, O4/A2B5 and GFAP expressions were significantly higher and lower, respectively, in CNS than in PNS Schwann cells. Taken together, this is the first evidence that CNS Schwann cells display specific properties not shared by their peripheral counterpart. Both Kv currents and increased O4/A2B5 expression were reminiscent of OLPs suggesting that CNS Schwann cells retain OLP features during maturation.

  13. Modeling subspecies and the tumor-immune system interaction: Steps toward understanding therapy

    NASA Astrophysics Data System (ADS)

    Menchón, S. A.; Ramos, R. A.; Condat, C. A.

    2007-12-01

    A mesoscopic nutrient competition model for cancer growth is generalized to describe the growth of a heterogeneous tumor and the interactions between the tumor and the immune system. Our simulations show that the success of a mutation depends not only on its intrinsic competitive advantages, but also on its location in the tumor mass. It is also shown that the simple killing of tumor cells by immune cells, even when their activity is increased by therapy, is not sufficient to stem tumor growth, but another mechanism (such as pinning) is needed for a successful therapy.

  14. 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

  15. Synthetic Tumor Networks for Screening Drug Delivery Systems

    PubMed Central

    Prabhakarpandian, Balabhaskar; Shen, Ming-Che; Nichols, Joseph B.; Garson, Charles J.; Mills, Ivy R.; Matar, Majed M.; Fewell, Jason G.; Pant, Kapil

    2015-01-01

    Tumor drug delivery is a complex phenomenon affected by several elements in addition to drug or delivery vehicle’s physico-chemical properties. A key factor is tumor microvasculature with complex effects including convective transport, high interstitial pressure and enhanced vascular permeability due to the presence of “leaky vessels”. Current in vitro models of the tumor microenvironment for evaluating drug delivery are oversimplified and, as a result, show poor correlation with in vivo performance. In this study, we report on the development of a novel microfluidic platform that models the tumor microenvironment more accurately, with physiologically and morphologically realistic microvasculature including endothelial cell lined leaky capillary vessels along with 3D solid tumors. Endothelial cells and 3D spheroids of cervical tumor cells were co-cultured in the networks. Drug vehicle screening was demonstrated using GFP gene delivery by different formulations of nanopolymers. The synthetic tumor network was successful in predicting in vivo delivery efficiencies of the drug vehicles. The developed assay will have critical applications both in basic research, where it can be used to develop next generation delivery vehicles, and in drug discovery where it can be used to study drug transport and delivery efficacy in realistic tumor microenvironment, thereby enabling drug compound and/or delivery vehicle screening. PMID:25599856

  16. Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors

    PubMed Central

    Nikiforova, Marina N.; Wald, Abigail I.; Melan, Melissa A.; Roy, Somak; Zhong, Shan; Hamilton, Ronald L.; Lieberman, Frank S.; Drappatz, Jan; Amankulor, Nduka M.; Pollack, Ian F.; Nikiforov, Yuri E.; Horbinski, Craig

    2016-01-01

    Background Identification of genetic changes in CNS tumors is important for the appropriate clinical management of patients. Our objective was to develop a next-generation sequencing (NGS) assay for simultaneously detecting the various types of genetic alterations characteristic for adult and pediatric CNS tumors that can be applied to small brain biopsies. Methods We report an amplification-based targeted NGS assay (GlioSeq) that analyzes 30 genes for single nucleotide variants (SNVs) and indels, 24 genes for copy number variations (CNVs), and 14 types of structural alterations in BRAF, EGFR, and FGFR3 genes in a single workflow. GlioSeq performance was evaluated in 54 adult and pediatric CNS tumors, and the results were compared with fluorescence in-situ hybridization, Sanger sequencing, and reverse transcription PCR. Results GlioSeq correctly identified 71/71 (100%) genetic alterations known to be present by conventional techniques, including 56 SNVs/indels, 9 CNVs, 3 EGFRvIII, and 3 KIAA1549-BRAF fusions. Only 20 ng of DNA and 10 ng of RNA were required for successful sequencing of 100% frozen and 96% formalin-fixed, paraffin-embedded tissue specimens. The assay sensitivity was 3%–5% of mutant alleles for SNVs and 1%–5% for gene fusions. The most commonly detected alterations were IDH1, TP53, TERT, ATRX. CDKN2A, and PTEN in high-grade gliomas, followed by BRAF fusions in low-grade gliomas and H3F3A mutations in pediatric gliomas. Conclusions GlioSeq NGS assay offers accurate and sensitive detection of a wide range of genetic alterations in a single workflow. It allows rapid and cost-effective profiling of brain tumor specimens and thus provides valuable information for patient management. PMID:26681766

  17. [Immunotherapy of tumors of the central nervous system].

    PubMed

    Monod, L; Sawamura, Y; De Tribolet, N

    1992-01-01

    Malignant brain tumors are rapidly fatal and adjunction of chemo- and radio-therapy to surgical treatment has little changed their poor prognosis. The development of basic and clinical research in immunology of brain tumors has lead to new therapeutic strategies: 1) Humoral factors: Monoclonal antibodies (MAbs): alone or conjugated (to toxins, radionucleides or chemotherapeutic agents), MAbs can theoretically recognize antigens expressed by tumor cells and reach this target with high specificity. Large amounts of tumoricidal agents could be given to the tumor with low toxic effects to normal tissues. 2) Cellular factors: LAK cells: (lymphokine-activated-killer-cells) and activated TILs (tumor-infiltrating-lymphocytes) are autologous cytotoxic cells which can be produced by ex-vivo culture techniques and infused to the patient. These are very potent tumor-killer cells in vitro, however their in vivo effect is far less dramatic at the moment. 3) Cytokines: interferons, interleukins and other biological modifiers can act either directly on the tumor cells (cytotoxic effect) or indirectly through the modulation of the host-to-tumor response. 4) Combination of humoral and cellular factors: bispecific monoclonal antibodies are hybrid-molecules built from two different MAbs which can recognize two different targets, usually a tumor antigen on one hand and the T-cell-receptor (T 3) on the other hand. This combination of humoral and cellular effectors can theoretically lead to a preferential binding of effector cells to the tumor. All these new techniques are extensively studied in research laboratories and clinical trials without clear therapeutical benefit for the moment.

  18. Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis

    PubMed Central

    Daneman, Richard; Agalliu, Dritan; Zhou, Lu; Kuhnert, Frank; Kuo, Calvin J.; Barres, Ben A.

    2009-01-01

    Despite the importance of CNS blood vessels, the molecular mechanisms that regulate CNS angiogenesis and blood−brain barrier (BBB) formation are largely unknown. Here we analyze the role of Wnt/β-catenin signaling in regulating the formation of CNS blood vessels. First, through the analysis of TOP-Gal Wnt reporter mice, we identify that canonical Wnt/β-catenin signaling is specifically activated in CNS, but not non-CNS, blood vessels during development. This activation correlates with the expression of different Wnt ligands by neural progenitor cells in distinct locations throughout the CNS, including Wnt7a and Wnt7b in ventral regions and Wnt1, Wnt3, Wnt3a, and Wnt4 in dorsal regions. Blockade of Wnt/β-catenin signaling in vivo specifically disrupts CNS, but not non-CNS, angiogenesis. These defects include reduction in vessel number, loss of capillary beds, and the formation of hemorrhagic vascular malformations that remain adherent to the meninges. Furthermore, we demonstrate that Wnt/β-catenin signaling regulates the expression of the BBB-specific glucose transporter glut-1. Taken together these experiments reveal an essential role for Wnt/β-catenin signaling in driving CNS-specific angiogenesis and provide molecular evidence that angiogenesis and BBB formation are in part linked. PMID:19129494

  19. Pathological and Clinical Features and Management of Central Nervous System Hemangioblastomas in von Hippel-Lindau Disease

    PubMed Central

    Kobayashi, Natsuki; Nakanowatari, Satoshi

    2014-01-01

    Central nervous system (CNS) hemangioblastoma is the most common manifestation of von Hippel-Lindau (VHL) disease. It is found in 70–80% of VHL patients. Hemangioblastoma is a rare form of benign vascular tumor of the CNS, accounting for 2.0% of CNS tumors. It can occur sporadically or as a familial syndrome. CNS hemangioblastomas are typically located in the posterior fossa and the spinal cord. VHL patients usually develop a CNS hemangioblastoma at an early age. Therefore, they require a special routine for diagnosis, treatment and follow-up. The surgical management of symptomatic tumors depend on many factors such as symptom, location, multiplicity, and progression of the tumor. The management of asymptomatic tumors in VHL patients are controversial since CNS hemangioblastomas grow with intermittent quiescent and rapid-growth phases. Preoperative embolization of large solid hemangioblastomas prevents perioperative hemorrhage but is not necessary in every case. Radiotherapy should be reserved for inoperable tumors. Because of complexities of VHL, a better understanding of the pathological and clinical features of hemangioblastoma in VHL is essential for its proper management. PMID:28326249

  20. An improved MRI guided ultrasound system for superficial tumor hyperthermia

    NASA Astrophysics Data System (ADS)

    Zhu, Mengyuan; Shen, Guofeng; Su, Zhiqiang; Chen, Sheng; Wu, Hao

    2017-03-01

    Among many methods in tumor treatment, ultrasound hyperthermia is characterized by non-invasiveness, and it has been proven very effective for clinical treatment. But the problem of monitoring temperature limits its development. MRI-based temperature mapping techniques are safe compared with invasive methods and have been applied to detect temperature changes for a variety of applications. Among these techniques, the proton resonance frequency (PRF) method is relatively advanced. With a temperature measuring experiment and experiment conducted on tumors inside rabbit legs, the effectiveness of PRF method has been proved. This paper is to introduce an MRI guided ultrasound superficial tumor hyperthermia instrument based on PRF method.

  1. User Incorporation of Tumor Registry Function within a Commercially Available Medical Information System

    PubMed Central

    Wei, Yee-Tyz; Cook, Bridgette A.; Casagrande, John T.; Bass, Adrianne Black

    1987-01-01

    This paper describes the incorporation of hospital tumor registry function within a computerized information system, The Medical Record (TMR), in a comprehensive cancer center. All required data items are stored in the TMR database and the items range from standard demographic data captured at registration through tumor registry specific items entered by the tumor registrar. User written programs are described for the generation of hard copy abstracts, automated follow-up letters and special statistical reports. To our knowledge, this is the first implementation of tumor registry function incorporated into a vendor supplied information system by a user.

  2. CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy.

    PubMed

    Foran, Emily; Kwon, Deborah Y; Nofziger, Jonathan H; Arnold, Eveline S; Hall, Matthew D; Fischbeck, Kenneth H; Burnett, Barrington G

    2016-04-01

    The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. We sought to determine if we could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. In cultured cells we show that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. This correlated with increased SMN protein levels and improved survival and motor function of SMA mice. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier.

  3. 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.

  4. 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

  5. A Philosophy for CNS Radiotracer Design

    PubMed Central

    2015-01-01

    Conspectus 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

  6. A philosophy for CNS radiotracer design

    DOE PAGES

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

    2014-10-01

    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 pitfallsmore » 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

  7. A philosophy for CNS radiotracer design

    SciTech Connect

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

    2014-10-01

    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

  8. Leptin and the CNS Control of Glucose Metabolism

    PubMed Central

    Morton, Gregory J.; Schwartz, Michael W.

    2012-01-01

    The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system (CNS) plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders. PMID:21527729

  9. 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

  10. 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

  11. Sports and childhood brain tumors: Can I play?

    PubMed Central

    Perreault, Sébastien; Lober, Robert M.; Davis, Carissa; Stave, Christopher; Partap, Sonia; Fisher, Paul G.

    2014-01-01

    Background It is unknown whether children with brain tumors have a higher risk of complications while participating in sports. We sought to estimate the prevalence of such events by conducting a systematic review of the literature, and we surveyed providers involved with pediatric central nervous system (CNS) tumor patients. Methods A systematic review of the literature in the PubMed, Scopus, and Cochrane databases was conducted for original articles addressing sport-related complications in the brain-tumor population. An online questionnaire was created to survey providers involved with pediatric CNS tumor patients about their current recommendations and experience regarding sports and brain tumors. Results We retrieved 32 subjects, including 19 pediatric cases from the literature. Most lesions associated with sport complications were arachnoid cysts (n = 21), followed by glioma (n = 5). The sports in which symptom onset most commonly occurred were soccer (n = 7), football (n = 5), and running (n = 5). We surveyed 111 pediatric neuro-oncology providers. Sport restriction varied greatly from none to 14 sports. Time to return to play in sports with contact also varied considerably between providers. Rationales for limiting sports activities were partly related to subspecialty. Responders reported 9 sport-related adverse events in patients with brain tumor. Conclusions Sport-related complications are uncommon in children with brain tumors. Patients might not be at a significantly higher risk and should not need to be excluded from most sports activities. PMID:26034627

  12. The Potential of the CNS as a Reservoir for HIV-1 Infection: Implications for HIV Eradication.

    PubMed

    Fois, Alessandro F; Brew, Bruce J

    2015-06-01

    The ability of HIV-1 to establish latent infection is a key obstacle to its eradication despite the existence of effective antiretroviral drugs. The brain has been postulated as a reservoir for latent infection, but its role in HIV persistence remains unclear. In this review, we discuss the evidence surrounding the role of the central nervous system (CNS) as a viral reservoir and the potential challenges this might present in eradicating HIV. The strategies for eradication of HIV and their application to latent CNS infection are explored. Finally, we outline new developments in drug delivery and new therapeutic modalities designed to target HIV infection in the CNS.

  13. Fatal lymphomatoid granulomatosis with primary CNS-involvement in an immunocompetent 80-year-old woman

    PubMed Central

    Olmes, David G; Agaimy, Abbas; Kloska, Stephan; Linker, Ralf A

    2014-01-01

    An 80-year-old woman presented with weight loss, fatigue, dizziness and a brain stem lesion. Extensive work-up revealed lymphomatoid granulomatosis (LYG) with primary clinical manifestation in the central nervous system (CNS), a rare Epstein-Barr virus-driven multisystem lymphoproliferative disorder, to be causative for the symptoms. Immunochemotherapy consisting of rituximab and temozolomide was started, but the disease progressed and the patient subsequently died. Histology, diagnostic criteria, differential diagnosis and treatment options for LYG with CNS involvement are discussed. This case demonstrates that LYG with CNS involvement may necessitate more aggressive treatment approaches than combination therapy with rituximab and temozolomide. PMID:25535225

  14. 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

  15. Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

    ClinicalTrials.gov

    2016-12-28

    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

  16. 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.

  17. 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.

  18. Apoptosis in the mammalian CNS: Lessons from animal models.

    PubMed

    Lossi, L; Cantile, C; Tamagno, I; Merighi, A

    2005-07-01

    It is generally assumed that about half of the neurons produced during neurogenesis die before completion of maturation of the central nervous system (CNS). Neural cell death is also relevant in aging and several neurodegenerative diseases. Among the modalities by which neurons die, apoptosis has very much attracted the interest of investigators because in this type of cell death neurons are actively responsible for their own demise by switching on a number of genes and activating a series of specific intracellular pathways. This review focuses on the cellular and molecular mechanisms of apoptosis in normal and transgenic animal models related to naturally occurring neuronal death within the CNS. We will also consider some examples of apoptotic cell death in canine neuropathologies. A thorough analysis of naturally occurring neuronal death in vivo will offer a basis for parallel and future studies involving secondary neuronal loss such as those in neurodegenerative disorders, trauma or ischaemia.

  19. Histone regulation in the CNS: basic principles of epigenetic plasticity.

    PubMed

    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.

  20. 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

  1. 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

  2. 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

  3. Additional value of hybrid SPECT/CT systems in neuroendocrine tumors, adrenal tumors, pheochromocytomas and paragangliomas.

    PubMed

    Wong, K K; Chondrogiannis, S; Fuster, D; Ruiz, C; Marzola, M C; Giammarile, F; Colletti, P M; Rubello, D

    The aim of this review was to evaluate the potential advantages of SPECT/CT hybrid imaging in the management of neuroendocrine tumors, adrenal tumors, pheochromocytomas and paragangliomas. From the collected data, the superiority of fused images was observed as providing both functional/molecular and morphological imaging compared to planar imaging. This provided an improvement in diagnostic imaging, with significant advantages as regards: (1) precise locating of the lesions; (2) an improvement in characterization of the findings, resulting higher specificity, improved sensitivity, and overall greater accuracy, (3) additional anatomical information derived from the CT component; (4) CT-based attenuation correction and potential for volumetric dosimetry calculations, and (5) improvement on the impact on patient management (e.g. in better defining treatment plans, in shortening surgical operating times). It can be concluded that SPECT/CT hybrid imaging provides the nuclear medicine physician with a powerful imaging modality in comparison to planar imaging, providing essential information about the location of lesions, and high quality homogeneous images.

  4. Behavior of parasite specific effector CD8+ T cells in the CNS and visualization of a kinesis-associated system of reticular fibers

    PubMed Central

    Wilson, Emma H.; Harris, Tajie H.; Mrass, Paulus; John, Beena; Tait, Elia D.; Wu, Gregory F.; Pepper, Marion; John Wherry, E.; Dzierzinski, Florence; Roos, David; Haydon, Philip G.; Laufer, Terri M.; Weninger, Wolfgang; Hunter, Christopher A.

    2009-01-01

    Summary To understand lymphocyte behavior in the brain, 2-photon microscopy was used to visualize effector CD8+ T cells during toxoplasmic encephalitis. These cells displayed multiple behaviors with two distinct populations of cells apparent: one with a constrained pattern of migration versus a highly migratory subset. The proportion of these populations varied over time associated with changes in antigen availability as well as T cell expression of the inhibitory receptor PD1. Unexpectedly, the movement of infiltrating cells was closely associated with an infection-induced reticular system of fibers. This observation suggests that, whereas in other tissues there are pre-existing scaffolds that guide lymphocyte migration, in the brain specialized structures are induced by inflammation that guide migration of T cells in this immune-privileged environment. PMID:19167248

  5. Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development

    PubMed Central

    Kosmac, Kate; Bantug, Glenn R.; Pugel, Ester P.; Cekinovic, Djurdjica; Jonjic, Stipan; Britt, William J.

    2013-01-01

    Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV. PMID:23505367

  6. 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

    2016-05-05

    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.

  7. Role of Academic Drug Discovery in the Quest for New CNS Therapeutics.

    PubMed

    Yokley, Brian H; Hartman, Matthew; Slusher, Barbara S

    2017-03-15

    There was a greater than 50% decline in central nervous system (CNS) drug discovery and development programs by major pharmaceutical companies from 2009 to 2014. This decline was paralleled by a rise in the number of university led drug discovery centers, many in the CNS area, and a growth in the number of public-private drug discovery partnerships. Diverse operating models have emerged as the academic drug discovery centers adapt to this changing ecosystem.

  8. 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

  9. 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

  10. Mechanisms of CNS invasion and damage by parasites.

    PubMed

    Kristensson, Krister; Masocha, Willias; Bentivoglio, Marina

    2013-01-01

    Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection.

  11. 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

  12. Ecrg4 expression and its product augurin in the choroid plexus: impact on fetal brain development, cerebrospinal fluid homeostasis and neuroprogenitor cell response to CNS injury

    PubMed Central

    2011-01-01

    Background The content and composition of cerebrospinal fluid (CSF) is determined in large part by the choroid plexus (CP) and specifically, a specialized epithelial cell (CPe) layer that responds to, synthesizes, and transports peptide hormones into and out of CSF. Together with ventricular ependymal cells, these CPe relay homeostatic signals throughout the central nervous system (CNS) and regulate CSF hydrodynamics. One new candidate signal is augurin, a newly recognized 14 kDa protein that is encoded by esophageal cancer related gene-4 (Ecrg4), a putative tumor suppressor gene whose presence and function in normal tissues remains unexplored and enigmatic. The aim of this study was to explore whether Ecrg4 and its product augurin, can be implicated in CNS development and the response to CNS injury. Methods Ecrg4 gene expression in CNS and peripheral tissues was studied by in situ hybridization and quantitative RT-PCR. Augurin, the protein encoded by Ecrg4, was detected by immunoblotting, immunohistochemistry and ELISA. The biological consequence of augurin over-expression was studied in a cortical stab model of rat CNS injury by intra-cerebro-ventricular injection of an adenovirus vector containing the Ecrg4 cDNA. The biological consequences of reduced augurin expression were evaluated by characterizing the CNS phenotype caused by Ecrg4 gene knockdown in developing zebrafish embryos. Results Gene expression and immunohistochemical analyses revealed that, the CP is a major source of Ecrg4 in the CNS and that Ecrg4 mRNA is predominantly localized to choroid plexus epithelial (CPe), ventricular and central canal cells of the spinal cord. After a stab injury into the brain however, both augurin staining and Ecrg4 gene expression decreased precipitously. If the loss of augurin was circumvented by over-expressing Ecrg4 in vivo, BrdU incorporation by cells in the subependymal zone decreased. Inversely, gene knockdown of Ecrg4 in developing zebrafish embryos caused

  13. On Study of Immune Response to Tumor Cells in Prey-Predator System.

    PubMed

    Kaur, Gurpreet; Ahmad, Naseem

    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.

  14. 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

  15. 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…

  16. [Chemotherapy of brain tumors in aduts].

    PubMed

    Roth, P; Weller, M

    2015-04-01

    The treatment of patients with brain tumors has long been the domain of neurosurgery and radiotherapy but chemotherapy is now well established as an additional treatment option for many tumor entities in neuro-oncology. This is particularly true for patients with newly diagnosed and relapsing glioblastoma and anaplastic glioma as well as the treatment of medulloblastoma and primary lymphoma of the central nervous system (CNS). In addition to purely histopathological features, treatment decisions including those for chemotherapy are now based increasingly more on molecular tumor profiling. Within the group of gliomas these markers include the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and the 1p/19q status, which reflects the loss of genetic material on chromosome arms 1p and 19q. The presence of a 1p/19q codeletion is associated with a better prognosis and increased sensitivity to alkylating chemotherapy in patients with anaplastic gliomas.

  17. Targeting blood–brain barrier changes during inflammatory pain: an opportunity for optimizing CNS drug delivery

    PubMed Central

    Ronaldson, Patrick T; Davis, Thomas P

    2012-01-01

    The blood–brain barrier (BBB) is the most significant obstacle to effective CNS drug delivery. It possesses structural and biochemical features (i.e., tight-junction protein complexes and, influx and efflux transporters) that restrict xenobiotic permeation. Pathophysiological stressors (i.e., peripheral inflammatory pain) can alter BBB tight junctions and transporters, which leads to drug-permeation changes. This is especially critical for opioids, which require precise CNS concentrations to be safe and effective analgesics. Recent studies have identified molecular targets (i.e., endogenous transporters and intracellular signaling systems) that can be exploited for optimization of CNS drug delivery. This article summarizes current knowledge in this area and emphasizes those targets that present the greatest opportunity for controlling drug permeation and/or drug transport across the BBB in an effort to achieve optimal CNS opioid delivery. PMID:22468221

  18. Cilia in the CNS: the Quiet Organelle Claims Center Stage

    PubMed Central

    Louvi, Angeliki; Grove, Elizabeth A.

    2011-01-01

    Summary The primary cilium is a cellular organelle that is almost ubiquitous in eukaryotes, yet its functions in vertebrates have been slow to emerge. The last fifteen years have been marked by accelerating insight into the biology of primary cilia, arising from the synergy of three major lines of research. These research programs describe a specialized mode of protein trafficking in cilia, reveal that genetic disruptions of primary cilia cause complex human disease syndromes, and establish that Sonic hedgehog (Shh) signal transduction requires the primary cilium. New lines of research have branched off to investigate the role of primary cilia in neuronal signaling, adult neurogenesis, and brain tumor formation. We review a fast expanding literature to determine what we now know about the primary cilium in the developing and adult CNS, and what new directions should lead to further clarity. PMID:21435552

  19. 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.

  20. Papillary glioneuronal tumor--a new tumor entity.

    PubMed

    Broholm, H; Madsen, F F; Wagner, A A; Laursen, H

    2002-01-01

    Glioneuronal neoplasms of the CNS comprises a heterogeneous group of generally low-grade tumors expressing glial and neuronal cells of varying differentiation. Recently, a new variant of the glioneuronal tumors has been identified. We present a case of a glioneuronal tumor located in the left frontal lobe of a 16-year-old boy who developed seizures 6 months after brain concussion. MR scan demonstrated an irregular, but well circumscribed, mixed cystic and solid tumor with contrast enhancement in the solid part. Histology showed a papillary glioneuronal tumor. The tumor is indolent with no sign of recurrence after gross total resection.

  1. 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

  2. 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.

  3. Orally Administered Bifidobacteria as Vehicles for Delivery of Agents to Systemic Tumors

    PubMed Central

    Cronin, Michelle; Morrissey, David; Rajendran, Simon; El Mashad, Shereen M; van Sinderen, Douwe; O'Sullivan, Gerald C; Tangney, Mark

    2010-01-01

    Certain bacteria have emerged as biological gene vectors with natural tumor specificity, capable of specifically delivering genes or gene products to the tumor environment when intravenously (i.v.) administered to rodent models. We show for the first time that oral administration of bacteria to mice resulted in their translocation from the gastrointestinal tract (GIT) with subsequent homing to and replication specifically in tumors. The commensal, nonpathogenic Bifidobacterium breve UCC2003 harboring a plasmid expressing lux fed to mice bearing subcutaneous (s.c.) tumors were readily detected specifically in tumors, by live whole-body imaging, at levels similar to i.v. administration. Reporter gene expression was visible for >2 weeks in tumors. Mice remained healthy throughout experiments. Cytokine analyses indicated a significant upregulation of interferon-γ (IFN-γ) in the GIT of bifidobacteria-fed mice, which is associated with increases in epithelial permeability. However, B. breve feeding did not increase systemic levels of other commensal bacteria. The presence of tumor was not necessary for translocation to systemic organs to occur. These findings indicate potential for safe and efficient gene-based treatment and/or detection of tumors via ingestion of nonpathogenic bacteria expressing therapeutic or reporter genes. PMID:20389288

  4. Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors

    PubMed Central

    Senzer, Neil; Nemunaitis, John; Nemunaitis, Derek; Bedell, Cynthia; Edelman, Gerald; Barve, Minal; Nunan, Robert; Pirollo, Kathleen F; Rait, Antonina; Chang, Esther H

    2013-01-01

    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. PMID:23609015

  5. Absence of regulation of tumor cholesterogenesis in cell-free synthesizing systems

    SciTech Connect

    Azrolan, N.; Coleman, P.S.

    1986-05-01

    In tumors, cholesterol synthesis de novo is deregulated relative to normal tissues. But no previous study has demonstrated the decontrol of tumor cholesterogenesis with cell-free cytosolic systems. They have utilized a lipid synthesizing, post-mitochondrial supernatant system (PMS), with /sup 14/C-citrate as substrate, to characterize the cholesterogenic pathway in Morris Hepatoma 3924A and normal rat liver. The rate of cholesterogenesis in the hepatoma PMS was 6-fold higher than that in the liver system on a per cell basis. The ratio of sterol-to-fatty acid synthesis was also significantly greater in the tumor versus the liver PMS. The authors determined the steady-state carbon flux through the early intermediates of the lipogenic pathways. Whereas the liver system displayed a metabolic crossover point at the HMG-CoA reductase reaction, the hepatoma system showed no evidence of control at this rate-limiting site of sterol synthesis. Furthermore, acetyl-CoA formation from added citrate (via ATP-citrate lyase) exhibited rates of 42% and 88% in excess of that required for lipidogenesis by liver and tumor PMS systems, respectively. Clearly, a cell-free PMS system from tumor tissue displays the property of deregulated lipidogenesis, especially cholesterol biosynthesis. The authors suggest that deregulated and continuously operating cholesterogenesis would provide for an increased level of a mevalonate-derived sterol pathway intermediate proposed as a trigger for DNA synthesis and cell proliferation in tumors.

  6. Role of the immune system in the peritoneal tumor spread of high grade serous ovarian cancer.

    PubMed

    Auer, Katharina; Bachmayr-Heyda, Anna; Sukhbaatar, Nyamdelger; Aust, Stefanie; Schmetterer, Klaus G; Meier, Samuel M; Gerner, Christopher; Grimm, Christoph; Horvat, Reinhard; Pils, Dietmar

    2016-09-20

    The immune system plays a critical role in cancer progression and overall survival. Still, it is unclear if differences in the immune response are associated with different patterns of tumor spread apparent in high grade serous ovarian cancer patients and previously described by us. In this study we aimed to assess the role of the immune system in miliary (widespread, millet-sized lesions) and non-miliary (bigger, exophytically growing implants) tumor spread. To achieve this we comprehensively analyzed tumor tissues, blood, and ascites from 41 patients using immunofluorescence, flow cytometry, RNA sequencing, multiplexed immunoassays, and immunohistochemistry. Results showed that inflammation markers were systemically higher in miliary. In contrast, in non-miliary lymphocyte and monocyte/macrophage infiltration into the ascites was higher as well as the levels of PD-1 expression in tumor associated cytotoxic T-lymphocytes and PD-L1 expression in tumor cells. Furthermore, in ascites of miliary patients more epithelial tumor cells were present compared to non-miliary, possibly due to the active down-regulation of anti-tumor responses by B-cells and regulatory T-cells. Summarizing, adaptive immune responses prevailed in patients with non-miliary spread, whereas in patients with miliary spread a higher involvement of the innate immune system was apparent while adaptive responses were counteracted by immune suppressive cells and factors.

  7. Role of the immune system in the peritoneal tumor spread of high grade serous ovarian cancer

    PubMed Central

    Auer, Katharina; Bachmayr-Heyda, Anna; Sukhbaatar, Nyamdelger; Aust, Stefanie; Schmetterer, Klaus G.; Meier, Samuel M.; Gerner, Christopher; Grimm, Christoph; Horvat, Reinhard; Pils, Dietmar

    2016-01-01

    The immune system plays a critical role in cancer progression and overall survival. Still, it is unclear if differences in the immune response are associated with different patterns of tumor spread apparent in high grade serous ovarian cancer patients and previously described by us. In this study we aimed to assess the role of the immune system in miliary (widespread, millet-sized lesions) and non-miliary (bigger, exophytically growing implants) tumor spread. To achieve this we comprehensively analyzed tumor tissues, blood, and ascites from 41 patients using immunofluorescence, flow cytometry, RNA sequencing, multiplexed immunoassays, and immunohistochemistry. Results showed that inflammation markers were systemically higher in miliary. In contrast, in non-miliary lymphocyte and monocyte/macrophage infiltration into the ascites was higher as well as the levels of PD-1 expression in tumor associated cytotoxic T-lymphocytes and PD-L1 expression in tumor cells. Furthermore, in ascites of miliary patients more epithelial tumor cells were present compared to non-miliary, possibly due to the active down-regulation of anti-tumor responses by B-cells and regulatory T-cells. Summarizing, adaptive immune responses prevailed in patients with non-miliary spread, whereas in patients with miliary spread a higher involvement of the innate immune system was apparent while adaptive responses were counteracted by immune suppressive cells and factors. PMID:27665539

  8. 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.

  9. 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

  10. Combining radiation and immunotherapy: a new systemic therapy for solid tumors?

    PubMed

    Tang, Chad; Wang, Xiaohong; Soh, Hendrick; Seyedin, Steven; Cortez, Maria Angelica; Krishnan, Sunil; Massarelli, Erminia; Hong, David; Naing, Aung; Diab, Adi; Gomez, Daniel; Ye, Huiping; Heymach, John; Komaki, Ristuko; Allison, James P; Sharma, Padmanee; Welsh, James W

    2014-09-01

    With the recent success of checkpoint inhibitors and other immunomodulating agents, there has been renewed interest in the combination of such agents with radiation. The biologic premise behind such a strategy is that the tumor-antigen release achieved by localized radiation will promote specific tumor targeting by the adaptive immune system, which can be augmented further by systemic immune-stimulating agents. In this manner, clinicians hope to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field. Herein, we present a comprehensive overview of the early clinical and preclinical evidence behind this approach.

  11. 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.

  12. 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)

  13. New mouse tumor model system (RIF-1) for comparison of end-point studies

    SciTech Connect

    Twentyman, P.R.; Brown, J.M.; Gray, J.W.; Franko, A.J.; Scoles, M.A.; Kallman, R.F.

    1980-03-01

    A new tumor model system (RIF-1) was developed that is very suitable for studies in which clonogenic survival is compared with growth delay and control probability following various forms of treatment. The tumor was a radiation-induced sarcoma in the inbred female C3H/Km mouse. It had a low median tumor dose, had a satisfactory plating efficiency direct from in vivo to in vitro, was nonimmunogenic or minimally immunogenic, and metastasized only at a relatively advanced stage of growth. The cell line grew either as a monolayer on plastic dishes, as tumor spheroids in spinner culture, as lung nodules following injection of a single-cell suspension into the tall veins of syngeneic mice, or as a solid tumor. Both diploid and tetraploid clonogenic cells were found in monolayer cultures of the RIF-1 line.

  14. 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

  15. The therapeutic potential of targeting the PI3K pathway in pediatric brain tumors.

    PubMed

    Rogers, Hazel A; Estranero, Jasper; Gudka, Keshni; Grundy, Richard G

    2017-01-10

    Central nervous system tumors are the most common cancer type in children and the leading cause of cancer related deaths. There is therefore a need to develop novel treatments. Large scale profiling studies have begun to identify alterations that could be targeted therapeutically, including the phosphoinositide 3-kinase (PI3K) signaling pathway, which is one of the most commonly activated pathways in cancer with many inhibitors under clinical development. PI3K signaling has been shown to be aberrantly activated in many pediatric CNS neoplasms. Pre-clinical analysis supports a role for PI3K signaling in the control of tumor growth, survival and migration as well as enhancing the cytotoxic effects of current treatments. Based on this evidence agents targeting PI3K signaling have begun to be tested in clinical trials of pediatric cancer patients. Overall, targeting the PI3K pathway presents as a promising strategy for the treatment of pediatric CNS tumors. In this review we examine the genetic alterations found in the PI3K pathway in pediatric CNS tumors and the pathological role it plays, as well as summarizing the current pre-clinical and clinical data supporting the use of PI3K pathway inhibitors for the treatment of these tumors.

  16. 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.

  17. T Model of Growth and its Application in Systems of Tumor-Immune Dynamics

    PubMed Central

    Tabatabai, Mohammad A.; Eby, Wayne M.; Singh, Karan P.; Bae, Sejong

    2015-01-01

    In this paper we introduce a new growth model called T growth model. This model is capable of representing sigmoidal growth as well as biphasic growth. This dual capability is achieved without introducing additional parameters. The T model is useful in modeling cellular proliferation or regression of cancer cells, stem cells, bacterial growth and drug dose-response relationships. We recommend usage of the T growth model for the growth of tumors as part of any system of differential equations. Use of this model within a system will allow more flexibility in representing the natural rate of tumor growth. For illustration, we examine some systems of tumor-immune interaction in which the T growth rate is applied. We also apply the model to a set of tumor growth data. PMID:23906156

  18. Systemic interleukin 2 therapy for human prostate tumors in a nude mouse model.

    PubMed

    Triest, J A; Grignon, D J; Cher, M L; Kocheril, S V; Montecillo, E J; Talati, B; Tekyi-Mensah, S; Pontes, J E; Hillman, G G

    1998-08-01

    Once the regional lymph nodes become involved in prostate carcinoma, 85% of patients develop distant metastases within 5 years, and metastatic disease is difficult to treat. We have investigated the effect of systemic interleukin 2 (IL-2) treatment on metastatic prostate carcinoma using a xenograft tumor model. Cells from a PC-3/IF cell line, produced by intrafemoral injection of human PC-3 prostate carcinoma cells, were injected in the prostate of Balb/c nude mice. Prostate tumors and para-aortic lymph nodes were resected, and tumor cells were recultured and passaged in the prostate in vivo to produce new cell lines. On day 6 following prostatic injection of these cell lines, mice were treated with i.p. injections of IL-2 at 25,000-50,000 units/ day for 5 consecutive days. The effect of IL-2 on tumor progression was assessed, and histological studies were performed on prostate tumor and lymph node sections. The tumor cell lines generated by serial prostate injection were tumorigenic and metastasized to regional para-aortic lymph nodes. Tumors of 0.4 cm were obtained by day 16 and grew to 1-1.5 cm by day 40 with metastasis to para-aortic lymph nodes. Following two to three weekly courses of 5 days of 25,000-40,000 units/day of IL-2, the growth of prostate tumors was inhibited by 94%. Higher doses of 50,000 units/ day were toxic. Histologically, prostate sections showed vascular damage manifested by multifocal hemorrhages and an influx of lymphocytes and polymorphonuclear cells into disintegrating tumors and areas of necrosis containing numerous apoptotic cells. In contrast to control mice, para-aortic lymph nodes were not enlarged in responding mice. These findings suggest that systemic IL-2 therapy can induce an antitumor response in prostate tumors and control their growth and metastasis.

  19. 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

  20. 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.

  1. Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network.

    PubMed

    Xu, Xiaohua; Warrington, Arthur E; Bieber, Allan J; Rodriguez, Moses

    2011-07-01

    Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies. By taking spinal cord injury, cerebral ischaemia and degenerative CNS disorders as examples for CNS repair, we discuss progress and potential problems in utilizing embryonic stem cells and adult neural/non-neural stem cells to repair cell loss in the CNS. Nevertheless, CNS repair is not simply a matter of cell transplantation. The major challenge is to induce regenerating neural cells to integrate into the neural network and compensate for damaged neural function. The neural cells confront an environment very different from that of the developmental stage in which these cells differentiate to form interwoven networks. During the repair process, one of the challenges is neurodegeneration, which can develop from interrupted innervations to/from the targets, chronic inflammation, ischaemia, aging or idiopathic neural toxicity. Neurodegeneration, which occurs on the basis of a characteristic vascular and neural web, usually presents as a chronically progressive process with unknown aetiology. Currently, there is no effective treatment to stop or slow down neurodegeneration. Pathological changes from patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis indicate a broken homeostasis in the CNS. We discuss how the blood-brain barrier and neural networks are formed to maintain CNS homeostasis and their contribution to neurodegeneration in diseased conditions. Another challenge is that some inhibitors produced by CNS injury do not facilitate the regenerating neural cells to incorporate into a pre-existing network. We review glial responses to CNS injury. Of note, the reactive astrocytes

  2. The Involvement of the Myelin-Associated Inhibitors and Their Receptors in CNS Plasticity and Injury.

    PubMed

    Boghdadi, Anthony G; Teo, Leon; Bourne, James A

    2017-02-22

    The limited capacity for the central nervous system (CNS) to repair itself was first described over 100 years ago by Spanish neuroscientist Ramon Y. Cajal. However, the exact mechanisms underlying this failure in neuronal regeneration remain unclear and, as such, no effective therapeutics yet exist. Numerous studies have attempted to elucidate the biochemical and molecular mechanisms that inhibit neuronal repair with increasing evidence suggesting that several inhibitory factors and repulsive guidance cues active during development actually persist into adulthood and may be contributing to the inhibition of repair. For example, in the injured adult CNS, there are various inhibitory factors that impede the outgrowth of neurites from damaged neurons. One of the most potent of these neurite outgrowth inhibitors is the group of proteins known as the myelin-associated inhibitors (MAIs), present mainly on the membranes of oligodendroglia. Several studies have shown that interfering with these proteins can have positive outcomes in CNS injury models by promoting neurite outgrowth and improving functional recovery. As such, the MAIs, their receptors, and downstream effectors are valid drug targets for the treatment of CNS injury. This review will discuss the current literature on MAIs in the context of CNS development, plasticity, and injury. Molecules that interfere with the MAIs and their receptors as potential candidates for the treatment of CNS injury will additionally be introduced in the context of preclinical and clinical trials.

  3. Protective Autoimmunity: A Unifying Model for the Immune Network Involved in CNS Repair.

    PubMed

    Schwartz, Michal; Raposo, Catarina

    2014-08-01

    Immune activity in the CNS parenchyma under various acute and chronic neurodegenerative conditions has been often interpreted as a sign of pathological inflammation. The apparent resemblance of the local neuroinflammatory processes to autoimmune diseases, such as multiple sclerosis (MS), generated the view that, despite differences in etiology and pathology, neurodegenerative disorders with a local inflammatory component can benefit from systemic anti-inflammatory therapy. In addition, as CNS self-reactive T cells are associated with the etiology of MS, autoimmunity was assumed to solely reflect pathology, and therefore, was universally linked to autoimmune disease. Yet, it is becoming increasingly clear that CNS-specific T cells, along with circulating and local innate immune cells, can enhance CNS healing processes following non-infectious injuries, or any deviation from homeostasis, including chronic pathological conditions. Here, we discuss the theory of "protective autoimmunity," which describes the activity of an immune cell network encompassing effector and regulatory T cells with specificity for CNS antigens, in CNS maintenance and repair. Such an immune network, evoked in response to external and internal threats, functions in a tightly regulated way, ensuring restoration of the brain's equilibrium and return to homeostasis.

  4. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND.

    PubMed

    Gaskill, Peter J; Calderon, Tina M; Coley, Jacqueline S; Berman, Joan W

    2013-06-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70 % of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers.

  5. CNS infections in Greenland: A nationwide register-based cohort study

    PubMed Central

    Nordholm, Anne Christine; Søborg, Bolette; Andersson, Mikael; Hoffmann, Steen; Skinhøj, Peter; Koch, Anders

    2017-01-01

    Background Indigenous Arctic people suffer from high rates of infectious diseases. However, the burden of central nervous system (CNS) infections is poorly documented. This study aimed to estimate incidence rates and mortality of CNS infections among Inuits and non-Inuits in Greenland and in Denmark. Methods We conducted a nationwide cohort study using the populations of Greenland and Denmark 1990–2012. Information on CNS infection hospitalizations and pathogens was retrieved from national registries and laboratories. Incidence rates were estimated as cases per 100,000 person-years. Incidence rate ratios were calculated using log-linear Poisson-regression. Mortality was estimated using Kaplan-Meier curves and Log Rank test. Results The incidence rate of CNS infections was twice as high in Greenland (35.6 per 100,000 person years) as in Denmark (17.7 per 100,000 person years), but equally high among Inuits in Greenland and Denmark (38.2 and 35.4, respectively). Mortality from CNS infections was 2 fold higher among Inuits (10.5%) than among non-Inuits (4.8%) with a fivefold higher case fatality rate in Inuit toddlers. Conclusion Overall, Inuits living in Greenland and Denmark suffer from twice the rate of CNS infections compared with non-Inuits, and Inuit toddlers carried the highest risk of mortality. Further studies regarding risk factors such as genetic susceptibility, life style and socioeconomic factors are warranted. PMID:28158207

  6. 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.

  7. The utility of MIB-1/Ki-67 immunostaining in the evaluation of central nervous system neoplasms.

    PubMed

    Prayson, Richard A

    2005-05-01

    The diagnosis and assignment of grade in neoplasms of the central nervous system (CNS), for the most part, are morphologically based and predicated on the interpretation of descriptions of what the phenotypic findings are for a particular tumor type. Not surprisingly, the application of various grading systems in CNS neoplasia has been limited somewhat by interobserver variability. Since assignment of grade and tumor type is the basis upon which therapeutic intervention is grounded, investigators have been searching for ancillary means by which morphologically based systems can be improved. Utilization of cell proliferation markers in the evaluation of tumors can be potentially useful in this endeavor. This review focuses on issues surrounding the utilization of MIB-1 or Ki-67 antibody in the evaluation of CNS neoplasms.

  8. Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system

    PubMed Central

    Telesca, Donato Alessandro; Ruggiero, Simona; Russo, Teresa; Amato, Maurizio; Bianco, Tommaso; Amato, Bruno; Formisano, Cesare; Avellino, Manuela; Napolitano, Vincenzo

    2016-01-01

    Abstract The authors evaluated the role of endoscopic techniques in the diagnosis and in the potential treatment of neuroendocrine tumors (NET) localized in the gastro-entero-pancreatic system, on the basis of their experience and of the international literature. NET are rare tumors that arise from neuroendocrine cells of the gastrointestinal tract and pancreas. It is a possibility that both the digestive endoscopy and EUS play an important role in the diagnosis, staging and surveillance of this disease. In some cases, especially in the early stages, surgical endoscopy allows the treatment of such tumors. PMID:28352822

  9. 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.

  10. Decellularization technology in CNS tissue repair.

    PubMed

    Wang, Hui; Lin, Xian-Feng; Wang, Li-Ren; Lin, Yi-Qian; Wang, Jiang-Tao; Liu, Wen-Yue; Zhu, Gui-Qi; Braddock, Martin; Zhong, Ming; Zheng, Ming-Hua

    2015-05-01

    Decellularization methodologies have been successfully used in a variety of tissue engineering and regenerative technologies and methods of decellularization have been developed for target tissues and organs of interest. The technology to promote regeneration and functional recovery in the CNS, including brain and spinal cord, has, however, made slow progress mainly because the intrinsic regenerative potential of the CNS is regarded as low. To date, currently available therapies have been unable to provide significant functional recovery and successful therapies, which could provide functional restoration to the injured brain and spinal cord are controversial. In this review, the authors provide a critical analysis, comparing the advantages and limitations of the major decellularization methods and considering the effects of these methods upon the biologic scaffold material. The authors also review studies that supplement decellularized grafts with exogenous factors, such as stem cells and growth factors, to both promote and enhance regeneration through decellularized allografts.

  11. Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth

    PubMed Central

    Al-Jamal, Khuloud T.; Al-Jamal, Wafa’ T.; Akerman, Simon; Podesta, Jennifer E.; Yilmazer, Açelya; Turton, John A.; Bianco, Alberto; Vargesson, Neil; Kanthou, Chryso; Florence, Alexander T.; Tozer, Gillian M.; Kostarelos, Kostas

    2010-01-01

    This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G6) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems. PMID:20150514

  12. From naturally-occurring neurotoxic agents to CNS shuttles for drug delivery.

    PubMed

    Soddu, Elena; Rassu, Giovanna; Giunchedi, Paolo; Sarmento, Bruno; Gavini, Elisabetta

    2015-07-10

    Central nervous system (CNS) diseases are hard to diagnose and therapeutically target due to the blood brain barrier (BBB), which prevents most drugs from reaching their sites of action within the CNS. Brain drug delivery systems were conceived to bypass the BBB and were derived from anatomical and functional analysis of the BBB; this analysis led researchers to take advantage of brain endothelial membrane physiology to allow drug access across the BBB. Both receptors and carriers can be used to transport endogenous and exogenous substances into the CNS. Combining a drug with substances that take advantage of these internalization mechanisms is a widely exploited strategy for drug delivery because it is an indirect method that overcomes the BBB in a non-invasive way and is therefore less dangerous and costly than invasive methods. Neurotoxins, among other naturally-occurring substances, may be used as drug carriers to specifically target the CNS. This review covers the current delivery systems that take advantage of the non-toxic components of neurotoxins to overcome the BBB and reach the CNS. We hope to give insights to researchers toward developing new delivery systems that exploit the positive features of substances usually regarded as natural hazards.

  13. [Application Progress of CRISPR/Cas9 System for Gene Editing in Tumor Research].

    PubMed

    Liu, Chao; Li, Zhiwei; Zhang, Yanqiao

    2015-09-20

    TCRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR-associated nuclease 9) gene editing system is a new type of gene editing technology developed based on the immune mechanism of archaea resisting the invasion of exogenous nucleic acid. Compared with traditional gene editing system, CRISPR/Cas9 system is more efficient, easier operating, and less cytotoxic. Currently, CRISPR/Cas9 gene editing technology has been applied to many aspects of cancer research, including research on cancer genes, constructing animal tumor models, screening tumor resistance-associated and phenotypic-related genes and cancer gene therapy. In this review, the application of the CRISPR/Cas9 system in tumor research were introduced.

  14. 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

  15. 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.

  16. Plant Derived Phytocompound, Embelin in CNS Disorders: A Systematic Review.

    PubMed

    Kundap, Uday P; Bhuvanendran, Saatheeyavaane; Kumari, Yatinesh; Othman, Iekhsan; Shaikh, Mohd Farooq

    2017-01-01

    A Central nervous system (CNS) disease is the one which affects either the spinal cord or brain and causing neurological or psychiatric complications. During the nineteenth century, modern medicines have occupied the therapy for many ailments and are widely used these days. Herbal medicines have often maintained popularity for historical and cultural reasons and also considered safer as they originate from natural sources. Embelin is a plant-based benzoquinone which is the major active constituent of the fruits of Embelia ribes Burm. It is an Indo-Malaysian species, extensively used in various traditional medicine systems for treating various diseases. Several natural products including quinone derivatives, which are considered to possess better safety and efficacy profile, are known for their CNS related activity. The bright orange hydroxybenzoquinone embelin-rich fruits of E. ribes have become popular in ethnomedicine. The present systematic review summarizes the effects of embelin on central nervous system and related diseases. A PRISMA model for systematic review was utilized for search. Various electronic databases such as Pubmed, Springer, Scopus, ScienceDirect, and Google Scholar were searched between January 2000 and February 2016. Based on the search criteria for the literature, 13 qualified articles were selected and discussed in this review. The results of the report showed that there is a lack of translational research and not a single study was found in human. This report gives embelin a further way to be explored in clinical trials for its safety and efficacy.

  17. Plant Derived Phytocompound, Embelin in CNS Disorders: A Systematic Review

    PubMed Central

    Kundap, Uday P.; Bhuvanendran, Saatheeyavaane; Kumari, Yatinesh; Othman, Iekhsan; Shaikh, Mohd. Farooq

    2017-01-01

    A Central nervous system (CNS) disease is the one which affects either the spinal cord or brain and causing neurological or psychiatric complications. During the nineteenth century, modern medicines have occupied the therapy for many ailments and are widely used these days. Herbal medicines have often maintained popularity for historical and cultural reasons and also considered safer as they originate from natural sources. Embelin is a plant-based benzoquinone which is the major active constituent of the fruits of Embelia ribes Burm. It is an Indo-Malaysian species, extensively used in various traditional medicine systems for treating various diseases. Several natural products including quinone derivatives, which are considered to possess better safety and efficacy profile, are known for their CNS related activity. The bright orange hydroxybenzoquinone embelin-rich fruits of E. ribes have become popular in ethnomedicine. The present systematic review summarizes the effects of embelin on central nervous system and related diseases. A PRISMA model for systematic review was utilized for search. Various electronic databases such as Pubmed, Springer, Scopus, ScienceDirect, and Google Scholar were searched between January 2000 and February 2016. Based on the search criteria for the literature, 13 qualified articles were selected and discussed in this review. The results of the report showed that there is a lack of translational research and not a single study was found in human. This report gives embelin a further way to be explored in clinical trials for its safety and efficacy. PMID:28289385

  18. Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

    PubMed

    Decrock, Elke; De Bock, Marijke; Wang, Nan; Bultynck, Geert; Giaume, Christian; Naus, Christian C; Green, Colin R; Leybaert, Luc

    2015-08-01

    The central nervous system (CNS) is composed of a highly heterogeneous population of cells. Dynamic interactions between different compartments (neuronal, glial, and vascular systems) drive CNS function and allow to integrate and process information as well as to respond accordingly. Communication within this functional unit, coined the neuro-glio-vascular unit (NGVU), typically relies on two main mechanisms: direct cell-cell coupling via gap junction channels (GJCs) and paracrine communication via the extracellular compartment, two routes to which channels composed of transmembrane connexin (Cx) or pannexin (Panx) proteins can contribute. Multiple isoforms of both protein families are present in the CNS and each CNS cell type is characterized by a unique Cx/Panx portfolio. Over the last two decades, research has uncovered a multilevel platform via which Cxs and Panxs can influence different cellular functions within a tissue: (1) Cx GJCs enable a direct cell-cell communication of small molecules, (2) Cx hemichannels and Panx channels can contribute to autocrine/paracrine signaling pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as cell-cell adhesion, interactions with the cytoskeleton, and the activation of intracellular signaling pathways. In this paper, we discuss current knowledge on their multifaceted contribution to brain development and to specific processes in the NGVU, including synaptic transmission and plasticity, glial signaling, vasomotor control, and blood-brain barrier integrity in the mature CNS. By highlighting both physiological and pathological conditions, it becomes evident that Cxs and Panxs can play a dual role in the CNS and that an accurate fine-tuning of each signaling mechanism is crucial for normal CNS physiology.

  19. Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair.

    PubMed

    Sharma, Aruna; Menon, Preeti; Muresanu, Dafin F; Ozkizilcik, Asya; Tian, Z Ryan; Lafuente, José V; Sharma, Hari S

    2016-01-01

    The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.

  20. Recognition of tumors by the innate immune system and natural killer cells

    PubMed Central

    Marcus, Assaf; Gowen, Benjamin G.; Thompson, Thornton W.; Iannello, Alexandre; Ardolino, Michele; Deng, Weiwen; Wang, Lin; Shifrin, Nataliya; Raulet, David H.

    2014-01-01

    In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells, particularly NK cells and other immune cells that express germline-encoded receptors that are often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression are summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion of some of the implications of the various findings with respect to possibly therapeutic approaches. PMID:24507156

  1. Recognition of tumors by the innate immune system and natural killer cells.

    PubMed

    Marcus, Assaf; Gowen, Benjamin G; Thompson, Thornton W; Iannello, Alexandre; Ardolino, Michele; Deng, Weiwen; Wang, Lin; Shifrin, Nataliya; Raulet, David H

    2014-01-01

    In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells. In particular, we focus on NK cells and other immune cells that express germline-encoded receptors, often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression is summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell-surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion on some of the implications of the various findings with respect to possible therapeutic approaches.

  2. Curcumin loaded NLC induces histone hypoacetylation in the CNS after intraperitoneal administration in mice.

    PubMed

    Puglia, Carmelo; Frasca, Giuseppina; Musumeci, Teresa; Rizza, Luisa; Puglisi, Giovanni; Bonina, Francesco; Chiechio, Santina

    2012-06-01

    The natural p300-specific histone acetyltransferase (HAT) inhibitor, curcumin (CUR), has been widely investigated for its potential therapeutic effect as an anticancer and anti-inflammatory agent. Notwithstanding this interesting pharmacological profile, CUR shows some drawbacks, such as poor absorption and a very fast metabolism and elimination, that limit its clinical use. Aim of the present study was to formulate CUR loaded nanostructured lipid carriers (NLC-CUR) in order to improve the bioavailability and stability of this compound after systemic administration with increased effects in the central nervous system (CNS). NLC-CUR were prepared and characterized on their physicochemical properties by PCS and DSC analyses. Thus, NLC-CUR were systemically injected and the effects in the CNS were compared with a CUR control formulation containing 0.05% DMSO (DMSO-CUR). Our results demonstrate that CUR is able to decrease histone acetylation in the CNS when included in NLCs. Western blot analysis shows that intraperitoneal injection of NLC-CUR (100mg/kg) in mice induces a marked hypoacetylation of histone 4 (H4) at lysine 12 (K12) in the spinal cord compared with control group. Notably, DMSO-CUR (100mg/kg) did not change the H4K12 acetylation level in the CNS. Our study suggests a novel approach to ameliorate the pharmacokinetics of CUR that allows a better permeation in the CNS.

  3. 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 Central

    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. PMID:26766908

  4. Separable Transition Density in the Hybrid Model for Tumor-Immune System Competition

    PubMed Central

    Cattani, Carlo; Ciancio, Armando

    2012-01-01

    A hybrid model, on the competition tumor cells immune system, is studied under suitable hypotheses. The explicit form for the equations is obtained in the case where the density function of transition is expressed as the product of separable functions. A concrete application is given starting from a modified Lotka-Volterra system of equations. PMID:22291853

  5. 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

  6. Etiologic theories of idiopathic scoliosis: neurodevelopmental concept of maturational delay of the CNS body schema ("body-in-the-brain").

    PubMed

    Burwell, R G; Freeman, B J C; Dangerfield, P H; Aujla, R K; Cole, A A; Kirby, A S; Polak, F; Pratt, R K; Webb, J K; Moulton, A

    2006-01-01

    Several workers consider that the etiology of adolescent idiopathic scoliosis (AIS) involves undetected neuromuscular dysfunction. During normal development the central nervous system (CNS) has to adapt to the rapidly growing skeleton of adolescence, and in AIS to developing spinal asymmetry from whatever cause. Examination of evidence from (1) anomalous extra-spinal left-right skeletal length asymmetries, (2) growth velocity and curve progression, and (3) the CNS body schema, parietal lobe and temporoparietal junction, led us to propose a new etiologic concept namely of delay in maturation of the CNS body schema during adolescence. In particular, the development of an early AIS deformity at a time of rapid spinal growth the association of CNS maturational delay results in the CNS attempting to balance a lateral spinal deformity in a moving upright trunk that is larger than the information on personal space (self) already established in the brain by that time of development. It is postulated that the CNS maturational delay allows scoliosis curve progression to occur - unless the delay is temporary when curve progression would cease. The putative maturational delay in the CNS body schema may arise (1) from impaired sensory input: (2) primarily in the brain; and/or (3) from impaired motor output. Oxidative stress with lipid peroxidation in the nervous system may be involved in some patients. The concept brings together many findings relating AIS to the nervous and musculo-skeletal systems and suggests brain morphometric studies in subjects with progressive AIS.

  7. Combined CNS and pituitary involvement as a primary manifestation of Wegener granulomatosis.

    PubMed

    Spísek, Radek; Kolouchová, Elena; Jensovský, Jirí; Rusina, Robert; Fendrych, Pavel; Plas, Jaroslav; Bartůnková, Jirina

    2006-09-01

    Wegener granulomatosis (WG) is a systemic vasculitis of small and medium vessels. It predominantly affects the upper and/or lower respiratory airway and kidneys. Its pathogenesis is not fully understood. WG relatively frequently affects the nervous system (in 30-50% according to the different studies). Most frequently, it manifests as necrotizing vasculitis that leads to the peripheral neuropathies or to the cranial nerves palsy. Impairment of the central nervous system (CNS) is less frequent and occurs in 2-8% of patients. Three major pathogenetic mechanisms were described: CNS vasculitis, spreading of granulomas from the adjacent anatomical areas (paranasal cavities, orbit etc.), and new formation of granulomas in brain tissue. This case report describes patients in whom WG manifested in the form of localized skin involvement and combined CNS involvement that included pituitary gland. Atypical presentation of WG impedes and slows down the process of diagnosis and emphasizes the need for collaboration between medical specialists.

  8. 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.

  9. 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.

  10. 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.

  11. Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS.

    PubMed

    Silva, Gabriel A

    2008-12-10

    Nanotechnologies are materials and devices that have a functional organization in at least one dimension on the nanometer (one billionth of a meter) scale, ranging from a few to about 100 nanometers. Nanoengineered materials and devices aimed at biologic applications and medicine in general, and neuroscience in particular, are designed fundamentally to interface and interact with cells and their tissues at the molecular level. One particularly important area of nanotechnology application to the central nervous system (CNS) is the development of technologies and approaches for delivering drugs and other small molecules such as genes, oligonucleotides, and contrast agents across the blood brain barrier (BBB). The BBB protects and isolates CNS structures (i.e. the brain and spinal cord) from the rest of the body, and creates a unique biochemical and immunological environment. Clinically, there are a number of scenarios where drugs or other small molecules need to gain access to the CNS following systemic administration, which necessitates being able to cross the BBB. Nanotechnologies can potentially be designed to carry out multiple specific functions at once or in a predefined sequence, an important requirement for the clinically successful delivery and use of drugs and other molecules to the CNS, and as such have a unique advantage over other complimentary technologies and methods. This brief review introduces emerging work in this area and summarizes a number of example applications to CNS cancers, gene therapy, and analgesia.

  12. Immune privilege of the CNS is not the consequence of limited antigen sampling

    PubMed Central

    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

    2014-01-01

    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. PMID:24651727

  13. Treatment of the lacrimal excretory system after resection of medial canthal and eyelid tumors.

    PubMed

    Older, J J

    1979-06-01

    A simplified method of lacrimal excretory system repair is presented. If part of a canaliculus is resected during removal of an eyelid tumor, the remaining section of the canaliculus can be exteriorized to the lacrimal lake. A silicone tube is threaded into the canaliculus and allowed to remain in place for one to two weeks. If both canaliculi and the common canaliculus are removed during resection for a medial canthal tumor, a silicone tube can be threaded into the nasolacrimal duct and brought out the area of the medial canthal angle. Conjunctiva which is wrapped around the tube can then form a new drainage canal into the remainder of the lacrimal excretory system.

  14. International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading.

    PubMed

    Louis, David N; Perry, Arie; Burger, Peter; Ellison, David W; Reifenberger, Guido; von Deimling, Andreas; Aldape, Kenneth; Brat, Daniel; Collins, V Peter; Eberhart, Charles; Figarella-Branger, Dominique; Fuller, Gregory N; Giangaspero, Felice; Giannini, Caterina; Hawkins, Cynthia; Kleihues, Paul; Korshunov, Andrey; Kros, Johan M; Beatriz Lopes, M; Ng, Ho-Keung; Ohgaki, Hiroko; Paulus, Werner; Pietsch, Torsten; Rosenblum, Marc; Rushing, Elisabeth; Soylemezoglu, Figen; Wiestler, Otmar; Wesseling, Pieter

    2014-09-01

    Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.

  15. 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.

  16. The proinflammatory cytokine network: interactions in the CNS and blood of rhesus monkeys.

    PubMed

    Reyes, T M; Coe, C L

    1998-01-01

    Proinflammatory cytokines [interleukin (IL)-1 and -6 and tumor necrosis factor-alpha] function within a complex network, stimulating the release of one another, as well as other cytokine agonists and antagonists. These interactions have not been as widely studied in vivo. Therefore, the following studies measured cytokines in blood and cerebrospinal fluid (CSF) from juvenile rhesus monkeys after intravenous administration of cytokines. IL-1 alpha and IL-1 beta were equally effective in elevating blood levels of IL-6. In contrast, IL-1 beta was the only cytokine that significantly elevated IL-6 levels in the CSF. Interestingly, both IL-1 and IL-6 increased levels of IL-1 receptor antagonist in the blood and comparably stimulated the release of cortisol. A second study confirmed that the IL-1-induced IL-6 in CSF was brain derived and not a result of diffusion from blood. This research extends studies of the cytokine cascade to the central nervous system (CNS), highlighting the brain response to peripheral activation.

  17. Enzyme-induced and tumor-targeted drug delivery system based on multifunctional mesoporous silica nanoparticles.

    PubMed

    Cheng, Yin-Jia; Luo, Guo-Feng; Zhu, Jing-Yi; Xu, Xiao-Ding; Zeng, Xuan; Cheng, Dong-Bing; Li, You-Mei; Wu, Yan; Zhang, Xian-Zheng; Zhuo, Ren-Xi; He, Feng

    2015-05-06

    Functional mesoporous silica particles have attracted growing research interest for controlled drug delivery in targeted cancer therapy. For the purpose of efficient targeting tumor cells and reducing the adverse effect of antitumor drug doxorubicin (DOX), biocompatible and enzyme-responsive mesoporous silica nanoparticles (MSNs) with tumor specificity were desired. To construct these functional MSNs, the classic rotaxane structure formed between alkoxysilane tether and α-cyclodextrin (α-CD) was employed to anchor onto the orifices of MSNs as gatekeeper in this work. After subsequent modification by multifunctional peptide (azido-GFLGR7RGDS with tumor-targeting, membrane-penetrating, and cathepsin B-responsive functions) to stabilize the gatekeeper, the resulting functional MSNs showed a strong ability to load and seal DOX in their nanopores. When incubating these DOX-loaded MSNs with tumor and normal cells, the nanoparticles could efficiently employ their surface-encoded RGDS and continuous seven arginine (R7) sequences to target tumor cells, penetrate the cell membrane, and enter tumor cells. Because cathepsin B overexpressed in late endosomes and lysosomes of tumor cells could specifically hydrolyze GFLG sequences of the nanovalves, the DOX-loaded MSNs showed an "off-on" drug release behavior that ∼80% loaded DOX could be released within 24 h and thus showed a high rate of apoptosis. Furthermore, in vitro cellular experiments indicated that DOX-loaded MSNs (DOX@MSN-GFLGR7RGDS/α-CD) had high growth inhibition toward αvβ3-positive HeLa cancerous cells. The research might offer a practical way for designing the tumor-targeted and enzyme-induced drug delivery system for cancer therapy.

  18. Application value of computer assisted surgery system in precision surgeries for pediatric complex liver tumors

    PubMed Central

    Su, Lin; Zhou, Xian-Jun; Dong, Qian; Zhang, Hong; Shen, Feng; Chen, Yong-Jian; Hao, Xi-Wei; Li, Xiao-Fei

    2015-01-01

    We discussed the diagnostic and treatment value and clinical significance of computer assisted surgery system (Higemi) in precision surgeries for pediatric complex liver tumors. A total of 21 pediatric cases receiving hepatectomy for tumors in the portal vein and giant liver tumors from June 2012 to January 2015 were analyzed. Higemi was used for 3-dimensional (3D) reconstruction of thin-slice CT images and surgical planning. Tumors were precisely located and blood vessel neighborhood was determined so as to evaluate surgical feasibility. In addition, pathological classification, surgical time, intraoperative blood loss, transfusion rate and complications were predicted. After 3D reconstruction using Higemi, the neighboring relationship of tumors with blood vessels and the running direction of the blood vessels were clearly visualized. Of 21 cases, 10 cases had tumors located in the left lobe, 5 cases in the right lobe, 3 cases showing involvement of right trilobes, and 3 cases in the middle lobe. Lobes exceeding one third of the total liver volume were resected in 18 cases. Postoperative pathological examination indicated 10 cases of hepatoblastoma, 3 cases of hepatocellular carcinoma, 3 cases of hamartoma, 3 cases of infantile hemangioendothelioma, 1 case of teratoma and 1 case of undifferentiated malignant mesenchymoma. The surgical time was 90-240 min with an average of 130 min; the medium intraoperative blood loss was 60 ml and the minimum blood loss was 3 ml; the transfusion rate was 42.9% (9/21). Surgeries were successful in 20 cases, who were discharged after recovery. However, one case had giant liver tumor combined with severe obstructive jaundice and hepatic insufficiency and died of postoperative liver failure and DIC. 3D reconstruction of CT data using Higemi can clearly visualize the running direction of blood vessels and the neighboring relationship with tumors. Higemi can improve the precision and safety of complex hepatectomy. PMID:26770445

  19. Obstructive hydrocephalus due to CNS toxocariasis.

    PubMed

    Choi, Jae-Hwan; Cho, Jae-Wook; Lee, Jae-Hyeok; Lee, Sang Weon; Kim, Hak-Jin; Choi, Kwang-Dong

    2013-06-15

    A 46-year-old man developed intermittent headache, diplopia, and visual obscuration for two months. Funduscopic examination showed optic disk swelling in both eyes. Brain MRI exhibited hydrocephalus and leptomeningeal enhancement at the prepontine cistern, left cerebellopontine angle cistern and bilateral cerebral hemisphere, and hemosiderin deposition along the cerebellar folia. CSF analysis revealed an elevated opening pressure with xanthochromic appearance and small amount of red blood cells. Antibody titer against Toxocariasis using ELISA was elevated both in blood and CSF. Obstructive hydrocephalus and hemosiderin deposition in this case may result from the active inflammatory process due to CNS toxocariasis within the subarachnoid space.

  20. Engineering Therapies in the CNS: What works and what can be translated

    PubMed Central

    Shoffstall, Andrew J.; Taylor, Dawn M.; Lavik, Erin B.

    2012-01-01

    Engineering is the art of taking what we know and using it to solve problems. As engineers, we build tool chests of approaches; we attempt to learn as much as possible about the problem at hand, and then we design, build, and test our approaches to see how they impact the system. The challenge of applying this approach to the central nervous system (CNS) is that we often do not know the details of what is needed from the biological side. New therapeutic options for treating the CNS range from new biomaterials to make scaffolds, to novel drug-delivery techniques, to functional electrical stimulation. However, the reality is that translating these new therapies and making them widely available to patients requires collaborations between scientists, engineers, clinicians, and patients to have the greatest chance of success. Here we discuss a variety of new treatment strategies and explore the pragmatic challenges involved with engineering therapies in the CNS. PMID:22330751

  1. Assessment of vascular regeneration in the CNS using the mouse retina.

    PubMed

    Miloudi, Khalil; Dejda, Agnieszka; Binet, François; Lapalme, Eric; Cerani, Agustin; Sapieha, Przemyslaw

    2014-06-23

    The rodent retina is perhaps the most accessible mammalian system in which to investigate neurovascular interplay within the central nervous system (CNS). It is increasingly being recognized that several neurodegenerative diseases such as Alzheimer's, multiple sclerosis, and amyotrophic lateral sclerosis present elements of vascular compromise. In addition, the most prominent causes of blindness in pediatric and working age populations (retinopathy of prematurity and diabetic retinopathy, respectively) are characterized by vascular degeneration and failure of physiological vascular regrowth. The aim of this technical paper is to provide a detailed protocol to study CNS vascular regeneration in the retina. The method can be employed to elucidate molecular mechanisms that lead to failure of vascular growth after ischemic injury. In addition, potential therapeutic modalities to accelerate and restore healthy vascular plexuses can be explored. Findings obtained using the described approach may provide therapeutic avenues for ischemic retinopathies such as that of diabetes or prematurity and possibly benefit other vascular disorders of the CNS.

  2. Immune cell trafficking from the brain maintains CNS immune tolerance.

    PubMed

    Mohammad, Mohammad G; Tsai, Vicky W W; Ruitenberg, Marc J; Hassanpour, Masoud; Li, Hui; Hart, Prue H; Breit, Samuel N; Sawchenko, Paul E; Brown, David A

    2014-03-01

    In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

  3. Combining Radiation and Immunotherapy: A New Systemic Therapy for Solid tumors?

    PubMed Central

    Tang, Chad; Wang, Xiaohong; Soh, Hendrick; Seyedin, Steven; Cortez, Maria Angelica; Krishnan, Sunil; Massarelli, Erminia; Hong, David; Naing, Aung; Diab, Adi; Gomez, Daniel; Ye, Huiping; Heymach, John; Komaki, Ristuko; Allison, James; Sharma, Padmanee; Welsh, James W.

    2017-01-01

    With the recent success of checkpoint inhibitors and other immune-modulating agents, there has been renewed interest in the combination of such agents with radiation. The biological premise behind such a strategy is that the tumor-antigen release achieved by localized radiation will promote specific tumor-targeting by the adaptive immune system, which can be augmented further by systemic immune-stimulating agents. In this manner, clinicians hope to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field. In this Crossroads in Cancer Immunology article, we will present a comprehensive overview of the early clinical and pre-clinical evidence behind this approach. PMID:25187273

  4. Systems Analysis of a Mouse Xenograft Model Reveals Annexin A1 as a Regulator of Gene Expression in Tumor Stroma

    PubMed Central

    Yi, Ming

    2012-01-01

    Annexin A1 is a multi functional molecule which is involved in inflammation, innate and adaptive immune systems, tumor progression and metastasis. We have previously showed the impaired tumor growth, metastasis, angiogenesis and wound healing in annexin A1 knockout mice. While tumor is a piece of heterogeneous mass including not only malignant tumor cells but also the stroma, the importance of the tumor stroma for tumor progression and metastasis is becoming increasingly clear. The tumor stroma is comprised by various components including extracellular matrix and non-malignant cells in the tumor, such as endothelial cells, fibroblasts, immune cells, inflammatory cells. Based on our previous finding of pro-angiogenic functions for annexin A1 in vascular endothelial cell sprouting, wound healing, tumor growth and metastasis, and the previously known properties for annexin A1 in immune cells and inflammation, this study hypothesized that annexin A1 is a key functional player in tumor development, linking the various components in tumor stroma by its actions in endothelial cells and immune cells. Using systems analysis programs commercially available, this paper further compared the gene expression between tumors from annexin A1 wild type mice and annexin A1 knockout mice and found a list of genes that significantly changed in the tumor stroma that lacked annexin A1. This revealed annexin A1 to be an effective regulator in tumor stroma and suggested a mechanism that annexin A1 affects tumor development and metastasis through interaction with the various components in the microenvironment surrounding the tumor cells. PMID:23077482

  5. 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

  6. GPCR drug discovery: novel ligands for CNS receptors.

    PubMed

    Lim, William K

    2007-06-01

    G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in humans. They convey extracellular signals into the cell interior by activating intracellular processes such as heterotrimeric G protein-dependent signaling pathways. They are widely distributed in the nervous system, and mediate key physiological processes including cognition, mood, appetite, pain and synaptic transmission. With at least 30% of marketed drugs being GPCR modulators, they are a major therapeutic target in the pharmaceutical industry's drug discovery programs. This review will survey recently patented ligands for GPCRs implicated in CNS disorders, in particular the metabotropic glutamate, adenosine and cannabinoid receptors. Metabotropic glutamate receptors regulate signaling by glutamate, the major excitatory brain neurotransmitter, while adenosine is a ubiquitous neuromodulater mediating diverse physiological effects. Recent patents for ligands of these receptors include mGluR5 antagonists and adenosine A(1) receptor agonists. Cannabinoid receptors remain one of the most important GPCR drug discovery target due to the intense interest in CB(1) receptor antagonists for treating obesity and metabolic syndrome. Such small molecule ligands are the outcome of the continuing focus of many pharmaceutical companies to identify novel GPCR agonist, antagonist or allosteric modulators useful for CNS disorders, for which more effective drugs are eagerly awaited.

  7. 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.

  8. The adaptive computer-aided diagnosis system based on tumor sizes for the classification of breast tumors detected at screening ultrasound.

    PubMed

    Moon, Woo Kyung; Chen, I-Ling; Chang, Jung Min; Shin, Sung Ui; Lo, Chung-Ming; Chang, Ruey-Feng

    2017-04-01

    Screening ultrasound (US) is increasingly used as a supplement to mammography in women with dense breasts, and more than 80% of cancers detected by US alone are 1cm or smaller. An adaptive computer-aided diagnosis (CAD) system based on tumor size was proposed to classify breast tumors detected at screening US images using quantitative morphological and textural features. In the present study, a database containing 156 tumors (78 benign and 78 malignant) was separated into two subsets of different tumor sizes (<1cm and ⩾1cm) to explore the improvement in the performance of the CAD system. After adaptation, the accuracies, sensitivities, specificities and Az values of the CAD for the entire database increased from 73.1% (114/156), 73.1% (57/78), 73.1% (57/78), and 0.790 to 81.4% (127/156), 83.3% (65/78), 79.5% (62/78), and 0.852, respectively. In the data subset of tumors larger than 1cm, the performance improved from 66.2% (51/77), 68.3% (28/41), 63.9% (23/36), and 0.703 to 81.8% (63/77), 85.4% (35/41), 77.8% (28/36), and 0.855, respectively. The proposed CAD system can be helpful to classify breast tumors detected at screening US.

  9. Magnetic Nanoparticles for Tumor Imaging and Therapy: A So-called Theranostic System

    PubMed Central

    He, Huining; David, Allan; Chertok, Beata; Cole, Adam; Lee, Kyuri; Zhang, Jian; Wang, Jianxin; Huang, Yongzhuo; Yang, Victor C.

    2014-01-01

    In this review, we discussed the establishment of a so-called “theranostic“ system by instituting the basic principles including the use of: [1] magnetic iron oxide nanoparticles (MION)-based drug carrier; [2] intra-arterial (I.A.) magnetic targeting; [3] macromolecular drugs with unmatched therapeutic potency and a repetitive reaction mechanism; [4] cell-penetrating peptide-mediated cellular drug uptake; and [5] heparin/protamine-regulated prodrug protection and tumor-specific drug re-activation into one single drug delivery system to overcome all possible obstacles, thereby achieving a potentially non-invasive, magnetic resonance imaging-guided, clinically enabled yet minimally toxic brain tumor drug therapy. By applying a topography-optimized I.A. magnetic targeting to dodge rapid organ clearance of the carrier during its first passage into the circulation, tumor capture of MION was enriched by >350 folds over that by conventional passive enhanced permeability and retention targeting. By adopting the prodrug strategy, we observed by far the first experimental success in a rat model of delivering micro-gram quantity of the large β-galactosidase model protein selectively into a brain tumor but not to the ipsi- or contra-lateral normal brain regions. With the therapeutic regimens of most toxin/siRNA drugs to fully (>99.9%) eradicate a tumor being in the nano-molar range, the prospects of reaching this threshold become practically accomplishable. PMID:23344909

  10. Systemic Delivery of Fusogenic Membrane Glycoprotein-expressing Neural Stem Cells to Selectively Kill Tumor Cells

    PubMed Central

    Zhu, Detu; Lam, Dang Hoang; Purwanti, Yovita Ida; Goh, Sal Lee; Wu, Chunxiao; Zeng, Jieming; Fan, Weimin; Wang, Shu

    2013-01-01

    Intravenously injected neural stem cells (NSCs) can infiltrate both primary and metastatic tumor sites; thus, they are attractive tumor-targeting vehicles for delivering anticancer agents. However, because the systemic distribution of the injected NSCs involves normal organs and might induce off-target actions leading to unintended side effects, clinical applications of this approach is impeded. Given that the vesicular stomatitis virus glycoprotein (VSV-G) can promote the formation of multinucleated syncytia to kill cells in a pH-dependent manner, we engineered a pH sensor of VSV-G and generated a novel VSV-G mutant that efficiently promotes syncytium formation at the tumor extracellular pH (pHe) but not at pH 7.4. Using transduced NSCs derived from induced pluripotent stem cells (iPSCs), the VSV-G mutant was delivered into mice with metastatic breast cancers in the lung through tail vein injection. Compared with the conventional stem cell-based gene therapy that uses the herpes simplex virus thymidine kinase (HSVtk) suicide gene, this treatment did not display toxicity to normal non-targeted organs while retaining therapeutic effects in tumor-bearing organs. Our findings demonstrate the effectiveness of a new approach for achieving tumor-selective killing effects following systemic stem cell administration. Its potential in stem cell-based gene therapy for metastatic cancer is worthy of further exploration. PMID:23752308

  11. Design of a novel pulsed laser diode induced photoacoustic imaging system for tumor diagnosis

    NASA Astrophysics Data System (ADS)

    Ren, Zhong; Zeng, Lvming; Liu, Guodong; Huang, Zhen

    2012-03-01

    The tumors are one of most dangerous diseases in lots of diseases Expect for the actively treating of antitumor, the early detection of tumors is a key important step in the course of tumor treatment. Since some drawbacks existed in the traditional methods of tumor detection, such as ultrasound imaging, X radiography, CT imaging, OCT and MRI, etc, a novel hybrid and promising imaging method, that is, photoacoustic imaging (PAI) technology, is used to the tumors diagnosis(TD) in this work. This novel method has higher resolution, contrast and penetration depth due to the merits combination of ultrasonic with optics. And the detected photoacoustic signal not only reflects the structural characteristic of tissue but also the metabolic and pathological changes. So, the novel TD based on the PAI is proposed in this paper. Meanwhile, a novel single pulsed laser diode with 905nm wavelength is used as the light source, and a focused ultrasonic transducer with the forward-mode is used to acquire the photoacoustic signal. Finally, PA images were reconstructed with the improved filtered back projection algorithm. Experimental results show the signal acquisition time is less than 0.2 s in each scan of 128 averages. And it is proved that the photoacoustic imaging system for TD with a high-power pulsed laser diode is available. Therefore, this system has the potential value in the biomedical research fields.

  12. Design of a novel pulsed laser diode induced photoacoustic imaging system for tumor diagnosis

    NASA Astrophysics Data System (ADS)

    Ren, Zhong; Zeng, Lvming; Liu, Guodong; Huang, Zhen

    2011-11-01

    The tumors are one of most dangerous diseases in lots of diseases Expect for the actively treating of antitumor, the early detection of tumors is a key important step in the course of tumor treatment. Since some drawbacks existed in the traditional methods of tumor detection, such as ultrasound imaging, X radiography, CT imaging, OCT and MRI, etc, a novel hybrid and promising imaging method, that is, photoacoustic imaging (PAI) technology, is used to the tumors diagnosis(TD) in this work. This novel method has higher resolution, contrast and penetration depth due to the merits combination of ultrasonic with optics. And the detected photoacoustic signal not only reflects the structural characteristic of tissue but also the metabolic and pathological changes. So, the novel TD based on the PAI is proposed in this paper. Meanwhile, a novel single pulsed laser diode with 905nm wavelength is used as the light source, and a focused ultrasonic transducer with the forward-mode is used to acquire the photoacoustic signal. Finally, PA images were reconstructed with the improved filtered back projection algorithm. Experimental results show the signal acquisition time is less than 0.2 s in each scan of 128 averages. And it is proved that the photoacoustic imaging system for TD with a high-power pulsed laser diode is available. Therefore, this system has the potential value in the biomedical research fields.

  13. 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.

  14. Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis

    PubMed Central

    Salou, Marion; Garcia, Alexandra; Michel, Laure; Gainche-Salmon, Anne; Loussouarn, Delphine; Nicol, Bryan; Guillot, Flora; Hulin, Philippe; Nedellec, Steven; Baron, Daniel; Ramstein, Gérard; Soulillou, Jean-Paul; Brouard, Sophie; Nicot, Arnaud B; Degauque, Nicolas; Laplaud, David A

    2015-01-01

    Objective In multiple sclerosis (MS), central nervous system (CNS), cerebrospinal fluid (CSF), and blood display TCR clonal expansions of CD8+ T cells. These clones have been assumed – but never demonstrated – to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8+ T cells in the disease. Methods For the first time, TCR Vβ repertoire from paired blood (purified CD8+ and CD4+ T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 (CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8+ T cells were characterized by fluorescent staining. Results TCR Vβ repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8+ T cells. In parallel, we showed that blood oligoclonal CD8+ T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS-infiltrating T cells were mainly CD8 expressing CD11a and GZM-B. Interpretation This study highlights the predominant implication of CD8+ T cells in MS pathophysiology and demonstrates that potentially aggressive CD8+ T cells can be easily identified and characterized from blood and CSF samples. PMID:26125037

  15. Brain-derived neurotrophic factor as a drug target for CNS disorders.

    PubMed

    Pezet, Sophie; Malcangio, Marzia

    2004-10-01

    Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of trophic factors. BDNF is widely and abundantly expressed in the CNS and is available to some peripheral nervous system neurons that uptake the neurotrophin produced by peripheral tissues. BDNF promotes survival and differentiation of certain neuronal populations during development. In adulthood, BDNF can modulate neuronal synaptic strength and has been implicated in hippocampal mechanisms of learning and memory and spinal mechanisms for pain. Several CNS disorders are associated with a decrease in trophic support. As BDNF and its high affinity receptor are abundant throughout the whole CNS, and BDNF is a potent neuroprotective agent, this trophic factor is a good candidate for therapeutic treatment of some of CNS disorders. This review aims to correlate the features of some CNS disorders (Parkinson's disease, Alzheimer's disease, depression, epilepsy and chronic pain) to changes in BDNF expression in the brain. The cellular and molecular mechanism by which BDNF might be a therapeutic strategy are critically examined.

  16. Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease.

    PubMed

    Greenhalgh, Andrew D; Passos Dos Santos, Rosmarini; Zarruk, Juan Guillermo; Salmon, Christopher K; Kroner, Antje; David, Samuel

    2016-08-01

    Resident microglia and infiltrating myeloid cells play important roles in the onset, propagation, and resolution of inflammation in central nervous system (CNS) injury and disease. Identifying cell type-specific mechanisms will help to appropriately target interventions for tissue repair. Arginase-1 (Arg-1) is a well characterised modulator of tissue repair and its expression correlates with recovery after CNS injury. Here we assessed the cellular localisation of Arg-1 in two models of CNS damage. Using microglia specific antibodies, P2ry12 and Fc receptor-like S (FCRLS), we show the LysM-EGFP reporter mouse is an excellent model to distinguish infiltrating myeloid cells from resident microglia. We show that Arg-1 is expressed exclusively in infiltrating myeloid cells but not microglia in models of spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE). Our in vitro studies suggest that factors in the CNS environment prevent expression of Arg-1 in microglia in vivo. This work suggests different functional roles for these cells in CNS injury and repair and shows that such repair pathways can be switched on in infiltrating myeloid cells in pro-inflammatory environments.

  17. Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma

    PubMed Central

    Ponzoni, M.; Issa, S.; Batchelor, T. T.; Rubenstein, J. L.

    2014-01-01

    Background While there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease. Patients and methods We reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology. Results While PCNSL tumors usually express a BCL6+, MUM1+ ‘activated, germinal center’ immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses. Conclusions There is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease. PMID:24265352

  18. Advances in Molecular Imaging of Locally Delivered Targeted Therapeutics for Central Nervous System Tumors

    PubMed Central

    Tosi, Umberto; Marnell, Christopher S.; Chang, Raymond; Cho, William C.; Ting, Richard; Maachani, Uday B.; Souweidane, Mark M.

    2017-01-01

    Thanks to the recent advances in the development of chemotherapeutics, the morbidity and mortality of many cancers has decreased significantly. However, compared to oncology in general, the field of neuro-oncology has lagged behind. While new molecularly targeted chemotherapeutics have emerged, the impermeability of the blood–brain barrier (BBB) renders systemic delivery of these clinical agents suboptimal. To circumvent the BBB, novel routes of administration are being applied in the clinic, ranging from intra-arterial infusion and direct infusion into the target tissue (convection enhanced delivery (CED)) to the use of focused ultrasound to temporarily disrupt the BBB. However, the current system depends on a “wait-and-see” approach, whereby drug delivery is deemed successful only when a specific clinical outcome is observed. The shortcomings of this approach are evident, as a failed delivery that needs immediate refinement cannot be observed and corrected. In response to this problem, new theranostic agents, compounds with both imaging and therapeutic potential, are being developed, paving the way for improved and monitored delivery to central nervous system (CNS) malignancies. In this review, we focus on the advances and the challenges to improve early cancer detection, selection of targeted therapy, and evaluation of therapeutic efficacy, brought forth by the development of these new agents. PMID:28208698

  19. Tumor Specific Gene Expression and Tumor Specific Vector Replication for Systemic Chemotherapy Sensitization Treatment of Breast Cancer

    DTIC Science & Technology

    2002-07-01

    directed at the use of the L-plastin tumor-specific transcriptional promoter to control the expression of a chemotherapy sensitization gene ( cytosine ... deaminase ) and a viral replication gene (ElA) so that any toxic effect is tumor specific. These vectors have been shown to suppress the growth of human

  20. Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

    PubMed

    de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E; Oliveira, Michelli F; Chaillon, Antoine; de Pereira, Ana Paula; Cunha, Ana Paula; Zonta, Marise; Bents, Joao França; Raboni, Sonia M; Smith, Davey; Letendre, Scott; Ellis, Ronald J

    2017-02-28

    Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

  1. Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen.

    PubMed

    Kinzel, Silke; Lehmann-Horn, Klaus; Torke, Sebastian; Häusler, Darius; Winkler, Anne; Stadelmann, Christine; Payne, Natalie; Feldmann, Linda; Saiz, Albert; Reindl, Markus; Lalive, Patrice H; Bernard, Claude C; Brück, Wolfgang; Weber, Martin S

    2016-07-01

    In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders.

  2. Do not judge a cell by its cover--diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation.

    PubMed

    Brendecke, Stefanie M; Prinz, Marco

    2015-11-01

    Specialized populations of tissue-resident myeloid cells inhabit every organ of the body. While many of these populations appear similar morphologically and phenotypically, they exhibit great functional diversity. The central nervous system (CNS), as an immune privileged organ, possesses a unique tissue-resident macrophage population, the microglia, as well as numerous myeloid cell subsets at its boarders and barriers in CNS-adjoining tissues, namely the meninges, the perivascular space, and the choroid plexus. Recent research has added much to our knowledge about microglia, whereas the populations of CNS-surrounding phagocytes are just starting to be appreciated. As guardians of CNS homeostasis, these myeloid cells perform immune surveillance and immune modulatory tasks in health and disease. As such, microglia and CNS-surrounding antigen-presenting cells have been shown to be crucially involved not only in the initiation and progression but also resolution of multiple sclerosis (MS). MS and its rodent model, experimental autoimmune encephalomyelitis, are autoimmune inflammatory demyelinating CNS pathologies. While some crucial aspects of the disease pathogenesis have been solved, much of the complex involvement and interplay of the innate immune compartment remains yet to be clarified. Here, we will discuss the current understanding of the scope of phenotypes and functions of myeloid cells involved in CNS neuroinflammation.

  3. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and CNS inflammation via the aryl hydrocarbon receptor

    PubMed Central

    Rothhammer, Veit; Mascanfroni, Ivan D.; Bunse, Lukas; Takenaka, Maisa C.; Kenison, Jessica E.; Mayo, Lior; Chao, Chun-Cheih; Patel, Bonny; Yan, Raymond; Blain, Manon; Alvarez, Jorge I.; Kébir, Hania; Anandasabapathy, Niroshana; Izquierdo, Guillermo; Jung, Steffen; Obholzer, Nikolaus; Pochet, Nathalie; Clish, Clary B.; Prinz, Marco; Prat, Alexandre; Antel, Jack; Quintana, Francisco J.

    2016-01-01

    Astrocytes play important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-I) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from multiple sclerosis (MS) patients. IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) and suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered IFN-β are partly mediated by AhR. Dietary tryptophan is metabolized by the gut microbiota into AhR agonists that act on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate (I3S), indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld), or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AhR agonists were decreased. These findings suggest that IFN-I produced in the CNS act in combination with metabolites derived from dietary tryptophan by the gut flora to activate AhR signaling in astrocytes and suppress CNS inflammation. PMID:27158906

  4. 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.

  5. Laser correlation spectroscopy in the diagnosis of tumor diseases of the female reproductive system (preliminary results)

    NASA Astrophysics Data System (ADS)

    Korneeva, A. A.; Sekerskaya, M. N.; Zhordaniya, K. I.; Sapezhinskiy, V. S.; Golubtsova, N. V.; Barmashov, A. E.; Gonchukov, S. A.; Ivanov, A. V.

    2017-01-01

    The study of blood serum of cancer patients by laser correlation spectroscopy to determine the possibility of differentiation of benign and malignant tumors of the female reproductive system. We analyzed the data and assessed the applicability of the method mentioned above target.

  6. 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

  7. Extra-CNS metastasis from glioblastoma: a rare clinical entity.

    PubMed

    Awan, Musaddiq; Liu, Stanley; Sahgal, Arjun; Das, Sunit; Chao, Samuel T; Chang, Eric L; Knisely, Jonathan P S; Redmond, Kristin; Sohn, Jason W; Machtay, Mitchell; Sloan, Andrew E; Mansur, David B; Rogers, Lisa R; Lo, Simon S

    2015-05-01

    Extra-CNS metastasis from glioblastoma (ECMGBM) is an emerging but little known clinical entity. We review pre-clinical and translational publications assessing the ability of GBM to spread locally and outside the CNS. Reported cases demonstrating ECMGBM are reviewed providing a summary of presentations for the entity. Special attention is placed on transmission of GBM through organ transplantation. Finally, predictions are made as to the future significance of ECMGBM, especially in the context of better outcomes in CNS GBM.

  8. [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.

  9. Systemic administration of attenuated Salmonella choleraesuis carrying thrombospondin-1 gene leads to tumor-specific transgene expression, delayed tumor growth and prolonged survival in the murine melanoma model.

    PubMed

    Lee, Che-Hsin; Wu, Chao-Liang; Shiau, Ai-Li

    2005-02-01

    Some anaerobic and facultative anaerobic bacteria have been used experimentally as anticancer agents because of their selective growth in the hypoxia regions of solid tumors after systemic administration. We have previously shown the feasibility of using attenuated Salmonella choleraesuis as a gene delivery vector. In this study, we exploited S. choleraesuis carrying thrombospondin-1 (TSP-1) gene for treating primary melanoma and experimental pulmonary metastasis in the syngeneic murine B16F10 melanoma model. Systemic administration of S. choleraesuis allowed targeted gene delivery to tumors. The bacteria accumulated preferentially in tumors over livers and spleens at ratios ranging from 1000:1 to 10,000:1. The level of transgene expression via S. choleraesuis-mediated gene transfer in tumors could reach more than 1800-fold higher than in livers and spleens. Notably, bacterial accumulation was also observed in the lungs with metastatic nodules, but not in healthy lungs. When administ