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1.
Childs Nerv Syst ; 39(1): 279-284, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35831710

RESUMEN

Craniopharyngiomas are rare, benign lesions that can be treated with surgery, radiation therapy, or a combination of these modalities. They have a propensity for local recurrence, but there have also been rare cases reported of ectopic recurrence. Here, we present the case of a 15-year-old girl with a recurrence of craniopharyngioma in the spine, which is the second-ever reported case of recurrence outside of the brain in a pediatric patient, and review the 19 reported cases of ectopic recurrence in pediatric patients due to cerebrospinal fluid dissemination.


Asunto(s)
Neoplasias Encefálicas , Craneofaringioma , Neoplasias Hipofisarias , Femenino , Humanos , Niño , Adolescente , Craneofaringioma/cirugía , Recurrencia Local de Neoplasia/patología , Neoplasias Hipofisarias/cirugía , Neoplasias Encefálicas/cirugía , Encéfalo/patología
2.
Acta Neuropathol ; 143(6): 697-711, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35501487

RESUMEN

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials.


Asunto(s)
Neoplasias del Sistema Nervioso Central , Neoplasias Neuroepiteliales , Tumor Rabdoide , Teratoma , Neoplasias del Sistema Nervioso Central/genética , Metilación de ADN , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Neuroepiteliales/genética , Pronóstico , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Teratoma/genética
3.
Clin Infect Dis ; 70(4): 692-695, 2020 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-31247065

RESUMEN

We report the cases of 3 patients with fatal, disseminated Mycobacterium chimaera infections following cardiac surgeries. Progressive neurocognitive decline and death were explained by active granulomatous encephalitis, with widespread involvement of other organs. This syndrome is clinically elusive and, thus, may have caused deaths in prior reported series.


Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Encefalitis , Infecciones por Mycobacterium no Tuberculosas , Infecciones por Mycobacterium , Mycobacterium , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Encefalitis/diagnóstico , Encefalitis/etiología , Humanos , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/etiología
4.
Ann Neurol ; 84(5): 781-787, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30246885

RESUMEN

Etiologic diagnosis is uncertain in 35% to 50% of patients with encephalitis, despite its substantial global prevalence and disease burden. We report on 2 adult female patients with fatal leukoencephalitis associated with human pegivirus-1 (HPgV-1) brain infection. Neuroimaging showed inflammatory changes in cerebral white matter. Brain-derived HPgV-1 RNA sequences clustered phylogenetically with other pegiviruses despite an 87-nucleotide deletion in the viral nonstructural (NS)2 gene. Neuropathology disclosed lymphocyte infiltration and gliosis predominantly in brain white matter. HPgV-1 NS5A antigen was detected in lymphocytes as well as in astrocytes and oligodendrocytes. HPgV-1 neuroadaptation should be considered in the differential diagnosis of progressive leukoencephalitis in humans. Ann Neurol 2018;84:789-795.


Asunto(s)
Encefalitis/patología , Encefalitis/virología , Infecciones por Flavivirus/patología , Leucoencefalopatías/patología , Leucoencefalopatías/virología , Resultado Fatal , Femenino , Flavivirus , Humanos , Persona de Mediana Edad
5.
Cell Tissue Res ; 354(2): 409-30, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23963648

RESUMEN

The extracellular matrix (ECM) protein tenascin-C (TN-C) is upregulated within glioma tissues and cultured glioma cell lines. TN-C possesses a multi-modular structure and a variety of functional properties have been reported for its domains. We describe five novel monoclonal antibodies identifying different domains of TN-C. The epitopes for these antibodies were investigated by using recombinantly expressed fibronectin type III domains of TN-C. The biological effects of TN-C fragments on glioma cell proliferation and adhesion were analyzed. The expression pattern of TN-C in human glioma tissue sections and in glioma cell lines was studied with the novel library of monoclonal antibodies. The immunocytochemical analyses of the established human glioma cell lines U-251-MG, U-373-MG and U-87-MG revealed distinct staining patterns for each antibody. Robust expression of TN-C was found within the tumor mass of surgery specimens from glioblastoma. In many cases, the expression of this ECM molecule was clearly associated with blood vessels, particularly with microvessels. Three of the new antibodies highlighted individual TN-C-expressing single cells in glioma tissues. The effect of TN-C domains on glioma cells was examined by a BrdU-proliferation assay and an adhesion assay. Short fragments of constitutively expressed TN-C-domains did not exert significant effects on the proliferation of glioma cells, whereas the intact molecule increased cell division rates. In contrast, the long fragment TNfnALL containing all of the FNIII domains of TN-C decreased proliferation. Additionally, we found strong differences between the adhesion-influencing properties of the recombinant fragments on glioma cells.


Asunto(s)
Neoplasias Encefálicas/irrigación sanguínea , Neoplasias del Sistema Nervioso Central/irrigación sanguínea , Glioma/irrigación sanguínea , Tenascina/análisis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Regulación Neoplásica de la Expresión Génica , Glioblastoma/irrigación sanguínea , Glioblastoma/genética , Glioblastoma/patología , Glioma/genética , Glioma/patología , Humanos , Inmunohistoquímica , Tenascina/genética
6.
Clin Cancer Res ; 29(2): 488-500, 2023 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-36239995

RESUMEN

PURPOSE: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. EXPERIMENTAL DESIGN: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. RESULTS: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. CONCLUSIONS: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Proteínas Proto-Oncogénicas c-akt , Resistencia a Antineoplásicos/genética , Temozolomida , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico
7.
J Endocr Soc ; 5(5): bvab043, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33928205

RESUMEN

The papillary subtype of craniopharyngioma (CP) rarely occurs in children and commonly presents as a suprasellar lesion. Patients with papillary CPs frequently harbor the BRAF-V600E mutation, and treatment with a BRAF inhibitor results in tumor shrinkage in several patients. Herein, we report a patient with childhood-onset papillary CP treated with vemurafenib for 40 months after multiple surgeries. At age 10, he presented with growth failure secondary to an intrasellar cystic lesion. He had 3 transsphenoidal surgeries before age 12 and a 4th surgery 25 years later for massive tumor recurrence. Pathology showed a papillary CP with positive BRAF-V600E mutation. Rapid tumor regrowth 4 months after surgery led to treatment with vemurafenib that resulted in tumor reduction within 6 weeks. Gradual tumor regrowth occurred after a dose reduction of vemurafenib because of elevated liver enzymes. He had further surgeries and within 7 weeks after stopping vemurafenib, there was massive tumor recurrence. He resumed treatment with vemurafenib before radiation therapy and similar tumor shrinkage occurred within 16 days. In this patient with childhood-onset papillary CP that was refractory to multiple surgeries, the use of vemurafenib resulted in significant tumor shrinkage that allowed for the completion of radiation therapy and tumor control.

8.
Endocr Pathol ; 32(3): 418-426, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32833164

RESUMEN

Corticotroph carcinomas and aggressive corticotroph tumors can be resistant to conventional therapy, including surgery, radiotherapy, and medical treatment. Recent evidence suggests that temozolomide (an oral alkylating agent) administered with capecitabine (pro-drug of 5-fluorouracil) may improve progression-free survival in patients with high-risk corticotroph tumors and carcinomas. This led to the use of capecitabine and temozolomide (CAPTEM) in two patients, one with a corticotroph carcinoma and the other with an aggressive corticotroph tumor, as well the in vitro analysis of capecitabine and 5-fluorouracil on cell growth and hormone production. Both patients had previous surgical and radiation therapy. The first patient developed leptomeningeal spread 2 years after his radiation treatment. He had 12 cycles of CAPTEM, which resulted in tumor control associated with clinical and radiological improvement. Twenty-seven months later, CAPTEM was restarted for disease recurrence with ongoing tumor response. The second patient had a rapid tumor regrowth 2 years after his third surgical resection. He was treated with 12 cycles of CAPTEM, which led to tumor shrinkage with no tumor regrowth 22 months after cessation of therapy. Experiments using mouse ACTH-producing pituitary tumor AtT20 cells demonstrated that treatment with 5-fluorouracil in combination with temozolomide had an additive effect in reducing cell viability and ACTH production in the culture medium. Our patients and experimental data in AtT20 cells support CAPTEM as a potential treatment option for aggressive corticotroph tumors and carcinomas. However, a prospective clinical trial is required to determine whether CAPTEM is superior to temozolomide in the treatment of these tumors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/administración & dosificación , Carcinoma Neuroendocrino/tratamiento farmacológico , Neoplasias Hipofisarias/tratamiento farmacológico , Temozolomida/administración & dosificación , Corticotrofos/patología , Humanos , Masculino , Persona de Mediana Edad
9.
Sci Rep ; 10(1): 19121, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33154496

RESUMEN

Histological visualizations are critical to clinical disease management and are fundamental to biological understanding. However, current approaches that rely on bright-field microscopy require extensive tissue preparation prior to imaging. These processes are both labor intensive and contribute to creating significant delays in clinical feedback for treatment decisions that can extend to 2-3 weeks for standard paraffin-embedded tissue preparation and interpretation, especially if ancillary testing is needed. Here, we present the first comprehensive study on the broad application of a novel label-free reflection-mode imaging modality known as photoacoustic remote sensing (PARS) for visualizing salient subcellular structures from various common histopathological tissue preparations and for use in unprocessed freshly resected tissues. The PARS modality permits non-contact visualizations of intrinsic endogenous optical absorption contrast to be extracted from thick and opaque biological targets with optical resolution. The technique was examined both as a rapid assessment tool that is capable of managing large samples (> 1 cm2) in under 10 min, and as a high contrast imaging modality capable of extracting specific biological contrast to simulate conventional histological stains such as hematoxylin and eosin (H&E). The capabilities of the proposed method are demonstrated in a variety of human tissue preparations including formalin-fixed paraffin-embedded tissue blocks and unstained slides sectioned from these blocks, including normal and neoplastic human brain, and breast epithelium involved with breast cancer. Similarly, PARS images of human skin prepared by frozen section clearly demonstrated basal cell carcinoma and normal human skin tissue. Finally, we imaged unprocessed murine kidney and achieved histologically relevant subcellular morphology in fresh tissue. This represents a vital step towards an effective real-time clinical microscope that overcomes the limitations of standard histopathologic tissue preparations and enables real-time pathology assessment.


Asunto(s)
Microscopía/métodos , Técnicas Fotoacústicas , Tecnología de Sensores Remotos , Animales , Humanos , Riñón/patología , Ratones , Piel/patología , Coloración y Etiquetado
10.
Sci Rep ; 10(1): 22013, 2020 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-33328490

RESUMEN

High intracranial pressure (ICP) can impede cerebral blood flow resulting in secondary injury or death following severe stroke. Compensatory mechanisms include reduced cerebral blood and cerebrospinal fluid volumes, but these often fail to prevent raised ICP. Serendipitous observations in intracerebral hemorrhage (ICH) suggest that neurons far removed from a hematoma may shrink as an ICP compliance mechanism. Here, we sought to critically test this observation. We tracked the timing of distal tissue shrinkage (e.g. CA1) after collagenase-induced striatal ICH in rat; cell volume and density alterations (42% volume reduction, 34% density increase; p < 0.0001) were highest day one post-stroke, and rebounded over a week across brain regions. Similar effects were seen in the filament model of middle cerebral artery occlusion (22% volume reduction, 22% density increase; p ≤ 0.007), but not with the Vannucci-Rice model of hypoxic-ischemic encephalopathy (2.5% volume increase, 14% density increase; p ≥ 0.05). Concerningly, this 'tissue compliance' appears to cause sub-lethal damage, as revealed by electron microscopy after ICH. Our data challenge the long-held assumption that 'healthy' brain tissue outside the injured area maintains its volume. Given the magnitude of these effects, we posit that 'tissue compliance' is an important mechanism invoked after severe strokes.


Asunto(s)
Hemorragia Cerebral/patología , Accidente Cerebrovascular Hemorrágico/patología , Accidente Cerebrovascular Isquémico/patología , Modelos Biológicos , Animales , Astrocitos/patología , Región CA1 Hipocampal/patología , Región CA1 Hipocampal/ultraestructura , Tamaño de la Célula , Masculino , Neuronas/patología , Ratas Sprague-Dawley
11.
Sci Rep ; 10(1): 17211, 2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33057037

RESUMEN

Malignant brain tumors are among the deadliest neoplasms with the lowest survival rates of any cancer type. In considering surgical tumor resection, suboptimal extent of resection is linked to poor clinical outcomes and lower overall survival rates. Currently available tools for intraoperative histopathological assessment require an average of 20 min processing and are of limited diagnostic quality for guiding surgeries. Consequently, there is an unaddressed need for a rapid imaging technique to guide maximal resection of brain tumors. Working towards this goal, presented here is an all optical non-contact label-free reflection mode photoacoustic remote sensing (PARS) microscope. By using a tunable excitation laser, PARS takes advantage of the endogenous optical absorption peaks of DNA and cytoplasm to achieve virtual contrast analogous to standard hematoxylin and eosin (H&E) staining. In conjunction, a fast 266 nm excitation is used to generate large grossing scans and rapidly assess small fields in real-time with hematoxylin-like contrast. Images obtained using this technique show comparable quality and contrast to the current standard for histopathological assessment of brain tissues. Using the proposed method, rapid, high-throughput, histological-like imaging was achieved in unstained brain tissues, indicating PARS' utility for intraoperative guidance to improve extent of surgical resection.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Glioma/diagnóstico por imagen , Glioma/cirugía , Microscopía/instrumentación , Procedimientos Neuroquirúrgicos/instrumentación , Técnicas Fotoacústicas/instrumentación , Tecnología de Sensores Remotos/instrumentación , Técnicas Estereotáxicas/instrumentación , Cirugía Asistida por Computador/instrumentación , Neoplasias Encefálicas/patología , Eosina Amarillenta-(YS) , Glioma/patología , Hematoxilina , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Márgenes de Escisión , Microscopía/métodos , Procedimientos Neuroquirúrgicos/métodos , Técnicas Fotoacústicas/métodos , Tecnología de Sensores Remotos/métodos , Cirugía Asistida por Computador/métodos
12.
Histopathology ; 54(2): 241-7, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19207949

RESUMEN

AIMS: Oligodendroglial tumours with loss of heterozygosity on 1p (LOH1p) respond better to treatment than oligodendrogliomas without LOH. Previous reports have assigned a crucial role of glutamate metabolism to glioma growth and invasion. The aim was to study the protein expression of different glutamate transporters in relation to LOH1p in low-grade oligodendroglial tumours. METHODS AND RESULTS: Seventeen oligodendrogliomas World Health Organization (WHO) grade II, 16 oligoastrocytomas WHO grade II and seven astrocytomas WHO grade II were examined. Eleven oligodendrogliomas and five oligoastrocytomas exhibited LOH1p. Immunoreactivity scores (IRS) for glutamate transporters excitatory amino acid transporter (EAAT)-1, -2 and -3 as well as the active cystine/glutamate antiporter subunit xCT were semiquantitatively rated by percentage of positive cells and intensity of immunoreactivity. Reactivity for xCT was lower in tumours with LOH1p than in those without (P = 0.03, Mann-Whitney U-test). No association was found between LOH status and IRS for EAAT-1, -2 or -3. High xCT immunoreactivity was associated with high expression of EAAT-1, -2 or -3. CONCLUSIONS: Expression of xCT is significantly reduced in low-grade oligodendroglial tumours harbouring LOH1p. Further studies should investigate a potential beneficial effect by inhibiting xCT in low-grade gliomas.


Asunto(s)
Sistema de Transporte de Aminoácidos y+/biosíntesis , Neoplasias Encefálicas/metabolismo , Cromosomas Humanos Par 1/genética , Glioma/genética , Glioma/metabolismo , Adulto , Anciano , Sistema de Transporte de Aminoácidos X-AG/biosíntesis , Neoplasias Encefálicas/genética , Femenino , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Análisis de Matrices Tisulares , Organización Mundial de la Salud
13.
Pediatr Res ; 65(6): 619-24, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19218878

RESUMEN

Because erythropoietin (Epo) is intensively studied as neuroprotective agent, Epo receptor (EpoR) regulation in neurons is of particular interest. Herein, we investigated molecular mechanisms of EpoR regulation in neuronal cells including the role of GATA transcription factors. First, developmental downregulation of EpoR expression in murine brain was observed. A differential expression pattern of the Gata factors was found in these specimens as well as in murine adult neural stem cells (NSC) and primary rat neurons, astrocytes, and microglia. Human SH-SY5Y cells served as a model to analyze EpoR regulation. In vitro binding of GATA-2, -3, and -4 to the 5'-flanking region was demonstrated. In reporter gene assays, the activity of a region containing two GATA binding sites was significantly induced when these GATA factors were overexpressed. However, GATA factors alone did not affect endogenous EpoR expression. Importantly, EpoR transcripts have doubled under hypoxia. Furthermore, we analyzed the methylation pattern close to the GATA motifs. Indeed, demethylation with 5-Aza-2'-deoxycytidine (Aza) resulted in upregulation of EpoR mRNA. Additionally, several CpGs were mostly nonmethylated in SH-SY5Y cells, but methylated in specific regions of the human adult brain. Thus, methylation may be involved in developmental EpoR downregulation.


Asunto(s)
Regulación de la Expresión Génica , Neuronas/fisiología , Receptores de Eritropoyetina/genética , Región de Flanqueo 5' , Animales , Secuencia de Bases , Línea Celular , Eritropoyetina/metabolismo , Factores de Transcripción GATA/genética , Factores de Transcripción GATA/metabolismo , Humanos , Ratones , Datos de Secuencia Molecular , Neuronas/citología , Regiones Promotoras Genéticas , Ratas , Ratas Wistar , Receptores de Eritropoyetina/metabolismo
14.
Diagnostics (Basel) ; 9(1)2019 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-30823396

RESUMEN

Bilirubin encephalopathy/kernicterus is relatively rare, but continues to occur despite universal newborn screening. What is more interesting is the spectrum of clinical and even neuropathological findings that have been reported in the literature to be associated with bilirubin encephalopathy and kernicterus. In this review, the authors discuss the array of clinicopathological findings reported in the context of bilirubin encephalopathy and kernicterus, as well as the types of diagnostic testing used in patients suspected of having bilirubin encephalopathy or kernicterus. The authors aim to raise the awareness of these features among both pediatric neurologists and neuropathologists.

15.
Nat Commun ; 10(1): 4343, 2019 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-31554817

RESUMEN

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.


Asunto(s)
Neoplasias Encefálicas/genética , Metilación de ADN , Epigenómica/métodos , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/metabolismo , Femenino , Glioma/clasificación , Glioma/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Análisis de Supervivencia , Secuenciación del Exoma/métodos
16.
J Mol Histol ; 39(5): 553-60, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18726700

RESUMEN

Objective Oligodendroglial tumors with a loss of heterozygosity of 1p (LOH1p) appear to have a better prognosis than oligodendrogliomas without LOH. Previously, we reported glucose uptake in low-grade oligodendroglial tumors to be related to LOH 1p status. Here, we performed an immunohistochemical study of the common glucose transporters (GLUT) in relation to LOH1p. Material and methods We examined 17 oligodendrogliomas (O II, 11 with LOH1p), 16 oligoastrocytomas (OA II, 5 with LOH1p) and 7 astrocytomas (A II, none with LOH1p). Confocal microscopy was performed for p53, GLUT-1, -3 and -12. Immunoreaction was rated semiquantitatively by percentage of positive cells and staining intensity on immunohistological stainings. Results Confocal microscopy depicted immunoreaction for GLUT-1, -3 and -12 in the cytoplasm of the tumor cells. Oligodendrogliomas revealed a lower immunoreactivity for GLUT-1 than oligoastrocytomas and astrocytomas (P = 0.0263). No differences in immunoreactivity were found for GLUT-3 and GLUT-12. GLUT-1 expression in tumors with LOH 1p was significantly lower than in tumors with wild type 1p status (P = 0.0017). GLUT-3 and GLUT-12 immunoreactivity was not correlated with LOH 1p. Conclusion Expression of GLUT-1 is significantly reduced in low-grade oligodendroglial tumors harboring LOH 1p. Further studies should address the functional role of GLUT-1 in regard to chemosensitivity of oligodendrogliomas.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Cromosomas Humanos Par 1/metabolismo , Glioma/metabolismo , Transportador de Glucosa de Tipo 1/biosíntesis , Pérdida de Heterocigocidad , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Cromosomas Humanos Par 1/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Glioma/genética , Glioma/patología , Proteínas Facilitadoras del Transporte de la Glucosa/biosíntesis , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 3/biosíntesis , Transportador de Glucosa de Tipo 3/genética , Humanos , Pérdida de Heterocigocidad/genética , Masculino , Microscopía Confocal/métodos , Persona de Mediana Edad , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genética
17.
Seizure ; 17(1): 76-83, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17728157

RESUMEN

Status epilepticus may cause long-term functional and structural consequences possibly resulting in brain dysfunctions such as chronic epilepsy. In epileptogenesis, the dentate gyrus plays a key role in regulating the excitability of highly vulnerable and potentially epileptogenic downstream structures in the hippocampus proper. One, four and eight weeks after electrically induced status epilepticus, excitability and neuronal degeneration in the rat dentate gyrus were examined with intracerebral electrodes and Fluoro Jade (FJ) staining, respectively. Half of the animals had developed chronic epilepsy by 8 weeks after status epilepticus. Sham-operated controls did not exhibit seizures, and the excitatory parameters remained unchanged. Compared to controls, 8 weeks after status epilepticus the population spike latency in the dentate gyrus was significantly reduced (p<0.05) and substantial neuronal degeneration was seen (p<0.05). In summary, status epilepticus results in functional and morphological alterations in the dentate gyrus likely contributing to epileptogenesis.


Asunto(s)
Giro Dentado/patología , Giro Dentado/fisiopatología , Estado Epiléptico/patología , Estado Epiléptico/fisiopatología , Animales , Enfermedad Crónica , Interpretación Estadística de Datos , Estimulación Eléctrica , Electrodos Implantados , Potenciales Postsinápticos Excitadores/fisiología , Fluoresceínas , Colorantes Fluorescentes , Masculino , Neuronas/patología , Compuestos Orgánicos , Ratas , Grabación de Cinta de Video
20.
Regul Pept ; 142(1-2): 52-9, 2007 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-17346813

RESUMEN

White matter oligodendrocytes have been shown to actively regulate extracellular glutamate levels in the CNS. Such function has yet not been examined in satellite oligodendrocytes of gray matter. Similar to those in white matter, satellite oligodendrocytes are involved in myelination. In addition, they modulate the activity of surrounding neurons. This study examined whether satellite oligodendrocytes express PACAP and glutamate transporter proteins and whether this expression is influenced by global ischemia. We demonstrated expression of PACAP27 and PACAP38 in a major fraction of satellite oligodendrocytes in normal neocortex and hippocampus of human brain tissues obtained post-mortem. All three glutamate transporters EAAT1, EAAT2 and EAAT3 were expressed in satellite oligodendrocytes from these tissues. Thus, satellite oligodendrocytes may participate in the perineuronal glutamate homeostasis. Following transient global ischemia, the total number of satellite oligodendrocytes expressing PACAP or glutamate transporter proteins was significantly decreased in cerebral neocortex and hippocampus. However, alterations of PACAP and glutamate transporter protein expression were region and time specific. In satellite oligodendrocytes of CA1 an early strong reduction of PACAP and glutamate transporter expression was observed. This contrasted with late reduction of PACAP27, PACAP38 and glutamate transporters EAAT1, EAAT2 and EAAT3 in satellite oligodendrocytes of neocortex. Further studies should clarify whether these alterations in protein expression are primary or secondary to neuronal cell death.


Asunto(s)
Proteínas de Transporte de Glutamato en la Membrana Plasmática/metabolismo , Oligodendroglía/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/metabolismo , Transportador 3 de Aminoácidos Excitadores/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Ácido Glutámico/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Humanos , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Neocórtex/citología , Neocórtex/metabolismo
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