RESUMO
Whole genome analyses were performed to test the hypothesis that temporal cortical gene expression differs between epilepsy patients rendered seizure-free versus non-seizure-free following anterior temporal lobectomy with amygdalohippocampectomy (ATL/AH). Twenty four patients underwent ATL/AH to treat medically intractable seizures of temporal lobe origin (mean age 35.5 years, mean follow-up 42.2 months); they were then dichotomized into seizure-free and non-seizure-free groups. Tissue RNA was isolated from the lateral temporal cortex and gene expression analysis was performed. Whole genome data were analyzed for prognostic value for seizure-free outcome following ATL/AH by logistic regression. Genes that could distinguish seizure outcome groups were identified based on providing an accuracy of >0.90 judging by area under the receiver operating characteristic curve, AUC, with a P value of the slope coefficient of <0.05. Four genes and seven RNA probes were with prognostic value for post-operative seizure-free outcome. Gene expression associated with seizure-free outcome included relative down-regulation of zinc finger protein 852 (ZNF852), CUB domain-containing protein 2 (CDCP2), proline-rich transmembrane protein 1 (PRRT1), hypothetical LOC440200 (FLJ41170), RNA probe 8047763, RNA probe 8126238, RNA probe 8113489, RNA probe 8092883, RNA probe 7935228, RNA probe 806293, and RNA probe 8104131. This study describes the predictive value of temporal cortical gene expression for seizure-free outcome after ATL/AH. Four genes and seven RNA probes were found to predict post-operative seizure-free outcome. Future prospective investigation of these genes and probes in human brain tissue and blood could establish new biomarkers predictive of seizure outcome following ATL/AH.
Assuntos
Tonsila do Cerebelo/cirurgia , Lobectomia Temporal Anterior , Epilepsia/genética , Epilepsia/cirurgia , Expressão Gênica , Hipocampo/cirurgia , Lobo Temporal/metabolismo , Adolescente , Adulto , Criança , Epilepsia/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA/genética , Lobo Temporal/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens including surgical resection, radiation and chemotherapy. EGFRvIII is a truncated extracellular mutant of the EGF receptor (EGFR) found in about a third of GBMs. It confers enhanced tumorigenic behavior and is associated with chemo- and radio-resistance. GBM patients testing positive for EGFRvIII have a bleaker prognosis than those who do not. Targeting EGFRvIII positive tumors via vaccines or antibody-drug-conjugates represents a new challenging therapeutic avenue with potential great clinical benefits. In this study, we developed a strategy to detect EGFRvIII deletion in the circulating tumor DNA. The overall goal is to identify a simple and robust biomarker in the peripheral blood of patients diagnosed with GBM in order to follow their disease status while on treatment. Thirteen patients were included in this study, three of which were found to carry the EGFRvIII deletion. The circulating DNA status for EGFRvIII correlates with the analysis performed on the respective tumor samples, and its level seems to correlate with the extent of the tumor resection. This semi-quantitative blood biomarker may represent a strategy to (1) screen patients for an anti-EGFRvIII therapy and (2) monitor the patients' response to treatment.
Assuntos
Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/genética , DNA de Neoplasias/sangue , Receptores ErbB/genética , Deleção de Genes , Mutação/genética , Adulto , Neoplasias Encefálicas/diagnóstico , Primers do DNA/genética , Receptores ErbB/sangue , Estudos de Viabilidade , Seguimentos , Humanos , Projetos Piloto , Reação em Cadeia da Polimerase , PrognósticoRESUMO
Eosinophil migration from circulation is controlled, in part, by chemokines through a family of G-protein-coupled chemokine receptors (CCR). Studies of human eosinophils have demonstrated that signaling through CCR3 receptors is a prominent pathway leading to chemotaxis, although several other receptor-ligand interactions also appear to mediate eosinophil recruitment. The availability of genetically unique strains of mice permits a reductionist approach to assess the signaling pathways in experimental models of human disease. However, despite similarities in these pathways between mice and humans, significant species differences exist, complicating the translation of results from animal models to humans. Purified mouse eosinophils were used in this study to investigate the chemokine receptor expression and the activities of 18 chemokines. Mouse eosinophils isolated from IL-5 transgenic mice expressed transcripts encoding the chemokine receptors CCR1, CCR2, CCR3, CCR5, CCR8, CXCR2, and CXCR4, but not CCR4. Mouse eosinophils also migrated in response to human and mouse eotaxin-1 and -2, but not human eotaxin-3. In addition, the induced migration of mouse eosinophils by TARC, MIP-1beta, and KC suggests that unidentified receptor-ligand interactions contribute to eosinophil recruitment. It is interesting that the potent chemoattractant of human eosinophils, RANTES, was unable to mediate mouse eosinophil migration. Furthermore, despite the ability of MIP-1alpha to bind receptors on purified mouse eosinophils, it was only able to induce significant eosinophil migration in a mixed splenocyte population and was unable to induce migration of highly purified eosinophils. Collectively, these observations reveal physiologically relevant distinctions in mechanisms mediating human and mouse eosinophil migration that potentially reflect evolutionary disparities between these species.
Assuntos
Quimiotaxia de Leucócito/fisiologia , Eosinófilos/fisiologia , Receptores de Quimiocinas/fisiologia , Sequência de Aminoácidos , Animais , Cálcio/sangue , Quimiocina CCL5/genética , Eosinófilos/imunologia , Humanos , Ligantes , Linfócitos/imunologia , Camundongos , Dados de Sequência Molecular , Filogenia , Receptores CCR3 , Receptores de Quimiocinas/sangue , Receptores de Quimiocinas/química , Receptores de Quimiocinas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Baço/citologiaRESUMO
Objectives Intracranial penetration by foreign bodies entering via the orbit represent an unusual form of traumatic brain injury. Nevertheless, much is at stake with high risk for cranial nerve and neurovascular injury. We present a case where the bristled end of a toothbrush entered the brain as a projectile via the superior orbital fissure and discuss considerations for surgical management. Setting A 35-year-old woman suffered a periorbital injury after her husband threw an electric toothbrush at a wall and the head of the toothbrush became a missile that projected through her superior orbital fissure and into her right temporal lobe. She complained of headache and incomplete vision loss in the affected eye. Intervention After obtaining a cerebrovascular angiogram, we proceeded with emergent orbital decompression and anterograde extraction of the foreign body via a modified frontotemporal orbitozygomatic approach with drilling of the skull base allowing for en bloc removal of the toothbrush. Conclusions The patient recovered well with improvement in her vision and partial third and sixth nerve palsies. This report illustrates a unique mechanism of injury with a novel intracranial foreign body. We review the neurosurgeon's need for prompt management with an approach customized to the structure of the offending object, the damaged elements, and the surrounding cranial nerves and vascular anatomy.
RESUMO
The complexity and magnitude of interactions leading to the selective infiltration of eosinophils in response to inhaled allergens are formidable obstacles to a larger understanding of the pulmonary pathology associated with allergic asthma. This study uses knockout mice to demonstrate a novel function for the heterotrimeric G protein, G(q), in the regulation of pulmonary eosinophil recruitment. In the absence of G(q) signaling, eosinophils failed to accumulate in the lungs following allergen challenge. These studies demonstrate that the inhibition of eosinophil accumulation in the airways is attributed to the failure of hemopoietically derived cells to elaborate GM-CSF in the airways. The data suggest that activation of a G(q)-coupled receptor(s) on resident leukocytes in the lung elicits expression of GM-CSF, which, in turn, is required for allergen-induced pulmonary eosinophilia, identifying a novel pathway of eosinophil-associated effector functions leading to pulmonary pathology in diseases such as asthma.
Assuntos
Alérgenos/administração & dosagem , Proteínas Heterotriméricas de Ligação ao GTP/fisiologia , Eosinofilia Pulmonar/imunologia , Aerossóis , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Fatores Quimiotáticos de Eosinófilos/farmacologia , Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , Citocinas/biossíntese , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Proteínas Heterotriméricas de Ligação ao GTP/deficiência , Proteínas Heterotriméricas de Ligação ao GTP/genética , Injeções Intraperitoneais , Intubação Intratraqueal , Contagem de Leucócitos , Ativação Linfocitária/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Eosinofilia Pulmonar/etiologia , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/patologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
Asthma and mouse models of allergic respiratory inflammation are invariably associated with a pulmonary eosinophilia; however, this association has remained correlative. In this report, a causative relationship between eosinophils and allergen-provoked pathologies was established using eosinophil adoptive transfer. Eosinophils were transferred directly into the lungs of either naive or OVA-treated IL-5(-/-) mice. This strategy resulted in a pulmonary eosinophilia equivalent to that observed in OVA-treated wild-type animals. A concomitant consequence of this eosinophil transfer was an increase in Th2 bronchoalveolar lavage cytokine levels and the restoration of intracellular epithelial mucus in OVA-treated IL-5(-/-) mice equivalent to OVA-treated wild-type levels. Moreover, the transfer also resulted in the development of airway hyperresponsiveness. These pulmonary changes did not occur when eosinophils were transferred into naive IL-5(-/-) mice, eliminating nonspecific consequences of the eosinophil transfer as a possible explanation. Significantly, administration of OVA-treated IL-5(-/-) mice with GK1.5 (anti-CD4) Abs abolished the increases in mucus accumulation and airway hyperresponsiveness following adoptive transfer of eosinophils. Thus, CD4(+) T cell-mediated inflammatory signals as well as signals derived from eosinophils are each necessary, yet alone insufficient, for the development of allergic pulmonary pathology. These data support an expanded view of T cell and eosinophil activities and suggest that eosinophil effector functions impinge directly on lung function.