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1.
Neurol Res ; 45(1): 81-85, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36208460

RESUMO

AIM: Peripheral nerve tumors (PNT) are rare lesions. To date, no systematic multicenter studies on epidemiology, clinical symptoms, treatment strategies and outcomes, genetic and histopathologic features, as well as imaging characteristics of PNT were published. The main goal of our PNT Registry is the systematic multicenter investigation to improve our understanding of PNT and to assist future interventional studies in establishing hypotheses, determining potential endpoints, and assessing treatment efficacy. METHODS: Aims of the PNT registry were set at the 2015 Meeting of the Section of Peripheral Nerve Surgery of the German Society of Neurosurgery. A study protocol was developed by specialists in PNT care. A minimal data set on clinical status, treatment types and outcomes is reported by each participating center at initial contact with the patient and after 1 year, 2 years, and 5 years. Since the study is coordinated by the Charité Berlin, the PNR Registry was approved by the Charité ethics committee (EA4/058/17) and registered with the German Trials Registry (www.drks.de). On a national level, patient inclusion began in June 2016. The registry was rolled out across Europe at the 2019 meeting of the European Association of Neurosurgery in Dublin. RESULTS: Patient recruitment has been initiated at 10 centers throughout Europe and 14 additional centers are currently applying for local ethics approval. CONCLUSION: To date, the PNT registry has grown into an international study group with regular scientific and clinical exchange awaiting the first results of the retrospective study arm.


Assuntos
Neoplasias do Sistema Nervoso Periférico , Humanos , Estudos Retrospectivos , Sistema de Registros , Europa (Continente) , Estudos de Coortes
2.
Neuropathology ; 33(1): 68-74, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22537231

RESUMO

Extrapleural solitary fibrous tumors are uncommon mesenchymal neoplasms frequently observed in middle-aged adults and are classified, according to the WHO classification of soft tissue tumors, as part of the hemangiopericytoma tumor group. However, these two entities remain separated in the WHO classification of tumors of the central nervous system. In fact, meningeal solitary fibrous tumors are believed to be benign lesion and only in a minority of cases local relapses have been described, although detailed survival clinical studies on solitary fibrous tumors of meninges are rare. In contrast to hemangiopericytoma, which frequently shows distant extracranial metastases, such an event is exceptional in patients with meningeal solitary fibrous tumors and has been clinically reported in a handful of cases only and their histopathological features have not been investigated in detail. In this report, we describe the detailed clinico-pathological features of a meningeal solitary fibrous tumor presenting during a 17-year follow-up period, multiple intra-, extracranial relapses and lung metastases.


Assuntos
Neoplasias Meníngeas/patologia , Tumores Fibrosos Solitários/secundário , Feminino , Humanos , Meninges/patologia , Pessoa de Meia-Idade , Recidiva
3.
J Mol Biol ; 396(5): 1260-70, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20070948

RESUMO

Clostridium difficile is a nosocomial bacterial pathogen causing antibiotic-associated diarrhea and fatal pseudomembranous colitis. Key virulence factors are toxin A and toxin B (TcdB), two highly related toxins that are members of the large clostridial toxin family. These large multifunctional proteins disrupt cell function using a glucosyltransferase domain that is translocated into the cytosol after vesicular internalization of intact holotoxin. Although substantial information about the biochemical mechanisms of intoxication exists, research has been hampered by limited structural information, particularly of intact holotoxin. Here, we used small-angle X-ray scattering (SAXS) methods to obtain an ab initio low-resolution structure of native TcdB, which demonstrated that this molecule is monomeric in solution and possesses a highly asymmetric shape with a maximum dimension of approximately 275 A. Combining this SAXS information with crystallographic or modeled structures of individual functional domains of TcdB reveals for the first time that the three-dimensional structure of TcdB is organized into four distinct structural domains. Structures of the N-terminal glucosyltransferase, the cysteine protease, and the C-terminal repeat region can be aligned within three domains of the SAXS envelope. A fourth domain, predicted to be involved in the translocation of the glucosyltransferase, appears as a large solvent-exposed protrusion. Knowledge of the shapes and relative orientations of toxin domains provides new insight into defining functional domain boundaries and provides a framework for understanding how potential intra-domain interactions enable conformational changes to propagate between domains to facilitate intoxication processes.


Assuntos
Proteínas de Bactérias/química , Toxinas Bacterianas/química , Clostridioides difficile/química , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/toxicidade , Toxinas Bacterianas/genética , Toxinas Bacterianas/toxicidade , Clostridioides difficile/genética , Clostridioides difficile/patogenicidade , Cristalografia por Raios X , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Sequências Repetitivas de Aminoácidos , Espalhamento a Baixo Ângulo , Homologia de Sequência de Aminoácidos , Homologia Estrutural de Proteína , Difração de Raios X
4.
Neoplasia ; 11(8): 743-52, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19649204

RESUMO

Because evasion of apoptosis can cause radioresistance of glioblastoma, there is a need to design rational strategies that counter apoptosis resistance. In the present study, we investigated the potential of targeting the antiapoptotic protein XIAP for the radiosensitization of glioblastoma. Here, we report that small-molecule XIAP inhibitors significantly enhance gamma-irradiation-induced loss of viability and apoptosis and cooperate with gamma-irradiation to suppress clonogenic survival of glioblastoma cells. Analysis of molecular mechanisms reveals that XIAP inhibitors act in concert with gamma-irradiation to cause mitochondrial outer membrane permeabilization, caspase activation, and caspase-dependent apoptosis. Importantly, XIAP inhibitors also sensitize primary cultured glioblastoma cells derived from surgical specimens as well as glioblastoma-initiating stemlike cancer stem cells for gamma-irradiation. In contrast, they do not increase the toxicity of gamma-irradiation on some nonmalignant cells of the central nervous system, including rat neurons or glial cells, pointing to some tumor selectivity. In conclusion, by demonstrating for the first time that small-molecule XIAP inhibitors increase the radiosensitivity of glioblastoma cells while sparing normal cells of the central nervous system, our findings build the rationale for further (pre)clinical development of XIAP inhibitors in combination with gamma-irradiation in glioblastoma.


Assuntos
Apoptose/efeitos dos fármacos , Raios gama/uso terapêutico , Glioblastoma/terapia , Radiossensibilizantes/farmacologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Animais , Apoptose/efeitos da radiação , Western Blotting , Caspases/efeitos dos fármacos , Terapia Combinada , Fragmentação do DNA/efeitos dos fármacos , Fragmentação do DNA/efeitos da radiação , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos da radiação , Tolerância a Radiação , Ratos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/efeitos dos fármacos
5.
Cancer Res ; 68(15): 6271-80, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18676851

RESUMO

The aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway has been reported to correlate with adverse clinical outcome in human glioblastoma in vivo. However, the question of how this survival network can be successfully targeted to restore the sensitivity of glioblastoma to apoptosis induction has not yet been answered. Here, we report that inhibition of PI3K by LY294002 broadly sensitizes wild-type and mutant PTEN glioblastoma cells to both death receptor- and chemotherapy-induced apoptosis, whereas mammalian target of rapamycin (mTOR) inhibition is not sufficient to restore apoptosis sensitivity. LY294002 significantly enhances apoptosis triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), agonistic anti-CD95 antibodies, or several anticancer drugs (i.e., doxorubicin, etoposide, and vincristine) in a highly synergistic manner. In addition, LY294002 cooperates with TRAIL or doxorubicin to suppress colony formation, thus also showing a strong effect on long-term survival. Similarly, genetic knockdown of PI3K subunits p110alpha and/or p110beta by RNA interference (RNAi) primes glioblastoma cells for TRAIL- or doxorubicin-mediated apoptosis. In contrast to PI3K inhibition, pharmacologic or genetic blockade of mTOR by RAD001 (everolimus), rapamycin, or RNAi fails to enhance TRAIL- or doxorubicin-induced apoptosis. Analysis of apoptosis pathways reveals that PI3K inhibition acts in concert with TRAIL or doxorubicin to trigger mitochondrial membrane permeabilization, caspase activation, and caspase-dependent apoptosis, which are abolished by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Most importantly, PI3K inhibition by LY294002 sensitizes primary cultured glioblastoma cells obtained from surgical specimens to TRAIL- or chemotherapy-induced cell death. By showing that PI3K inhibition broadly primes glioblastoma cells for apoptosis, our findings provide the rationale for using PI3K inhibitors in combination regimens to enhance TRAIL- or chemotherapy-induced apoptosis in glioblastoma.


Assuntos
Apoptose/fisiologia , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Inibidores de Fosfoinositídeo-3 Quinase , Receptores de Morte Celular/fisiologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Neoplasias Encefálicas/enzimologia , Doxorrubicina/farmacologia , Glioblastoma/enzimologia , Humanos , Microscopia Confocal , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases/efeitos dos fármacos , Interferência de RNA , Transdução de Sinais , Serina-Treonina Quinases TOR
6.
J Neurosurg Spine ; 8(3): 237-45, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18312075

RESUMO

OBJECT: Although transpedicular fixation is a biomechanically superior technique, it is not routinely used in the cervical spine. The risk of neurovascular injury in this region is considered high because the diameter of cervical pedicles is very small and their angle of insertion into the vertebral body varies. This study was conducted to analyze the clinical accuracy of stereotactically guided transpedicular screw insertion into the cervical spine. METHODS: Twenty-seven patients underwent posterior stabilization of the cervical spine for degenerative instability resulting from myelopathy, fracture/dislocation, tumor, rheumatoid arthritis, and pyogenic spondylitis. Fixation included 1-6 motion segments (mean 2.2 segments). Transpedicular screws (3.5-mm diameter) were placed using 1 of 2 computer-assisted guidance systems and lateral fluoroscopic control. The intraoperative mean deviation of frameless stereotaxy was < 1.9 mm for all procedures. RESULTS: No neurovascular complications resulted from screw insertion. Postoperative computed tomography (CT) scans revealed satisfactory positioning in 104 (90%) of 116 cervical pedicles and in all 12 thoracic pedicles. A noncritical lateral or inferior cortical breach was seen with 7 screws (6%). Critical malplacement (4%) was always lateral: 5 screws encroached into the vertebral artery foramen by 40-60% of its diameter; Doppler sonographic controls revealed no vascular compromise. Screw malplacement was mostly due to a small pedicle diameter that required a steep trajectory angle, which could not be achieved because of anatomical limitation in the exposure of the surgical field. CONCLUSIONS: Despite the use of frameless stereotaxy, there remains some risk of critical transpedicular screw malpositioning in the subaxial cervical spine. Results may be improved by the use of intraoperative CT scanning and navigated percutaneous screw insertion, which allow optimization of the transpedicular trajectory.


Assuntos
Artrite Reumatoide/cirurgia , Fraturas Ósseas/cirurgia , Fixadores Internos , Laminectomia/instrumentação , Mielite/cirurgia , Neuronavegação/instrumentação , Radiocirurgia/instrumentação , Neoplasias da Coluna Vertebral/cirurgia , Espondilite/cirurgia , Adolescente , Adulto , Idoso , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/patologia , Parafusos Ósseos , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mielite/diagnóstico por imagem , Mielite/patologia , Cuidados Pós-Operatórios , Complicações Pós-Operatórias/epidemiologia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/patologia , Espondilite/diagnóstico por imagem , Espondilite/patologia , Cirurgia Assistida por Computador/instrumentação , Tomografia Computadorizada por Raios X
7.
Z Med Phys ; 17(4): 250-7, 2007.
Artigo em Alemão | MEDLINE | ID: mdl-18254547

RESUMO

Information concerning the tissue adjacent to a brain tumour is crucial for planning and performing a neurosurgical intervention. In this study, we evaluated the usefulness of functional imaging of working memory in terms of working memory preservation. Working memory performance of 14 patients with prefrontal tumours was tested preoperatively by means of a standardized neuropsychological test battery. Also, functional magnetic resonance imaging (fMRI) using a so-called two-back paradigm was performed to visualize brain areas related to that task. Working memory areas were reliably detected in all patients. Surgery was then planned on the basis of this information, and the data were used for intra-operative cranial neuronavigation. Three to twelve months after surgery, patients were tested again with the test battery in order to detect possible changes in working memory performance. In 13 cases the memory performance was unchanged, only one female patient had a slight impairment of working memory compared to the pre-operative status.


Assuntos
Mapeamento Encefálico/métodos , Neoplasias Encefálicas/cirurgia , Imageamento por Ressonância Magnética/métodos , Memória , Procedimentos Neurocirúrgicos , Cuidados Pré-Operatórios , Neoplasias Encefálicas/patologia , Humanos , Testes Neuropsicológicos , Cuidados Pós-Operatórios
8.
J Neurosurg ; 97(2 Suppl): 207-12, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12296680

RESUMO

OBJECT: Botulinum toxin injections are the best therapeutic option in patients with spasmodic torticollis. Although a small number of patients do not benefit from such therapy, the majority respond well but may develop antibodies to the toxin after repeated applications. In those termed primary nonresponders, no improvement related to botulinum toxin has been shown. In patients in whom no response was shown and those in whom resistance to the therapy developed, selective peripheral denervation is a neurosurgical option. METHODS: Between June 1988 and August 2001, 155 patients underwent selective peripheral denervation. Surgery was performed at a mean of 8.5 years after the onset of symptoms (range 0.5-37 years). The mean age of the patients at the onset of dystonia was 39.7 years (range 17-77 years). For evaluation of results, patients' responses were assessed. Results were obtained in 140 patients in whom the follow-up period ranged from 3 to 124 months (mean 32.8 months): 18 reported complete relief of their symptoms, 50 significant relief, and 34 moderate relief; 19 noted only minor relief and the remaining 19 no improvement. The results differ substantially when compared with those previously demonstrated in patients who received botulinum toxin injections. Although 80% of the secondary nonresponders were satisfied with the result of surgery, only 62% of the primary nonresponders considered the operation helpful. There were no major side effects. The recurrence rate was 11%. CONCLUSIONS: The injection of botulinum toxin should be the first-choice treatment. If surgery is required, selective peripheral denervation provides the best results and has the fewest side effects compared with all surgical options.


Assuntos
Denervação Muscular/métodos , Músculos do Pescoço/inervação , Nervos Periféricos/cirurgia , Torcicolo/cirurgia , Adolescente , Adulto , Idoso , Toxinas Botulínicas Tipo A/uso terapêutico , Estimulação Elétrica , Feminino , Seguimentos , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Nervos Periféricos/fisiopatologia , Complicações Pós-Operatórias/etiologia , Recidiva , Raízes Nervosas Espinhais/fisiopatologia , Raízes Nervosas Espinhais/cirurgia , Torcicolo/tratamento farmacológico , Torcicolo/fisiopatologia , Falha de Tratamento
9.
Acta Neuropathol ; 104(3): 231-40, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12172908

RESUMO

Cavernous malformations are vascular anomalies that can cause severe neurological deficits, seizures and hemorrhagic stroke if these lesions are located in the brain. In patients with cavernomas, constitutional mutations of the KRIT1 gene have been identified. The pathogenetic mechanisms leading to cerebral cavernous malformations (CCM) development are poorly understood. CCM development might be induced in utero owing to the underlying KRIT1 defect, and is triggered by environmental factors. Another model suggests that CCM develop according to the two-hit model of tumorigenesis associated with biallelic inactivation of KRIT1. So far, CCM specimens themselves have not been subjected to mutation analysis. We identified two somatic mutations in the cavernoma of a sporadic case, suggesting that pathogenesis is associated with somatic KRIT1 alterations. To gain a better understanding of the role of KRIT1 during morphogenesis, the main goal of this study was to provide a detailed description of the spatio-temporal expression pattern of Krit1 and its interaction partner Rap1A during mouse embryogenesis. We did not observe enhanced expression of either gene in the heart or large vessels; however, their expression in the developing small vessels or capillaries could not be assessed by the methods applied. At early embryonic stages, Krit1 and, to a lesser extent, Rap1A are expressed in the developing nervous system. During later phases of fetal development, specific expression of both genes is observed in regions of ossification, the dermis, tendons and in the meninges. These findings provide evidence of differential Krit1 and Rap1A expression during mouse ontogenesis and suggest a more widespread functional significance of Krit1, not restricted to vascular endothelial cells.


Assuntos
Malformações Vasculares do Sistema Nervoso Central/genética , Desenvolvimento Embrionário e Fetal/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas/genética , Proteínas rap1 de Ligação ao GTP/biossíntese , Proteínas rap1 de Ligação ao GTP/genética , Adulto , Animais , Animais Recém-Nascidos , Humanos , Hibridização In Situ , Proteína KRIT1 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Mutação Puntual , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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