RESUMO
Ubiquitin-like proteins (Ubls) in eukaryotes and bacteria mediate sulfur transfer for the biosynthesis of sulfur-containing biomolecules and form conjugates with specific protein targets to regulate their functions. Here, we investigated the functions and physiological importance of Ubls in a hyperthermophilic archaeon by constructing a series of deletion mutants. We found that the Ubls (TK1065, TK1093, and TK2118) in Thermococcus kodakarensis are conjugated to their specific target proteins, and all three are involved in varying degrees in the biosynthesis of sulfur-containing biomolecules such as tungsten cofactor (Wco) and tRNA thiouridines. TK2118 (named UblB) is involved in the biosynthesis of Wco in a glyceraldehyde 3-phosphate:ferredoxin oxidoreductase, which is required for glycolytic growth, whereas TK1093 (named UblA) plays a key role in the efficient thiolation of tRNAs, which contributes to cellular thermotolerance. Intriguingly, in the presence of elemental sulfur (S0) in the culture medium, defective synthesis of these sulfur-containing molecules in Ubl mutants was restored, indicating that T. kodakarensis can use S0 as an alternative sulfur source without Ubls. Our analysis indicates that the Ubl-mediated sulfur-transfer system in T. kodakarensis is important for efficient sulfur assimilation, especially under low S0 conditions, which may allow this organism to survive in a low sulfur environment.IMPORTANCESulfur is a crucial element in living organisms, occurring in various sulfur-containing biomolecules including iron-sulfur clusters, vitamins, and RNA thionucleosides, as well as the amino acids cysteine and methionine. In archaea, the biosynthesis routes and sulfur donors of sulfur-containing biomolecules are largely unknown. Here, we explored the functions of Ubls in the deep-blanched hyperthermophilic archaeon, Thermococcus kodakarensis. We demonstrated functional redundancy of these proteins in the biosynthesis of tungsten cofactor and tRNA thiouridines and the significance of these sulfur-carrier functions, especially in low sulfur environments. We propose that acquisition of a Ubl sulfur-transfer system, in addition to an ancient inorganic sulfur assimilation pathway, enabled the primordial archaeon to advance into lower-sulfur environments and expand their habitable zone.
Assuntos
Proteínas Arqueais , Enxofre , Thermococcus , Thermococcus/genética , Thermococcus/metabolismo , Enxofre/metabolismo , Proteínas Arqueais/genética , Proteínas Arqueais/metabolismo , Ubiquitinas/metabolismo , Ubiquitinas/genética , RNA de Transferência/metabolismo , RNA de Transferência/genéticaRESUMO
PURPOSE: The humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184). MATERIALS AND METHODS: VEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response. RESULTS: Sixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas. CONCLUSION: This study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.
Assuntos
Vacinas Anticâncer , Neurilemoma , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Neurilemoma/imunologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neurofibromatose 2 , Adulto Jovem , Idoso , NeurofibromatosesRESUMO
N6-methyladenosine (m6A) is a modification that plays pivotal roles in RNA metabolism and function, although its functions in spliceosomal U6 snRNA remain unknown. To elucidate its role, we conduct a large-scale transcriptome analysis of a Schizosaccharomyces pombe strain lacking this modification and found a global change of pre-mRNA splicing. The most significantly impacted introns are enriched for adenosine at the fourth position pairing the m6A in U6 snRNA, and exon sequences weakly recognized by U5 snRNA. This suggests cooperative recognition of 5' splice site by U6 and U5 snRNPs, and also a role of m6A facilitating efficient recognition of the splice sites weakly interacting with U5 snRNA, indicating that U6 snRNA m6A relaxes the 5' exon constraint and allows protein sequence diversity along with explosively increasing number of introns over the course of eukaryotic evolution.
Assuntos
Regulação Fúngica da Expressão Gênica , Splicing de RNA , RNA Fúngico/metabolismo , RNA Nuclear Pequeno/metabolismo , Schizosaccharomyces/genética , Regiões 3' não Traduzidas/genética , Regiões 5' não Traduzidas/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Éxons/genética , Espectrometria de Massas , Metiltransferases/genética , Metiltransferases/isolamento & purificação , Metiltransferases/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , Sítios de Splice de RNA/genética , RNA Fúngico/genética , RNA Nuclear Pequeno/genética , RNA-Seq , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6 , Ribonucleoproteína Nuclear Pequena U5 , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/isolamento & purificação , Proteínas de Schizosaccharomyces pombe/metabolismoRESUMO
Delivery systems to lymph node-resident T cells around tumor tissues are essential for cancer immunotherapy, in order to boost the immune responses. We previously reported that anionic dendrimers, such as carboxyl-, sulfonyl-, and phosphate-terminal dendrimers, were efficiently accumulated in lymph nodes via the intradermal injection. Depending on the terminal structure, their cell association properties were different, and the carboxyl-terminal dendrimers did not associate with any immune cells majorly. In this study, we investigated the delivery of carboxyl-terminal dendrimers with different hydrophobicity to lymph node-resident lymphocytes. Four types of carboxyl-terminal dendrimers-succinylated (C) and 2-carboxy-cyclohexanoylated (Chex) dendrimers with and without phenylalanine (Phe)-were synthesized and named C-den, C-Phe-den, Chex-den, and Chex-Phe-den, respectively. Chex-Phe-den was well associated with lymphocytes, but others were not. Chex-Phe-den, intradermally injected at the footpads of mice, was accumulated in the lymph node, and was highly associated with the lymphocytes, including T cells. Our results suggest that Chex-Phe-den has the potential for delivery to the lymph node-resident T cells, without any specific T cell-targeted ligands.
RESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
The development of drug delivery vehicles to cancer and/or immune cells in lymph nodes is important for cancer diagnosis, therapy, and immunotherapy. We previously reported that anionic carboxyl-terminal dendrimers were accumulated in lymph nodes. In this study, three anionic dendrimers with carboxyl-, sulfonyl-, and phosphate-terminal groups were prepared to examine the lymph node targeting and the association with immune cells in the lymph nodes. These anionic dendrimers were accumulated in the lymph node by intradermal injection. Although the carboxyl- and sulfonyl-terminal dendrimers were diffused from the injection site, the phosphate-terminal dendrimers were mostly retained. The phosphate-terminal dendrimer was recognized by the macrophages, dendritic cells, and B cells in the lymph node, whereas the carboxyl- and sulfonyl-terminal dendrimers were not. Our results show that these anionic dendrimers were accumulated in the lymph node where the association with immune cells could be controlled by the terminal structure of the dendrimer. The phosphate-terminal dendrimer can be used as a nanoplatform for the delivery of some bioactive molecules to some immune cells, including B cells, in the lymph node.
Assuntos
Dendrímeros/farmacocinética , Portadores de Fármacos , Corantes Fluorescentes/farmacocinética , Linfonodos/metabolismo , Nanopartículas , Imagem Óptica , Animais , Dendrímeros/administração & dosagem , Dendrímeros/síntese química , Composição de Medicamentos , Feminino , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/química , Injeções Intradérmicas , Linfonodos/diagnóstico por imagem , Linfonodos/imunologia , Camundongos Endogâmicos BALB C , Fosforilação , Distribuição TecidualRESUMO
The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2.
Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Neurofibromatose 2/terapia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Adolescente , Adulto , Bevacizumab/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neurofibromatose 2/imunologia , Neurofibromatose 2/patologia , Radiocirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral/imunologia , Vacinação/efeitos adversos , Vacinação/métodos , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto JovemRESUMO
Pure aqueductal tumor (PAT) typically originates from pure aqueductal region and is extremely rare. It is radiographically similar to tectal glioma. We examined two patients with PATs who were diagnosed with pilocytic astrocytoma and rosette-forming glioneuronal tumor. Both cases showed a progressive clinical course. It is important to distinguish between PAT and tectal glioma by radiographic imaging because the treatment strategy is different. While observation is common for tectal gliomas, a biopsy is recommended at the same time of endoscopic third ventriculostomy for PAT with hydrocephalus. Low-grade PATs show an aggressive clinical course in some cases. Our two cases also showed aggressive course in spite of no genetic aggressive mutations. Sagittal view by constructive interference in steady state (CISS) imaging was helpful to make an accurate diagnosis of PAT. Close observation is needed if PAT is diagnosed as low-grade tumor.
Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Aqueduto do Mesencéfalo/patologia , Adulto , Astrocitoma/diagnóstico por imagem , Astrocitoma/genética , Astrocitoma/cirurgia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Aqueduto do Mesencéfalo/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Isocitrato Desidrogenase/genética , Masculino , Proteínas Proto-Oncogênicas B-raf/genética , VentriculostomiaRESUMO
OBJECTIVE: The purpose of this study was to clarify the clinical and molecular characteristics associated with long-term survival in patients with glioblastoma. METHODS: We analyzed the characteristics of 96 glioblastoma patients. Long-term survivors (LTSs) were classified into moderate LTSs (mLTSs), who survived >3 years, and LTSs, who survived >5 years, and compared with short-term survivors (STSs). Clinical and molecular factors were investigated. RESULTS: Younger age, better recursive partitioning analysis class, lack of subventricular zone (SVZ) involvement, promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, and loss of 19q were associated with mLTSs as compared with STSs. After adjustment for these factors, younger age and MGMT methylation remained independently associated with mLTSs. Younger age, better recursive partitioning analysis class, lack of SVZ involvement, and loss of 19q were associated with LTSs as compared with STSs. After adjustment, younger age and better preoperative Karnofsky performance scale (KPS) score remained independently associated with LTSs. Kaplan-Meier analyses revealed that younger age (<50 years), better preoperative KPS score (≥70), lack of SVZ involvement, and loss of 19q were associated with longer overall survival. In the multivariate analysis, only age was significantly associated with overall survival. CONCLUSIONS: Younger age and better preoperative KPS score were the characteristics associated with LTSs as compared with STSs. MGMT promoter methylation was associated with mLTSs, but not with LTSs. In addition, lack of SVZ involvement and loss of 19q might be prognostic for longer survival.
Assuntos
Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Adulto , Fatores Etários , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Terapia Combinada , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Leukoencephalopathy, cerebral calcifications, and cysts (LCC) is a rare disease that was first reported by Labrune in 1996. A case of adult-onset LCC was successfully followed up for a long period. CASE PRESENTATION: A 30-year-old female presented with visual field disturbance and seizure on several occasions. Radiographic images revealed multiple supratentorial cysts and calcifications in the bilateral nucleus basalis and cerebella. Aspiration, Ommaya reservoir placement, and nodule removal were performed for the responsible cysts, and the patient had a good postoperative course. DISCUSSION: A tiny, strongly enhanced nodule was identified before cyst formation on her radiographic images. Thus, cyst growth may be related to nodule microbleeding. According to our review, if the responsible cyst is located on the noneloquent area, surgical removal of the cyst should be considered. However, if the responsible cyst is located on the eloquent area, the nodule should be first removed because nodules can bleed and enlarge cysts. CONCLUSION: Careful follow-up is needed, especially for cysts with a strongly enhanced nodule.
Assuntos
Calcinose/diagnóstico , Calcinose/terapia , Cistos do Sistema Nervoso Central/diagnóstico , Cistos do Sistema Nervoso Central/terapia , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/terapia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/cirurgia , Calcinose/diagnóstico por imagem , Calcinose/patologia , Cistos do Sistema Nervoso Central/diagnóstico por imagem , Cistos do Sistema Nervoso Central/patologia , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologiaRESUMO
S-adenosylmethionine (SAM)-dependent methyltransferases regulate a wide range of biological processes through the modification of proteins, nucleic acids, polysaccharides, as well as various metabolites. TYW3/Taw3 is a SAM-dependent methyltransferase responsible for the formation of a tRNA modification known as wybutosine and its derivatives that are required for accurate decoding in protein synthesis. Here, we report the crystal structure of Taw3, a homolog of TYW3 from Sulfolobus solfataricus, which revealed a novel α/ß fold. The sequence motif (S/T)xSSCxGR and invariant aspartate and histidine, conserved in TYW3/Taw3, cluster to form the catalytic center. These structural and sequence features indicate that TYW3/Taw3 proteins constitute a distinct class of SAM-dependent methyltransferases. Using site-directed mutagenesis along with in vivo complementation assays combined with mass spectrometry as well as ligand docking and cofactor binding assays, we have identified the active site of TYW3 and residues essential for cofactor binding and methyltransferase activity.
Assuntos
Proteínas Arqueais/química , Metiltransferases/química , Nucleosídeos/química , S-Adenosilmetionina/química , Sulfolobus solfataricus/química , Motivos de Aminoácidos , Proteínas Arqueais/genética , Proteínas Arqueais/metabolismo , Domínio Catalítico , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Cinética , Metiltransferases/genética , Metiltransferases/metabolismo , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Nucleosídeos/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , S-Adenosilmetionina/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Sulfolobus solfataricus/enzimologiaRESUMO
The trigeminocerebellar artery (TCA) is a unique branch of the basilar artery. We treated two cases of trigeminal neuralgia caused by the TCA. A 72-year-old woman had severe typical trigeminal neuralgia for â¼ 3 years. Thin-slice T2-weighted magnetic resonance imaging revealed an offending TCA. During microvascular decompression (MVD), we found that the TCA was compressing the medial aspect of the trigeminal nerve. We therefore transposed the TCA loop medially and anteriorly away from the nerve and inserted shredded Teflon between the TCA and the trigeminal nerve. Postoperatively, this patient's trigeminal neuralgia resolved, and she remained pain free at her 24-month follow-up. An 80-year-old man had trigeminal neuralgia. Magnetic resonance cisternography revealed that the course of the offending artery was the same as that of the TCA, originating from the superior cerebellar artery. During the MVD, we performed the same procedure as in case 1. Postoperatively, this patient's trigeminal neuralgia resolved, and he remained pain free at his 24-month follow-up. Because the TCA has a unique anatomical course, its decompression may sometimes be difficult.
Assuntos
Artéria Basilar/diagnóstico por imagem , Cirurgia de Descompressão Microvascular/métodos , Neuralgia do Trigêmeo/etiologia , Idoso , Idoso de 80 Anos ou mais , Artéria Basilar/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Resultado do Tratamento , Neuralgia do Trigêmeo/diagnóstico por imagem , Neuralgia do Trigêmeo/cirurgiaRESUMO
In patients with a high-degree of internal carotid artery stenosis, cerebral hemodynamics and metabolism are compromised during ischemia. Revascularization improves cortical hemodynamics and oxygen metabolism during functional activity, but the process by which it occurs is still controversial. Therefore, using functional near-infrared spectroscopy (fNIRS), we investigated the process by which cerebral hemodynamics improve after revascularization surgery. Eight patients with severe carotid artery stenosis were examined using fNIRS during a motor task before and after surgery. We evaluated postoperative changes in total hemoglobin and deoxyhemoglobin (HbR), at 2 weeks after surgery, and again at 3 months after surgery. Parameters measured were the TTP (time to peak) value, defined as the time taken to reach 70% of the maximum total hemoglobin concentration, and the increase in HbR during the motor task. TTP was higher in four patients preoperatively, but this was no longer evident in two of the patients at 2 weeks after surgery. An increase in HbR during the task was observed in six patients before surgery, and was maintained at 2 weeks after surgery. However, in three of these patients, this increase was no longer evident 3 months later. These changes observed using fNIRS suggest that the increase in cerebral blood flow after revascularization surgery is followed by improvement in parenchymal vasodilation and neuronal oxygen metabolism.
Assuntos
Isquemia Encefálica/terapia , Revascularização Cerebral/métodos , Hemodinâmica , Resultado do Tratamento , Idoso , Feminino , Hemeritrina/metabolismo , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Functional preservation is critical in glioma surgery, and the extent of resection influences survival outcome. Neoadjuvant chemotherapy is a promising option because of its potential to facilitate tumor shrinkage and maximum tumor resection. The object of this study was to assess the utility of the neoadjuvant strategy in a prospective series of gliomas with favorable molecular status. Twenty-six consecutive cases of diffuse gliomas of WHO grade II or III with either 1p19q codeletion or MGMT methylation were treated with upfront chemotherapy following maximal safe removal. In cases of incomplete initial surgery, second-look resection was intended after tumor volume decrease by chemotherapy. Among 22 evaluable cases, chemotherapy led to a median change in the sum of the product of perpendicular diameters of -35 %, and 14 out of the 22 cases (64 %) showed objective response. Second-look resection after tumor volume decrease was performed in 12 out of 19 cases of incomplete initial surgery (GTR/STR 9, removal of residual methionine PET uptake 3). The median progression-free survival among the 22 patients with grade II tumors was 57 months, with some cases showing durable progression-free survival after second-look resection. MIB-1 indices of the second-look resected tumors were lower than those of the initial tumors, and the methylation status of the MGMT gene was unchanged. Neoadjuvant chemotherapy based on molecular guidance often produces significant volume decrease of incompletely resected gliomas. Radical second-look resection is an optional advantage of upfront chemotherapy for chemosensitive gliomas compared with initial radiotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/cirurgia , Adulto , Neoplasias Encefálicas/diagnóstico , Deleção Cromossômica , Cromossomos Humanos Par 1 , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Feminino , Glioma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/uso terapêutico , Estudos Prospectivos , Temozolomida , Resultado do Tratamento , Proteínas Supressoras de Tumor/genéticaRESUMO
A neuroendoscopic biopsy is a minimally invasive and useful procedure for the diagnosis and initial management of tumor-associated hydrocephalus. We describe the nationwide investigation of the current status of neuroendoscopic biopsy for intra- and paraventricular tumors in children, as well as the treatment of tumor-associated hydrocephalus in pediatric patients. The main items examined included the patient's age and sex, location of the tumor, pathological diagnosis, complications, treatment and efficacy of treatment of the tumor-associated hydrocephalus, and the dissemination during the postoperative course. Two hundred twenty-one pediatric patients (mean 8.6 years) from 67 institutions were registered. Endoscopic tumor biopsies were performed in 206 patients (93.2 %), and a histopathological diagnosis could be performed in 195 of these 206 patients (94.7 %). The most frequently histopathologically diagnosed tumor was a germ cell tumor (41.5 %), followed by astrocytic tumors (24.1 %) and cystic lesions (15.9 %). Associated hydrocephalus was observed in 177 patients (80.1 %), 101 of whom underwent endoscopic third ventriculostomy (ETV). The efficacy rate of the ETV in the perioperative period was 99.0 %, and the long-term response rate was 90.1 %. Perioperative complications other than fever were found in 24 patients (10.9 %). In the statistical analysis, pediatric long-term response rate to ETV (p = 0.025) showed significantly more favorable results for pediatric than adult patients (p < 0.05). Neuroendoscopic procedures involving pediatric intra- and paraventricular tumors were considered to be very useful, with a low incidence of complication, and were associated with higher safety.
Assuntos
Biópsia/métodos , Neoplasias do Ventrículo Cerebral/complicações , Neoplasias do Ventrículo Cerebral/diagnóstico , Hidrocefalia/diagnóstico , Hidrocefalia/etiologia , Neuroendoscopia/métodos , Adolescente , Biópsia/efeitos adversos , Neoplasias do Ventrículo Cerebral/cirurgia , Derivações do Líquido Cefalorraquidiano , Criança , Pré-Escolar , Feminino , Humanos , Hidrocefalia/cirurgia , Lactente , Recém-Nascido , Complicações Intraoperatórias/epidemiologia , Complicações Intraoperatórias/terapia , Japão , Masculino , Neuroendoscopia/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Resultado do Tratamento , Derivação Ventriculoperitoneal , Ventriculostomia/métodosRESUMO
INTRODUCTION: The greater superficial petrosal nerve (GSPN) is especially important in anterior transpetrosal approach (ATPA) as the most reliable superficial landmark of Kawase's triangle. The GSPN can be considered as the superficial lateral border of anterior petrosectomy on the middle fossa to avoid internal carotid artery (ICA) injury. Although experienced operators can find the GSPN, its confirmation is not always easy to achieve. METHODS: We introduce our recent GSPN confirmation methods using facial nerve monitoring. In 10 recent cases, antidromic GSPN stimulation and free-running facial muscle electromyography (EMG) monitoring were performed. RESULTS: Facial nerve evoked-EMG by antidromic GSPN stimulation confirmed the location of the GSPN course with precision in all cases. Free-running facial muscle EMG informed the mechanical stress of facial nerves through the GSPN. There was no postoperative facial palsy or dry eye in these cases. CONCLUSIONS: GSPN confirmation and preservation are not always easy to achieve. These monitoring methods are useful for the confirmation of the GSPN, which is a landmark for safe extradural anterior petrosectomy, and for the preservation of the GSPN itself.
Assuntos
Craniotomia/métodos , Músculos Faciais/fisiologia , Nervo Facial/fisiologia , Monitorização Intraoperatória/métodos , Procedimentos Neurocirúrgicos/métodos , Anestesia Geral , Neoplasias do Tronco Encefálico/cirurgia , Fossa Craniana Média/anatomia & histologia , Craniotomia/normas , Estimulação Elétrica/instrumentação , Estimulação Elétrica/métodos , Eletromiografia/instrumentação , Eletromiografia/métodos , Humanos , Monitorização Intraoperatória/instrumentação , Procedimentos Neurocirúrgicos/instrumentação , Osso Petroso/cirurgia , Neoplasias da Base do Crânio/cirurgiaRESUMO
Cranioplasty using custom-made hydroxyapatite (HAP) ceramic implants is a common procedure for the repair of skull defects. The advantages of using HAP are that it is nonmetallic, unlike titanium; biocompatible; and osteoconductive. Furthermore, it can be molded to any complex shape that may be needed. A disadvantage is that titanium screws and plates are in development for its fixation. We developed a technique for implant fixation using bioabsorbable screws and plates, and named this technique RIVET: resorbable immobilization for vacuolar en bloc technique.Before each operation, the implant was customized for the patient in question on the basis of models prepared using computed tomography data. The bioabsorbable plates were attached to the implant by drilling, tapping, and screwing, as shown in the video (http://links.lww.com/SCS/A43). The interior portion of the screw was then melted to flatten it against the internal surface of the implant, forming a rivet to join the plate and HAP implant.We used this technique for cranial reconstruction in 2 patients, with satisfying and functional results. We did not encounter any complications.In conclusion, the technique described here allows surgeons to fix implants and plates together more rigidly, giving a better result than possible with previous methods.
Assuntos
Implantes Absorvíveis , Materiais Biocompatíveis/uso terapêutico , Placas Ósseas , Parafusos Ósseos , Substitutos Ósseos/uso terapêutico , Durapatita/uso terapêutico , Procedimentos de Cirurgia Plástica/instrumentação , Crânio/cirurgia , Adolescente , Adulto , Idoso , Materiais Biocompatíveis/química , Cimentos Ósseos/uso terapêutico , Criança , Pré-Escolar , Craniotomia/instrumentação , Desenho de Equipamento , Feminino , Humanos , Ácido Láctico/química , Masculino , Pessoa de Meia-Idade , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Adulto JovemRESUMO
We report the first documented case of IgG4-related inflammatory pseudotumours (IPTs) along the bilateral oculomotor nerves. A man in his 60s complained of decreased vision. He exhibited bilateral optic nerve atrophy without any extraocular movement deficits. MRI revealed enhanced masses that reached from the bilateral cavernous sinus to within the bilateral orbits. The tumours extended along the lines of the bilateral oculomotor nerves. The patient's serum level of IgG4 was high, 147 mg/dl. A biopsy specimen showed inflammatory cell-rich lesions against a collagenous stroma. Immunostaining revealed infiltration of CD138-positive plasma cells, which were mainly IgG and IgG4 positive. The IgG4/IgG ratio was greater than 0.4. These factors led us to a diagnosis of IgG4-related IPTs. Oral administration of prednisolone (30 mg/day) was started 3 months after the operation and continued for 6 months with gradual tapering. The tumour was significantly reduced by prednisolone.
Assuntos
Granuloma de Células Plasmáticas/diagnóstico , Imunoglobulina G/imunologia , Doenças do Nervo Oculomotor/diagnóstico , Granuloma de Células Plasmáticas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Nervo Oculomotor/imunologiaRESUMO
In human mitochondria, 10 mRNAs species are generated from a long polycistronic precursor that is transcribed from the heavy chain of mitochondrial DNA, in theory yielding equal copy numbers of mRNA molecules. However, the steady-state levels of these mRNAs differ substantially. Through absolute quantification of mRNAs in HeLa cells, we show that the copy numbers of all mitochondrial mRNA species range from 6000 to 51,000 molecules per cell, indicating that mitochondria actively regulate mRNA metabolism. In addition, the copy numbers of mitochondrial mRNAs correlated with their cellular half-life. Previously, mRNAs with longer half-lives were shown to be stabilized by the LRPPRC/SLIRP complex, which we find that cotranscriptionally binds to coding sequences of mRNAs. We observed that the LRPPRC/SLIRP complex suppressed 3' exonucleolytic mRNA degradation mediated by PNPase and SUV3. Moreover, LRPPRC promoted the polyadenylation of mRNAs mediated by mitochondrial poly(A) polymerase (MTPAP) in vitro. These findings provide a framework for understanding the molecular mechanism of mRNA metabolism in human mitochondria.
Assuntos
Proteínas de Neoplasias/metabolismo , Poliadenilação , Polirribonucleotídeo Nucleotidiltransferase/metabolismo , Estabilidade de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , RNA Helicases DEAD-box/metabolismo , RNA Polimerases Dirigidas por DNA/metabolismo , Células HeLa , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/genética , Proteínas Mitocondriais/metabolismo , Polirribonucleotídeo Nucleotidiltransferase/antagonistas & inibidores , RNA/análise , RNA/química , Precursores de RNA/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/química , RNA MitocondrialRESUMO
OBJECT: The authors report their investigation on the current status of neuroendoscopic biopsy for ventricular and paraventricular tumors as well as treatment for associated hydrocephalus in Japan. METHODS: Patients who had undergone therapeutic neuroendoscopy between 2005 and 2009 were included in this study. The main items examined were age; sex; localization of tumor; pathological diagnosis using biopsy; the presence, treatment, and efficacy of treatment of associated hydrocephalus; perioperative complications; activities of daily living (ADL) before and after therapeutic neuroendoscopy; and the presence of dissemination during the postoperative course. RESULTS: Seven hundred fourteen patients from 123 sites (462 male and 252 female patients, mean age 33.3 years) were enrolled. Localization of the tumor was mainly classified into the lateral ventricle in 91 patients, the third ventricle in 339, the fourth ventricle in 18, the suprasellar region in 75, and other paraventricular areas in 191 patients. The most commonly observed tumors were germ cell tumors in the third ventricle (177 cases [39%]), cystic lesions in the suprasellar region (56 cases [75%]), and astrocytic tumors in the thalamus-basal ganglia (71 cases [38%]). Although 641 (92.8%) of 691 patients could receive neuroendoscopic diagnosis using biopsy, the diagnosis obtained with endoscopic biopsy differed from the final diagnosis based on subsequent craniotomy in 18 patients and clinical course in 3 patients. Of these 21 patients, 7 had astrocytic tumors, 4 had pineal tumors, 6 had germ cell tumors, and 4 had other tumors. The final diagnostic accuracy rate was 89.7%. Associated hydrocephalus was observed in 517 patients (72.4%), of whom 316 and 39 underwent third ventriculostomy and fenestration of the septum, respectively. The response rates were 96.2% and 89.7%, respectively. Third ventriculostomy was required for recurrence of hydrocephalus in 41 patients (13.0%), and the long-term response rate was therefore 83.2% (263 of 316 patients). Perioperative complications other than fever, such as new onset of or progressive hydrocephalus, infection due to CSF leakage, and bleeding in the ventricle or tumor, were found in 81 patients (11.3%). The median Karnofsky Performance Scale score before endoscopic surgery was 80, but it increased to 90 after surgery. The score was thus significantly increased after surgery (p < 0.0001, Mann-Whitney U-test). Activities of daily living after surgery decreased due to perioperative complications in 15 patients (2.1%). The incidence of new dissemination after endoscopic biopsy was 6.8% and not high compared with routine surgical treatment. CONCLUSIONS: The authors concluded that neuroendoscopic diagnosis using biopsy for ventricular and paraventricular tumors is adequately accurate and safe. It was demonstrated that endoscopic procedures play important roles not only in the treatment of hydrocephalus associated with intra- and paraventricular tumors but also in significantly improving ADL. Furthermore, the long-term outcome of endoscopic third ventriculostomy was clearly favorable.