Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0630-1) contains supplementary material, which is available to authorized users.
BackgroundPandemic influenza A(H1N1) virus infection quickly circulated worldwide in 2009. In Japan, the first case was reported in May 2009, one month after its outbreak in Mexico. Thereafter, A(H1N1) infection spread widely throughout the country. It is of great importance to profile and understand the situation regarding viral mutations and their circulation in Japan to accumulate a knowledge base and to prepare clinical response platforms before a second pandemic (pdm) wave emerges.MethodologyA total of 253 swab samples were collected from patients with influenza-like illness in the Osaka, Tokyo, and Chiba areas both in May 2009 and between October 2009 and January 2010. We analyzed partial sequences of the hemagglutinin (HA) and neuraminidase (NA) genes of the 2009 pdm influenza virus in the collected clinical samples. By phylogenetic analysis, we identified major variants of the 2009 pdm influenza virus and critical mutations associated with severe cases, including drug-resistance mutations.Results and ConclusionsOur sequence analysis has revealed that both HA-S220T and NA-N248D are major non-synonymous mutations that clearly discriminate the 2009 pdm influenza viruses identified in the very early phase (May 2009) from those found in the peak phase (October 2009 to January 2010) in Japan. By phylogenetic analysis, we found 14 micro-clades within the viruses collected during the peak phase. Among them, 12 were new micro-clades, while two were previously reported. Oseltamivir resistance-related mutations, i.e., NA-H275Y and NA-N295S, were also detected in sporadic cases in Osaka and Tokyo.
Classical NMDA receptors (NMDARs), activated by glycine and glutamate, are heteromultimers comprised of NR1 and NR2 subunits. Coexpression of the novel NR3 family of NMDAR subunits decreases the magnitude of NR1/NR2 receptor-mediated currents or forms glycine-activated channels with the NR1 subunit alone. The second (M2) and third (M3) membrane segments of NR1 and NR2 subunits of classical NMDARs form the core of the channel permeation pathway. Structural information regarding NR1/NR3 channels remains unknown. Using the Xenopus oocyte expression system and the SCAM (substituted cysteine accessibility method), we found that M3 segments of both NR1 and NR3A form a narrow constriction in the outer vestibule of the channel, which prevents passage of externally applied sulfhydryl-specific agents. The most internal reactive residue in each M3 segment is the threonine in the conserved SYTANLAAF motif. These threonines appear to be symmetrically aligned. Several NR3A M3 mutations change the behavior of NR1/NR3A channels. Unlike NR1, however, the M3 segment of NR3A does not undergo extensive molecular rearrangement during channel gating by added glycine. Additionally, in the M2 segment, our data suggest that the amino acid at the asparagine (N) site of NR1, but not NR3A, contributes to the selectivity filter of NR1/3A channels. We therefore conclude that NR3A modulates the NR1/NR3A permeation pathway via a novel mechanism of forming a narrow constriction at the outer channel vestibule. This modified channel vestibule may also explain the dominant-negative effect of the NR3 subunit on channel behavior when coexpressed with NR1 and NR2 subunits.
Transsphenoidal cephalocele rarely occurs in adults. We describe two adult cases with transsphenoidal cephaloceles. The first case was a 53-year-old female who presented with spontaneous cerebrospinal fluid (CSF) rhinorrhea. Magnetic resonance (MR) imaging demonstrated a transsphenoidal meningocele. Surgical repair was attempted via the transsphenoidal route. Rhinorrhea recurred at one month and also two years later. Transsphenoidal surgical repairs were repeated. There has been no evidence of CSF leakage in the four years of follow-up after the last surgery. Transsphenoidal repair seems to be the most suitable approach in this case. The second case was a 26-year-old female with secondary amenorrhea, diabetes insipidus, bitemporal hemianopsia, and see-saw nystagmus. MR imaging demonstrated a transsphenoidal encephalocele with the optic chiasma and infundibular recesses descending into the meningocele and an agenesis of the corpus callosum. The first operation was performed via the transnasal route and the second by sublabial transmaxillary transsphenoidal approach six months later. Postoperative MR imaging revealed reduction of the encephalocele. There was neither worsening nor noticeable improvement in the neurological or endocrinological function. However, in this type, complete repair is often impossible, and non-radical surgery such as transsphenoidal repair may be indicated as most suitable. They should be selected with careful assessment referring to MR findings and clinical symptoms and signs.
Objectives: Orbitofrontal fibrous dysplasia often involves the bony orbit and optic canal. Although fibrous dysplasia reportedly produces compression of the optic nerve leading to visual disturbances, optic nerve decompression in patients without clinical signs of optic neuropathy remains controversial. We describe the recent development of surgical techniques and equipment for optic nerve decompression in orbitofrontal fibrous dysplasia. Methods: Optic nerve decompression was performed prophylactically for five patients and therapeutically for one patient using the transcranial extradural route. A high-speed drill and continuous suctionirrigation system has been used in five patients since 1998, and an ultrasonic bone curette in two patients since 2004. Results: The continuous suction-irrigation system was particularly effective for decreasing heat transfer and thus preventing thermal injury to the optic nerve from the high-speed drill. The ultrasonic bone curette was also effective, allowing bone removal with minimal pressure from the tip of the handpiece and without catching cotton pledgets or damaging surrounding tissues. Orbital dystopias and craniofacial deformities induced by fibrous dysplasia were also successfully corrected. Postoperatively, disturbance in visual function was present in only two patients. Mean follow-up period was 4.9 years. Conclusions: This equipment may contribute to the development of new modalities for optic nerve decompression in orbitofrontal fibrous dysplasia.
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