Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma

Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF (V600E) mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF (V600E) mutation was strongly associated with extra-cerebellar location (p?=?0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF (V600E) mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF (V600E) mutant brain tumor patients will benefit from BRAF (V600E)-directed targeted therapies.     

MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma

The contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MB patients, and is associated with a dismal prognosis. Using microRNA expression profiling, we demonstrate that the retinal miR-183-96-182 cluster on chromosome 7q32 is highly overexpressed in non-sonic hedgehog MBs (non-SHH-MBs). Expression of miR-182 and miR-183 is associated with cerebellar midline localization, and miR-182 is significantly overexpressed in metastatic MB as compared to non-metastatic tumors. Overexpression of miR-182 in non-SHH-MB increases and knockdown of miR-182 decreases cell migration in vitro. Xenografts overexpressing miR-182 invaded adjacent normal tissue and spread to the leptomeninges, phenotypically reminiscent of clinically highly aggressive large cell anaplastic MB. Hence, our study provides strong in vitro and in vivo evidence that miR-182 contributes to leptomeningeal metastatic dissemination in non-SHH-MB. We therefore reason that targeted inhibition of miR-182 may prevent leptomeningeal spread in patients with non-SHH-MB.     

Magnetic Collapse in Fe3Se4 under High Pressure

Electronic structure and magnetic properties of Fe3Se4 are calculated using the density functional approach. Due to the metallic properties, magnetic moments of the iron atoms in two nonequivalent positions in the unit cell are different from ionic values for Fe3+ and Fe2+ and are equal to M1=2.071μB and M2=−2.042μB, making the system ferrimagnetic. The total magnetic moment for the unit cell is 2.135μB. Under isotropic compression, the total magnetic moment decreases non-monotonically and correlates with the non-monotonic dependence of the density of states at the Fermi level N(EF). For 7% compression, the magnetic order changes from the ferrimagnetic to the ferromagnetic. At 14% compression, the magnetic order disappears and the total magnetic moment becomes zero, leaving the system in a paramagnetic state. This compression corresponds to the pressure of 114 GPa. The magnetic ordering changes faster upon application of an isotropic external pressure due to the sizeable anisotropy of the chemical bondings in Fe3Se4. The ferrimagnetic and paramagnetic states occur under pressures of 5.0 and 8.0 GPa, respectively. The system remains in the metallic state for all values of compression.     

Inertial, Substratal and Landmark Cue Control of Hippocampal CA1 Place Cell Activity

Hippocampal 'place cells' discharge when a rat occupies a location that is fixed in relation to environmental landmarks. A principal goal of this study was to determine whether hippocampal place cell activity could be influenced by inertial cues. Water-deprived rats were trained in a square-walled open field in a dark room. The behavioural task required alternating visits to water reservoirs in the centre and in the four corners of the arena. The rat and arena were rotated in total darkness through ±90, 180 or 270°. The next water reward was then presented in the corner at the same position relative to the outside room as before the rotation. A cue card was later illuminated in this corner as a visual cue for the extra-arena (room) reference frame. Fifteen out of 97 recorded hippocampal CA1 complex spike cells had spatially selective discharges in non-central parts of the arena. After arena rotations, the firing fields of three units shifted between corners of the arena to maintain a fixed orientation relative to the room. This indicates that the hippocampus updated its representation of the position and heading direction of the rat using vestibular-derived inputs concerning rotation angle. Other spatially selective discharges were guided to landmark cues (cue card or position of the reward: two units) or arena-locked 'substratal' cues (eight units). In six cells, place cell activity suddenly ceased or appeared following rotations. These results provide evidence for contributions of inertial as well as substratal and landmark information to hippocampal spatial representations.     

Characteristics of the course of peritonitis in relation to the degree of perforation of the gastrointestinal tract

An examination and treatment of 80 patients with general forms of peritonitis has shown that the course of the disease is greatly dependent on the character of the bacterial dissemination of the abdominal cavity. A microbiological examination has shown that in all the levels of perforation of the gastro-intestinal tract there are associations of various microorganisms. The most severe course of peritonitis is observed when caused by infection by colonic contents with prevailing anaerobic ++non-clostridial microflora in the exudate. The method of repeated revisions of the abdominal cavity should be used for these forms of peritonitis.