The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

From a previous study of achondroplasia as well as from the observation of patients with hydrocephalus associated with craniostenosis, the authors have concluded that an increased superior sagittal sinus venous pressure (SSVP) could be the cause of the enlarged ventricles. However, other workers have demonstrated that an increased SSVP could be the consequence of increased intracranial pressure (ICP). Therefore, the authors undertook a study to determine if there was a physiological test that could distinguish between rare instances of increased SSVP caused by structural and irreversible narrowing of the sinus and those caused by increased ICP. In 20 hydrocephalic infants and children, pressure was simultaneously measured in the lateral ventricle, the superior sagittal sinus, and the jugular vein. Stable baseline pressures were recorded, as well as the variations observed after the withdrawal of an amount of cerebrospinal fluid (CSF) sufficient to lower ICP to zero. Similar recordings were taken after reinjection of an equal quantity of CSF. In all of the patients, SSVP was increased, but not as much as the ICP. In the cases of hydrocephalus without any associated cranial malformation, and therefore without any likely anatomical interruption of the sinus, CSF withdrawal induced a simultaneous decrease of ICP and SSVP. However, whereas ICP could be lowered to zero, SSVP never fell below the jugular venous pressure, which remained stable (around 5 mm Hg) throughout the recording session. Results were different when sinography demonstrated an anatomical interruption of the sinus, as in cases of hydrocephalus associated with achondroplasia or craniostenosis. In these cases, although ICP was normally lowered by CSF withdrawal, SSVP remained nearly unchanged, usually greater than the jugular venous pressure. The present study demonstrated that SSVP recording during ICP variations induced by CSF withdrawal permits differentiation between a reversible collapse of the sigmoid sinus due to increased ICP and a fixed obstructive lesion of the sinuses. Based upon this test and the results of sinography, the authors inserted a venous bypass between the lateral sinus and a jugular vein in three patients.

Neuropeptides play a major role in the modulation of information processing in neural networks. Somatostatin, one of the most concentrated neuropeptides in the brain, is found in many sensory systems including the olfactory pathway. However, its cellular distribution in the mouse main olfactory bulb (MOB) is yet to be characterized. Here we show that approximately 95% of mouse bulbar somatostatin-immunoreactive (SRIF-ir) cells describe a homogeneous population of interneurons. These are restricted to the inner lamina of the external plexiform layer (iEPL) with dendritic field strictly confined to the region. iEPL SRIF-ir neurons share some morphological features of Van Gehuchten short-axon cells, and always express glutamic acid decarboxylase, calretinin, and vasoactive intestinal peptide. One-half of SRIF-ir neurons are parvalbumin-ir, revealing an atypical neurochemical profile when compared to SRIF-ir interneurons of other forebrain regions such as cortex or hippocampus. Somatostatin is also present in fibers and in a few sparse presumptive deep short-axon cells in the granule cell layer (GCL), which were previously reported in other mammalian species. The spatial distribution of somatostatin interneurons in the MOB iEPL clearly outlines the region where lateral dendrites of mitral cells interact with GCL inhibitory interneurons through dendrodendritic reciprocal synapses. Symmetrical and asymmetrical synaptic contacts occur between SRIF-ir dendrites and mitral cell dendrites. Such restricted localization of somatostatin interneurons and connectivity in the bulbar synaptic network strongly suggest that the peptide plays a functional role in the modulation of olfactory processing.

Clear cell meningioma (CCM) is a rare grade II histopathological subtype that usually occurs in young patients and displays high recurrence rate. Germline SMARCE1 mutations have been described in hereditary forms of this disease and more recently in small syndromic and sporadic CCM series. The diagnostic value of SMARCE1 in distinguishing between CCM and other meningioma variants has not been yet established. The aim of our study was to investigate the status of SMARCE1 in a series of CCMs and its morphological mimickers. We compared the performance of an anti-SMARCE1 antibody and the molecular analysis of the SMARCE1 gene in a retrospective multicenter series of CCMs. All CCMs lossed SMARCE1 immunoexpression. Bi-allelic inactivating events were found by NGS-based sequencing in all of these cases, except for one, which was incompletely explored, but had a wild-type sequence. We then validated the anti-SMARCE1 antibody specificity by analyzing additional 305 pediatric and adult meningiomas of various subtypes and 15 non-meningioma clear cell tumors by SMARCE1 immunohistochemistry. A nuclear immunostaining was preserved in all other meningioma variants, as well as non-meningioma clear cell tumors. In conclusion, our series showed, for the first time, that SMARCE1 immunostaining is a highly sensitive biomarker for CCM, useful as a routine diagnostic biomarker.

Diffuse Instrinsic Pontine Glioma is the most aggressive form of High Grade Gliomas in children. The lack of biological material and the absence of relevant models have hampered the development of new therapeutics. Their extensive infiltration of the brainstem renders any surgical resection impossible and until recently biopsies were considered not informative enough and therefore not recommended. Thus, most models were derived from autopsy material. We aimed to develop relevant in vivo DIPG models that mimic this specific disease and its molecular diversity from tumor material obtained at diagnosis. Eight patient-derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain.These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss in vivo and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naïve human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease.

A series of 1174 operations performed on 802 hydrocephalic children was analyzed in an effort to find the factors causing acute postoperative infection. Culture of the cerebrospinal fluid (CSF) samples during the operation was positive in 33 cases. These cases were excluded from the series. Ninety infections were observed in the remaining 1141 operations, an overall rate of 7.9%. Most of these infections were meningitis (56 cases). Staphylococcus epidermidis was the bacterium most frequent identified (44%). Statistically significant relationships were found between shunt infection and the following factors: 1) age: infection was 2.6 times as frequent before 6 months than after 1 year of age (p = 0.03); 2) poor condition of the skin; 3) presence of intercurrent seats of infection at the time of surgery; 4) type of operation: the rate of infection was 8.4% in primary shunt insertions, 5% in shunt revisions, and 17.5% in reinsertions following shunt removal for infection (p = 0.0001); 5) end of the shunt requiring revision: an infection rate of 7.7% followed revision of the ventricular catheter alone, and 2.6% followed revision of the other end alone (p = 0.012); and 6) postoperative wound dehiscence or scalp necrosis. The surgical team involved was poorly correlated with the rate of infection (p = 0.12). No statistically significant relationships have been found between infection and 1) etiology of hydrocephalus: 2) sex; 3) recent neurosurgical operation before the shunt procedure; 4) preoperative presence of an external drainage tube or CSF fistula; 5) lumbar or ventricular taps, or ventriculography; 6) number of previous operations performed on the shunt; 7) time (month and year) of operation; or 8) sugar level and cell count in the CSF.

The expression of the five somatostatin receptor subtypes, sst1-5 was compared on tissue containing glial tumours (glioblastomas or oligodendrogliomas), medulloblastomas, and on normal human cortex. By semiquantitative reverse transcription coupled to polymerase chain reaction, the receptor expression profiles were high in cortex and in tissue containing oligodendrogliomas. It was moderate in medulloblastomas. Tissue containing glioblastomas displayed lower expression of somatostatin receptor subtypes, sst1 and sst3 being mostly expressed. By 125I-Tyr0DTrp8 somatostatin-14 or 125I-Leu8DTrp22 Tyr25 somatostatin-28 autoradiography combined with synaptophysin immunohistochemistry, it was possible to differentiate between isolated tumoral cell component infiltrating the cerebral parenchyma (cortex or white matter) and tumoral tissue (without residual parenchyma) in glioblastomas or oligodendrogliomas. Glial tumoral tissue per se presented few somatostatin receptors. By contrast, medulloblastoma tumoral cells exhibited numerous octreotide sensitive somatostatin receptors. sst2 immunocytochemistry demonstrated immunostaining of neuronal cells and neuropile; sst2 and sst3 immunostaining was identified on glioblastoma proliferating vessels endothelial cells and on medulloblastomas tumoral cells. Faint sst2 immunostaining among glial tumoral cells was due to microglia, while glioma cells did not significantly stain. In summary, medulloblastoma tumoral cells express sst2/sst3 receptors at a high level while glioma cells do not. In gliomas, sst expression is restricted to endothelial cells on proliferating vessels (displaying both sst2 and sst3 receptors), including parenchyma and reactive microglia (only sst2). The differential expression of sst2/sst3 receptors on gliomas and medulloblastomas has implications for the therapy of these tumours.

LP(A1) (also termed Edg-2 or VZG-1) is a G-protein-coupled receptor for lysophosphatidic acid and its gene transcripts have been found selectively expressed by mature myelin-producing cells. We have raised in rabbit a polyclonal antibody against a sequence unique to LP(A1) and common to rat, mouse, and human orthologues. In Western blots, LP(A1) immunoreactivity appeared as 44-53 kDa bands in extracts from recombinant RH7777 cells expressing LP(A1), mouse purified oligodendrocytes, or human white matter, but not from wild-type RH7777 cells or purified astrocytes. In glial cultures, LP(A1) immunoreactivity was restricted to oligodendrocytes, appeared at cell membrane and processes, colocalized with myelin basic protein, and appeared before myelin/oligodendrocyte glycoprotein. In slices of rat and human brains, LP(A1) immunoreactivity was found in myelinated tracts, as well as in oligodendrocyte somata and their myelinating fibers. Immunoreactivities of LP(A1) and myelin basic protein colocalized in the brain, but oligodendrocyte soma showed stronger signals for LP(A1) than myelinated fibers, whereas the reverse was true for myelin basic protein. These results strengthen the view that LP(A1) is involved in myelin formation or maintenance.