Neuropathological and Reelin Deficiencies in the Hippocampal Formation of Rats Exposed to MAM; Differences and Similarities with Schizophrenia

Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied.Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged.Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia

Clinical Relevance of Tumor Cells with Stem-Like Properties in Pediatric Brain Tumors

BACKGROUND: Primitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting. CONCLUSIONS/SIGNIFICANCE: In brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors

CD133, CD15/SSEA-1, CD34 or side populations do not resume tumor-initiating properties of long-term cultured cancer stem cells from human malignant glio-neuronal tumors

<p>Abstract</p> <p>Background</p> <p>Tumor initiating cells (TICs) provide a new paradigm for developing original therapeutic strategies.</p> <p>Methods</p> <p>We screened for TICs in 47 human adult brain malignant tumors. Cells forming floating spheres in culture, and endowed with all of the features expected from tumor cells with stem-like properties were obtained from glioblastomas, medulloblastoma but not oligodendrogliomas.</p> <p>Results</p> <p>A long-term self-renewal capacity was particularly observed for cells of malignant glio-neuronal tumors (MGNTs). Cell sorting, karyotyping and proteomic analysis demonstrated cell stability throughout prolonged passages. Xenografts of fewer than 500 cells in Nude mouse brains induced a progressively growing tumor. CD133, CD15/LeX/Ssea-1, CD34 expressions, or exclusion of Hoechst dye occurred in subsets of cells forming spheres, but was not predictive of their capacity to form secondary spheres or tumors, or to resist high doses of temozolomide.</p> <p>Conclusions</p> <p>Our results further highlight the specificity of a subset of high-grade gliomas, MGNT. TICs derived from these tumors represent a new tool to screen for innovative therapies.</p

Restricting Fermentative Potential by Proteome Remodeling AN ADAPTIVE STRATEGY EVIDENCED IN BACILLUS CEREUS.

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Neuronal organization of entorhinal cortex in MAM and control rats.

<p>Coronal sections of the entorhinal cortex at Bregma −3.8mm from control animals stained with Bodian-Luxol (A) and NeuN immunostaining (B). (C) Bodian-Luxol staining of the entorhinal cortex from control animals. A well defined columnar organization and myelin with parallel directions can be observed. Arrows point to myelin pathways. (D) Anti-NeuN immunostaining of the entorhinal cortex from control animals showing axon hillocks with a parallel orientation and neuronal bodies regularly organized. (E) Neuronal somas and axon hillocks are clearly distinguished in this picture magnified 400×. Arrows point to axon-hillock direction. (F) Bodian-Luxol staining of the entorhinal cortex from MAM rats reveals a less obvious columnar organization while myelin direction appears random. (G) NeuN immunostaining of the entorhinal cortex from MAM animals. Neuronal disorganization with clusters of neurons is evident mainly in layers II and III. Circles highlight neuronal clusters. (H) Neuronal disorganization, neuronal size variability and axon hillocks with random directions can be observed in this picture magnified 400×. Arrows point to axon-hillock direction.</p

Morphometric effects of MAM E17 treatment on brain structures.

<p>(A) Brain diagrams reproduced with permission from The Rat Brain Atlas by Paxinos and Watson 6 edition illustrating how anatomical areas were delineated. Bregma −3.8mm on left and Bregma −5.8mm on right. Areas and thicknesses were measured as delineated in the pictures. (B–C) Graphs indicating differences in brain area (B) and circumference (C) between control (white bars) and MAM-exposed animals (black bars). (D–E) Graphs indicating area differences between MAM and control animals at Bregma −3.6 (D) and −5.8mm (E). (F–G) Graphs indicating differences in thickness between MAM and control animals at Bregma −3.6 (F) and −5.8mm (G). Results represent the mean ± S.E.M. of 9 animals per group from which slides done by duplicate were analyzed. Amygdala (AMG), associative parietal cortex (PtA), cornu ammonis (CA), dentate gyrus (DG), entorhinal cortex (ERC), hippocampus (HIP), mediodorsal thalamic nucleus (MDT), perirhinal cortex (PER), piriform cortex (PIR), somato-sensory cortex barrel field 1 (S1BF), substantia nigra (SN), thalamus (THAL), ventral tegmental area (VTA). *p<0.05 **p<0.01 and ***p<0.001.</p