Infant high grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histological review, methylation profiling, custom panel and genome/exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an 'intrinsic' spectrum of disease specific to the infant population. These included those with targetable MAP-kinase alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n=31), NTRK1/2/3 (n=21), ROS1 (n=9) and MET (n=4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly supports the concept that infant gliomas require a change in diagnostic practice and management.

Acidic and basic fibroblast growth factors (FGFs) are members of a family of proteins that are broad-spectrum mitogens, have diverse hormone-like activities, and function in tumorigenesis. FGF's ability to raise the concentration of intracellular calcium ion suggests that FGF could induce the synthesis of endothelium-derived relaxing factor (EDRF) and consequently vasodilation. Systemic administration of FGF decreased arterial blood pressure. This effect was mediated by EDRF and by adenosine triphosphate-sensitive potassium ion channels. The hypotensive effect of FGF was segregated from its mitogenic activity by protein engineering. These results extend the range of FGF autocrine activities and potential therapeutic applications, emphasize the role of endothelium as an arterial blood pressure--regulating organ, and provide insight on the structural basis of FGF functions.

Adult bone marrow contains stem cells that have attracted interest through their possible use for cell therapy in neurological diseases. Bone marrow stromal cells (MSCs) were harvested from donor adult rats, cultured and pre-labeled with bromodeoxyuridine (BrdU) previously to be injected in the distal stump of transected sciatic nerve of the rats. Distal nerve stump of control rats received culture medium solution. MSCs-treated rats exhibit significant improvement on walking track test at days 18 and 33 compared to controls. Dual immunofluorescence labeling shows that BrdU reactive cells survive in the injected area of transected sciatic nerve at least 33 days after implantation, and almost 5% of BrdU cells express Schwann cell-like phenotype (S100 immunoreactivity). Because MSCs injected in a lesioned peripheral nerve can survive, migrate, differentiate in Schwann cells, and promote functional recovery, they may be an important source for cellular therapy in several neurological diseases.

Cell therapy using bone marrow stromal cells is a new promising therapy for regenerative medicine. Previous studies demonstrated that local bone marrow stromal cells implantation in the distal stump of transected sciatic nerve of rats promotes early functional recovery. The purpose of this study was to expand on the preliminary research by investigating the long-term efficacy of bone marrow stromal cells using the same experimental setting. Functional test and histological studies demonstrate that bone marrow stromal cell-treated rats exhibit significant improvement on a walking tract test at day 180 after surgery compared with control rats. Taken together, these data suggest that bone marrow stromal cell therapy is a safe and effective strategy for peripheral nerve injuries.

BackgroundFor children with cancer, the clinical integration of precision medicine to enable predictive biomarker–based therapeutic stratification is urgently needed.MethodsWe have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)–specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings.ResultsA total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma.ConclusionWe demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel–based approach can identify actionable genetic alterations in a high proportion of patients.

Background and Purpose-Even though the utilization of substrates alternative to glucose may play an important role in the survival of brain cells under ischemic conditions, evidence on changes in substrate selection by the adult brain in vivo during ischemic episodes remains very limited. This study investigates the utilization of glutamate, glutamine, and GABA as fuel by the neuronal and glial tricarboxylic acid cycles of both cerebral hemispheres after partially reversible focal cerebral ischemia (FCI). Methods-Right hemisphere infarct was induced in adult Long-Evans rats by permanent occlusion of the right middle cerebral artery and transitory occlusion of both common carotid arteries.(1,2-13 C 2 ) acetate was infused for 60 minutes in the right carotid artery immediately after carotid recirculation had been re-established (1-hour group) or 23 hours later (24-hour group). Extracts from both cerebral hemispheres were prepared and analyzed separately by 13 C nuclear magnetic resonance and computer-assisted metabolic modeling. Results-FCI decreased the oxidative metabolism of glucose in the brain in a time-dependent manner. Reduced glucose oxidation was compensated for by increased oxidations of ( 13 C) glutamate and ( 13 C) GABA in the astrocytes of the ipsilateral hemispheres of both groups. Increased oxidative metabolism of ( 13 C) glutamine in the neurons was favored by increased activity of the neuronal pyruvate recycling system in the 24 -hour group. Conclusions-Data were obtained consistent with time-dependent changes in the utilization of glutamate and GABA or glutamine as metabolic substrates for the glial or neuronal compartments of rat brain after FCI. (Stroke.

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Pattern recognition techniques (factor analysis and neural networks) were used to investigate and classify human brain tumors based on the 1H NMR spectra of chemically extracted biopsies (n = 118). After removing information from lactate (because of variable ischemia times), unsupervised learning suggested that the spectra separated naturally into two groups: meningiomas and other tumors. Principal component analysis reduced the dimensionality of the data. A back-propagation neural network using the first 30 principal components gave 85% correct classification of meningiomas and nonmeningiomas. Simplification by vector rotation gave vectors that could be assigned to various metabolites, making it possible to use or to reject their information for neural network classification. Using scores calculated from the four rotated vectors due to creatine and glutamine gave the best classification into meningiomas and nonmeningiomas (89% correct). Classification of gliomas (n = 47) gave 62% correct within one grade. Only inositol showed a significant correlation with glioma grade.