In glioblastoma multiforme, the most common adult primary brain tumor, the glycolytic enzyme hexokinase 2 facilitates growth and therapeutic resistance.

Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p < 0.0001) and TP53 (p < 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p < 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.

We present a comprehensive data description for Ks-band measurements of Sgr A*. We characterize the statistical properties of the variability of Sgr A* in the near-infrared, which we find to be consistent with a single-state process forming a power-law distribution of the flux density. We discover a linear rms-flux relation for the flux-density range up to 12 mJy on a timescale of 24 minutes. This and the power-law flux density distribution implies a phenomenological, formally non-linear statistical variability model with which we can simulate the observed variability and extrapolate its behavior to higher flux levels and longer timescales. We present reasons why data with our cadence cannot be used to decide on the question whether the power spectral density of the underlying random process shows more structure at timescales between 25 min and 100 min compared to what is expected from a red noise random process.

Context. There are a number of faint compact infrared excess sources in the central stellar cluster of the Milky Way. Their nature and origin is unclear. In addition to several isolated objects of this kind there is a small but dense cluster of comoving sources (IRS13N) located ∼3 west of SgrA* just 0.5 north of the bright IRS13E cluster of Wolf-Rayet and O-type stars. Based on the analysis of their color and brightness, there are two main possibilities: (1) they may be dust-embedded stars older than a few Myr; or (2) very young, dusty stars with ages younger than 1 Myr. Aims. We present a first K s -band identification and proper motions of the IRS13N members, the high-velocity dusty S-cluster object (DSO, also referred to as G2), and other infrared excess sources in the central field. Goal is to constrain the nature of these source. Methods. The L -(3.8 μm) K s -(2.2 μm) and H-band (1.65 μm) observations were carried out using the NACO adaptive optics system at the ESO VLT. Proper motions were obtained by linear fitting of the stellar positions extracted by StarFinder as a function of time, weighted by positional uncertainties, and by Gaussian fitting from high-pass filtered and deconvolved images. We also present results of near-infrared (NIR) H-and K s -band ESO-SINFONI integral field spectroscopy of the Galactic center cluster ISR13N. Results. We show that within the uncertainties, the positions and proper motions of the IRS13N sources in K s -and L -band are identical. The HK−sL colors then indicate that the bright L -band IRS13N sources are indeed dust-enshrouded stars rather than core-less dust clouds. The proper motions also show that the IRS13N sources are not strongly gravitationally bound to each other. Combined with their NIR colors, this implies that they have been formed recently. For the DSO we obtain proper motions and a K s -L -color. Conclusions. Most of the compact L -band excess emission sources have a compact H-or K s -band counterpart and therefore are likely stars with dust shells or disks. Our new results and orbital analysis from our previous work favor the hypothesis that the infrared excess IRS13N members and other dusty sources close to SgrA* are young dusty stars and that star formation at the Galactic center (GC) is a continuously ongoing process. For the DSO the color information indicates that it may be a dust cloud or a dust-embedded star.

Context. We report on new simultaneous observations and modeling of the millimeter, near-infrared, and X-ray flare emission of the source Sagittarius A* (SgrA*) associated with the super-massive (4 × 10 6 M ) black hole at the Galactic center. Aims. We study the applicability of the adiabatic synchrotron source expansion model and study physical processes giving rise to the variable emission of SgrA* from the radio to the X-ray domain. Methods. Our observations were carried out on 18 May 2009 using the NACO adaptive optics (AO) instrument at the European Southern Observatory's Very Large Telescope, the ACIS-I instrument aboard the Chandra X-ray Observatory, the LABOCA bolometer at the Atacama Pathfinder EXperiment (APEX), and the CARMA mm telescope array at Cedar Flat, California. Results. The X-ray flare had an excess 2−8 keV luminosity between 6 and 12×10 33 erg s −1 . The observations reveal flaring activity in all wavelength bands that can be modeled as the signal from an adiabatically expanding synchrotron self-Compton (SSC) component.Modeling of the light curves shows that the sub-mm follows the NIR emission with a delay of about three-quarters of an hour with an expansion velocity of about v exp ∼ 0.009c. We find source component sizes of around one Schwarzschild radius, flux densities of a few Janskys, and spectral indices α of about +1 (S (ν) ∝ ν −α ). At the start of the flare, the spectra of the two main components peak just short of 1 THz. To statistically explain the observed variability of the (sub-)mm spectrum of SgrA*, we use a sample of simultaneous NIR/X-ray flare peaks and model the flares using a synchrotron and SSC mechanism. Conclusions. These parameters suggest that either the adiabatically expanding source components have a bulk motion larger than v exp or the expanding material contributes to a corona or disk, confined to the immediate surroundings of SgrA*. For the bulk of the synchrotron and SSC models, we find synchrotron turnover frequencies in the range of 300−400 GHz. For the pure synchrotron models, this results in densities of relativistic particles of the order of 10 6.5 cm −3 and for the SSC models, the median densities are about one order of magnitude higher. However, to obtain a realistic description of the frequency-dependent variability amplitude of SgrA*, models with higher turnover frequencies and even higher densities are required.

abbreviatioNs BBB = blood-brain barrier; GTR = gross-total resection; IQR = interquartile range; NHA = normal human astrocyte; PBS = phosphate-buffered saline; PDGF = platelet-derived growth factor; PDGFB = PDGF beta; PDGFR = PDGF receptor; PDGFRA = PDGFR alpha; RCAS = replication-competent avian sarcoma-leukosis; RFP = red fluorescent protein; tva = tumor virus A. 6 Department of Pathology and Laboratory Medicine, Indiana University; and 7 Goodman Campbell Brain and Spine, Department of Neurological Surgery, Indiana University, Indianapolis, Indiana obJect Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. methods The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. results The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell-specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI-guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. coNclusioNs Fluorescein sodiu...

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Context. We report on the results of new simulations of near-infrared (NIR) observations of the Sagittarius A* (Sgr A*) counterpart associated with the super-massive black hole at the Galactic Center. Aims. Our goal is to investigate and understand the physical processes behind the variability associated with the NIR flaring emission from Sgr A*. 2007 and 28 may 2008). We used a model of synchrotron emission from relativistic electrons in the inner parts of an accretion disk. The relativistic simulations have been carried out using the Karas-Yaqoob (KY) ray-tracing code. Results. We probe the existence of a correlation between the modulations of the observed flux density light curves and changes in polarimetric data. Furthermore, we confirm that the same correlation is also predicted by the hot spot model. Correlations between intensity and polarimetric parameters of the observed light curves as well as a comparison of predicted and observed light curve features through a pattern recognition algorithm result in the detection of a signature of orbiting matter under the influence of strong gravity. This pattern is detected statistically significant against randomly polarized red noise. Expected results from future observations of VLT interferometry like GRAVITY experiment are also discussed. Conclusions. The observed correlations between flux modulations and changes in linear polarization degree and angle can be a sign that the NIR flares have properties that are not expected from purely random red-noise. We find that the geometric shape of the emission region plays a major role in the predictions of the model. From fully relativistic simulations of a spiral shape emitting region, we conclude that the observed swings of the polarization angle during NIR flares support the idea of compact orbiting spots instead of extended patterns. The effects of gravitational shearing, fast synchrotron cooling of the components and confusion from a variable accretion disk have been taken into account. Simulated centroids of NIR images lead us to the conclusion that a clear observation of the position wander of the center of NIR images with future infrared interferometers will prove the existence of orbiting hot spots in the vicinity of our Galactic super-massive black hole.