Constraining the High-Energy Emission from Gamma-Ray Bursts with Fermi

NASA Technical Reports Server (NTRS)

Gehrels, Neil; Harding, A. K.; Hays, E.; Racusin, J. L.; Sonbas, E.; Stamatikos, M.; Guirec, S.

2012-01-01

We examine 288 GRBs detected by the Fermi Gamma-ray Space Telescope's Gamma-ray Burst Monitor (GBM) that fell within the field-of-view of Fermi's Large Area Telescope (LAT) during the first 2.5 years of observations, which showed no evidence for emission above 100 MeV. We report the photon flux upper limits in the 0.1-10 GeV range during the prompt emission phase as well as for fixed 30 s and 100 s integrations starting from the trigger time for each burst. We compare these limits with the fluxes that would be expected from extrapolations of spectral fits presented in the first GBM spectral catalog and infer that roughly half of the GBM-detected bursts either require spectral breaks between the GBM and LAT energy bands or have intrinsically steeper spectra above the peak of the nuF(sub v) spectra (E(sub pk)). In order to distinguish between these two scenarios, we perform joint GBM and LAT spectral fits to the 30 brightest GBM-detected bursts and find that a majority of these bursts are indeed softer above E(sub pk) than would be inferred from fitting the GBM data alone. Approximately 20% of this spectroscopic subsample show statistically significant evidence for a cut-off in their high-energy spectra, which if assumed to be due to gamma gamma attenuation, places limits on the maximum Lorentz factor associated with the relativistic outflow producing this emission. All of these latter bursts have maximum Lorentz factor estimates that are well below the minimum Lorentz factors calculated for LAT-detected GRBs, revealing a wide distribution in the bulk Lorentz factor of GRB outflows and indicating that LAT-detected bursts may represent the high end of this distribution.

Constraining the high-energy emission from gamma-ray bursts with Fermi

DOE PAGES

Ackermann, M.; Ajello, M.; Baldini, L.; ...

2012-07-17

Here, we examine 288 gamma-ray bursts (GRBs) detected by the Fermi Gamma-ray Space Telescope's Gamma-ray Burst Monitor (GBM) that fell within the field of view of Fermi's Large Area Telescope (LAT) during the first 2.5 years of observations, which showed no evidence for emission above 100 MeV. We report the photon flux upper limits in the 0.1-10 GeV range during the prompt emission phase as well as for fixed 30 s and 100 s integrations starting from the trigger time for each burst. We also compare these limits with the fluxes that would be expected from extrapolations of spectral fitsmore » presented in the first GBM spectral catalog and infer that roughly half of the GBM-detected bursts either require spectral breaks between the GBM and LAT energy bands or have intrinsically steeper spectra above the peak of the νF ν spectra (E pk). In order to distinguish between these two scenarios, we perform joint GBM and LAT spectral fits to the 30 brightest GBM-detected bursts and find that a majority of these bursts are indeed softer above E pk than would be inferred from fitting the GBM data alone. Approximately 20% of this spectroscopic subsample show statistically significant evidence for a cutoff in their high-energy spectra, which if assumed to be due to γγ attenuation, places limits on the maximum Lorentz factor associated with the relativistic outflow producing this emission. Furthermore, all of these latter bursts have maximum Lorentz factor estimates that are well below the minimum Lorentz factors calculated for LAT-detected GRBs, revealing a wide distribution in the bulk Lorentz factor of GRB outflows and indicating that LAT-detected bursts may represent the high end of this distribution.« less

Constraining the High-energy Emission from Gamma-Ray Bursts with Fermi

NASA Astrophysics Data System (ADS)

Fermi Large Area Telescope Team; Ackermann, M.; Ajello, M.; Baldini, L.; Barbiellini, G.; Baring, M. G.; Bechtol, K.; Bellazzini, R.; Blandford, R. D.; Bloom, E. D.; Bonamente, E.; Borgland, A. W.; Bottacini, E.; Bouvier, A.; Brigida, M.; Buehler, R.; Buson, S.; Caliandro, G. A.; Cameron, R. A.; Cecchi, C.; Charles, E.; Chekhtman, A.; Chiang, J.; Ciprini, S.; Claus, R.; Cohen-Tanugi, J.; Cutini, S.; D'Ammando, F.; de Palma, F.; Dermer, C. D.; Silva, E. do Couto e.; Drell, P. S.; Drlica-Wagner, A.; Favuzzi, C.; Fukazawa, Y.; Fusco, P.; Gargano, F.; Gasparrini, D.; Gehrels, N.; Germani, S.; Giglietto, N.; Giordano, F.; Giroletti, M.; Glanzman, T.; Granot, J.; Grenier, I. A.; Grove, J. E.; Hadasch, D.; Hanabata, Y.; Harding, A. K.; Hays, E.; Horan, D.; Jóhannesson, G.; Kataoka, J.; Knödlseder, J.; Kocevski, D.; Kuss, M.; Lande, J.; Longo, F.; Loparco, F.; Lovellette, M. N.; Lubrano, P.; Mazziotta, M. N.; McEnery, J.; McGlynn, S.; Michelson, P. F.; Mitthumsiri, W.; Monzani, M. E.; Moretti, E.; Morselli, A.; Moskalenko, I. V.; Murgia, S.; Naumann-Godo, M.; Norris, J. P.; Nuss, E.; Nymark, T.; Ohsugi, T.; Okumura, A.; Omodei, N.; Orlando, E.; Panetta, J. H.; Parent, D.; Pelassa, V.; Pesce-Rollins, M.; Piron, F.; Pivato, G.; Racusin, J. L.; Rainò, S.; Rando, R.; Razzaque, S.; Reimer, A.; Reimer, O.; Ritz, S.; Ryde, F.; Sgrò, C.; Siskind, E. J.; Sonbas, E.; Spandre, G.; Spinelli, P.; Stamatikos, M.; Stawarz, Łukasz; Suson, D. J.; Takahashi, H.; Tanaka, T.; Thayer, J. G.; Thayer, J. B.; Tibaldo, L.; Tinivella, M.; Tosti, G.; Uehara, T.; Vandenbroucke, J.; Vasileiou, V.; Vianello, G.; Vitale, V.; Waite, A. P.; Fermi Gamma-ray Burst Monitor Team; Connaughton, V.; Briggs, M. S.; Guirec, S.; Goldstein, A.; Burgess, J. M.; Bhat, P. N.; Bissaldi, E.; Camero-Arranz, A.; Fishman, J.; Fitzpatrick, G.; Foley, S.; Gruber, D.; Jenke, P.; Kippen, R. M.; Kouveliotou, C.; McBreen, S.; Meegan, C.; Paciesas, W. S.; Preece, R.; Rau, A.; Tierney, D.; van der Horst, A. J.; von Kienlin, A.; Wilson-Hodge, C.; Xiong, S.

2012-08-01

We examine 288 gamma-ray bursts (GRBs) detected by the Fermi Gamma-ray Space Telescope's Gamma-ray Burst Monitor (GBM) that fell within the field of view of Fermi's Large Area Telescope (LAT) during the first 2.5 years of observations, which showed no evidence for emission above 100 MeV. We report the photon flux upper limits in the 0.1-10 GeV range during the prompt emission phase as well as for fixed 30 s and 100 s integrations starting from the trigger time for each burst. We compare these limits with the fluxes that would be expected from extrapolations of spectral fits presented in the first GBM spectral catalog and infer that roughly half of the GBM-detected bursts either require spectral breaks between the GBM and LAT energy bands or have intrinsically steeper spectra above the peak of the νF ν spectra (E pk). In order to distinguish between these two scenarios, we perform joint GBM and LAT spectral fits to the 30 brightest GBM-detected bursts and find that a majority of these bursts are indeed softer above E pk than would be inferred from fitting the GBM data alone. Approximately 20% of this spectroscopic subsample show statistically significant evidence for a cutoff in their high-energy spectra, which if assumed to be due to γγ attenuation, places limits on the maximum Lorentz factor associated with the relativistic outflow producing this emission. All of these latter bursts have maximum Lorentz factor estimates that are well below the minimum Lorentz factors calculated for LAT-detected GRBs, revealing a wide distribution in the bulk Lorentz factor of GRB outflows and indicating that LAT-detected bursts may represent the high end of this distribution.

The Fermi-GBM Three-year X-Ray Burst Catalog

NASA Astrophysics Data System (ADS)

Jenke, P. A.; Linares, M.; Connaughton, V.; Beklen, E.; Camero-Arranz, A.; Finger, M. H.; Wilson-Hodge, C. A.

2016-08-01

The Fermi Gamma-ray Burst Monitor (GBM) is an all-sky gamma-ray monitor well known in the gamma-ray burst (GRB) community. Although GBM excels in detecting the hard, bright extragalactic GRBs, its sensitivity above 8 keV and its all-sky view make it an excellent instrument for the detection of rare, short-lived Galactic transients. In 2010 March, we initiated a systematic search for transients using GBM data. We conclude this phase of the search by presenting a three-year catalog of 1084 X-ray bursts. Using spectral analysis, location, and spatial distributions we classified the 1084 events into 752 thermonuclear X-ray bursts, 267 transient events from accretion flares and X-ray pulses, and 65 untriggered gamma-ray bursts. All thermonuclear bursts have peak blackbody temperatures broadly consistent with photospheric radius expansion (PRE) bursts. We find an average rate of 1.4 PRE bursts per day, integrated over all Galactic bursters within about 10 kpc. These include 33 and 10 bursts from the ultra-compact X-ray binaries 4U 0614+09 and 2S 0918-549, respectively. We discuss these recurrence times and estimate the total mass ejected by PRE bursts in our Galaxy.

Searching the Gamma-Ray Sky for Counterparts to Gravitational Wave Sources: FERMI Gamma Ray Burst MONITO R and Large Area Telescope Observations of LVT151012 and GW151226

DOE PAGES

Racusin, J. L.; Burns, E.; Goldstein, A.; ...

2017-01-19

Here, we present the Fermi Gamma-ray Burst Monitor (GBM) and Large Area Telescope (LAT) observations of the LIGO binary black hole merger event GW151226 and candidate LVT151012. At the time of the LIGO triggers on LVT151012 and GW151226, GBM was observing 68% and 83% of the localization regions, and LAT was observing 47% and 32%, respectively. No candidate electromagnetic counterparts were detected by either the GBM or LAT. We present a detailed analysis of the GBM and LAT data over a range of timescales from seconds to years, using automated pipelines and new techniques for characterizing the flux upper boundsmore » across large areas of the sky. Finally, due to the partial GBM and LAT coverage of the large LIGO localization regions at the trigger times for both events, differences in source distances and masses, as well as the uncertain degree to which emission from these sources could be beamed, these non-detections cannot be used to constrain the variety of theoretical models recently applied to explain the candidate GBM counterpart to GW150914.« less

SEARCHING THE GAMMA-RAY SKY FOR COUNTERPARTS TO GRAVITATIONAL WAVE SOURCES: FERMI GAMMA-RAY BURST MONITO R AND LARGE AREA TELESCOPE OBSERVATIONS OF LVT151012 AND GW151226

DOE Office of Scientific and Technical Information (OSTI.GOV)

Racusin, J. L.; Camp, J.; Singer, L.

2017-01-20

We present the Fermi Gamma-ray Burst Monitor (GBM) and Large Area Telescope (LAT) observations of the LIGO binary black hole merger event GW151226 and candidate LVT151012. At the time of the LIGO triggers on LVT151012 and GW151226, GBM was observing 68% and 83% of the localization regions, and LAT was observing 47% and 32%, respectively. No candidate electromagnetic counterparts were detected by either the GBM or LAT. We present a detailed analysis of the GBM and LAT data over a range of timescales from seconds to years, using automated pipelines and new techniques for characterizing the flux upper bounds acrossmore » large areas of the sky. Due to the partial GBM and LAT coverage of the large LIGO localization regions at the trigger times for both events, differences in source distances and masses, as well as the uncertain degree to which emission from these sources could be beamed, these non-detections cannot be used to constrain the variety of theoretical models recently applied to explain the candidate GBM counterpart to GW150914.« less

Terrestrial Gamma-Ray Flashes (TGFs) Observed with the Fermi-Gamma-Ray Burst Monitor: The First Hundred TGFs

NASA Technical Reports Server (NTRS)

Fishman, G J.; Briggs, M. S.; Connaughton, V.; Bhat, P. N.

2010-01-01

The Gamma-ray Burst Monitor (GBM) on the Fermi Gamma-ray Space Telescope Observatory (Fermi) is now detecting 2.1 TGFs per week. At this rate, nearly a hundred TGFs will have been detected by the time of this Meeting. This rate has increased by a factor of 8 since new flight software was uploaded to the spacecraft in November 2009 in order to increase the sensitivity of GBM to TGFs. The high time resolution (2 microseconds) allows temporal features to be resolved so that some insight may be gained on the origin and transport of the gamma-ray photons through the atmosphere. The absolute time of the TGFs, known to several microseconds, also allows accurate correlations of TGFs with lightning networks and other lightning-related phenomena. The thick bismuth germanate (BGO) scintillation detectors of the GBM system have observed photon energies from TGFs at energies above 40 MeV. New results on the some temporal aspects of TGFs will be presented.

Terrestrial Gamma-ray Flashes (TGFs) Observed with the Fermi-Gamma-ray Burst Monitor: Temporal and Spectral Properties

NASA Technical Reports Server (NTRS)

Fishman, G. J.; Briggs, M. S.; Connaughton, W.; Wilson-Hodge, C.; Bhat, P. N.

2010-01-01

The Gamma-ray Burst Monitor (GBM) on the Fermi Gamma-ray Space Telescope Observatory (Fermi) was detecting 2.1 TGFs per week. This rate has increased by a factor of 8 since new flight software was uploaded to the spacecraft in November 2009 in order to increase the sensitivity of GBM to TGFs. Further upgrades to Fermi-GBM to allow observations of weaker TGFs are in progress. The high time resolution (2 s) allows temporal features to be resolved so that some insight may be gained on the origin and transport of the gamma-ray photons through the atmosphere. The absolute time of the TGFs, known to several microseconds, also allows accurate correlations of TGFs with lightning networks and other lightning-related phenomena. The thick bismuth germanate (BGO) scintillation detectors of the GBM system have observed photon energies from TGFs at energies above 40 MeV. New results on the some temporal aspects of TGFs will be presented along with spectral characteristics and properties of several electron-positron TGF events that have been identified.

What Can Geolocated Sferics Tell Us About Terrestrial Gamma-Ray Flashes?

NASA Technical Reports Server (NTRS)

Connaughton, V.; Briggs, M. S.; Holzworth, R. H.; Hutchins, M. L.; Fishman, G. J.; Smith, D. M.

2010-01-01

The Fermi Gamma-ray Burst Monitor (GBM) has been detecting TGFs with increasing sensitivity over the past two years, owing to changes in flight software that have lowered its threshold for triggering and, recently, allowed a search for TGFs weaker than those which would cause an onboard trigger. Associations between TGFs detected in the first 18 months of operation and sferics detected using the World Wide Lightning Location Network (WWLLN) show that TGF peaks and lightning discharges are simultaneous to within tens of microseconds, and that GBM triggered on TGFs that occurred up to a distance of 300 km from the sub-spacecraft position. In the work presented here, we look for associations between TGFs detected by the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) and WWLLN sferics over the same 18 months, and we compare the match rate and detection horizon of the two instruments. We also look for associations between WWLLN sferics and more recent GBM TGFs, both triggered events and weaker TGFs uncovered in our untriggered search. We discuss whether in this new mode, GBM is detecting TGFs that are more distant from the sub-spacecraft point than 300 km, or whether the weaker TGFs are instead indicative of a luminosity distribution, either because the weaker ones originate deeper in the atmosphere or because they are intrinsically dimmer.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldstein, A.; Veres, P.; Burns, E.

We present the Fermi Gamma-ray Burst Monitor (GBM) and Large Area Telescope (LAT) observations of the LIGO binary black hole merger (BBH) event GW170104. No candidate electromagnetic counterparts was detected by either GBM or LAT. A detailed analysis of the GBM and LAT data over timescales from seconds to days covering the LIGO localization region is presented. The resulting ux upper bound from the GBM is (5.2{9.4) 10 -7 erg cm -2 s -1 in the 10-1000 keV range and from the LAT is (0.2{13) 10 -9 erg cm -2 s -1 in the 0.1{1 GeV range. We also describemore » the improvements to our automated pipelines and analysis techniques for searching for and characterizing the potential electromagnetic counterparts for future gravitational wave events from Advanced LIGO/VIRGO.« less

All-Sky Monitoring of Variable Sources with Fermi GBM

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Finger, Mark; Camero-Arranz, Ascension; Becklen, Elif; Jenke, Peter; Cpe. K/ K/; Steele, Iain; Case, Gary; Cherry, Mike; Rodi, James;

All-Sky Monitoring of Variable Sources with Fermi GBM

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Cherry, Michael L.; Case, Gary L.; Camero-Arranz, Ascension; Chaplin, Vandiver; Connaughton, Valerie; Finger, Mark H.; Jenke, Pater; Rodi, James C.; Baumgartner, Wayne H.;

THE THIRD FERMI GBM GAMMA-RAY BURST CATALOG: THE FIRST SIX YEARS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhat, P. Narayana; Meegan, Charles A.; Briggs, Michael S.

2016-04-01

Since its launch in 2008, the Fermi Gamma-ray Burst Monitor (GBM) has triggered and located on average approximately two γ -ray bursts (GRBs) every three days. Here, we present the third of a series of catalogs of GRBs detected by GBM, extending the second catalog by two more years through the middle of 2014 July. The resulting list includes 1405 triggers identified as GRBs. The intention of the GBM GRB catalog is to provide information to the community on the most important observables of the GBM-detected GRBs. For each GRB, the location and main characteristics of the prompt emission, themore » duration, peak flux, and fluence are derived. The latter two quantities are calculated for the 50–300 keV energy band where the maximum energy release of GRBs in the instrument reference system is observed, and also for a broader energy band from 10 to 1000 keV, exploiting the full energy range of GBM's low-energy [Nai[Tl)] detectors. Using statistical methods to assess clustering, we find that the hardness and duration of GRBs are better fit by a two-component model with short-hard and long-soft bursts than by a model with three components. Furthermore, information is provided on the settings and modifications of the triggering criteria and exceptional operational conditions during years five and six in the mission. This third catalog is an official product of the Fermi GBM science team, and the data files containing the complete results are available from the High-Energy Astrophysics Science Archive Research Center.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jenke, P. A.; Linares, M.; Connaughton, V.

The Fermi Gamma-ray Burst Monitor (GBM) is an all-sky gamma-ray monitor well known in the gamma-ray burst (GRB) community. Although GBM excels in detecting the hard, bright extragalactic GRBs, its sensitivity above 8 keV and its all-sky view make it an excellent instrument for the detection of rare, short-lived Galactic transients. In 2010 March, we initiated a systematic search for transients using GBM data. We conclude this phase of the search by presenting a three-year catalog of 1084 X-ray bursts. Using spectral analysis, location, and spatial distributions we classified the 1084 events into 752 thermonuclear X-ray bursts, 267 transient eventsmore » from accretion flares and X-ray pulses, and 65 untriggered gamma-ray bursts. All thermonuclear bursts have peak blackbody temperatures broadly consistent with photospheric radius expansion (PRE) bursts. We find an average rate of 1.4 PRE bursts per day, integrated over all Galactic bursters within about 10 kpc. These include 33 and 10 bursts from the ultra-compact X-ray binaries 4U 0614+09 and 2S 0918-549, respectively. We discuss these recurrence times and estimate the total mass ejected by PRE bursts in our Galaxy.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldstein, A.; Cleveland, W. H.; Connaughton, V.

We present the Fermi Gamma-ray Burst Monitor (GBM) and Large Area Telescope (LAT) observations of the LIGO binary black hole merger (BBH) event GW170104. No candidate electromagnetic counterpart was detected by either GBM or LAT. A detailed analysis of the GBM and LAT data over timescales from seconds to days covering the Laser Interferometer Gravitational-wave Observatory (LIGO) localization region is presented. The resulting flux upper bound from the GBM is (5.2–9.4) × 10{sup −7} erg cm{sup −2} s{sup −1} in the 10–1000 keV range and from the LAT is (0.2–90) × 10{sup −9} erg cm{sup −2} s{sup −1} in themore » 0.1–1 GeV range. We also describe the improvements to our automated pipelines and analysis techniques for searching for and characterizing the potential electromagnetic counterparts for future gravitational-wave events from Advanced LIGO/Virgo.« less

Finding Sub-threshold Short Gamma-ray Bursts in Fermi GBM Data

NASA Astrophysics Data System (ADS)

Burns, Eric; Fermi Gamma-ray Burst Monitor Team

2018-01-01

The all-sky monitoring capability of Fermi GBM makes it ideal for finding transients, and the most prolific detector of short gamma-ray bursts with about 40 on-board triggers per year. Because the observed brightness of short gamma-ray bursts has no correlation with redshift, weak short gamma-ray bursts are important during the gravitational wave era. With this in mind, we discuss two searches of GBM data to find short gamma-ray which were below the on-board trigger threshold. The untargeted search looks for significant background-subtracted signals in two or more detectors at various timescales in the continuous data, detecting ~80 additional short GRB candidates per year. The targeted search is the most sensitive search for weak gamma-ray signals in GBM data and is run over limited time intervals around sources of interest like gravitational waves.

The Five Year Fermi/GBM Magnetar Burst Catalog

NASA Astrophysics Data System (ADS)

Collazzi, A. C.; Kouveliotou, C.; van der Horst, A. J.; Younes, G. A.; Kaneko, Y.; Göğüş, E.; Lin, L.; Granot, J.; Finger, M. H.; Chaplin, V. L.; Huppenkothen, D.; Watts, A. L.; von Kienlin, A.; Baring, M. G.; Gruber, D.; Bhat, P. N.; Gibby, M. H.; Gehrels, N.; McEnery, J.; van der Klis, M.; Wijers, R. A. M. J.

2015-05-01

Since launch in 2008, the Fermi Gamma-ray Burst Monitor (GBM) has detected many hundreds of bursts from magnetar sources. While the vast majority of these bursts have been attributed to several known magnetars, there is also a small sample of magnetar-like bursts of unknown origin. Here, we present the Fermi/GBM magnetar catalog, providing the results of the temporal and spectral analyses of 440 magnetar bursts with high temporal and spectral resolution. This catalog covers the first five years of GBM magnetar observations, from 2008 July to 2013 June. We provide durations, spectral parameters for various models, fluences, and peak fluxes for all the bursts, as well as a detailed temporal analysis for SGR J1550-5418 bursts. Finally, we suggest that some of the bursts of unknown origin are associated with the newly discovered magnetar 3XMM J185246.6+0033.7.

Fermi Observations of the LIGO Event GW170104

DOE PAGES

Goldstein, A.; Veres, P.; Burns, E.; ...

2017-08-28

We present the Fermi Gamma-ray Burst Monitor (GBM) and Large Area Telescope (LAT) observations of the LIGO binary black hole merger (BBH) event GW170104. No candidate electromagnetic counterparts was detected by either GBM or LAT. A detailed analysis of the GBM and LAT data over timescales from seconds to days covering the LIGO localization region is presented. The resulting ux upper bound from the GBM is (5.2{9.4) 10 -7 erg cm -2 s -1 in the 10-1000 keV range and from the LAT is (0.2{13) 10 -9 erg cm -2 s -1 in the 0.1{1 GeV range. We also describemore » the improvements to our automated pipelines and analysis techniques for searching for and characterizing the potential electromagnetic counterparts for future gravitational wave events from Advanced LIGO/VIRGO.« less

Photospheric Emission in the Joint GBM and Konus Prompt Spectra of GRB 120323A

NASA Technical Reports Server (NTRS)

Guiriec, S.; Gehrels, N.; McEnery, J.; Kouveliotou, C.; Hartmann, D. H.

2017-01-01

GRB 120323A is a very intense short gamma-ray burst (GRB) detected simultaneously during its prompt gamma-ray emission phase with the Gamma-Ray Burst Monitor (GBM) on board the Fermi Gamma-Ray Space Telescope and the Konus experiment on board the Wind satellite. GBM and Konus operate in the kiloelectronvolt - megaelectronvolt regime; however, the GBM range is broader toward both the low and the high parts of the gamma-ray spectrum. Analyses of such bright events provide a unique opportunity to check the consistency of the data analysis as well as cross-calibrate the two instruments. We performed time-integrated and coarse time-resolved spectral analysis of GRB 120323A prompt emission. We conclude that the analyses of GBM and Konus data are only consistent when using a double-hump spectral shape for both data sets; in contrast, the single hump of the empirical Band function, traditionally used to fit GRB prompt emission spectra, leads to significant discrepancies between GBM and Konus analysis results. Our two-hump model is a combination of a thermal-like and a non-thermal component. We interpret the first component as a natural manifestation of the jet photospheric emission.

Fermi GBM Observations of Terrestrial Gamma Flashes

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Briggs, M. S.; Fishman, G. J.; Bhat, P. N.; Paciesas, W. S.; Preece, R.; Kippen, R. M.; von Kienlin, A.; Dwyer, J. R.; Smith, D. M.;

On the Interpretation of the Fermi-GBM Transient Observed in Coincidence with LIGO Gravitational-wave Event GW150914

NASA Astrophysics Data System (ADS)

Connaughton, V.; Burns, E.; Goldstein, A.; Blackburn, L.; Briggs, M. S.; Christensen, N.; Hui, C. M.; Kocevski, D.; Littenberg, T.; McEnery, J. E.; Racusin, J.; Shawhan, P.; Veitch, J.; Wilson-Hodge, C. A.; Bhat, P. N.; Bissaldi, E.; Cleveland, W.; Giles, M. M.; Gibby, M. H.; von Kienlin, A.; Kippen, R. M.; McBreen, S.; Meegan, C. A.; Paciesas, W. S.; Preece, R. D.; Roberts, O. J.; Stanbro, M.; Veres, P.

2018-01-01

The weak transient detected by the Fermi Gamma-ray Burst Monitor (GBM) 0.4 s after GW150914 has generated much speculation regarding its possible association with the black hole binary merger. Investigation of the GBM data by Connaughton et al. revealed a source location consistent with GW150914 and a spectrum consistent with a weak, short gamma-ray burst. Greiner et al. present an alternative technique for fitting background-limited data in the low-count regime, and call into question the spectral analysis and the significance of the detection of GW150914-GBM presented in Connaughton et al. The spectral analysis of Connaughton et al. is not subject to the limitations of the low-count regime noted by Greiner et al. We find Greiner et al. used an inconsistent source position and did not follow the steps taken in Connaughton et al. to mitigate the statistical shortcomings of their software when analyzing this weak event. We use the approach of Greiner et al. to verify that our original spectral analysis is not biased. The detection significance of GW150914-GBM is established empirically, with a false-alarm rate (FAR) of ∼ {10}-4 Hz. A post-trials false-alarm probability (FAP) of 2.2× {10}-3 (2.9σ ) of this transient being associated with GW150914 is based on the proximity in time to the gravitational-wave event of a transient with that FAR. The FAR and the FAP are unaffected by the spectral analysis that is the focus of Greiner et al.

MODELING THE AFTERGLOW OF THE POSSIBLE FERMI -GBM EVENT ASSOCIATED WITH GW150914

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morsony, Brian J.; Workman, Jared C.; Ryan, Dominic M., E-mail: morsony@astro.umd.edu

2016-07-10

We model the possible afterglow of the Fermi Gamma-ray Burst Monitor (GBM) event associated with LIGO detection GW150914, under the assumption that the gamma-rays are produced by a short GRB-like relativistic outflow. We model GW150914-GBM as both a weak, on-axis short GRB and normal short GRB seen far off-axis. Given the large uncertainty in the position of GW150914, we determine that the best chance of finding the afterglow is with ASKAP or possibly the Murchinson Widefield Array (MWA), with the flux from an off-axis short GRB reaching 0.2–4 mJy (0.12–16 mJy) at 150 MHz (863.5 MHz) by 1–12 months aftermore » the initial event. At low frequencies, the source would evolve from a hard to soft spectrum over several months. The radio afterglow would be detectable for several months to years after it peaks, meaning the afterglow may still be detectable and increasing in brightness NOW (2016 mid-July). With a localization from the MWA or ASKAP, the afterglow would be detectable at higher radio frequencies with the ATCA and in X-rays with Chandra or XMM .« less

Photospheric Emission in the Joint GBM and Konus Prompt Spectra of GRB 120323A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guiriec, S.; Kouveliotou, C.; Gehrels, N.

GRB 120323A is a very intense short gamma -ray burst (GRB) detected simultaneously during its prompt γ -ray emission phase with the Gamma-ray Burst Monitor (GBM) on board the Fermi Gamma-ray Space Telescope and the Konus experiment on board the Wind satellite. GBM and Konus operate in the keV–MeV regime; however, the GBM range is broader toward both the low and the high parts of the γ -ray spectrum. Analyses of such bright events provide a unique opportunity to check the consistency of the data analysis as well as cross-calibrate the two instruments. We performed time-integrated and coarse time-resolved spectralmore » analysis of GRB 120323A prompt emission. We conclude that the analyses of GBM and Konus data are only consistent when using a double-hump spectral shape for both data sets; in contrast, the single hump of the empirical Band function, traditionally used to fit GRB prompt emission spectra, leads to significant discrepancies between GBM and Konus analysis results. Our two-hump model is a combination of a thermal-like and a non-thermal component. We interpret the first component as a natural manifestation of the jet photospheric emission.« less

Two Decades in the Life of EXO 2030+375

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Jenke, Pete; Finger, Mark; Camero-Arranz, Ascension; Fabregat, Juan; Reig, Pablo; Steele, Iain

2011-01-01

EXO 2030+375, a 42-s accreting pulsar in a 46-day orbit around a Be star, has undergone a detected outburst at nearly every periastron passage since 1991. It has been monitored with BATSE, RXTE, and Fermi/GBM. We will present preliminary results of long-term monitoring, including a long-term frequency history, long-term pulsed flux measurements, and available long ]term optical/ir monitoring results.

All Sky Observations with BATSE and GBM

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.

2008-01-01

The Burst and Transient Source Experiment (BATSE) on board the Compton Gamma Ray Observatory (CGRO) monitored the entire sky from 1991-2000. I will review highlights of BATSE observations including gamma ray bursts, black hole candidates, accreting pulsars, and active galaxies. On 2008 June 11, the Fermi Gamma Ray Space Telescope was launched. The Gamma ray Burst Monitor (GBM) on board Fermi continues the all-sky monitoring legacy started with BATSE. I will review early results and planned observations with GBM.

The Latest Space-Borne Observations of TGFs from Fermi-GBM

NASA Technical Reports Server (NTRS)

Fishman, Gerald J.

2010-01-01

The Gamma-ray Burst Monitor (GBM) on the Fermi Gamma-ray Space Telescope Observatory (Fermi) is detecting about two TGFs per week. This rate has increased by a factor of approx.eight since launch when flight software was uploaded to the spacecraft in November 2009 in order to increase the sensitivity of GBM to TGFs. Weaker, un-triggered TGFs are now also being observed about once per day over selected low-latitude regions Americas. The high efficiency and time resolution (2 s) of GBM allows temporal features to be resolved so that some insight may be gained on the origin and transport of the gamma-ray photons through the atmosphere. TGFs are observed to be shorter than previously thought, with an average duration of approx.100 micro-s. The absolute times of TGFs are known to approx.10 micro-s, allowing accurate correlations of TGFs with lightning networks and other lightning-related phenomena. The events are observed in the thick bismuth germanate (BGO) scintillation detectors of GBM with photon energies above 40 MeV. Other new results on the temporal and spectral characteristics of TGFs will be presented, along with properties of several electron-positron TGF events that have been identified.

IMPLICATIONS OF THE TENTATIVE ASSOCIATION BETWEEN GW150914 AND A FERMI -GBM TRANSIENT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Xiang; Yuan, Qiang; Jin, Zhi-Ping

2016-08-10

The merger-driven gamma-ray bursts (GRBs) and their associated gravitational-wave (GW) radiation, if both are successfully detected, have some far-reaching implications, including, for instance: (i) the statistical comparison of the physical properties of the short/long-short GRBs with and without GW detection can test the general origin model; (ii) revealing the physical processes taking place at the central engine; (iii) measuring the velocity of the gravitational wave directly/accurately. In this work, we discuss these implications in the case of a possible association of GW150914/Gamma-ray Burst Monitor (GBM) transient 150914. We compared GBM transient 150914 with other SGRBs and found that such anmore » event may be a distinct outlier in some statistical diagrams, possibly due to its specific binary black hole merger origin. However, the presence of a “new” group of SGRBs with “unusual” physical parameters is also possible. If the outflow of GBM transient 150914 was launched by the accretion onto the nascent black hole, the magnetic activity rather than the neutrino process is likely responsible for the energy extraction, and the accretion disk mass is estimated to be ∼10{sup −5} M {sub ⊙}. The GW150914/GBM transient 150914 association, if confirmed, would provide the first opportunity to directly measure the GW velocity, and its departure from the speed of the light should be within a factor of ∼10{sup −17}.« less

FERMI observations of high-energy gamma-ray emission from GRB 090217A

DOE PAGES

Ackermann, M.; Ajello, M.; Baldini, L.; ...

2010-06-22

The Fermi observatory is advancing our knowledge of gamma-ray bursts (GRBs) through pioneering observations at high energies, covering more than seven decades in energy with the two on-board detectors, the Large Area Telescope (LAT) and the Gamma-ray Burst Monitor (GBM). Here, we report on the observation of the long GRB 090217A which triggered the GBM and has been detected by the LAT with a significance greater than 9σ. We present the GBM and LAT observations and on-ground analyses, including the time-resolved spectra and the study of the temporal profile from 8 keV up to ~1 GeV. All spectra are wellmore » reproduced by a Band model. We compare these observations to the first two LAT-detected, long bursts GRB 080825C and GRB 080916C. These bursts were found to have time-dependent spectra and exhibited a delayed onset of the high-energy emission, which are not observed in the case of GRB 090217A. We discuss some theoretical implications for the high-energy emission of GRBs.« less

Routinely used immunoassays do not detect circulating anti-GBM antibodies against native NC1 hexamer and EA epitope of the α3 chain of type IV collagen.

PubMed

Clavarino, Giovanna; Gauthier, Arnaud; Hellmark, Thomas; Carron, Pierre-Louis; Giovannini, Diane; Colliard, Sophie; Dragon-Durey, Marie-Agnès; Segelmark, Mårten; Cesbron, Jean-Yves; Dumestre-Pérard, Chantal

2018-04-12

Detection of circulating anti-GBM antibodies has a key role for the diagnosis of Goodpasture syndrome but immunoassays using purified or recombinant alpha3(IV)NC1 as antigen do not recognize all anti-GBM antibodies. We show that anti-GBM antibodies directed against epitopes in their native conformation or cryptic epitopes are detected by indirect immunofluorescence. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Clustering ENTLN sferics to improve TGF temporal analysis

NASA Astrophysics Data System (ADS)

Pradhan, E.; Briggs, M. S.; Stanbro, M.; Cramer, E.; Heckman, S.; Roberts, O.

2017-12-01

Using TGFs detected with Fermi Gamma-ray Burst Monitor (GBM) and simultaneous radio sferics detected by Earth Network Total Lightning Network (ENTLN), we establish a temporal co-relation between them. The first step is to find ENTLN strokes that that are closely associated to GBM TGFs. We then identify all the related strokes in the lightning flash that the TGF-associated-stroke belongs to. After trying several algorithms, we found out that the DBSCAN clustering algorithm was best for clustering related ENTLN strokes into flashes. The operation of DBSCAN was optimized using a single seperation measure that combined time and distance seperation. Previous analysis found that these strokes show three timescales with respect to the gamma-ray time. We will use the improved identification of flashes to research this.

Monitoring the Low-Energy Gamma-Ray Sky Using Earth Occultation with GLAST GBM

NASA Technical Reports Server (NTRS)

Case, G.; Wilson-Hodge, C.; Cherry, M.; Kippen, M.; Ling, J.; Radocinski, R.; Wheaton, W.

2007-01-01

Long term all-sky monitoring of the 20 keV - 2 MeV gamma-ray sky using the Earth occultation technique was demonstrated by the BATSE instrument on the Compton Gamma Ray Observatory. The principles and techniques used for the development of an end-to-end earth occultation data analysis system for BATSE can be extended to the GLAST Gamma-ray Burst Monitor (GBM), resulting in multiband light curves and time-resolved spectra in the energy range 8 keV to above 1 MeV for known gamma-ray sources and transient outbursts, as well as the discovery of new sources of gamma-ray emission. In this paper we describe the application of the technique to the GBM. We also present the expected sensitivity for the GBM.

Possible role of magnetic reconnection in the electromagnetic counterpart of binary black hole merger

NASA Astrophysics Data System (ADS)

Fraschetti, F.

2018-04-01

We propose a qualitative scenario to interpret the argued association between the direct measurement of the gravitational wave event GW150914 by Laser Interferometer Gravitational Wave Observatory (LIGO)-Virgo collaborations and the hard X-ray transient detected by Fermi-Gamma-ray Burst Monitor (GBM) 0.4 sec after. In a binary system of two gravitationally collapsing objects with a non-vanishing electric charge, the compenetration of the two magnetospheres occurring during the coalescence, through magnetic reconnection, produces a highly collimated relativistic outflow that becomes optically thin and shines in the GBM field of view. We propose that this process should be expected as a commonplace in the future joint gravitational/electromagnetic detections and, in case of neutron star-neutron star merger event, might lead to detectable X- or γ-ray precursors to, or transients associated with, the gravitational bursts.

The First Unambiguous Electromagnetic Counterpart to a Gravitational-Wave Signal: GRB 170817A and GW170817

NASA Astrophysics Data System (ADS)

Goldstein, Adam

2018-01-01

On 2017 August 17 at 12:41:06 UTC the Fermi Gamma-ray Burst Monitor (GBM) detected and triggered on the short gamma-ray burst (GRB) 170817A. Approximately 2 s prior to this GRB, the LIGO gravitational-wave observatory triggered on a binary compact merger candidate associated with the GRB. This is the first unambiguous coincident observation of gravitational waves and electromagnetic radiation from a single astrophysical source and marks the start of gravitational-wave multi-messenger astronomy. We report the GBM observations and analysis of this short GRB and the joint science that results from this discovery.

Earth Occultation Monitoring with the Fermi Gamma Ray Burst Monitor

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.

2014-01-01

Using the Gamma Ray Burst Monitor (GBM) on-board Fermi, we are monitoring the hard X-ray/soft gamma ray sky using the Earth occultation technique (EOT). Each time a source in our catalog is occulted by (or exits occultation by) the Earth, we measure its flux using the change in count rates due to the occultation. Currently we are using CTIME data with 8 energy channels spanning 8 keV to 1 MeV for the GBM NaI detectors for daily monitoring. Light curves, updated daily, are available on our website http://heastro.phys.lsu.edu/gbm. Our software is also capable of performing the Earth occultation monitoring using up to 128 energy bands, or any combination of those bands, using our 128-channel, 4-s CSPEC data. The GBM BGO detectors, sensitive from about 200 keV to 40 keV, can also be used with this technique. In our standard application of the EOT, we use a catalog of sources to drive the measurements. To ensure that our catalog is complete, our team has developed an Earth occultation imaging method. In this talk, I will describe both techniques and the current data products available. I will highlight recent and important results from the GBM EOT, including the current status of our observations of hard X-ray variations in the Crab Nebula.

Magnetars: Challenging the Extremes of Nature

NASA Technical Reports Server (NTRS)

Kouveliotou, Chryssa

2011-01-01

Magnetars are magnetically powered rotating neutron stars with extreme magnetic fields (over 10(exp 14) Gauss). They are discovered and emit predominantly in the X- and gamma-rays. Very few sources (roughly 15) have been found since their discovery in 1987. NASA s Fermi Observatory was launched June 11, 2009; the Fermi Gamma Ray Burst Monitor (GBM) began normal operations on July 14, about a month after launch, when the trigger algorithms were enabled. Since then, we recorded emission from four magnetar sources; of these, only one was an old magnetar: SGR 1806+20. The other three detections were two brand new sources, SGR J0501+4516, discovered with Swift and extensively monitored with both Swift and GBM, SGR J0418+5729, discovered with GBM and the Interplanetary Network (IPN), and SGR J1550-5418, a source originally classified as an Anomalous X-ray Pulsar (AXP 1E1547.0-5408). In my talk I will give a short history of the discovery of magnetars and describe how this, once relatively esoteric field, has emerged as a link between several astrophysical areas including Gamma-Ray Bursts. Finally, I will describe the properties of these sources and the current status of our knowledge of the magnetar population and birth rate.

Diagnosis and classification of Goodpasture's disease (anti-GBM).

PubMed

Hellmark, Thomas; Segelmark, Mårten

2014-01-01

Goodpasture's disease or anti-glomerular basement membrane disease (anti-GBM-disease) is included among immune complex small vessel vasculitides. The definition of anti-GBM disease is a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM autoantibodies. The disease is a prototype of autoimmune disease, where the patients develop autoantibodies that bind to the basement membranes and activate the classical pathway of the complement system, which start a neutrophil dependent inflammation. The diagnosis of anti-GBM disease relies on the detection of anti-GBM antibodies in conjunction with glomerulonephritis and/or alveolitis. Overt clinical symptoms are most prominent in the glomeruli where the inflammation usually results in a severe rapidly progressive glomerulonephritis. Despite modern treatment less than one third of the patients survive with a preserved kidney function after 6 months follow-up. Frequencies vary from 0.5 to 1 cases per million inhabitants per year and there is a strong genetic linkage to HLA-DRB1(∗)1501 and DRB1(∗)1502. Essentially, anti-GBM disease is now a preferred term for what was earlier called Goodpasture's syndrome or Goodpasture's disease; anti-GBM disease is now classified as small vessel vasculitis caused by in situ immune complex formation; the diagnosis relies on the detection of anti-GBM in tissues or circulation in conjunction with alveolar or glomerular disease; therapy is effective only when detected at an early stage, making a high degree of awareness necessary to find these rare cases; 20-35% have anti-GBM and MPO-ANCA simultaneously, which necessitates testing for anti-GBM whenever acute test for ANCA is ordered in patients with renal disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

Magnetar Observations in the Swift-Fermi/GBM Era

NASA Technical Reports Server (NTRS)

Kouveliotou, Chryssa

2010-01-01

NASA's Fermi Observatory was launched June 11, 2008; the Fermi Gamma Ray Burst Monitor (GBM) began normal operations on July 14, about a month after launch, when the trigger algorithms were enabled. Since then, and against all odds, GBM recorded over 600 bursts from 4 SGRs. Of these four sources, only one was an old magnetar: SGR J1806+20. SGR J0501+4516, was discovered with Swift and extensively monitored with GBM. A source originally classified as AXP 1E1547.0-5408 exhibited SGR-like bursting behavior and we reclassified it as SGR J1550-5418. Finally, GBM discovered SGR J0418+5729 on 2009 June. Finally, on March 2010, a third new magnetar was discovered with Swift, SGR J1833-0832. I report below on the current status of the field and on several results combining multi-satellite and ground-based data

Three years of Transients with Fermi GBM

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.

2012-01-01

The Gamma-ray Burst Monitor (GBM) is an all-sky monitoring instrument, sensitive between 8 keV and 40 MeV, with a primary objective of supporting the Large Area Telescope (LAT) in observations of Gamma-Ray Bursts (GRBs). Both instruments are part of the Fermi Gamma-ray Space Telescope. Together, the GBM and LAT instruments have provided ground-breaking measurements of GRBs that have, after 10 years of focus on GRB afterglows, inspired renewed interest in the prompt emission phase of GRBs and the physical mechanisms that fuel them. In addition to GRB science, GBM has made significant contributions to the astrophysics of galactic transient sources including long-term variations in the Crab nebula, spin state transitions in accretion powered pulsars, state transitions in black hole X-ray binaries, and unprecedented time-resolved spectral studies of soft gamma-ray repeater bursts. Closer to home, GBM also contributes to solar flare and terrestrial gamma flash science.

Performance evaluation of a novel chemiluminescence assay for detection of anti-GBM antibodies: an international multicenter study.

PubMed

Mahler, Michael; Radice, Antonella; Sinico, Renato A; Damoiseaux, Jan; Seaman, Andrea; Buckmelter, Kristen; Vizjak, Alenka; Buchner, Carol; Binder, Walter L; Fritzler, Marvin J; Cui, Zhao

2012-01-01

Autoantibodies to the non-collagen region (NC1) of the alpha-3 subunit of collagen IV represent a serological hallmark in the diagnosis of Goodpasture's syndrome (GPS). The objective of our study was to carefully analyze the performance characteristics of a novel anti-glomerular basement membrane (GBM) chemiluminescence immunoassay (CIA). Sera from patients with GPS (n = 90) were collected from four clinical centers. Samples from different disease groups (n = 397) and healthy individuals (n = 400) were used as controls. All samples were tested for anti-GBM antibodies by a rapid, random access CIA (QUANTA Flash™ GBM). Most of the samples were also tested using other methods including different commercial anti-GBM IgG assays and research assays for anti-GBM IgA and IgM. The sensitivity and specificity of the novel CIA was 95.6% [95% confidence interval (CI) 89.0-98.8%] and 99.6% (95% CI 98.9-99.9%), respectively. Receiver operating characteristic analysis showed good discrimination between GPS patients and controls. The area under the curve was 0.98 (CI 0.96-1.0). The three anti-GBM antibody-positive samples from the control group were from two healthy individuals and one human immunodeficiency virus (HIV)-infected patient. All three individuals had low levels of anti-GBM antibodies [20, 24 and 25 chemiluminescent unit (CU), cutoff 20 CU]. When the results of the new CIA were compared to other methods, good agreement was observed: 95.8% (kappa = 0.92) versus EliA™ GBM, 97.4% (kappa = 0.95) versus both BINDAZYME™ Anti-GBM and QUANTA Lite® GBM. Anti-GBM IgA was detectable in low concentrations in patients with GPS and was associated with anti-GBM IgG but was less useful in discriminating GPS patients and controls. No discrimination was found for anti-GBM IgM. The novel QUANTA Flash™ GBM CIA demonstrated good sensitivity and specificity and had good agreement with other methods. Our data confirm that ∼5% of patients with GPS do not have detectable levels of anti-GBM antibodies.

Test of the Weak Equivalence Principle using LIGO observations of GW150914 and Fermi observations of GBM transient 150914

NASA Astrophysics Data System (ADS)

Liu, Molin; Zhao, Zonghua; You, Xiaohe; Lu, Jianbo; Xu, Lixin

2017-07-01

About 0.4 s after the Laser Interferometer Gravitational-Wave Observatory (LIGO) detected a transient gravitational-wave (GW) signal GW150914, the Fermi Gamma-ray Burst Monitor (GBM) also found a weak electromagnetic transient (GBM transient 150914). Time and location coincidences favor a possible association between GW150904 and GBM transient 150914. Under this possible association, we adopt Fermi's electromagnetic (EM) localization and derive constraints on possible violations of the Weak Equivalence Principle (WEP) from the observations of two events. Our calculations are based on four comparisons: (1) The first is the comparison of the initial GWs detected at the two LIGO sites. From the different polarizations of these initial GWs, we obtain a limit on any difference in the parametrized post-Newtonian (PPN) parameter Δγ ≲10-10. (2) The second is a comparison of GWs and possible EM waves. Using a traditional super-Eddington accretion model for GBM transient 150914, we again obtain an upper limit Δγ ≲10-10. Compared with previous results for photons and neutrinos, our limits are five orders of magnitude stronger than those from PeV neutrinos in blazar flares, and seven orders stronger than those from MeV neutrinos in SN1987A. (3) The third is a comparison of GWs with different frequencies in the range [35 Hz, 250 Hz]. (4) The fourth is a comparison of EM waves with different energies in the range [1 keV, 10 MeV]. These last two comparisons lead to an even stronger limit, Δγ ≲10-8. Our results highlight the potential of multi-messenger signals exploiting different emission channels to strengthen existing tests of the WEP.

Characterization of glioblastoma in an orthotopic mouse model with magnetic resonance elastography.

PubMed

Schregel, Katharina; Nazari, Navid; Nowicki, Michal O; Palotai, Miklos; Lawler, Sean E; Sinkus, Ralph; Barbone, Paul E; Patz, Samuel

2017-11-29

Glioblastoma (GBM) is the most common primary brain tumor. It is highly malignant and has a correspondingly poor prognosis. Diagnosis and monitoring are mainly accomplished with MRI, but remain challenging in some cases. Therefore, complementary methods for tumor detection and characterization would be beneficial. Using magnetic resonance elastography (MRE), we performed a longitudinal study of the biomechanical properties of intracranially implanted GBM in mice and compared the results to histopathology. The biomechanical parameters of viscoelastic modulus, shear wave speed and phase angle were significantly lower in tumors compared with healthy brain tissue and decreased over time with tumor progression. Moreover, some MRE parameters revealed sub-regions at later tumor stages, which were not easily detectable on anatomical MRI images. Comparison with histopathology showed that softer tumor regions contained necrosis and patches of viable tumor cells. In contrast, areas of densely packed tumor cells and blood vessels identified with histology coincided with higher values of viscoelastic modulus and shear wave speed. Interestingly, the phase angle was independent from these anatomical variations. In summary, MRE depicted longitudinal and morphological changes in GBM and may prove valuable for tumor characterization in patients. Copyright © 2017 John Wiley & Sons, Ltd.

Fermi GBM Observations of LIGO Gravitational-Wave Event Gw150914

NASA Technical Reports Server (NTRS)

Connaughton, V.; Burns, E.; Goldstein, A.; Blackburn, L.; Briggs, M. S.; Zhang, B.-B.; Camp, J.; Christensen, N.; Hui, C. M.; Jenke, P.;

All-Sky Earth Occultation Observations with the Fermi Gamma Ray Burst Monitor

NASA Technical Reports Server (NTRS)

Wilson-Hodge, C. A.; Beklen, E.; Bhat, P. N.; Briggs, M.; Camero-Arranz, A.; Case, G.; Chaplin, V.; Cherry, M.; Connaughton, V.; Finger, M.;

The Interplanetary Network Supplement to the Fermi GBM Catalog - An AO-2 and AO-3 Guest Investigator Project

NASA Technical Reports Server (NTRS)

Hurley, K.; Briggs, M.; Connaughton, V.; Meegan, C.; von Kienlin, A.; Rau, A.; Zhang, X.; Golenetskii, S.; Aptekar, R.; Mazets, E.;

The First FERMI-LAT Gamma-Ray Burst Catalog

NASA Technical Reports Server (NTRS)

Ackermann, M.; Ajello, M.; Asano, K.; Axelsson, M.; Baldini, L.; Ballet, J.; Barbiellini, G.; Bastieri, D.; Bechtol, K.; Bellazzini, R.;

The first Fermi-LAT Gamma-Ray burst catalog

DOE PAGES

Ackermann, M.; Ajello, M.; Asano, K.; ...

2013-10-23

In three years of observations since the beginning of nominal science operations in 2008 August, the Large Area Telescope (LAT) on board the Fermi Gamma-Ray Space Telescope has observed high-energy (gsim 20 MeV) γ-ray emission from 35 gamma-ray bursts (GRBs). Among these, 28 GRBs have been detected above 100 MeV and 7 GRBs above ~20 MeV. The first Fermi-LAT catalog of GRBs is a compilation of these detections and provides a systematic study of high-energy emission from GRBs for the first time. To generate the catalog, we examined 733 GRBs detected by the Gamma-Ray Burst Monitor (GBM) on Fermi andmore » processed each of them using the same analysis sequence. Details of the methodology followed by the LAT collaboration for the GRB analysis are provided. Here, we summarize the temporal and spectral properties of the LAT-detected GRBs. We also discuss characteristics of LAT-detected emission such as its delayed onset and longer duration compared with emission detected by the GBM, its power-law temporal decay at late times, and the fact that it is dominated by a power-law spectral component that appears in addition to the usual Band model.« less

Discoveries by the Fermi Gamma Ray Space Telescope

NASA Technical Reports Server (NTRS)

Gehrels, Neil

2011-01-01

Fermi is a large space gamma-ray mission developed by NASA and the DOE with major contributions from France, Germany, Italy, Japan and Sweden. It was launched in June 2008 and has been performing flawlessly since then. The main instrument is the Large Area Telescope (LAT) operating in the 20 MeV to 300 GeV range and a smaller monitor instrument is the Gamma-ray Burst Monitor (GBM) operating in the 8 keV to 40 MeV range. New findings are occurring every week. Some of the key discoveries are: 1) Discovery of many new gamma-ray pulsars, including gamma-ray only and millisecond pulsars. 2) Detection of high energy gamma-ray emission from globular clusters, most likely due to summed emission from msec pulsars. 3) Discovery of delayed and extended high energy gamma-ray emission from short and long gamma-ray busts. 4) Detection of approximately 250 gamma-ray bursts per year with the GBM instrument. 5) Most accurate measurement of the cosmic ray electron spectrum between 30 GeV and 1 TeV, showing some excess above the conventional diffusion model. The talk will present the new discoveries and their implications.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakahira, S.; Yamaoka, K.; Yoshida, A.

We propose to provide a gamma-ray burst monitor (GBM) for the CALET mission to monitor gamma-ray bursts (GRBs) together with the CALET Imaging Calorimeter detector. The major purpose is to derive a wide-band energy spectrum of GRBs over an unprecedented 9 decades of energy (from a few keV to a few TeV) in combination with the CALET tower detector. Hence it is desirable to have the CALET-GBM covering an energy range from a few keV to about 20 MeV to avoid a gap in the observational energy bands. The design of GBM is underway to fulfill this requirement. The currentmore » detector candidate is BGO, and a LaBr (Ce) scintillator which has a superior energy resolution to that of NaI(Tl). In this paper, design and expected performance of the CALET-GBM is shown.« less

All-Sky Earth Occultation Observations with the Fermi Gamma-Ray Burst Monitor

NASA Technical Reports Server (NTRS)

Wilson-Hodge, C. A.; Beklen, E.; Bhat, P. N.; Briggs, M.; Camero-Arranz, A.; Case, G.; Jenke, P.; Chaplin, V.; Cherry, M.; Connaughton, V.;

Observations of Accreting Pulsars with the FERMI-GBM

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen

2012-01-01

The Gamma-ray Burst Monitor (GBM) on-board Fermi comprises 12 NaI detectors spanning the 8-1000 keV band and 2 BGO detectors spanning the 100 keV to 40 MeV band. These detectors view the entire unocculted sky, providing long (approximately 40 ks/day) observations of accreting pulsars daily, which allow long-term monitoring of spin-frequencies and pulsed uxes via epoch-folded searches plus daily blind searches for new pulsars. Phase averaged uxes can be measured using the Earth occultation technique. In this talk I will present highlights of GBM accretion-powered pulsar monitoring such as the discovery of a torque reversal in 4U1626-67, a high-energy QPO in A0535+26, and evidence for a stable accretion disk in OAO 1657-415.

Autocorrelated process control: Geometric Brownian Motion approach versus Box-Jenkins approach

NASA Astrophysics Data System (ADS)

Salleh, R. M.; Zawawi, N. I.; Gan, Z. F.; Nor, M. E.

2018-04-01

Existing of autocorrelation will bring a significant effect on the performance and accuracy of process control if the problem does not handle carefully. When dealing with autocorrelated process, Box-Jenkins method will be preferred because of the popularity. However, the computation of Box-Jenkins method is too complicated and challenging which cause of time-consuming. Therefore, an alternative method which known as Geometric Brownian Motion (GBM) is introduced to monitor the autocorrelated process. One real case of furnace temperature data is conducted to compare the performance of Box-Jenkins and GBM methods in monitoring autocorrelation process. Both methods give the same results in terms of model accuracy and monitoring process control. Yet, GBM is superior compared to Box-Jenkins method due to its simplicity and practically with shorter computational time.

Fermi and Swift as supernova alarms: Alert, localization, and diagnosis of future Galactic Type Ia explosions

NASA Astrophysics Data System (ADS)

Wang, Xilu; Fields, Brian D.; Lien, Amy Y.

2017-01-01

A Galactic SNIa event could go entirely unnoticed due to the large optical and near-IR extinction in the Milky Way plane, low radio and X-ray luminosities, and a weak neutrino signal. But the recent SN2014J confirms that Type Ia supernovae emit nuclear γ- ray lines, from the 56Ni → 56Co → 56Fe radioactive decay. The energy released in these decays powers the SNIa UVOIR light curve at times after ~1 week, leading to an exponential decline. Importantly for Swift and Fermi, these decays are accompanied by γ-ray line emission, with distinct series of lines for both the 56Ni and 56Co decays, spanning 158 keV to 2.6 MeV. These lines are squarely within the Fermi/GBM energy range, and the 56Ni 158 keV line is detectable by Swift/BAT. The Galaxy is optically thin to γ-rays, so the supernova line flux will suffer negligible extinction. Both GBM and BAT have continuous and nearly all-sky coverage. Thus GBM and BAT are ideal Galactic SNIa monitors and early warning systems. We will illustrate expected GBM and BAT light curves and spectra, based on our model for SNIa γ-ray emission and transfer. We show that the supernova signal emerges as distinct from the GBM background within days after the explosion in the SN2014J shell model. Therefore, if a Galactic SNIa were to explode, there are two possibilities of confirming and sounding the alert: 1) Swift/BAT discovers the SNIa first and localizes it within arcminutes; 2) Fermi/GBM finds the SNIa first and localizes it to within ~1 degree, using the Earth occultation technique, followed up by BAT to localize it within arcminutes. After the alert of either BAT or GBM, Swift localizes it to take spectra in optical, UV, soft and hard X-rays simultaneously with both XRT and UVOT instruments.

A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool.

PubMed

Manterola, Lorea; Guruceaga, Elizabeth; Gállego Pérez-Larraya, Jaime; González-Huarriz, Marisol; Jauregui, Patricia; Tejada, Sonia; Diez-Valle, Ricardo; Segura, Victor; Samprón, Nicolás; Barrena, Cristina; Ruiz, Irune; Agirre, Amaia; Ayuso, Angel; Rodríguez, Javier; González, Alvaro; Xipell, Enric; Matheu, Ander; López de Munain, Adolfo; Tuñón, Teresa; Zazpe, Idoya; García-Foncillas, Jesús; Paris, Sophie; Delattre, Jean Yves; Alonso, Marta M

2014-04-01

Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults, and its prognosis remains dismal despite intensive research and therapeutic advances. Diagnostic biomarkers would be clinically meaningful to allow for early detection of the tumor and for those cases in which surgery is contraindicated or biopsy results are inconclusive. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. The aim of this hypothesis-generating study was to assess the diagnostic potential of miRNAs found in microvesicles isolated from the serum of GBM patients. To control disease heterogeneity, we used patients with newly diagnosed GBM. In the discovery stage, PCR-based TaqMan Low Density Arrays followed by individual quantitative reverse transcriptase polymerase chain reaction were used to test the differences in the miRNA expression levels of serum microvesicles among 25 GBM patients and healthy controls paired by age and sex. The detected noncoding RNAs were then validated in another 50 GBM patients. We found that the expression levels of 1 small noncoding RNA (RNU6-1) and 2 microRNAs (miR-320 and miR-574-3p) were significantly associated with a GBM diagnosis. In addition, RNU6-1 was consistently an independent predictor of a GBM diagnosis. Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.

High Energy Astrophysics with the Fermi Large Area Telescope

NASA Technical Reports Server (NTRS)

Hays, Elizabeth

2009-01-01

This slide presentation reviews some of the findings of the Large Area Telescope (LAT) aboard the Fermi Observatory. It includes information about the LAT, and the Gamma-Ray Burst Monitor (GBM), detection of the quiet sun and the moon in gamma rays, Pulsars observed by the observatory, Globular Star Clusters, Active Galactic Nucleus, and Gamma-Ray Bursts, with specific information about GRB 080916C.

FERMI Observations of High-Energy Gamma-Ray Emission from GRB 080825C

DOE PAGES

Abdo, A. A.; Ackermann, M.; Asano, K.; ...

2009-11-24

The Fermi Gamma-ray Space Telescope has opened a new high-energy window in the study of gamma-ray bursts (GRBs). Here in this paper, we present a thorough analysis of GRB 080825C, which triggered the Fermi Gamma-ray Burst Monitor (GBM), and was the first firm detection of a GRB by the Fermi Large Area Telescope (LAT). We discuss the LAT event selections, background estimation, significance calculations, and localization for Fermi GRBs in general and GRB 080825C in particular. We show the results of temporal and time-resolved spectral analysis of the GBM and LAT data. Finally, we also present some theoretical interpretation ofmore » GRB 080825C observations as well as some common features observed in other LAT GRBs.« less

A Proposal to Localize Fermi GBM GRBs Through Coordinated Scanning of the GBM Error Circle via Optical Telescopes

NASA Technical Reports Server (NTRS)

Ukwatta, T. N.; Linnemann, J. T.; Tollefson, K.; Abeysekara, A. U.; Bhat, P. N.; Sonbas, E.; Gehrels, N.

2011-01-01

We investigate the feasibility of implementing a system that will coordinate ground-based optical telescopes to cover the Fermi GBM Error Circle (EC). The aim of the system is to localize GBM detected GRBs and facilitate multi-wavelength follow-up from space and ground. This system will optimize the observing locations in the GBM EC based on individual telescope location, Field of View (FoV) and sensitivity. The proposed system will coordinate GBM EC scanning by professional as well as amateur astronomers around the world. The results of a Monte Carlo simulation to investigate the feasibility of the project are presented.

Search for Gravitational Wave Counterparts with Fermi GBM

NASA Technical Reports Server (NTRS)

Hui, C. M.

2017-01-01

The progenitor of short gamma-ray bursts (GRBs) is believed to be the merger of two compact objects. This type of events will also produce gravitational waves. Since the gravitational waves discovery by LIGO, the search for a joint detection with an electromagnetic counterpart has been ongoing. Fermi GBM detects approximately 40 short GRBs per year, and we have been expanding our search looking for faint events in the GBM data that did not trigger onboard.

Detection of Spectral Evolution in the Bursts Emitted During the 2008-2009 Active Episode of SGR J1550 - 5418

NASA Technical Reports Server (NTRS)

von Kienlin, Andreas; Gruber, David; Kouveliotou, Chryssa; Granot, Jonathan; Baring, Matthew G.; Gogus, Ersin; Huppenkothen, Daniela; Kaneko, Yuki; Lin, Lin; Watts, Anna L.;

Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain.

PubMed

Lee, Se Jeong; Kang, Won Young; Yoon, Yeup; Jin, Ju Youn; Song, Hye Jin; Her, Jung Hyun; Kang, Sang Mi; Hwang, Yu Kyeong; Kang, Kyeong Jin; Joo, Kyeung Min; Nam, Do-Hyun

2015-12-24

Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain. Patient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgamma(null) (NSG) mice. Human NK cells were isolated from peripheral blood mononucleated cells and expanded in vitro. Patient-derived GBM cells in the brains of NSG mice unexpectedly induced spontaneous lung metastasis although no metastasis was detected in BALB/c-nude mice. Based on the difference of the innate immunity between two mouse strains, NK cell activities of orthotopic GBM xenograft models based on BALB/c-nude mice were inhibited. NK cell inactivation induced spontaneous lung metastasis of GBM cells, which indicated that NK cells inhibit the systemic metastasis. In vitro cytotoxic activities of human NK cells against GBM cells indicated that cytotoxic activity of NK cells against GBM cells prevents systemic metastasis of GBM and that NK cells could be effective cell therapeutics against GBM. Accordingly, NK cells transplanted into orthotopic GBM xenograft models intravenously or intratumorally induced apoptosis of GBM cells in the brain and showed significant therapeutic effects. Our results suggest that innate NK immunity is responsible for rare systemic metastasis of GBM and that sufficient supplementation of NK cells could be a promising immunotherapeutic strategy for GBM in the brain.

Stereotactic intracranial implantation and in vivo bioluminescent imaging of tumor xenografts in a mouse model system of glioblastoma multiforme.

PubMed

Baumann, Brian C; Dorsey, Jay F; Benci, Joseph L; Joh, Daniel Y; Kao, Gary D

2012-09-25

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality treatment consisting of surgical resection, post-operative radiation therapy and temozolomide chemotherapy. New therapeutic approaches are clearly needed to improve patient survival and quality of life. The development of more effective treatment strategies would be aided by animal models of GBM that recapitulate human disease yet allow serial imaging to monitor tumor growth and treatment response. In this paper, we describe our technique for the precise stereotactic implantation of bio-imageable GBM cancer cells into the brains of nude mice resulting in tumor xenografts that recapitulate key clinical features of GBM. This method yields tumors that are reproducible and are located in precise anatomic locations while allowing in vivo bioluminescent imaging to serially monitor intracranial xenograft growth and response to treatments. This method is also well-tolerated by the animals with low perioperative morbidity and mortality.

Awakening the BALROG: BAyesian Location Reconstruction Of GRBs

NASA Astrophysics Data System (ADS)

Burgess, J. Michael; Yu, Hoi-Fung; Greiner, Jochen; Mortlock, Daniel J.

2018-05-01

The accurate spatial location of gamma-ray bursts (GRBs) is crucial for both accurately characterizing their spectra and follow-up observations by other instruments. The Fermi Gamma-ray Burst Monitor (GBM) has the largest field of view for detecting GRBs as it views the entire unocculted sky, but as a non-imaging instrument it relies on the relative count rates observed in each of its 14 detectors to localize transients. Improving its ability to accurately locate GRBs and other transients is vital to the paradigm of multimessenger astronomy, including the electromagnetic follow-up of gravitational wave signals. Here we present the BAyesian Location Reconstruction Of GRBs (BALROG) method for localizing and characterizing GBM transients. Our approach eliminates the systematics of previous approaches by simultaneously fitting for the location and spectrum of a source. It also correctly incorporates the uncertainties in the location of a transient into the spectral parameters and produces reliable positional uncertainties for both well-localized sources and those for which the GBM data cannot effectively constrain the position. While computationally expensive, BALROG can be implemented to enable quick follow-up of all GBM transient signals. Also, we identify possible response problems that require attention and caution when using standard, public GBM detector response matrices. Finally, we examine the effects of including the uncertainty in location on the spectral parameters of GRB 080916C. We find that spectral parameters change and no extra components are required when these effects are included in contrast to when we use a fixed location. This finding has the potential to alter both the GRB spectral catalogues and the reported spectral composition of some well-known GRBs.

GRB110721A: An Extreme Peak Energy and Signatures of the Photosphere

NASA Technical Reports Server (NTRS)

Axelsson, M.; Baldini, L.; Barbiellini, G.; Baring, M. G.; Bellazzini, R.; Bregeon, J.; Brigida, M.; Bruel, P.; Buehler, R.; Caliandro, G. A.;

Urinary cystatin C as a renal biomarker and its immunohistochemical localization in anti-GBM glomerulonephritis rats.

PubMed

Togashi, Yuko; Imura, Naoko; Miyamoto, Yohei

2013-11-01

The usefulness of urinary cystatin C for the early detection of renal damage in anti-glomerular basement membrane (GBM) glomerulonephritis rats was investigated and compared to other biomarkers (β2-microglobulin, calbindin, clusterin, epidermal growth factor (EGF), alpha-glutathione S-transferase (GST-α), mu-glutathione S-transferase (GST-μ), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin, tissue inhibitor of metalloprotease-1 (TIMP-1), and vascular endothelial growth factor (VEGF)). Urinary levels of cystatin C increased in anti-GBM glomerulonephritis rats, whereas the conventional markers, plasma creatinine and UN did not, demonstrating its usefulness for the early detection of renal damage associated with anti-GBM glomerulonephritis. As well as cystatin C, urinary β2-microglobulin, clusterin, GST-α, GST-μ, KIM-1, and NGAL also had the potential to detect renal damage associated with anti-GBM glomerulonephritis. Furthermore, the immunohistochemical localization of cystatin C in the kidney was examined. Cystatin C expression was mainly observed in the proximal renal tubules in anti-GBM glomerulonephritis rats, and its expression barely changed with the progression of glomerulonephritis. Cystatin C expression was also observed in the tubular lumen of the cortex and medulla when glomerulonephritis was marked, which was considered to be characteristic of renal damage. In conclusion, urinary cystatin C, β2-microglobulin, clusterin, GST-α, GST-μ, KIM-1, and NGAL could be useful biomarkers of renal damage in anti-GBM glomerulonephritis rats. Immunohistochemical cystatin C expression in the proximal renal tubules was barely changed by the progression of glomerulonephritis, but it was newly observed in the tubular lumen when renal damage was apparent. Crown Copyright © 2013. Published by Elsevier GmbH. All rights reserved.

Extremely Bright GRB 160625B with Multiple Emission Episodes: Evidence for Long-term Ejecta Evolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lü, Hou-Jun; Lü, Jing; Zhong, Shu-Qing

GRB 160625B is an extremely bright GRB with three distinct emission episodes. By analyzing its data observed with the Gamma-Ray Burst Monitor (GBM) and Large Area Telescope (LAT) on board the Fermi mission, we find that a multicolor blackbody (mBB) model can be used to fit very well the spectra of the initial short episode (Episode I) within the hypothesis of photosphere emission of a fireball model. The time-resolved spectra of its main episode (Episode II), which was detected with both GBM and LAT after a long quiescent stage (∼180 s) following the initial episode, can be fitted with amore » model comprising an mBB component plus a cutoff power-law (CPL) component. This GRB was detected again in the GBM and LAT bands with a long extended emission (Episode III) after a quiescent period of ∼300 s. The spectrum of Episode III is adequately fitted with CPL plus single power-law models, and no mBB component is required. These features may imply that the emission of the three episodes are dominated by distinct physics processes, i.e., Episode I is possible from the cocoon emission surrounding the relativistic jet, Episode II may be from photosphere emission and internal shock of the relativistic jet, and Episode III is contributed by internal and external shocks of the relativistic jet. On the other hand, both X-ray and optical afterglows are consistent with the standard external shocks model.« less

Extremely Bright GRB 160625B with Multiple Emission Episodes: Evidence for Long-term Ejecta Evolution

NASA Astrophysics Data System (ADS)

Lü, Hou-Jun; Lü, Jing; Zhong, Shu-Qing; Huang, Xiao-Li; Zhang, Hai-Ming; Lan, Lin; Xie, Wei; Lu, Rui-Jing; Liang, En-Wei

2017-11-01

GRB 160625B is an extremely bright GRB with three distinct emission episodes. By analyzing its data observed with the Gamma-Ray Burst Monitor (GBM) and Large Area Telescope (LAT) on board the Fermi mission, we find that a multicolor blackbody (mBB) model can be used to fit very well the spectra of the initial short episode (Episode I) within the hypothesis of photosphere emission of a fireball model. The time-resolved spectra of its main episode (Episode II), which was detected with both GBM and LAT after a long quiescent stage (˜180 s) following the initial episode, can be fitted with a model comprising an mBB component plus a cutoff power-law (CPL) component. This GRB was detected again in the GBM and LAT bands with a long extended emission (Episode III) after a quiescent period of ˜300 s. The spectrum of Episode III is adequately fitted with CPL plus single power-law models, and no mBB component is required. These features may imply that the emission of the three episodes are dominated by distinct physics processes, I.e., Episode I is possible from the cocoon emission surrounding the relativistic jet, Episode II may be from photosphere emission and internal shock of the relativistic jet, and Episode III is contributed by internal and external shocks of the relativistic jet. On the other hand, both X-ray and optical afterglows are consistent with the standard external shocks model.

VizieR Online Data Catalog: New spectral lag measurements of 50 Fermi/GBM GRBs (Shao+, 2017)

NASA Astrophysics Data System (ADS)

Shao, L.; Zhang, B.-B.; Wang, F.-R.; Wu, X.-F.; Cheng, Y.-H.; Zhang, Xi; Yu, B.-Y.; Xi, B.-J.; Wang, X.; Feng, H.-X.; Zhang, M.; Xu, D.

2018-03-01

This work made extensive use of the data from the Gamma-Ray Burst Monitor (GBM) on board the Fermi Gamma-ray Space Telescope. For the first step, we searched in the official GBM online burst catalog (Gruber+ 2014ApJS..211...12G ; von Kienlin+ 2014, J/ApJS/211/13) for bright bursts with a total fluence F>5x10-6erg/cm-2 in 10-1000keV. See section 2 for the details on the sample selection. (1 data file).

Absence of giant blood Marseille-like virus DNA detection by polymerase chain reaction in plasma from healthy US blood donors and serum from multiply transfused patients from Cameroon.

PubMed

Phan, Tung Gia; Desnues, Christelle; Switzer, William M; Djoko, Cyrille F; Schneider, Bradley S; Deng, Xutao; Delwart, Eric

2015-06-01

A new Marseilleviridae virus family member, giant blood Marseille-like (GBM) virus, was recently reported in persons from France in the serum of an infant with adenitis, in the blood of 4% of healthy blood donors, and in 9% of multiply transfused thalassemia patients. These results suggested the presence of a nucleocytoplasmic large DNA virus potentially transmissible by blood product transfusion. To investigate this possibility we tested the plasma from 113 US blood donors and 74 multiply transfused Cameroon patients for GBM viral DNA using highly sensitive polymerase chain reaction (PCR) assays. GBM DNA was not detected by nested PCR in any of these 187 human specimens. Further testing is required to confirm the occurrence of human GBM virus infections. © 2015 AABB.

DNM3, p65 and p53 from exosomes represent potential clinical diagnosis markers for glioblastoma multiforme

PubMed Central

Yang, Jian-kai; Song, Jian; Huo, Hao-ran; Zhao, Yin-long; Zhang, Guang-yu; Zhao, Zong-mao; Sun, Guo-zhu; Jiao, Bao-hua

2017-01-01

Background: Glioblastoma multiforme (GBM) is the most aggressive and deadly primary brain cancer that arises from astrocytes and classified as grade IV. Recently, exosomes have been reported as an essential mediator in diverse cancer carcinogenesis and metastasis. However, their role in GBM is still unclear. In this study, we aimed to investigate whether blood exosomes can be potential clinical diagnostic markers for GBM. Methods: We used a xenograft orthotopic mouse model to detect the differentially expressed genes in the brain and blood exosomes of original/recurrent GBM. Results: We found that recurrent GBM had stronger growth capacity and lethality than original GBM in the mouse model. A gene microarray of original tumors and blood exosomes from GBM orthotopic xenografts results showed that DNM3, p65 and CD117 expressions increased, whereas PTEN and p53 expressions decreased in both original tumors and blood exosomes. In the recurrent GBM tumor model, DNM3 and p65 showed increased expressions, whereas ST14 and p53 showed decreased expressions in tumor and blood exosomes of the recurrent GBM mouse model. Conclusion: In summary, we found that DNM3, p65 and p53 had a similar trend in brain and blood exosomes both for original and recurrent GBM, and could serve as potential clinical diagnostic markers for GBM. PMID:29449895

Monitoring Accreting X-ray Pulsars with the GLAST Burst Monitor

NASA Technical Reports Server (NTRS)

Wilson, Colleen A.; Finger, Mark H.; Patel, Sandeep K.; Bhat, P. Narayana; Preece, Robert D.; Meegan, Charles A.

2007-01-01

Accreting pulsars are exceptionally good laboratories for probing the detailed physics of accretion onto magnetic stars. While similar accretion flows also occur in other types of astrophysical systems, e.g. magnetic CVs, only neutron stars have a small enough moment of inertia for the accretion of angular momentum to result in measurable changes in spin-frequency in a timescale of days. Long-term monitoring of accreting pulsar spin-frequencies and fluxes was demonstrated with the Burst and Transient Source Experiment (BATSE) on the Compton Gamma Ray Observatory. Here we present sample results from BATSE, discuss measurement techniques appropriate for GBM, and estimate the expected GBM sensitivity.

FERMI Observations of GRB 090902B: A Distinct Spectral Component in the Prompt and Delayed Emission

DOE PAGES

Abdo, A. A.; Ackermann, M.; Ajello, M.; ...

2009-11-03

Here, we report on the observation of the bright, long gamma-ray burst (GRB), GRB 090902B, by the Gamma-ray Burst Monitor (GBM) and Large Area Telescope (LAT) instruments on-board the Fermi observatory. This was one of the brightest GRBs to have been observed by the LAT, which detected several hundred photons during the prompt phase. With a redshift of z = 1.822, this burst is among the most luminous detected by Fermi. Time-resolved spectral analysis reveals a significant power-law component in the LAT data that is distinct from the usual Band model emission that is seen in the sub-MeV energy range.more » This power-law component appears to extrapolate from the GeV range to the lowest energies and is more intense than the Band component, both below ~50 keV and above 100 MeV. The Band component undergoes substantial spectral evolution over the entire course of the burst, while the photon index of the power-law component remains constant for most of the prompt phase, then hardens significantly toward the end. After the prompt phase, power-law emission persists in the LAT data as late as 1 ks post-trigger, with its flux declining as t –1.5. The LAT detected a photon with the highest energy so far measured from a GRB, 33.4 +2.7 –3.5 GeV. This event arrived 82 s after the GBM trigger and ~50 s after the prompt phase emission had ended in the GBM band. In conclusion, we discuss the implications of these results for models of GRB emission and for constraints on models of the extragalactic background light.« less

A Case of Alport Syndrome with Posttransplant Antiglomerular Basement Membrane Disease despite Negative Antiglomerular Basement Membrane Antibodies by EIA Treated with Plasmapheresis and Intravenous Immunoglobulin.

PubMed

Armstead, Sumiko I; Hellmark, Thomas; Wieslander, Jorgen; Zhou, Xin J; Saxena, Ramesh; Rajora, Nilum

2013-01-01

Posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in approximately 5% of Alport patients and usually ends in irreversible graft failure. Recent research has focused on characterizing the structure of the anti-GBM alloepitope. Here we present a case of a 22-year-old male with end-stage renal disease secondary to Alport syndrome, with a previously failed renal allograft, who received a second deceased-donor kidney transplant. Six days after transplantation, he developed acute kidney injury. The serum anti-GBM IgG was negative by enzyme immunoassay (EIA). On biopsy, he had crescentic glomerulonephritis with linear GBM fixation of IgG. With further analysis by western blotting, we were able to detect antibodies to an unidentified protein from the basement membrane. This patient was treated with plasmapheresis twice per week and monthly intravenous immunoglobulin (IVIG) for a total of five months. At the end of treatment, these unknown antibodies were no longer detected. His renal function improved, and he has not required dialysis. We conclude that anti-GBM disease in patients with Alport Syndrome may be caused by circulating antibodies to other components of the basement membrane that are undetectable by routine anti-GBM EIA and may respond to treatment with plasmapheresis and IVIG.

When a Standard Candle Flickers: Crab Nebula Variations in Hard X-rays

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.

2012-01-01

The Crab Nebula was surprisingly variable from 2001-2010, with less variability before 2001 and since mid-2010. We presented evidence for spectral softening from RXTE, Swift/BAT, and Fermi GBM during the mid-2008-2010 flux decline. We will miss RXTE, but will continue our monitoring program using Fermi/GBM, MAXI, and Swift/BAT.

p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells

PubMed Central

Cen, Ling; Carlson, Brett L.; Schroeder, Mark A.; Ostrem, Jamie L.; Kitange, Gaspar J.; Mladek, Ann C.; Fink, Stephanie R.; Decker, Paul A.; Wu, Wenting; Kim, Jung-Sik; Waldman, Todd; Jenkins, Robert B.; Sarkaria, Jann N.

2012-01-01

Deregulation of the p16INK4a-Cdk4/6-Rb pathway is commonly detected in patients with glioblastoma multiforme (GBM) and is a rational therapeutic target. Here, we characterized the p16INK4a-Cdk4/6-Rb pathway in the Mayo panel of GBM xenografts, established from primary tissue samples from patients with GBM, and evaluated their response to PD0332991, a specific inhibitor of Cdk4/6. All GBM xenograft lines evaluated in this study had disruptions in the p16INK4a-Cdk4/6-Rb pathway. In vitro evaluation using short-term explant cultures from selected GBM xenograft lines showed that PD0332991 effectively arrested cell cycle in G1-phase and inhibited cell proliferation dose-dependently in lines deleted for CDKN2A/B-p16INK4a and either single-copy deletion of CDK4 (GBM22), high-level CDK6 amplification (GBM34), or deletion of CDKN2C/p18INK4c (GBM43). In contrast, 2 GBM lines with p16INK4a expression and either CDK4 amplification (GBM5) or RB mutation (GBM28) were completely resistant to PD0332991. Additional xenograft lines were screened, and GBM63 was identified to have p16INK4a expression and CDK4 amplification. Similar to the results with GBM5, GBM63 was resistant to PD0332991 treatment. In an orthotopic survival model, treatment of GBM6 xenografts (CDKN2A/B-deleted and CDK4 wild-type) with PD0332991 significantly suppressed tumor cell proliferation and prolonged survival. Collectively, these data support the concept that GBM tumors lacking p16INK4a expression and with nonamplified CDK4 and wild-type RB status may be more susceptible to Cdk4/6 inhibition using PD0332991. PMID:22711607

High-Energy Electromagnetic Offline Follow-Up of Ligo-Virgo Gravitational-Wave Binary Coalescence Candidate Events

NASA Technical Reports Server (NTRS)

Blackburn, L.; Briggs, M. S.; Camp, J.; Christensen, N.; Connaughton, V.; Jenke, P.; Remillard, R. A.; Veitch, J.

2015-01-01

We present two different search methods for electromagnetic counterparts to gravitational-wave (GW) events from ground-based detectors using archival NASA high-energy data from the Fermi Gamma-ray Burst Monitor (GBM) and RXTE All-sky Monitor (ASM) instruments. To demonstrate the methods, we use a limited number of representative GW background noise events produced by a search for binary neutron star coalescence over the last two months of the LIGO-Virgo S6/VSR3 joint science run. Time and sky location provided by the GW data trigger a targeted search in the high-energy photon data. We use two custom pipelines: one to search for prompt gamma-ray counterparts in GBM, and the other to search for a variety of X-ray afterglow model signals in ASM. We measure the efficiency of the joint pipelines to weak gamma-ray burst counterparts, and a family of model X-ray afterglows. By requiring a detectable signal in either electromagnetic instrument coincident with a GW event, we are able to reject a large majority of GW candidates. This reduces the signal-to-noise ratio of the loudest surviving GW background event by around 15-20 percent.

HIGH-ENERGY ELECTROMAGNETIC OFFLINE FOLLOW-UP OF LIGO-VIRGO GRAVITATIONAL-WAVE BINARY COALESCENCE CANDIDATE EVENTS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blackburn, L.; Camp, J.; Briggs, M. S.

2015-03-15

We present two different search methods for electromagnetic counterparts to gravitational-wave (GW) events from ground-based detectors using archival NASA high-energy data from the Fermi Gamma-ray Burst Monitor (GBM) and RXTE All-sky Monitor (ASM) instruments. To demonstrate the methods, we use a limited number of representative GW background noise events produced by a search for binary neutron star coalescence over the last two months of the LIGO-Virgo S6/VSR3 joint science run. Time and sky location provided by the GW data trigger a targeted search in the high-energy photon data. We use two custom pipelines: one to search for prompt gamma-ray counterpartsmore » in GBM, and the other to search for a variety of X-ray afterglow model signals in ASM. We measure the efficiency of the joint pipelines to weak gamma-ray burst counterparts, and a family of model X-ray afterglows. By requiring a detectable signal in either electromagnetic instrument coincident with a GW event, we are able to reject a large majority of GW candidates. This reduces the signal-to-noise ratio of the loudest surviving GW background event by around 15–20%.« less

Targeting MT1-MMP as an ImmunoPET-Based Strategy for Imaging Gliomas

PubMed Central

Oteo, M.; Romero, E.; Cámara, J. A.; de Martino, A.; Arroyo, A. G.; Morcillo, M. Á.; Squatrito, M.; Martinez-Torrecuadrada, J. L.; Mulero, F.

2016-01-01

Background A critical challenge in the management of Glioblastoma Multiforme (GBM) tumors is the accurate diagnosis and assessment of tumor progression in a noninvasive manner. We have identified Membrane-type 1 matrix metalloproteinase (MT1-MMP) as an attractive biomarker for GBM imaging since this protein is actively involved in tumor growth and progression, correlates with tumor grade and is closely associated with poor prognosis in GBM patients. Here, we report the development of an immunoPET tracer for effective detection of MT1-MMP in GBM models. Methods An anti-human MT1-MMP monoclonal antibody (mAb), LEM2/15, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (DFO-NCS) for 89Zr labeling. Biodistribution and PET imaging studies were performed in xenograft mice bearing human GBM cells (U251) expressing MT1-MMP and non-expressing breast carcinoma cells (MCF-7) as negative control. Two orthotopic brain GBM models, patient-derived neurospheres (TS543) and U251 cells, with different degrees of blood-brain barrier (BBB) disruption were also used for PET imaging experiments. Results 89Zr labeling of DFO-LEM2/15 was achieved with high yield (>90%) and specific activity (78.5 MBq/mg). Biodistribution experiments indicated that 89Zr-DFO-LEM2/15 showed excellent potential as a radiotracer for detection of MT1-MMP positive GBM tumors. PET imaging also indicated a specific and prominent 89Zr-DFO-LEM2/15 uptake in MT1-MMP+ U251 GBM tumors compared to MT1-MMP- MCF-7 breast tumors. Results obtained in orthotopic brain GBM models revealed a high dependence of a disrupted BBB for tracer penetrance into tumors. 89Zr-DFO-LEM2/15 showed much higher accumulation in TS543 tumors with a highly disrupted BBB than in U251 orthotopic model in which the BBB permeability was only partially increased. Histological analysis confirmed the specificity of the immunoconjugate in all GBM models. Conclusion A new anti MT1-MMP-mAb tracer, 89Zr-DFO-LEM2/15, was synthesized efficiently. In vivo validation showed high-specific-contrast imaging of MT1-MMP positive GBM tumors and provided strong evidence for utility of MT1-MMP-targeted immunoPET as an alternate to nonspecific imaging of GBM. PMID:27462980

Agrin is a major heparan sulfate proteoglycan in the human glomerular basement membrane.

PubMed

Groffen, A J; Ruegg, M A; Dijkman, H; van de Velden, T J; Buskens, C A; van den Born, J; Assmann, K J; Monnens, L A; Veerkamp, J H; van den Heuvel, L P

1998-01-01

Agrin is a heparan sulfate proteoglycan (HSPG) that is highly concentrated in the synaptic basal lamina at the neuromuscular junction (NMJ). Agrin-like immunoreactivity is also detected outside the NMJ. Here we show that agrin is a major HSPG component of the human glomerular basement membrane (GBM). This is in addition to perlecan, a previously characterized HSPG of basement membranes. Antibodies against agrin and against an unidentified GBM HSPG produced a strong staining of the GBM and the NMJ, different from that observed with anti-perlecan antibodies. In addition, anti-agrin antisera recognized purified GBM HSPG and competed with an anti-GBM HSPG monoclonal antibody in ELISA. Furthermore, both antibodies recognized a molecule that migrated in SDS-PAGE as a smear and had a molecular mass of approximately 200-210 kD after deglycosylation. In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. This was again different from perlecan, which was exclusively present on the endothelial side of the GBM and was distributed in a nonlinear manner. Quantitative ELISA showed that, compared with perlecan, the agrin-like GBM HSPG showed a sixfold higher molarity in crude glomerular extract. These results show that agrin is a major component of the GBM, indicating that it may play a role in renal ultrafiltration and cell matrix interaction. (J Histochem Cytochem 46:19-27, 1998)

Performance of two strategies for urgent ANCA and anti-GBM analysis in vasculitis.

PubMed

de Joode, Anoek A E; Roozendaal, Caroline; van der Leij, Marcel J; Bungener, Laura B; Sanders, Jan Stephan F; Stegeman, Coen A

2014-02-01

In anti-neutrophil cytoplasmic antibodies (ANCA) associated small vessel vasculitis (AAV), rapid testing for ANCA and anti-glomerular basement membrane (GBM) antibodies may be beneficial for therapeutic purpose. We analysed the diagnostic performance of two rapid ANCA and anti-GBM test methods in 260 patients with suspected AAV. Between January 2004 and November 2010, we analysed 260 samples by qualitative Dotblot (Biomedical Diagnostics); retrospective analysis followed with directly coated highly sensitive automated Phadia ELiA and ELiA anti-GBM. Results were related to the final clinical diagnosis and compared with routine capture ELISA. Seventy-four patients had a final diagnosis of AAV (n=62) or anti-GBM disease (n=12). Both Dotblot and ELiA detected all 12 cases of anti-GBM disease; 2 false positive results were found. Dotblot detected ANCA in 56 of 62 AAV patients (sensitivity 90%, NPV 97%), and showed 5 false positives (specificity 97%, PPV 90%). The Phadia ELiA anti-PR3(s) or anti-MPO(s) was positive in 57 of 62 AAV patients (sensitivity 92%, NPV 97%), and had 5 false positives (specificity 97%, PPV 88%). Routine capture ELISA was equally accurate (sensitivity 94%, specificity 97%, PPV 88%, NPV 98%). The Dotblot and Phadia ELiA on anti-GBM, anti-PR3(s) and anti-MPO(s) performed excellently; results were almost identical to routine ELISA. When suspicion of AAV or anti-GBM disease is high and diagnosis is urgently needed, both tests are very powerful for rapid serological diagnosis. Further studies have to confirm the test performances in samples routinely presented for ANCA testing and in follow-up of positive patients. Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

CD44v6 Regulates Growth of Brain Tumor Stem Cells Partially through the AKT-Mediated Pathway

PubMed Central

Jijiwa, Mayumi; Demir, Habibe; Gupta, Snehalata; Leung, Crystal; Joshi, Kaushal; Orozco, Nicholas; Huang, Tiffany; Yildiz, Vedat O.; Shibahara, Ichiyo; de Jesus, Jason A.; Yong, William H.; Mischel, Paul S.; Fernandez, Soledad; Kornblum, Harley I.; Nakano, Ichiro

2011-01-01

Identification of stem cell-like brain tumor cells (brain tumor stem-like cells; BTSC) has gained substantial attention by scientists and physicians. However, the mechanism of tumor initiation and proliferation is still poorly understood. CD44 is a cell surface protein linked to tumorigenesis in various cancers. In particular, one of its variant isoforms, CD44v6, is associated with several cancer types. To date its expression and function in BTSC is yet to be identified. Here, we demonstrate the presence and function of the variant form 6 of CD44 (CD44v6) in BTSC of a subset of glioblastoma multiforme (GBM). Patients with CD44high GBM exhibited significantly poorer prognoses. Among various variant forms, CD44v6 was the only isoform that was detected in BTSC and its knockdown inhibited in vitro growth of BTSC from CD44high GBM but not from CD44low GBM. In contrast, this siRNA-mediated growth inhibition was not apparent in the matched GBM sample that does not possess stem-like properties. Stimulation with a CD44v6 ligand, osteopontin (OPN), increased expression of phosphorylated AKT in CD44high GBM, but not in CD44low GBM. Lastly, in a mouse spontaneous intracranial tumor model, CD44v6 was abundantly expressed by tumor precursors, in contrast to no detectable CD44v6 expression in normal neural precursors. Furthermore, overexpression of mouse CD44v6 or OPN, but not its dominant negative form, resulted in enhanced growth of the mouse tumor stem-like cells in vitro. Collectively, these data indicate that a subset of GBM expresses high CD44 in BTSC, and its growth may depend on CD44v6/AKTpathway. PMID:21915300

The State of Magnetars

NASA Technical Reports Server (NTRS)

Kouveliotou, Chryssa

2014-01-01

The launch of the Fermi mission has enabled critical improvements in the field of magnetars, in particular with the Gamma-ray Burst Monitor, which is a all sky high-energy transient detector (8 keV - 40 MeV). In the last six years, the instrument has detected emission from 8 sources, and co-discovered two in synergy with the Swift mission. I will present the 5-year GBM magnetar results, focusing on the burst emission properties (spectral and temporal) per source as well as comparisons across sources.

Microfluidics in Malignant Glioma Research and Precision Medicine

PubMed Central

Logun, Meghan; Zhao, Wujun

2018-01-01

Glioblastoma multiforme (GBM) is an aggressive form of brain cancer that has no effective treatments and a prognosis of only 12–15 months. Microfluidic technologies deliver microscale control of fluids and cells, and have aided cancer therapy as point-of-care devices for the diagnosis of breast and prostate cancers. However, a few microfluidic devices are developed to study malignant glioma. The ability of these platforms to accurately replicate the complex microenvironmental and extracellular conditions prevailing in the brain and facilitate the measurement of biological phenomena with high resolution and in a high-throughput manner could prove useful for studying glioma progression. These attributes, coupled with their relatively simple fabrication process, make them attractive for use as point-of-care diagnostic devices for detection and treatment of GBM. Here, the current issues that plague GBM research and treatment, as well as the current state of the art in glioma detection and therapy, are reviewed. Finally, opportunities are identified for implementing microfluidic technologies into research and diagnostics to facilitate the rapid detection and better therapeutic targeting of GBM. PMID:29780878

GRB110721A: An extreme peak energy and signatures of the photosphere

DOE PAGES

Axelsson, M.; Baldini, L.; Barbiellini, G.; ...

2012-09-17

GRB110721A was observed by the Fermi Gamma-ray Space Telescope using its two instruments, the Large Area Telescope (LAT) and the Gamma-ray Burst Monitor (GBM). This burst consisted of one major emission episode which lasted for ~24.5 s (in the GBM) and had a peak flux of (5.7 ± 0.2) × 10 –5 erg s –1 cm –2. The time-resolved emission spectrum is best modeled with a combination of a Band function and a blackbody spectrum. The peak energy of the Band component was initially 15 ± 2 MeV, which is the highest value ever detected in a GRB. We mademore » this measurement by combining GBM/BGO data with LAT Low Energy events to achieve continuous 10-100 MeV coverage. The peak energy later decreased as a power law in time with an index of –1.89 ± 0.10. The temperature of the blackbody component also decreased, starting from ~80 keV, and the decay showed a significant break after ~2 s. The spectrum provides strong constraints on the standard synchrotron model, indicating that alternative mechanisms may give rise to the emission at these energies.« less

FERMI GBM OBSERVATIONS OF V404 CYG DURING ITS 2015 OUTBURST

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jenke, P. A.; Veres, P.; Briggs, M. S.

2016-07-20

V404 Cygni was discovered in 1989 by the Ginga X-ray satellite during its only previously observed X-ray outburst and soon after confirmed as a black hole binary. On 2015 June 15, the Gamma-ray Burst Monitor (GBM) triggered on a new outburst of V404 Cygni. We present 13 days of GBM observations of this outburst, including Earth occultation flux measurements and spectral and temporal analysis. The Earth occultation fluxes reached 30 Crab with detected emission to 100 keV and determined, via hardness ratios, that the source was in a hard state. At high luminosity, spectral analysis between 8 and 300 keVmore » showed that the electron temperature decreased with increasing luminosity. This is expected if the protons and electrons are in thermal equilibrium during an outburst with the electrons cooled by the Compton scattering of softer seed photons from the disk. However, the implied seed photon temperatures are unusually high, suggesting a contribution from another source, such as the jet. No evidence of state transitions is seen during this time period. The temporal analysis reveals power spectra that can be modeled with two or three strong, broad Lorentzians, similar to the power spectra of black hole binaries in their hard state.« less

Phenotypic characterization of glioblastoma identified through shape descriptors

NASA Astrophysics Data System (ADS)

Chaddad, Ahmad; Desrosiers, Christian; Toews, Matthew

2016-03-01

This paper proposes quantitatively describing the shape of glioblastoma (GBM) tissue phenotypes as a set of shape features derived from segmentations, for the purposes of discriminating between GBM phenotypes and monitoring tumor progression. GBM patients were identified from the Cancer Genome Atlas, and quantitative MR imaging data were obtained from the Cancer Imaging Archive. Three GBM tissue phenotypes are considered including necrosis, active tumor and edema/invasion. Volumetric tissue segmentations are obtained from registered T1˗weighted (T1˗WI) postcontrast and fluid-attenuated inversion recovery (FLAIR) MRI modalities. Shape features are computed from respective tissue phenotype segmentations, and a Kruskal-Wallis test was employed to select features capable of classification with a significance level of p < 0.05. Several classifier models are employed to distinguish phenotypes, where a leave-one-out cross-validation was performed. Eight features were found statistically significant for classifying GBM phenotypes with p <0.05, orientation is uninformative. Quantitative evaluations show the SVM results in the highest classification accuracy of 87.50%, sensitivity of 94.59% and specificity of 92.77%. In summary, the shape descriptors proposed in this work show high performance in predicting GBM tissue phenotypes. They are thus closely linked to morphological characteristics of GBM phenotypes and could potentially be used in a computer assisted labeling system.

The GLAST Burst Monitor

NASA Technical Reports Server (NTRS)

Meegan, Charles A.

2004-01-01

The Gamma Ray Large Area Space Telescope (GLAST) observatory, scheduled for launch in 2007, comprises the Large Area Telescope (LAT) and the GLAST Burst Monitor (GBM). spectral changes that are known to occur within GRBs. between the NASA Marshall Space Flight Center, the University of Alabama in Huntsville, and the Max Planck Institute for Extraterrestrial Physics. It consists of an array of NaI and BGO scintillation detectors operating in the 10 kev to 25 MeV range. The field of view includes the entire unocculted sky when the observatory is pointing close to the zenith. The GBM will enhance LAT observations of GRBs by extending the spectral coverage into the range of current GRB databases, and will provide a trigger for reorienting the spacecraft to observe delayed emission from bursts outside the LAT field of view. GBM is expected to trigger on about 200 bursts per year, and will provide on-board locations of strong bursts accurate to better than 10 degrees.

Fermi/GBM Results of Magnetars

NASA Technical Reports Server (NTRS)

Kouveliotou, chryssa

2011-01-01

Magnetars are magnetically powered rotating neutron stars with extreme magnetic fields (over 10(exp 14) Gauss). They were discovered in the X- and gamma-rays where they predominantly emit their radiation. Very few sources (roughly 18) have been found since their discovery in 1987. NASA's Fermi Gamma-ray Space Telescope was launched June 11,2009; since then the Fermi Gamma-ray Burst Monitor (GBM) recorded emission from four magnetar sources. Two of these were brand new sources, SGR J0501 +4516, discovered with Swift and extensively monitored with Swift and GBM, SGR J0418+5729, discovered with GBM and the Interplanetary Network (IPN). A third was SGR Jl550-5418, a source originally classified as an Anomalous X-ray Pulsar (AXP IEI547.0-5408), but exhibiting a very prolific outburst with over 400 events recorded in January 2009. In my talk I will give a short history of magnetars and describe how this, once relatively esoteric field, has emerged as a link between several astrophysical areas including Gamma-Ray Bursts. Finally, I will describe the exciting new results of Fermi in this field and the current status of our knowledge of the magnetar population properties and magnetic fields.

Vaccine-preventable anal human papillomavirus in Australian gay and bisexual men.

PubMed

Poynten, I Mary; Tabrizi, Sepehr N; Jin, Fengyi; Templeton, David J; Machalek, Dorothy A; Cornall, Alyssa; Phillips, Samuel; Fairley, Christopher K; Garland, Suzanne M; Law, Carmella; Carr, Andrew; Hillman, Richard J; Grulich, Andrew E

2017-06-01

HPV causes ~90% of anal cancer and HPV16 is the type most commonly associated with anal cancer. Gay and bisexual men (GBM) are at greatly increased risk. We investigated patterns of vaccine-preventable anal HPV in older GBM. The Study of the Prevention of Anal Cancer (SPANC) is an ongoing, prospective cohort study of HIV-positive and HIV-negative Australian GBM. Participants completed questionnaires and underwent an anal swab for HPV genotyping using Roche Linear Array. We analysed baseline data from SPANC by HPV type, mean number of types, stratified by age and HIV status. Anal HPV results from 606 (98.2%) of 617 participants (median age 49 years, 35.7% HIV-positive) showed 525 (86.7%) had ≥1 HPV type and 178 (29.4%) had HPV16. Over one third of participants (214, 35.3%) had no nonavalent vaccine-preventable types detected. Two (0.3%) participants had all quadrivalent types and none had all nonavalent vaccine types. HIV-positive participants (p<0.001) and younger participants (p=0.059) were more likely to have more vaccine-preventable HPV types detected. Anal HPV was highly prevalent in this largely community-based GBM cohort. Vaccine-preventable HPV16 was detected in approximately one third of participants. These findings suggest that the potential efficacy of HPV vaccination of older GBM should be explored. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Quantitative Magnetization Transfer in Monitoring Glioblastoma (GBM) Response to Therapy.

PubMed

Mehrabian, Hatef; Myrehaug, Sten; Soliman, Hany; Sahgal, Arjun; Stanisz, Greg J

2018-02-06

Quantitative magnetization transfer (qMT) was used as a biomarker to monitor glioblastoma (GBM) response to chemo-radiation and identify the earliest time-point qMT could differentiate progressors from non-progressors. Nineteen GBM patients were recruited and MRI-scanned before (Day 0 ), two weeks (Day 14 ), and four weeks (Day 28 ) into the treatment, and one month after the end of the treatment (Day 70 ). Comprehensive qMT data was acquired, and a two-pool MT model was fit to the data. Response was determined at 3-8 months following the end of chemo-radiation. The amount of magnetization transfer ([Formula: see text]) was significantly lower in GBM compared to normal appearing white matter (p < 0.001). Statistically significant difference was observed in [Formula: see text] at Day 0 between non-progressors (1.06 ± 0.24) and progressors (1.64 ± 0.48), with p = 0.006. Changes in several qMT parameters between Day 14 and Day 0 were able to differentiate the two cohorts with [Formula: see text] providing the best separation (relative [Formula: see text] = 1.34 ± 0.21, relative [Formula: see text] = 1.07 ± 0.08, p = 0.031). Thus, qMT characteristics of GBM are more sensitive to treatment effects compared to clinically used metrics. qMT could assess tumor aggressiveness and identify early progressors even before the treatment. Changes in qMT parameters within the first 14 days of the treatment were capable of separating early progressors from non-progressors, making qMT a promising biomarker to guide adaptive radiotherapy for GBM.

The InterPlanetary Network Supplement to the Second Fermi GBM Catalog of Cosmic Gamma-Ray Bursts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hurley, K.; Aptekar, R. L.; Golenetskii, S. V.

InterPlanetary Network (IPN) data are presented for the gamma-ray bursts in the second Fermi Gamma-Ray Burst Monitor (GBM) catalog. Of the 462 bursts in that catalog between 2010 July 12 and 2012 July 11, 428, or 93%, were observed by at least 1 other instrument in the 9-spacecraft IPN. Of the 428, the localizations of 165 could be improved by triangulation. For these bursts, triangulation gives one or more annuli whose half-widths vary between about 2.′3° and 16°, depending on the peak flux, fluence, time history, arrival direction, and the distance between the spacecraft. We compare the IPN localizations withmore » the GBM 1 σ , 2 σ , and 3 σ error contours and find good agreement between them. The IPN 3 σ error boxes have areas between about 8 square arcminutes and 380 square degrees, and are an average of 2500 times smaller than the corresponding GBM 3 σ localizations. We identify four bursts in the IPN/GBM sample whose origins were given as “uncertain,” but may in fact be cosmic. This leads to an estimate of over 99% completeness for the GBM catalog.« less

Downregulation of TES by hypermethylation in glioblastoma reduces cell apoptosis and predicts poor clinical outcome.

PubMed

Bai, Yu; Zhang, Quan-Geng; Wang, Xin-Hua

2014-12-11

Gliomas are the most common human brain tumors. Glioblastoma, also known as glioblastoma multiform (GBM), is the most aggressive, malignant, and lethal glioma. The investigation of prognostic and diagnostic molecular biomarkers in glioma patients to provide direction on clinical practice is urgent. Recent studies demonstrated that abnormal DNA methylation states play a key role in the pathogenesis of this kind of tumor. In this study, we want to identify a novel biomarker related to glioma initiation and find the role of the glioma-related gene. We performed a methylation-specific microarray on the promoter region to identify methylation gene(s) that may affect outcome of GBM patients. Normal and GBM tissues were collected from Tiantan Hospital. Genomic DNA was extracted from these tissues and analyzed with a DNA promoter methylation microarray. Testis derived transcript (TES) protein expression was analyzed by immunohistochemistry in paraffin-embedded patient tissues. Western blotting was used to detect TES protein expression in the GBM cell line U251 with or without 5-aza-dC treatment. Cell apoptosis was evaluated by flow cytometry analysis using Annexin V/PI staining. We found that the TES promoter was hypermethylated in GBM compared to normal brain tissues under DNA promoter methylation microarray analysis. The GBM patients with TES hypermethylation had a short overall survival (P <0.05, log-rank test). Among GBM samples, reduced TES protein level was detected in 33 (89.2%) of 37 tumor tissues by immunohistochemical staining. Down regulation of TES was also correlated with worse patient outcome (P <0.05, log-rank test). Treatment on the GBM cell line U251 with 5-aza-dC can greatly increase TES expression, confirming the hypermethylation of TES promoter in GBM. Up-regulation of TES prompts U251 apoptosis significantly. This study demonstrated that both TES promoter hypermethylation and down-regulated protein expression significantly correlated with worse patient outcome. Treatment on the GBM cell line (U251) with 5-aza-dC can highly release TES expression resulting in significant apoptosis in these cells. Our findings suggest that the TES gene is a novel tumor suppressor gene and might represent a valuable prognostic marker for glioblastoma, indicating a potential target for future GBM therapy.

Fermi GBM Observations of Terrestrial Gamma-Ray Flashes

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Briggs, M. S.; Connaughton, V.; Fishman, G. J.; Bhat, P. N.; Paciesas, W. S.; Preece, R.; Kippen, R. M.; vonKienlin, A.; Dwyer, J. R.;

Comparative analyses of gene copy number and mRNA expression in GBM tumors and GBM xenografts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hodgson, J. Graeme; Yeh, Ru-Fang; Ray, Amrita

2009-04-03

Development of model systems that recapitulate the molecular heterogeneity observed among glioblastoma multiforme (GBM) tumors will expedite the testing of targeted molecular therapeutic strategies for GBM treatment. In this study, we profiled DNA copy number and mRNA expression in 21 independent GBM tumor lines maintained as subcutaneous xenografts (GBMX), and compared GBMX molecular signatures to those observed in GBM clinical specimens derived from the Cancer Genome Atlas (TCGA). The predominant copy number signature in both tumor groups was defined by chromosome-7 gain/chromosome-10 loss, a poor-prognosis genetic signature. We also observed, at frequencies similar to that detected in TCGA GBM tumors,more » genomic amplification and overexpression of known GBM oncogenes, such as EGFR, MDM2, CDK6, and MYCN, and novel genes, including NUP107, SLC35E3, MMP1, MMP13, and DDX1. The transcriptional signature of GBMX tumors, which was stable over multiple subcutaneous passages, was defined by overexpression of genes involved in M phase, DNA replication, and chromosome organization (MRC) and was highly similar to the poor-prognosis mitosis and cell-cycle module (MCM) in GBM. Assessment of gene expression in TCGA-derived GBMs revealed overexpression of MRC cancer genes AURKB, BIRC5, CCNB1, CCNB2, CDC2, CDK2, and FOXM1, which form a transcriptional network important for G2/M progression and/or checkpoint activation. Our study supports propagation of GBM tumors as subcutaneous xenografts as a useful approach for sustaining key molecular characteristics of patient tumors, and highlights therapeutic opportunities conferred by this GBMX tumor panel for testing targeted therapeutic strategies for GBM treatment.« less

VizieR Online Data Catalog: Quasi-periodic pulsations in solar flares (Inglis+, 2016)

NASA Astrophysics Data System (ADS)

Inglis, A. R.; Ireland, J.; Dennis, B. R.; Hayes, L.; Gallagher, P.

2018-04-01

We have used data from the Geostationary Operational Environmental Satellite (GOES) instrument series, and from Fermi/Gamma-ray Burst Monitor (GBM). For this reason, we choose the interval 2011 February 1 - 2015 December 31, as it not only coincides with the availability of GOES-15 satellite data, but also includes regular solar observations by GBM. GOES satellites are equipped with solar X-ray detectors that record the incident flux in the 0.5-4Å and 1-8Å wavelength ranges. Solar X-ray data from the most recent satellite, GOES-15, has been available since 2010 at a nominal 2s cadence. To access the GOES catalog, we use the Heliophysics Event Knowledgebase (HEK). Fermi/GBM operates in the 8keV-40MeV range and regularly observes emission from solar flares, with a solar duty cycle of ~60%, similar to the solar-dedicated Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI). To accumulate the database of Fermi/GBM events, we use the GBM trigger catalog produced by the instrument team, selecting all events marked as flares. (2 data files).

HIGH-ENERGY EMISSION OF GRB 130427A: EVIDENCE FOR INVERSE COMPTON RADIATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fan, Yi-Zhong; Zhang, Fu-Wen; He, Hao-Ning

2013-10-20

A nearby superluminous burst GRB 130427A was simultaneously detected by six γ-ray space telescopes (Swift, the Fermi GLAST Burst Monitor (GBM)/Large Area Telescope, Konus-Wind, SPI-ACS/INTEGRAL, AGILE, and RHESSI) and by three RAPTOR full-sky persistent monitors. The isotropic γ-ray energy release is ∼10{sup 54} erg, rendering it the most powerful explosion among gamma-ray bursts (GRBs) with a redshift z ≤ 0.5. The emission above 100 MeV lasted about one day, and four photons are at energies greater than 40 GeV. We show that the count rate of 100 MeV-100 GeV emission may be mainly accounted for by the forward shock synchrotronmore » radiation and the inverse Compton radiation likely dominates at GeV-TeV energies. In particular, an inverse Compton radiation origin is favored for the ∼(95.3, 47.3, 41.4, 38.5, 32) GeV photons arriving at t ∼ (243, 256.3, 610.6, 3409.8, 34366.2) s after the trigger of Fermi-GBM. Interestingly, the external inverse Compton scattering of the prompt emission (the second episode, i.e., t ∼ 120-260 s) by the forward-shock-accelerated electrons is expected to produce a few γ-rays at energies above 10 GeV, while five were detected in the same time interval. A possible unified model for the prompt soft γ-ray, optical, and GeV emission of GRB 130427A, GRB 080319B, and GRB 090902B is outlined. Implications of the null detection of >1 TeV neutrinos from GRB 130427A by IceCube are discussed.« less

Fermi GBM Observations of Terrestrial Gamma-ray Flashes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Briggs, Michael S.

2011-09-21

Terrestrial Gamma-ray Flashes are short pulses of energetic radiation associated with thunderstorms and lightning. While the Gamma-ray Burst Monitor (GBM) on Fermi was designed to observe gamma-ray bursts, its large BGO detectors are excellent for observing TGFs. Using GBM, TGF pulses are seen to either be symmetrical or have faster rise time than fall times. Some TGFs are resolved into double, partially overlapping pulses. Using ground-based radio observations of lightning from the World Wide Lightning Location Network (WWLLN), TGFs and their associated lightning are found to be simultaneous to {approx_equal}40 {mu} s. The lightning locations are typically within 300 kmmore » of the sub-spacecraft point.« less

ATP binding cassette (ABC) transporters: expression and clinical value in glioblastoma.

PubMed

Dréan, Antonin; Rosenberg, Shai; Lejeune, François-Xavier; Goli, Larissa; Nadaradjane, Aravindan Arun; Guehennec, Jérémy; Schmitt, Charlotte; Verreault, Maïté; Bielle, Franck; Mokhtari, Karima; Sanson, Marc; Carpentier, Alexandre; Delattre, Jean-Yves; Idbaih, Ahmed

2018-03-08

ATP-binding cassette transporters (ABC transporters) regulate traffic of multiple compounds, including chemotherapeutic agents, through biological membranes. They are expressed by multiple cell types and have been implicated in the drug resistance of some cancer cells. Despite significant research in ABC transporters in the context of many diseases, little is known about their expression and clinical value in glioblastoma (GBM). We analyzed expression of 49 ABC transporters in both commercial and patient-derived GBM cell lines as well as from 51 human GBM tumor biopsies. Using The Cancer Genome Atlas (TCGA) cohort as a training dataset and our cohort as a validation dataset, we also investigated the prognostic value of these ABC transporters in newly diagnosed GBM patients, treated with the standard of care. In contrast to commercial GBM cell lines, GBM-patient derived cell lines (PDCL), grown as neurospheres in a serum-free medium, express ABC transporters similarly to parental tumors. Serum appeared to slightly increase resistance to temozolomide correlating with a tendency for an increased expression of ABCB1. Some differences were observed mainly due to expression of ABC transporters by microenvironmental cells. Together, our data suggest that the efficacy of chemotherapeutic agents may be misestimated in vitro if they are the targets of efflux pumps whose expression can be modulated by serum. Interestingly, several ABC transporters have prognostic value in the TCGA dataset. In our cohort of 51 GBM patients treated with radiation therapy with concurrent and adjuvant temozolomide, ABCA13 overexpression is associated with a decreased progression free survival in univariate (p < 0.01) and multivariate analyses including MGMT promoter methylation (p = 0.05) suggesting reduced sensitivity to temozolomide in ABCA13 overexpressing GBM. Expression of ABC transporters is: (i) detected in GBM and microenvironmental cells and (ii) better reproduced in GBM-PDCL. ABCA13 expression is an independent prognostic factor in newly diagnosed GBM patients. Further prospective studies are warranted to investigate whether ABCA13 expression can be used to further personalize treatments for GBM.

DW-MRI as a Predictive Biomarker of Radiosensitization of GBM through Targeted Inhibition of Checkpoint Kinases.

PubMed

Williams, Terence M; Galbán, Stefanie; Li, Fei; Heist, Kevin A; Galbán, Craig J; Lawrence, Theodore S; Holland, Eric C; Thomae, Tami L; Chenevert, Thomas L; Rehemtulla, Alnawaz; Ross, Brian D

2013-04-01

The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2)-mediated increased DNA repair capability, which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM. We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. DW-MRI and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively. AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53 wild-type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy. DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA damage-induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.

Podocyte Depletion in Thin GBM and Alport Syndrome.

PubMed

Wickman, Larysa; Hodgin, Jeffrey B; Wang, Su Q; Afshinnia, Farsad; Kershaw, David; Wiggins, Roger C

2016-01-01

The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2-17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at <30% podocyte depletion, minor pathologic changes (mesangial expansion and adhesions to Bowman's capsule) were present at 30-50% podocyte depletion, and FSGS was progressively present above 50% podocyte depletion. eGFR did not change measurably until >70% podocyte depletion. Low level proteinuria was an early event at about 25% podocyte depletion and increased in proportion to podocyte depletion. These quantitative data parallel those from model systems where podocyte depletion is the causative event. This result supports a hypothesis that in AS podocyte adherence to the GBM is defective resulting in accelerated podocyte detachment causing progressive podocyte depletion leading to FSGS-like pathologic changes and eventual End Stage Kidney Disease. Early intervention to reduce podocyte depletion is projected to prolong kidney survival in AS.

Differential molecular genetic analysis in glioblastoma multiforme of long- and short-term survivors: a clinical study in Chinese patients.

PubMed

Zhang, Guo-Bin; Cui, Xiang-Li; Sui, Da-Li; Ren, Xiao-Hui; Zhang, Zhe; Wang, Zhong-Cheng; Lin, Song

2013-06-01

This study was designed to find whether long-term survivors (LTSs) exhibit molecular genetic differences compared with short-term survivors (STSs) in patients with GBM. Tumors from 12 patients initially diagnosed with GBM and survived longer than 36 months (LTSs) were compared with 30 patients with GBM and STSs (survival <18 months) for detecting of MGMT promoter methylation, 1p/19q LOH and IDH1 mutation. IDH1 mutation and MGMT promoter methylation were significantly more frequent in the LTSs group (P = 0.039 and 0.017, respectively). The incidence of 1p/19q co-deletion was not significantly different (P = 1.0). IDH1 mutation and MGMT promoter methylation might be independent, significant, and favorable factors for LTSs with GBM.

The Successful Synergy of Swift and Fermi/GBM in Magnetars

NASA Technical Reports Server (NTRS)

Kouveliotou, Chryssa

2011-01-01

The magnetar rate of discovery has increased dramatically in the last decade. Five sources were discovered in the last three years alone as a result of the very efficient synergy among three X- and .gamma-ray instruments on NASA satellites: the Swift/Burst Alert Telescope (BAT), the Fermi/Gamma ray Burst Monitor (GBM), and the Rossi X-Ray Timing Explorer; RXTE/Proportional Counter Array (PCA). To date, there are approx. 25 magnetar candidates, of which two are (one each) in the Large and Small Magellanic Cloud and the rest reside on the Galactic plane of our Milky Way. I will discuss here the main properties of the Magnetar Population and the common projects that can be achieved with the synergy of Swift and GBM.

Monitoring autocorrelated process: A geometric Brownian motion process approach

NASA Astrophysics Data System (ADS)

Li, Lee Siaw; Djauhari, Maman A.

2013-09-01

Autocorrelated process control is common in today's modern industrial process control practice. The current practice of autocorrelated process control is to eliminate the autocorrelation by using an appropriate model such as Box-Jenkins models or other models and then to conduct process control operation based on the residuals. In this paper we show that many time series are governed by a geometric Brownian motion (GBM) process. Therefore, in this case, by using the properties of a GBM process, we only need an appropriate transformation and model the transformed data to come up with the condition needs in traditional process control. An industrial example of cocoa powder production process in a Malaysian company will be presented and discussed to illustrate the advantages of the GBM approach.

Growth of glioblastoma is inhibited by miR-133-mediated EGFR suppression.

PubMed

Xu, Fulin; Li, Feng; Zhang, Weifeng; Jia, Pifeng

2015-12-01

Glioblastoma multiforme (GBM) is a severe and highly lethal brain cancer, which malignancy largely stems from its growing in a relatively restrained area in the brain. Hence, the understanding of the molecular regulation of the growth of GBM is critical for improving its treatment. Dysregulation of microRNAs (miRNAs) has recently been shown to contribute to the development of GBM, whereas the role of miR-133 in GBM is unknown. Here, by qualitative reverse transcription polymerase chain reaction (RT-qPCR), we detected lower miR-133 levels in GBM tissues, compared to the paired normal brain tissue. We overexpressed or inhibited miR-133 in GBM cells. Cell growth and apoptosis were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. We found that overexpression of miR-133 decreased GBM cell growth and increased cell apoptosis, while depletion of miR-133 increased cell growth and decreased cell apoptosis. Bioinformatic analysis was performed, showing that miR-133 may target the 3'-untranslated region (3'-UTR) of the epidermal growth factor receptor (EGFR) that transduces cell growth signals. Further, the protein translation inhibition of EGFR by miR-133 was confirmed by a dual luciferase reporter assay. Together, these data suggest that reduced miR-133 levels in GBM tissues promotes cell growth and decreases cell apoptosis, possibly through targeting mRNA of EGFR to suppress its translation.

Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma.

PubMed

Guastella, Anthony R; Michelhaugh, Sharon K; Klinger, Neil V; Kupsky, William J; Polin, Lisa A; Muzik, Otto; Juhász, Csaba; Mittal, Sandeep

2016-01-01

Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM. © The Author(s) 2016.

Fermi GBM: Highlights from the First Year

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.

2009-01-01

The Fermi Gamma ray Burst Monitor is an all-sky instrument sensitive to photons from about 8 keV to 40 MeV. I will summarize highlights from the first year, including triggered observations of gamma ray bursts, soft gamma ray repeaters, and terrestrial gamma flashes, and observations in the continuous data of X-ray binaries and accreting X-ray pulsars. GBM provides complementary observations to Swift/BAT, observing many of the same sources, but over a wider energy range.

Magnetar Bursts

NASA Technical Reports Server (NTRS)

Kouveliotou, Chryssa

2014-01-01

The Fermi/Gamma-ray Burst Monitor (GBM) was launched in June 2008. During the last five years the instrument has observed several hundreds of bursts from 8 confirmed magnetars and 19 events from unconfirmed sources. I will discuss the results of the GBM magnetar burst catalog, expand on the different properties of their diverse source population, and compare these results with the bursting activity of past sources. I will then conclude with thoughts of how these properties fit the magnetar theoretical models.

Detecting opinion spams through supervised boosting approach.

PubMed

Hazim, Mohamad; Anuar, Nor Badrul; Ab Razak, Mohd Faizal; Abdullah, Nor Aniza

2018-01-01

Product reviews are the individual's opinions, judgement or belief about a certain product or service provided by certain companies. Such reviews serve as guides for these companies to plan and monitor their business ventures in terms of increasing productivity or enhancing their product/service qualities. Product reviews can also increase business profits by convincing future customers about the products which they have interest in. In the mobile application marketplace such as Google Playstore, reviews and star ratings are used as indicators of the application quality. However, among all these reviews, hereby also known as opinions, spams also exist, to disrupt the online business balance. Previous studies used the time series and neural network approach (which require a lot of computational power) to detect these opinion spams. However, the detection performance can be restricted in terms of accuracy because the approach focusses on basic, discrete and document level features only thereby, projecting little statistical relationships. Aiming to improve the detection of opinion spams in mobile application marketplace, this study proposes using statistical based features that are modelled through the supervised boosting approach such as the Extreme Gradient Boost (XGBoost) and the Generalized Boosted Regression Model (GBM) to evaluate two multilingual datasets (i.e. English and Malay language). From the evaluation done, it was found that the XGBoost is most suitable for detecting opinion spams in the English dataset while the GBM Gaussian is most suitable for the Malay dataset. The comparative analysis also indicates that the implementation of the proposed statistical based features had achieved a detection accuracy rate of 87.43 per cent on the English dataset and 86.13 per cent on the Malay dataset.

Terrestrial Gamma-Ray Flashes (TGFs)

NASA Technical Reports Server (NTRS)

Fishman, Gerald J.

2010-01-01

This slide presentation reviews the observation of Terrestrial Gamma Ray Flashes (TGFs) by Gamma-Ray Telescopes. These were: (1) BATSE /Compton Observatory, (2) Solar Spectroscopic Imager, (3) AGILE Gamma-ray Telescope, and (4) Gamma-ray Burst Monitor (GBM) on the Fermi Gamma-ray Space Telescope. It contains charts which display the counts over time, a map or the TGFs observed by the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI). and a map showing the latitude and longitude of 85 of the TGFs observed by the Fermi GBM.

γ-Glutamyl transferase 7 is a novel regulator of glioblastoma growth.

PubMed

Bui, Timothy T; Nitta, Ryan T; Kahn, Suzana A; Razavi, Seyed-Mostafa; Agarwal, Maya; Aujla, Parvir; Gholamin, Sharareh; Recht, Lawrence; Li, Gordon

2015-04-07

Glioblastoma (GBM) is the most malignant primary brain tumor in adults, with a median survival time of one and a half years. Traditional treatments, including radiation, chemotherapy, and surgery, are not curative, making it imperative to find more effective treatments for this lethal disease. γ-Glutamyl transferase (GGT) is a family of enzymes that was shown to control crucial redox-sensitive functions and to regulate the balance between proliferation and apoptosis. GGT7 is a novel GGT family member that is highly expressed in brain and was previously shown to have decreased expression in gliomas. Since other members of the GGT family were found to be altered in a variety of cancers, we hypothesized that GGT7 could regulate GBM growth and formation. To determine if GGT7 is involved in GBM tumorigenesis, we modulated GGT7 expression in two GBM cell lines (U87-MG and U138) and monitored changes in tumorigenicity in vitro and in vivo. We demonstrated for the first time that GBM patients with low GGT7 expression had a worse prognosis and that 87% (7/8) of primary GBM tissue samples showed a 2-fold decrease in GGT7 expression compared to normal brain samples. Exogenous expression of GGT7 resulted in a 2- to 3-fold reduction in proliferation and anchorage-independent growth under minimal growth conditions (1% serum). Decreasing GGT7 expression using either short interfering RNA or short hairpin RNA consistently increased proliferation 1.5- to 2-fold. In addition, intracranial injections of U87-MG cells with reduced GGT7 expression increased tumor growth in mice approximately 2-fold, and decreased mouse survival. To elucidate the mechanism by which GGT7 regulates GBM growth, we analyzed reactive oxygen species (ROS) levels in GBM cells with modulated GGT7 expression. We found that enhanced GGT7 expression reduced ROS levels by 11-33%. Our study demonstrates that GGT7 is a novel player in GBM growth and that GGT7 can play a critical role in tumorigenesis by regulating anti-oxidative damage. Loss of GGT7 may increase the cellular ROS levels, inducing GBM occurrence and growth. Our findings suggest that GGT7 can be a promising biomarker and a potential therapeutic target for GBM.

Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist.

PubMed

Wang, Haiyan; Cai, Shanbao; Bailey, Barbara J; Reza Saadatzadeh, M; Ding, Jixin; Tonsing-Carter, Eva; Georgiadis, Taxiarchis M; Zachary Gunter, T; Long, Eric C; Minto, Robert E; Gordon, Kevin R; Sen, Stephanie E; Cai, Wenjing; Eitel, Jacob A; Waning, David L; Bringman, Lauren R; Wells, Clark D; Murray, Mary E; Sarkaria, Jann N; Gelbert, Lawrence M; Jones, David R; Cohen-Gadol, Aaron A; Mayo, Lindsey D; Shannon, Harlan E; Pollok, Karen E

2017-02-01

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions.

Activation of PPARγ mediates icaritin-induced cell cycle arrest and apoptosis in glioblastoma multiforme.

PubMed

Liu, Yongji; Shi, Ling; Liu, Yuan; Li, Peng; Jiang, Guoping; Gao, Xiaoning; Zhang, Yongbin; Jiang, Chuanwu; Zhu, Weiping; Han, Hongxing; Ju, Fang

2018-04-01

Glioblastoma multiforme (GBM) is the most prevalent primary malignancy of the brain. This study was designed to investigate whether icaritin exerts anti-neoplastic activity against GBM in vitro. Cell Counting Kit-8 (CCK-8) assay was utilized to examine the viability of GBM cells. The apoptotic cell population was measured by flow cytometry analysis. Cell cycle distribution was detected by flow cytometry as well. Western blot analysis was performed to examine the level of biomarker proteins in GBM cells. Levels of PPARγ mRNA and protein were detected by qPCR and western blot analysis, respectively. To examine the role of PPARγ in the anti-neoplastic activity of icaritin, PPARγ antagonist GW9662 or PPARγ siRNA was used. The activity of PPARγ was determined by DNA binding and luciferase assays. Our findings revealed that icaritin markedly suppresses cell growth in a dose-dependent and time-dependent fashion. The cell population at the G0/G1 phase of the cell cycle was significantly increased following icaritin treatment. Meanwhile, icaritin promoted apoptotic cell death in T98G and U87MG cells. Further investigation showed upregulation of PPARγ played a key role in the anti-neoplastic activities of icaritin. Moreover, our result demonstrated activation of AMPK signaling by icaritin mediated the modulatory effect of icaritin on PPARγ. Our results suggest the PPARγ may mediate anti-neoplastic activities against GBM. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

A low-latency pipeline for GRB light curve and spectrum using Fermi/GBM near real-time data

NASA Astrophysics Data System (ADS)

Zhao, Yi; Zhang, Bin-Bin; Xiong, Shao-Lin; Long, Xi; Zhang, Qiang; Song, Li-Ming; Sun, Jian-Chao; Wang, Yuan-Hao; Li, Han-Cheng; Bu, Qing-Cui; Feng, Min-Zi; Li, Zheng-Heng; Wen, Xing; Wu, Bo-Bing; Zhang, Lai-Yu; Zhang, Yong-Jie; Zhang, Shuang-Nan; Shao, Jian-Xiong

2018-05-01

Rapid response and short time latency are very important for Time Domain Astronomy, such as the observations of Gamma-ray Bursts (GRBs) and electromagnetic (EM) counterparts of gravitational waves (GWs). Based on near real-time Fermi/GBM data, we developed a low-latency pipeline to automatically calculate the temporal and spectral properties of GRBs. With this pipeline, some important parameters can be obtained, such as T 90 and fluence, within ∼ 20 min after the GRB trigger. For ∼ 90% of GRBs, T 90 and fluence are consistent with the GBM catalog results within 2σ errors. This pipeline has been used by the Gamma-ray Bursts Polarimeter (POLAR) and the Insight Hard X-ray Modulation Telescope (Insight-HXMT) to follow up the bursts of interest. For GRB 170817A, the first EM counterpart of GW events detected by Fermi/GBM and INTEGRAL/SPI-ACS, the pipeline gave T 90 and spectral information 21 min after the GBM trigger, providing important information for POLAR and Insight-HXMT observations.

Decitabine Nano-conjugate Sensitizing Human Glioblastoma Cells to Temozolomide

PubMed Central

Cui, Yi; Naz, Asia; Thompson, David H.; Irudayaraj, Joseph

2015-01-01

In this study we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) based nano-conjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells. After synthesis, the highly efficient uptake process and intracellular dynamics of this nano-conjugate was monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nano-vector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing a “positive feedback” to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to excellent internalization and endo-lysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than free drug molecules. Hence, the synthesized nano-conjugate and temozolomide could act in synergy to deliver a more potent and long-term anti-proliferation effect against malignant GBM cells. PMID:25751281

Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance.

PubMed

Strohbehn, Garth; Coman, Daniel; Han, Liang; Ragheb, Ragy R T; Fahmy, Tarek M; Huttner, Anita J; Hyder, Fahmeed; Piepmeier, Joseph M; Saltzman, W Mark; Zhou, Jiangbing

2015-02-01

Current therapy for glioblastoma multiforme (GBM) is largely ineffective, with nearly universal tumor recurrence. The failure of current therapy is primarily due to the lack of approaches for the efficient delivery of therapeutics to diffuse tumors in the brain. In our prior study, we developed brain-penetrating nanoparticles that are capable of penetrating brain tissue and distribute over clinically relevant volumes when administered via convection-enhanced delivery (CED). We demonstrated that these particles are capable of efficient delivery of chemotherapeutics to diffuse tumors in the brain, indicating that they may serve as a groundbreaking approach for the treatment of GBM. In the original study, nanoparticles in the brain were imaged using positron emission tomography (PET). However, clinical translation of this delivery platform can be enabled by engineering a non-invasive detection modality using magnetic resonance imaging (MRI). For this purpose, we developed chemistry to incorporate superparamagnetic iron oxide (SPIO) into the brain-penetrating nanoparticles. We demonstrated that SPIO-loaded nanoparticles, which retain the same morphology as nanoparticles without SPIO, have an excellent transverse (T(2)) relaxivity. After CED, the distribution of nanoparticles in the brain (i.e., in the vicinity of injection site) can be detected using MRI and the long-lasting signal attenuation of SPIO-loaded brain-penetrating nanoparticles lasted over a one-month timecourse. Development of these nanoparticles is significant as, in future clinical applications, co-administration of SPIO-loaded nanoparticles will allow for intraoperative monitoring of particle distribution in the brain to ensure drug-loaded nanoparticles reach tumors as well as for monitoring the therapeutic benefit with time and to evaluate tumor relapse patterns.

SGR J1550-5418 Bursts Detected with the Fermi Gamma-Ray Burst Monitor during Its Most Prolific Activity

NASA Technical Reports Server (NTRS)

vanderHorst, A. J.; Kouveliotou, C.; Gorgone, N. M.; Kaneko, Y.; Baring, M. G.; Guiriec, S.; Gogus, E,; Granot, J.; Watts, A. L.; Lin, L.;

Study Protocol: Early Stereotactic Gamma Knife Radiosurgery to Residual Tumor After Surgery of Newly Diagnosed Glioblastoma (Gamma-GBM).

PubMed

Brehmer, Stefanie; Grimm, Mario Alexander; Förster, Alex; Seiz-Rosenhagen, Marcel; Welzel, Grit; Stieler, Florian; Wenz, Frederik; Groden, Christoph; Mai, Sabine; Hänggi, Daniel; Giordano, Frank Anton

2018-04-24

Glioblastoma (GBM) is the most common malignant brain tumor in adult patients. Tumor recurrence commonly occurs around the resection cavity, especially after subtotal resection (STR). Consequently, the extent of resection correlates with overall survival (OS), suggesting that depletion of postoperative tumor remnants will improve outcome. To assess safety and efficacy of adding stereotactic radiosurgery (SRS) to the standard treatment of GBM in patients with postoperative residual tumor. Gamma-GBM is a single center, open-label, prospective, single arm, phase II study that includes patients with newly diagnosed GBM (intraoperative via frozen sections) who underwent STR (residual tumor will be identified by native and contrast enhanced T1-weighted magnetic resonance imaging scans). All patients will receive SRS with 15 Gy (prescribed to the 50% isodose enclosing all areas of residual tumor) early (within 24-72 h) after surgery. Thereafter, all patients undergo standard-of-care therapy for GBM (radiochemotherapy with 60 Gy external beam radiotherapy [EBRT] plus concomitant temozolomide and 6 cycles of adjuvant temozolomide chemotherapy). The primary outcome is median progression-free survival, secondary outcomes are median OS, occurrence of radiation induced acute (<3 wk), early delayed (<3 mo), and late (>3 mo post-SRS) neurotoxicity and incidence of symptomatic radionecrosis. We expect to detect efficacy and safety signals by the immediate application of SRS to standard-of-care therapy in newly diagnosed GBM. Early postoperative SRS to areas of residual tumor could bridge the therapeutic gap between surgery and adjuvant therapies.

Fermi Large Area Telescope

Science.gov Websites

Home Mission Instrument Institutions Publications NASA Pictures Internal lock The Fermi Large Area Monitor (GBM). Wikipedia Country Funding Agencies United States NASA; Department of Energy France

Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma—results from the DIRECTOR trial

PubMed Central

Suchorska, Bogdana; Weller, Michael; Tabatabai, Ghazaleh; Senft, Christian; Hau, Peter; Sabel, Michael C.; Herrlinger, Ulrich; Ketter, Ralf; Schlegel, Uwe; Marosi, Christine; Reifenberger, Guido; Wick, Wolfgang; Tonn, Jörg C.; Wirsching, Hans-Georg

2016-01-01

Background The role of reoperation for recurrent glioblastoma (GBM) remains unclear. Prospective studies are lacking. Here, we studied the association of clinical outcome with extent of resection upon surgery for recurrent GBM in the patient cohort of DIRECTOR, a prospective randomized multicenter trial comparing 2 dose-intensified temozolomide regimens at recurrence of GBM. Methods We analyzed prospectively collected clinical and imaging data from the DIRECTOR cohort (N = 105). Volumetric analysis was performed on gadolinium contrast-enhanced MRI as well as fluid attenuated inversion recovery/T2 MRI and correlated with PFS after initial progression (PFS2) and post-recurrence survival (PRS). Quality of life was monitored by the EORTC QLQ-C30 and QLQ-BN20 questionnaires at 8-week intervals. Results Seventy-one patients received surgery at first recurrence. Prognostic factors, including age, MGMT promoter methylation, and Karnofsky performance score, were balanced between patients with and without reoperation. Outcome in patients with versus without surgery at recurrence was similar for PFS2 (2.0 mo vs 1.9 mo, P = .360) and PRS (11.4 mo vs 9.8 mo, P = .633). Among reoperated patients, post-surgery imaging was available in 59 cases. In these patients, complete resection of contrast-enhancing tumor (N = 40) versus residual detection of contrast enhancement (N = 19) was associated with improved PRS (12.9 mo [95% CI: 11.5–18.2] vs 6.5 mo [95% CI: 3.6–9.9], P < .001) and better quality of life. Incomplete tumor resection was associated with inferior PRS compared with patients who did not undergo surgery (6.5 vs 9.8 mo, P = .052). Quality of life was similar in these 2 groups. Conclusion Surgery at first recurrence of GBM improves outcome if complete resection of contrast-enhancing tumor is achieved. PMID:26823503

Broadband Spectral Investigations of SGR J1550-5418 Bursts

NASA Technical Reports Server (NTRS)

Lin, Lin; Goegues, Ersin; Baring, Matthew G.; Granot, Jonathan; Kouveliotou, Chryssa; Kaneko, Yuki; van der Horst, Alexander; Gruber, David; von Kienlin, Andreas; Younes, George;

Harnessing the cross-talk between tumor cells and tumor-associated macrophages with a nano-drug for modulation of glioblastoma immune microenvironment.

PubMed

Li, Tong-Fei; Li, Ke; Wang, Chao; Liu, Xin; Wen, Yu; Xu, Yong-Hong; Zhang, Quan; Zhao, Qiu-Ya; Shao, Ming; Li, Yan-Ze; Han, Min; Komatsu, Naoki; Zhao, Li; Chen, Xiao

2017-12-28

Glioblastoma (GBM) is the most frequent and malignant brain tumor with a high mortality rate. The presence of a large population of macrophages (Mφ) in the tumor microenvironment is a prominent feature of GBM and these so-called tumor-associated Mφ (TAM) closely interact with the GBM cells to promote the survival, progression and therapy resistance of the GBM. Various therapeutic strategies have been devised either targeting the GBM cells or the TAM but few have addressed the cross-talks between the two cell populations. The present study was carried out to explore the possibility of exploiting the cross-talks between the GBM cells (GC) and TAM for modulation of the GBM microenvironment through using Nano-DOX, a drug composite based on nanodiamonds bearing doxorubicin. In the in vitro work on human cell models, Nano-DOX-loaded TAM were first shown to be viable and able to infiltrate three-dimensional GC spheroids and release cargo drug therein. GC were then demonstrated to encourage Nano-DOX-loaded TAM to unload Nano-DOX back into GC which consequently emitted damage-associated molecular patterns (DAMPs) that are powerful immunostimulatory agents as well as indicators of cell damage. Nano-DOX was next proven to be a more potent inducer of GC DAMPs emission than doxorubicin. As a result, Nano-DOX-damaged GC exhibited an enhanced ability to attract both TAM and Nano-DOX-loaded TAM. Most remarkably, Nano-DOX-damaged GC reprogrammed the TAM from a pro-GBM phenotype to an anti-GBM phenotype that suppressed GC growth. Finally, the in vivo relevance of the in vitro findings was tested in animal study. Mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mouse TAM which were found releasing drug in the GBM xenografts 24h after injection. GC damage was evidenced by the induction of DAMPs emission within the xenografts and a shift of TAM phenotype was detected as well. Taken together, our results demonstrate a novel way with therapeutic potential to harness the cross-talk between GBM cells and TAM for modulation of the tumor immune microenvironment. Copyright © 2017 Elsevier B.V. All rights reserved.

The Extreme Case of Magnetars

NASA Technical Reports Server (NTRS)

Kouveliotou, Chryssa

2011-01-01

Magnetars are magnetically powered rotating neutron stars with extreme magnetic fields (over 10(exp 14) Gauss). They were discovered in the X- and gamma-rays where they predominantly emit their radiation. Very few sources (roughly 18) have been found since their discovery in 1987. NASA's Fermi Gamma-ray Space Telescope was launched June 11, 2009; since then the Fermi Gamma-ray Burst Monitor (GBM) recorded emission from four magnetar sources. Two of these were brand new sources, SGR J0501+4516, discovered with Swift and extensively monitored with Swift and GBM, SGR J0418+5729, discovered with GBM and the Interplanetary Network (IPN). A third was SGR J1550-5418, a source originally classified as an Anomalous X-ray Pulsar (AXP 1E1547.0-5408), but exhibiting a very prolific outburst with over 400 events recorded in January 2009. In my talk I will give a short history of magnetars and describe how this, once relatively esoteric field, has emerged as a link between several astrophysical areas including Gamma-Ray Bursts. Finally, I will describe the exciting new results of Fermi in this field and the current status of our knowledge of the magnetar population properties and magnetic fields.

Glomerular basement membrane injuries in IgA nephropathy evaluated by double immunostaining for α5(IV) and α2(IV) chains of type IV collagen and low-vacuum scanning electron microscopy.

PubMed

Masuda, Yukinari; Yamanaka, Nobuaki; Ishikawa, Arimi; Kataoka, Mitue; Arai, Takashi; Wakamatsu, Kyoko; Kuwahara, Naomi; Nagahama, Kiyotaka; Ichikawa, Kaori; Shimizu, Akira

2015-06-01

The glomerulus contains well-developed capillaries, which are at risk of injury due to high hydrostatic pressure, hyperfiltration, hypertension and inflammation. However, the pathological alterations of the injured glomerular basement membrane (GBM), the main component of the glomerular filtration barrier, are still uncertain in cases of glomerulonephritis. We examined the alterations of the GBM in 50 renal biopsy cases with IgA nephropathy (31.8 ± 17.6 years old) using double immunostaining for the α2(IV) and α5(IV) chains of type IV collagen, and examining the ultrastructural alterations by transmission electron microscopy (TEM) and low-vacuum scanning electron microscopy (LV-SEM). The GBM of IgA nephropathy cases showed various morphological and qualitative alterations. In the TEM findings, thinning, gaps, rupture, thickening with a lamellar and reticular structure and double contours were detected in the GBM. Double immunostaining for α5(IV) and α2(IV) showed thickening of the GBM with reduced α5(IV) and increased α2(IV), or mosaic images of α5(IV) and α2(IV), and holes, fractures, spiny projections and rupture of α5(IV) in the GBM. In addition, LV-SEM showed an etched image and multiple holes in a widening and wavy GBM. These findings might be associated with the development of a brittle GBM in IgA nephropathy. Glomerular basement membrane alterations were frequently noted in IgA nephropathy, and were easily evaluated by double immunostaining for α2(IV) and α5(IV) of type IV collagen and LV-SEM. The application of these analyses to human renal biopsy specimens may enhance our understanding of the alterations of the GBM that occur in human glomerular diseases.

In search of druggable targets for GBM amino acid metabolism.

PubMed

Panosyan, Eduard H; Lin, Henry J; Koster, Jan; Lasky, Joseph L

2017-02-28

Amino acid (AA) pathways may contain druggable targets for glioblastoma (GBM). Literature reviews and GBM database ( http://r2.amc.nl ) analyses were carried out to screen for such targets among 95 AA related enzymes. First, we identified the genes that were differentially expressed in GBMs (3 datasets) compared to non-GBM brain tissues (5 datasets), or were associated with survival differences. Further, protein expression for these enzymes was also analyzed in high grade gliomas (HGGs) (proteinatlas.org). Finally, AA enzyme and gene expression were compared among the 4 TCGA (The Cancer Genome Atlas) subtypes of GBMs. We detected differences in enzymes involved in glutamate and urea cycle metabolism in GBM. For example, expression levels of BCAT1 (branched chain amino acid transferase 1) and ASL (argininosuccinate lyase) were high, but ASS1 (argininosuccinate synthase 1) was low in GBM. Proneural and neural TCGA subtypes had low expression of all three. High expression of all three correlated with worse outcome. ASL and ASS1 protein levels were mostly undetected in high grade gliomas, whereas BCAT1 was high. GSS (glutathione synthetase) was not differentially expressed, but higher levels were linked to poor progression free survival. ASPA (aspartoacylase) and GOT1 (glutamic-oxaloacetic transaminase 1) had lower expression in GBM (associated with poor outcomes). All three GABA related genes -- glutamate decarboxylase 1 (GAD1) and 2 (GAD2) and 4-aminobutyrate aminotransferase (ABAT) -- were lower in mesenchymal tumors, which in contrast showed higher IDO1 (indoleamine 2, 3-dioxygenase 1) and TDO2 (tryptophan 2, 3-diaxygenase). Expression of PRODH (proline dehydrogenase), a putative tumor suppressor, was lower in GBM. Higher levels predicted poor survival. Several AA-metabolizing enzymes that are higher in GBM, are also linked to poor outcome (such as BCAT1), which makes them potential targets for therapeutic inhibition. Moreover, existing drugs that deplete asparagine and arginine may be effective against brain tumors, and should be studied in conjunction with chemotherapy. Last, AA metabolism is heterogeneous in TCGA subtypes of GBM (as well as medulloblastomas and other pediatric tumors), which may translate to variable responses to AA targeted therapies.

MERTK Inhibition Induces Polyploidy and Promotes Cell Death and Cellular Senescence in Glioblastoma Multiforme

PubMed Central

Sufit, Alexandra; Lee-Sherick, Alisa B.; DeRyckere, Deborah; Rupji, Manali; Dwivedi, Bhakti; Varella-Garcia, Marileila; Pierce, Angela M.; Kowalski, Jeanne; Wang, Xiaodong; Frye, Stephen V.; Earp, H. Shelton

2016-01-01

Background MER receptor tyrosine kinase (MERTK) is expressed in a variety of malignancies, including glioblastoma multiforme (GBM). Our previous work demonstrated that inhibition of MERTK using RNA interference induced cell death and chemosensitivity in GBM cells, implicating MERTK as a potential therapeutic target. Here we investigate whether a novel MERTK-selective small molecule tyrosine kinase inhibitor, UNC2025, has similar anti-tumor effects in GBM cell lines. Methods Correlations between expression of GAS6, a MERTK ligand, and prognosis were determined using data from the TCGA database. GBM cell lines (A172, SF188, U251) were treated in vitro with increasing doses of UNC2025 (50-400nM). Cell count and viability were determined by trypan blue exclusion. Cell cycle profiles and induction of apoptosis were assessed by flow cytometric analysis after BrdU or Po-Pro-1/propidium iodide staining, respectively. Polyploidy was detected by propidium iodide staining and metaphase spread. Cellular senescence was determined by β-galactosidase staining and senescence-associated secretory cytokine analysis. Results Decreased overall survival significantly correlated with high levels of GAS6 expression in GBM, highlighting the importance of TAM kinase signaling in GBM tumorigenesis and/or therapy resistance and providing strong rationale for targeting these pathways in the clinic. All three GBM cell lines exhibited dose dependent reductions in cell number and colony formation (>90% at 200nM) after treatment with UNC2025. Cell cycle analysis demonstrated accumulation of cells in the G2/M phase and development of polyploidy. After extended exposure, 60–80% of cells underwent apoptosis. The majority of surviving cells (65–95%) were senescent and did not recover after drug removal. Thus, UNC2025 mediates anti-tumor activity in GBM by multiple mechanisms. Conclusions The findings described here provide further evidence of oncogenic roles for MERTK in GBM, demonstrate the importance of kinase activity for MERTK tumorigenicity and validate UNC2025, a novel MERTK inhibitor, as a potential therapeutic agent for treatment of GBM. PMID:27783662

Engineering a High-Throughput 3-D In Vitro Glioblastoma Model

PubMed Central

Fan, Yantao; Avci, Naze G.; Nguyen, Duong T.; Dragomir, Andrei; Xu, Feng; Akay, Metin

2015-01-01

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults because of its highly invasive behavior. The existing treatment for GBM, which involves a combination of resection, chemotherapy, and radiotherapy, has a very limited success rate with a median survival rate of <1 year. This is mainly because of the failure of early detection and effective treatment. We designed a novel 3-D GBM cell culture model based on microwells that could mimic in vitro environment and help to bypass the lack of suitable animal models for preclinical toxicity tests. Microwells were fabricated from simple and inexpensive polyethylene glycol material for the control of in vitro 3-D culture. We applied the 3-D micropatterning system to GBM (U-87) cells using the photolithography technique to control the cell spheroids’ shape, size, and thickness. Our preliminary results suggested that uniform GBM spheroids can be formed in 3-D, and the size of these GBM spheroids depends on the size of microwells. The viability of the spheroids generated in this manner was quantitatively evaluated using live/dead assay and shown to improve over 21 days. We believe that in vitro 3-D cell culture model could help to reduce the time of the preclinical brain tumor growth studies. The proposed novel platform could be useful and cost-effective for high-throughput screening of cancer drugs and assessment of treatment responses. PMID:27170911

Anti-GBM disease and ANCA during dengue infection.

PubMed

Lizarraga, Karlo J; Florindez, Jorge A; Daftarian, Pirouz; Andrews, David M; Ortega, Luis M; Mendoza, Jair Munoz; Contreras, Gabriel N; Nayer, Ali

2015-02-01

Anti-glomerular basement membrane (GBM) disease is a severe inflammatory renal disorder due to pathogenic autoantibodies directed mainly against the α3 chain of type IV collagen. In ~1/4 of patients with anti-GBM disease, antineutrophil cytoplasmic antibodies (ANCA) predominantly with myeloperoxidase (MPO) specificity can be detected. Although the inciting stimuli leading to the development of an immune response against the type IV collagen and neutrophils are unknown, evidence indicates that both genetic and environmental factors play a role. Of note, molecular mimicry between self-antigens and nonself-antigens such as antigenic determinants of microorganisms has been implicated in the pathogenesis of anti-GBM disease and ANCA-associated vasculitis. A mosquito-borne viral illness highly prevalent in the tropics and subtropics, dengue can be complicated by acute renal failure, proteinuria, hematuria and glomerulonephritis. We present a 66-year-old woman who was diagnosed with dengue infection and rapidly progressive glomerulonephritis during an outbreak of dengue in Honduras in the summer of 2013. Renal biopsy revealed severe crescentic glomerulonephritis. Immunofluorescence examination demonstrated strong linear IgG deposition along glomerular capillary walls. Serologic tests demonstrated antibodies against GBM, MPO and platelet glycoproteins. The patient was diagnosed with anti-GBM disease associated with p-ANCA with MPO specificity. Despite heavy immunosuppression and plasmapheresis, IgG titers against dengue virus continued to rise confirming the diagnosis of acute dengue infection. We present the first reported case of anti-GBM disease associated with p-ANCA with MPO specificity during dengue infection. This report calls for a heightened awareness of autoimmunity leading to crescentic glomerulonephritis in patients with dengue infection.

SOCS3 promoter hypermethylation is a favorable prognosticator and a novel indicator for G-CIMP-positive GBM patients.

PubMed

Feng, Ying; Wang, Zheng; Bao, Zhaoshi; Yan, Wei; You, Gan; Wang, Yinyan; Hu, Huimin; Zhang, Wei; Zhang, Quangeng; Jiang, Tao

2014-01-01

Hypermethylation of the suppressor of cytokine signaling 3(SOCS3) promoter has been reported to predict a poor prognosis in several cancers including glioblastoma multiforme (GBM). We explored the function of SOCS3 promoter hypermethylation in GBM cohorts, including analysis of the CpG island methylator phenotype (CIMP), when a large number of gene loci are simultaneously hypermethylated. A whole genome promoter methylation profile was performed in a cohort of 33 GBM samples, with 13 long-term survivors (LTS; overall survival ≥ 18 months) and 20 short-term survivors (STS; overall survival ≤ 9 months). The SOCS3 promoter methylation status was compared between the two groups. In addition, we investigated the relationship of SOCS3 promoter methylation and G-CIMP status. Interestingly, in our present study, we found that SOCS3 promoter methylation was statistically significantly higher in the 13 LTS than that in the 20 STS. Furthermore, high SOCS3 promoter methylation detected via pyro-sequencing predicted a better prognosis in an independent cohort containing 62 GBM patients. This correlation was validated by the dataset from the Cancer Genome Atlas(TCGA) and the Chinese Cancer Genome Atlas(CGGA). In addition, we found that hypermethylation of the SOCS3 promoter was tightly associated with the G-CIMP-positive GBM patients. Using a total of 359 clinical samples, we demonstrate that SOCS3 promoter hypermethylation status has a favorable prognostic value in GBM patients because of whole genome methylation status. Particularly, the hypermethylation of the SOCS3 promoter indicates positive G-CIMP status.

Implications of survey labels and categorisations for understanding drug use in the context of sex among gay and bisexual men in Melbourne, Australia.

PubMed

Ryan, Kathleen E; Wilkinson, Anna L; Pedrana, Alisa; Quinn, Brendan; Dietze, Paul; Hellard, Margaret; Stoové, Mark

2018-05-01

Reliably measuring drug use by gay, bisexual and other men who have sex with men (GBM) in the context of sex can inform sexual health service responses. We report changing drug use patterns among GBM testing for HIV at a community-based service in Melbourne in response to behavioural survey modifications. Surveys were completed by GBM prior to all HIV tests. Survey one asked about use of "party drugs for the purpose of sex" and survey two asked about specific drug use (alcohol, amyl nitrate, methamphetamine, cocaine, ecstasy, GHB, Viagra ® /Cialis ® ) before or during sex. Differences in drug use prevalence and demographic and sexual risk correlates are reported. Reported drug use increased from 16.9% in survey one to 54.0% in survey two. Among GBM completing both surveys, 45% who reported no drug use in survey one reported drug use in survey two. Drug use was associated with high HIV risk behaviours across both surveys. Survey modification improved ascertainment of drug use in the context of sex among GBM. Continued monitoring of drug use in this setting will improve our understanding the relationship between use of specific drugs and sexual health and help inform client focused health promotion. Copyright © 2018 Elsevier B.V. All rights reserved.

Alantolactone, a natural sesquiterpene lactone, has potent antitumor activity against glioblastoma by targeting IKKβ kinase activity and interrupting NF-κB/COX-2-mediated signaling cascades.

PubMed

Wang, Xun; Yu, Zhenlong; Wang, Chao; Cheng, Wei; Tian, Xiangge; Huo, Xiaokui; Wang, Yan; Sun, Chengpeng; Feng, Lei; Xing, Jinshan; Lan, Yulong; Sun, Dongdong; Hou, Qingjuan; Zhang, Baojing; Ma, Xiaochi; Zhang, Bo

2017-07-12

Glioblastoma multiforme (GBM) is one of the most refractory and palindromic central nervous system (CNS) neoplasms, and current treatments have poor effects in GBM patients. Hence, the identification of novel therapeutic targets and the development of effective treatment strategies are essential. Alantolactone (ATL) has a wide range of pharmacological activities, and its anti-tumor effect is receiving increasing attention. However, the molecular mechanism underlying the anti-GBM activity of ATL remains poorly understood. The biological functions of ATL in GBM cells were investigated using migration/invasion, colony formation and cell cycle/apoptosis assays. The localization of nuclear factor kappa B (NF-κB) p50/p65 and its binding to the cyclooxygenase 2 (COX-2) promoter were determined using confocal immunofluorescence, a streptavidin-agarose pulldown assay and a chromatin immunoprecipitation (ChIP) assay. IKKβ kinase activity was determined using a cell IKKβ kinase activity spectrophotometry quantitative detection kit and a molecular docking study. LC-MS/MS analysis was performed to determine the ability of ATL to traverse the blood-brain barrier (BBB). The in vivo anti-tumor efficacy of ATL was also analyzed in xenografted nude mice. Western blot analysis was performed to detect the protein expression levels. ATL significantly suppressed the growth of GBM in vivo and in vitro. ATL significantly reduced the expression of COX-2 by inhibiting the kinase activity of IKKβ by targeting the ATP-binding site and then attenuating the binding of NF-κB to the COX-2 promoter region. Furthermore, ATL induced apoptosis by activating the cytochrome c (cyt c)/caspase cascade signaling pathway. Moreover, ATL could penetrate the BBB. ATL exerts its anti-tumor effects in human GBM cells at least in part via NF-κB/COX-2-mediated signaling cascades by inhibiting IKKβ kinase activity. ATL, which is a natural small molecule inhibitor, is a promising candidate for clinical applications in the treatment of CNS tumors.

A Comparison of RNA-Seq Results from Paired Formalin-Fixed Paraffin-Embedded and Fresh-Frozen Glioblastoma Tissue Samples

PubMed Central

Esteve-Codina, Anna; Arpi, Oriol; Martinez-García, Maria; Pineda, Estela; Mallo, Mar; Gut, Marta; Carrato, Cristina; Rovira, Anna; Lopez, Raquel; Tortosa, Avelina; Dabad, Marc; Del Barco, Sonia; Heath, Simon; Bagué, Silvia; Ribalta, Teresa; Alameda, Francesc; de la Iglesia, Nuria

2017-01-01

The molecular classification of glioblastoma (GBM) based on gene expression might better explain outcome and response to treatment than clinical factors. Whole transcriptome sequencing using next-generation sequencing platforms is rapidly becoming accepted as a tool for measuring gene expression for both research and clinical use. Fresh frozen (FF) tissue specimens of GBM are difficult to obtain since tumor tissue obtained at surgery is often scarce and necrotic and diagnosis is prioritized over freezing. After diagnosis, leftover tissue is usually stored as formalin-fixed paraffin-embedded (FFPE) tissue. However, RNA from FFPE tissues is usually degraded, which could hamper gene expression analysis. We compared RNA-Seq data obtained from matched pairs of FF and FFPE GBM specimens. Only three FFPE out of eleven FFPE-FF matched samples yielded informative results. Several quality-control measurements showed that RNA from FFPE samples was highly degraded but maintained transcriptomic similarities to RNA from FF samples. Certain issues regarding mutation analysis and subtype prediction were detected. Nevertheless, our results suggest that RNA-Seq of FFPE GBM specimens provides reliable gene expression data that can be used in molecular studies of GBM if the RNA is sufficiently preserved. PMID:28122052

The Synergy between the LAT and GBM in GLAST's Study of Gamma-Ray Bursts

NASA Technical Reports Server (NTRS)

Band, David L.

2007-01-01

Using semi-analytic calculations I characterize the gamma-ray bursts to which GLAST's LAT and GBM detectors will be sensitive. The thresholds of both instruments are at approximately the same vfv proportional to E(sup 2)N(E) values, i.e., the thresholds can be connected by an E(sup -2) spectrum. Therefore simultaneous detections by both instruments will be biased towards spectral components flatter than E(sup -2).

Targeted Proteomics to Assess the Response to Anti-Angiogenic Treatment in Human Glioblastoma (GBM).

PubMed

Demeure, Kevin; Fack, Fred; Duriez, Elodie; Tiemann, Katja; Bernard, Amandine; Golebiewska, Anna; Bougnaud, Sébastien; Bjerkvig, Rolf; Domon, Bruno; Niclou, Simone P

2016-02-01

Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future analysis in clinical GBM samples. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Targeted Proteomics to Assess the Response to Anti-Angiogenic Treatment in Human Glioblastoma (GBM)*

PubMed Central

Demeure, Kevin; Fack, Fred; Duriez, Elodie; Tiemann, Katja; Bernard, Amandine; Golebiewska, Anna; Bougnaud, Sébastien; Bjerkvig, Rolf; Domon, Bruno; Niclou, Simone P.

2016-01-01

Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future analysis in clinical GBM samples. PMID:26243272

CABOZANTINIB IS EFFECTIVE IN A SUBSET OF XENOGRAFT GBM TUMORS AND AFFECTS MULTIPLE SIGNALING PATHWAYS

PubMed Central

Mikkelsen, Tom; deCarvalho, Ana C.; Arnold, Kimberly; Mueller, Claudius; Petricoin, Emanuel F; Poisson, Laila M.; Irtenkauf, Susan; Hasselbach, Laura

2014-01-01

BACKGROUND: (blind field). METHODS: Neurospheres enriched in CSCs were cultured from resected GBM tumors. Sensitivity to cabozantinib was determined in vitro. Cells were treated (IC40) in triplicate, and cell lysates were analyzed by reverse phase protein microarrays (RPPAs). GBM CSCs were implanted intracranially into nude mice. Cabozantinib was administered by oral gavage at a dose of 60 mg/kg for 4 weeks (5 days/week) as a single agent or in combination with 40 mg/kg TMZ. Tumor growth and response to treatment were monitored by non-invasive in vivo bioluminescence imaging (BLI) using the Xenogen IVIS System (Caliper Life Sciences), and overall survival. RESULTS: Sensitivity to cabozantinib treatment varied for the different GBM CSCs. From 70 proteins and phosphoproteins measured, 29 distributed among several signaling pathways were significantly altered after treatment in both resistant and sensitive GBM CSCs, including Met, Ret, AKT, MAPK/ERK. Cabozantinib single agent treatment reduced GBM tumor growth and increased mouse survival in two xenograft lines. Cabozantinib monotherapy reduced tumor size, as measured by BLI, but had no significant effect on overall survival for another xenograft line, however, the combination treatment resulted in sensitization of these xenografts to TMZ treatment. RPPA confirmed downregulation of the described targets for XL184, including activated Met, VEGFR2 and Ret (in vitro). CONCLUSIONS: Consistent with the clinical experience, both sensitive and resistant GBMs are represented in our CSC xenografts. More extensive evaluation will likely identify baseline biomarkers which might be valuable in identifying potentially sensitive sub-populations for subsequent clinical trials. RPPA and next-gen sequencing (NGS) on terminal tumors is underway. SECONDARY CATEGORY: Tumor Biology.

Human herpesvirus multiplex ddPCR detection in brain tissue from low- and high-grade astrocytoma cases and controls.

PubMed

Lin, Cheng-Te Major; Leibovitch, Emily C; Almira-Suarez, M Isabel; Jacobson, Steven

2016-01-01

Glioblastoma (GBM) is a fatal CNS malignancy, representing 50 % of all gliomas with approximately 12-18 months survival time after initial diagnosis. Recently, the human herpesvirus cytomegalovirus (CMV) has been suggested to have an oncogenic role, yet this association remains controversial. In addition, human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have also been associated with low-grade gliomas, but few studies have examined HHV-6 and EBV in glioblastomas. Droplet digital PCR (ddPCR) is a highly precise diagnostic tool that enables the absolute quantification of target DNA. This study examines the association between multiple human herpesviruses and astrocytomas. This study analyzed 112 brain tissue specimens, including 45 glioblastoma, 12 astrocytoma grade III, 2 astrocytoma grade II, 4 astrocytoma grade I, and 49 controls. All brain tissue samples were de-identified and pathologically confirmed. Each tissue block was sectioned for DNA extraction and CMV, EBV, HHV-6A and HHV-6B, and a cellular housekeeping gene were amplified by ddPCR. Neither CMV nor HHV-6A were detected in any of the astrocytoma samples. However, HHV-6B (p = 0.147) and EBV (p = 0.049) had a higher positivity frequency in the GBM compared to the controls. The undetectable CMV DNA in the astrocytoma cohort does not support the observation of an increased prevalence of CMV DNA in GBM, as reported in other studies. EBV has a significantly higher positivity in the GBM cohort compared to the controls, while HHV-6B has a higher but not statistically significant positivity in the case cohort. Whether these viruses play an oncogenic role in GBM remains to be further investigated.

Modulation of interferon-induced genes by lipoxin analogue in anti-glomerular basement membrane nephritis.

PubMed

Ohse, Takamoto; Ota, Tatsuru; Kieran, Niamh; Godson, Catherine; Yamada, Koei; Tanaka, Tetsuhiro; Fujita, Toshiro; Nangaku, Masaomi

2004-04-01

Immune complex deposition is associated with the accumulation of neutrophils, which play an important role in the various immune-mediated diseases. A novel anti-inflammatory agent, the lipoxin A (LXA) analogue (15-epi-16-(FPhO)-LXA-Me)), a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A4 (ATLa), was used in experimental anti-glomerular basement membrane (GBM) antibody nephritis in mice. ATLa was administered before the induction of the disease, and 2 h later, the animals were killed. ATLa reduced the infiltrating neutrophils and nitrotyrosine staining in glomeruli. Subsequent changes of gene expression in the early phase were evaluated, and 5674 genes were present under the basal conditions in kidneys from normal mice; 54 upregulated genes and 25 downregulated genes were detected in anti-GBM nephritis. Eighteen of these upregulated genes were those induced by IFN-gamma. Real-time quantitative PCR analysis confirmed the results of the microarrays. To investigate a role of IFN-gamma in neutrophil infiltration, anti-GBM nephritis was induced in IFN-gamma knockout mice. The number of infiltrating neutrophils in these mice did not differ from those in wild-type mice. Also examined were CD11b expression on neutrophils from mice treated with ATLa by flow cytometry, but suppression of this adhesion molecule was not observed. Neutrophil infiltration was successfully inhibited by ATLa in the early phase of murine anti-GBM nephritis. Microarray analysis detected the change of mRNA expression in anti-GBM nephritis and demonstrated amelioration of various genes by ATLa, which may provide a clue to the development of novel therapeutic approaches in immune renal injury.

Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM.

PubMed

Ge, Haitao; Mu, Luyan; Jin, Linchun; Yang, Changlin; Chang, Yifan Emily; Long, Yu; DeLeon, Gabriel; Deleyrolle, Loic; Mitchell, Duane A; Kubilis, Paul S; Lu, Dunyue; Qi, Jiping; Gu, Yunhe; Lin, Zhiguo; Huang, Jianping

2017-10-01

Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM. © 2017 UICC.

Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor.

PubMed

Autry, Adam; Phillips, Joanna J; Maleschlijski, Stojan; Roy, Ritu; Molinaro, Annette M; Chang, Susan M; Cha, Soonmee; Lupo, Janine M; Nelson, Sarah J

2017-12-01

Although the contrast-enhancing (CE) lesion on T 1 -weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T 2 -weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden. Fifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy. The Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data. The similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Asiatic acid induces endoplasmic reticulum stress and apoptotic death in glioblastoma multiforme cells both in vitro and in vivo

PubMed Central

Kavitha, Chandagirikoppal V.; Jain, Anil K.; Agarwal, Chapla; Pierce, Angela; Keating, Amy; Huber, Kendra M.; Serkova, Natalie J.; Wempe, Michael F.; Agarwal, Rajesh; Deep, Gagan

2014-01-01

Glioblastoma multiforme (GBM) is an untreatable malignancy. Existing therapeutic options are insufficient, and adversely affect functional and non-cancerous cells in the brain impairing different functions of the body. Therefore, there is an urgent need for additional preventive and therapeutic non-toxic drugs against GBM. Asiatic acid (AsA; 2,3,23-trihydroxy-12-ursen-28-oic acid, C30H48O5) is a natural small molecule widely used to treat various neurological disorders, and the present research investigates AsA’s efficacy against GBM both in vitro and in vivo. Results showed that AsA treatment (10–100 μM) decreased the human GBM cell (LN18, U87MG, and U118MG) viability, with better efficacy than temozolomide at equimolar doses. Orally administered AsA (30 mg/kg/day) strongly decreased tumor volume in mice when administered immediately after ectopic U87MG xenograft implantation (54% decrease, p≤0.05) or in mice with established xenografts (48% decrease, p≤0.05) without any apparent toxicity. Importantly, AsA feeding (30 mg/kg/twice a day) also decreased the orthotopic U87MG xenografts growth in nude mice as measured by magnetic resonance imaging. Using LC/MS-MS methods, AsA was detected in mice plasma and brain tissue, confirming that AsA crosses blood-brain barrier. Mechanistic studies showed that AsA induces apoptotic death by modulating the protein expression of several apoptosis regulators (caspases, Bcl2 family members, and survivin) in GBM cells. Furthermore, AsA induced ER stress (increased GRP78 and Calpain, and decreased Calnexin and IRE1α expression), enhanced free intra-cellular calcium, and damaged cellular organization in GBM cells. These experimental results demonstrate that AsA is effective against GBM, and advocate further pre-clinical and clinical evaluations of AsA against GBM. PMID:25252179

A comprehensive characterization of mitochondrial DNA mutations in glioblastoma multiforme.

PubMed

Vidone, Michele; Clima, Rosanna; Santorsola, Mariangela; Calabrese, Claudia; Girolimetti, Giulia; Kurelac, Ivana; Amato, Laura Benedetta; Iommarini, Luisa; Trevisan, Elisa; Leone, Marco; Soffietti, Riccardo; Morra, Isabella; Faccani, Giuliano; Attimonelli, Marcella; Porcelli, Anna Maria; Gasparre, Giuseppe

2015-06-01

Glioblastoma multiforme (GBM) is the most malignant brain cancer in adults, with a poor prognosis, whose molecular stratification still represents a challenge in pathology and clinics. On the other hand, mitochondrial DNA (mtDNA) mutations have been found in most tumors as modifiers of the bioenergetics state, albeit in GBM a characterization of the mtDNA status is lacking to date. Here, a characterization of the burden of mtDNA mutations in GBM samples was performed. First, investigation of tumor-specific vs. non tumor-specific mutations was carried out with the MToolBox bioinformatics pipeline by analyzing 45 matched tumor/blood samples, from whole genome or whole exome sequencing datasets obtained from The Cancer Genome Atlas (TCGA) consortium. Additionally, the entire mtDNA sequence was obtained in a dataset of 104 fresh-frozen GBM samples. Mitochondrial mutations with potential pathogenic interest were prioritized based on heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. A preliminary biochemical analysis of the activity of mitochondrial respiratory complexes was also performed on fresh-frozen GBM samples. Although a high number of mutations was detected, we report that the large majority of them does not pass the prioritization filters. Therefore, a relatively limited burden of pathogenic mutations is indeed carried by GBM, which did not appear to determine a general impairment of the respiratory chain. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Clinical and Immunologic Features of Patients With Combined Anti-GBM Disease and Castleman Disease.

PubMed

Gu, Qiu-Hua; Jia, Xiao-Yu; Hu, Shui-Yi; Wang, Su-Xia; Zou, Wan-Zhong; Cui, Zhao; Zhao, Ming-Hui

2018-06-01

Patients with both anti-glomerular basement membrane (anti-GBM) disease and Castleman disease have been rarely reported. In this study, we report 3 patients with this combination. They had immunologic features similar to patients with classic anti-GBM disease. Sera from the 3 patients recognized the noncollagenous (NC) domain of the α3 chain of type IV collagen (α3(IV)NC1) and its 2 major epitopes, EA and EB. All 4 immunogloblin G (IgG) subclasses against α3(IV)NC1 were detectable, with predominance of IgG1. In one patient with lymph node biopsy specimens available, sporadic plasma cells producing α3(IV)NC1-IgG were found, suggesting a causal relationship between the 2 diseases. One patient, who achieved remission with antibody clearance and normalization of serum creatinine and interleukin 6 concentrations after plasma exchange and 3 cycles of chemotherapy, experienced recurrence of anti-GBM antibodies and an increase in interleukin 6 concentration after chemotherapy discontinuation because of adverse effects, but both returned to normal after another cycle of chemotherapy. This clinical course and the pathologic findings support the hypothesis that the Castleman disease-associated tumor cells are the source of the anti-GBM autoantibodies. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

The First Fermi-GBM Terrestrial Gamma Ray Flash Catalog

NASA Astrophysics Data System (ADS)

Roberts, O. J.; Fitzpatrick, G.; Stanbro, M.; McBreen, S.; Briggs, M. S.; Holzworth, R. H.; Grove, J. E.; Chekhtman, A.; Cramer, E. S.; Mailyan, B. G.

2018-05-01

We present the first Fermi Space Telescope Gamma Ray Burst Monitor (GBM) catalog of 4,144 terrestrial gamma ray flashes (TGFs), detected since launch in 11 July 2008 through 31 July 2016. We discuss the updates and improvements to the triggered data and off-line search algorithms, comparing this improved detection rate of ˜800 TGFs per year with event rates from previously published TGF catalogs from other missions. A Bayesian block algorithm calculated the temporal and spectral properties of the TGFs, revealing a delay between the hard (>300 keV) and soft (≤300 keV) photons of around 27 μs. Detector count rates of "low-fluence" events were found to have average rates exceeding 150 kHz. Searching the World-Wide Lightning Location Network data for radio sferics within ±5 min of each TGF revealed a clean sample of 1,314 World-Wide Lightning Location Network locations, which were used to to accurately locate TGF-producing storms. It also revealed lightning and storm activity for specific regions, as well as seasonal and daily variations of global lightning patterns. Correcting for the orbit of Fermi, we quantitatively find a marginal excess of TGFs being produced from storms over land near oceans (i.e., narrow isthmuses and small islands). No difference was observed between the duration of TGFs over the ocean and land. The distribution of TGFs at a given local solar time for predefined American, Asian, and African regions were confirmed to correlate well with known regional lightning rates.

Testing the Isotropic Universe Using the Gamma-Ray Burst Data of Fermi/GBM

NASA Astrophysics Data System (ADS)

Řípa, Jakub; Shafieloo, Arman

2017-12-01

The sky distribution of gamma-ray bursts (GRBs) has been intensively studied by various groups for more than two decades. Most of these studies test the isotropy of GRBs based on their sky number density distribution. In this work, we propose an approach to test the isotropy of the universe through inspecting the isotropy of the properties of GRBs such as their duration, fluences, and peak fluxes at various energy bands and different timescales. We apply this method on the Fermi/Gamma-ray Burst Monitor (GBM) data sample containing 1591 GRBs. The most noticeable feature we found is near the Galactic coordinates l≈ 30^\\circ , b≈ 15^\\circ , and radius r≈ 20^\\circ {--}40^\\circ . The inferred probability for the occurrence of such an anisotropic signal (in a random isotropic sample) is derived to be less than a percent in some of the tests while the other tests give results consistent with isotropy. These are based on the comparison of the results from the real data with the randomly shuffled data samples. Considering the large number of statistics we used in this work (some of which are correlated with each other), we can anticipate that the detected feature could be a result of statistical fluctuations. Moreover, we noticed a considerably low number of GRBs in this particular patch, which might be due to some instrumentation or observational effects that can consequently affect our statistics through some systematics. Further investigation is highly desirable in order to clarify this result, e.g., utilizing a larger future Fermi/GBM data sample as well as data samples of other GRB missions and also looking for possible systematics.

PDGFRα depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals.

PubMed

Cenciarelli, Carlo; Marei, Hany E; Felsani, Armando; Casalbore, Patrizia; Sica, Gigliola; Puglisi, Maria Ausiliatrice; Cameron, Angus J M; Olivi, Alessandro; Mangiola, Annunziato

2016-08-16

Platelet derived growth factor receptors (PDGFRs) play an important role in tumor pathogenesis, and they are frequently overexpressed in glioblastoma (GBM). Earlier we have shown a higher protein expression of PDGFR isoforms (α and β) in peritumoral-tissue derived cancer stem cells (p-CSC) than in tumor core (c-CSC) of several GBM affected patients. In the current study, in order to assess the activity of PDGFRα/PDGF-AA signaling axis, we performed time course experiments to monitor the effects of exogenous PDGF-AA on the expression of downstream target genes in c-CSC vs p-CSC. Interestingly, in p-CSC we detected the upregulation of Y705-phosphorylated Stat3, concurrent with a decrement of Rb1 protein in its active state, within minutes of PDGF-AA addition. This finding prompted us to elucidate the role of PDGFRα in self-renewal, invasion and differentiation in p-CSC by using short hairpin RNA depletion of PDGFRα expression. Notably, in PDGFRα-depleted cells, protein analysis revealed attenuation of stemness-related and glial markers expression, alongside early activation of the neuronal marker MAP2a/b that correlated with the induction of tumor suppressor Rb1. The in vitro reduction of the invasive capacity of PDGFRα-depleted CSC as compared to parental cells correlated with the downmodulation of markers of epithelial-mesenchymal transition phenotype and angiogenesis. Surprisingly, we observed the induction of anti-apoptotic proteins and compensatory oncogenic signals such as EDN1, EDNRB, PRKCB1, PDGF-C and PDGF-D. To conclude, we hypothesize that the newly discovered PDGFRα/Stat3/Rb1 regulatory axis might represent a potential therapeutic target for GBM treatment.

Methods and results of a search for gravitational waves associated with gamma-ray bursts using the GEO 600, LIGO, and Virgo detectors

NASA Astrophysics Data System (ADS)

Aasi, J.; Abbott, B. P.; Abbott, R.; Abbott, T.; Abernathy, M. R.; Acernese, F.; Ackley, K.; Adams, C.; Adams, T.; Addesso, P.; Adhikari, R. X.; Affeldt, C.; Agathos, M.; Aggarwal, N.; Aguiar, O. D.; Ajith, P.; Alemic, A.; Allen, B.; Allocca, A.; Amariutei, D.; Andersen, M.; Anderson, R. A.; Anderson, S. B.; Anderson, W. G.; Arai, K.; Araya, M. C.; Arceneaux, C.; Areeda, J. S.; Ast, S.; Aston, S. M.; Astone, P.; Aufmuth, P.; Augustus, H.; Aulbert, C.; Aylott, B. E.; Babak, S.; Baker, P. T.; Ballardin, G.; Ballmer, S. W.; Barayoga, J. C.; Barbet, M.; Barish, B. C.; Barker, D.; Barone, F.; Barr, B.; Barsotti, L.; Barsuglia, M.; Barton, M. A.; Bartos, I.; Bassiri, R.; Basti, A.; Batch, J. C.; Bauchrowitz, J.; Bauer, Th. S.; Baune, C.; Bavigadda, V.; Behnke, B.; Bejger, M.; Beker, M. G.; Belczynski, C.; Bell, A. S.; Bell, C.; Bergmann, G.; Bersanetti, D.; Bertolini, A.; Betzwieser, J.; Bilenko, I. A.; Billingsley, G.; Birch, J.; Biscans, S.; Bitossi, M.; Biwer, C.; Bizouard, M. A.; Black, E.; Blackburn, J. K.; Blackburn, L.; Blair, D.; Bloemen, S.; Bock, O.; Bodiya, T. P.; Boer, M.; Bogaert, G.; Bogan, C.; Bond, C.; Bondu, F.; Bonelli, L.; Bonnand, R.; Bork, R.; Born, M.; Boschi, V.; Bose, Sukanta; Bosi, L.; Bradaschia, C.; Brady, P. R.; Braginsky, V. B.; Branchesi, M.; Brau, J. E.; Briant, T.; Bridges, D. O.; Brillet, A.; Brinkmann, M.; Brisson, V.; Brooks, A. F.; Brown, D. A.; Brown, D. D.; Brückner, F.; Buchman, S.; Buikema, A.; Bulik, T.; Bulten, H. J.; Buonanno, A.; Burman, R.; Buskulic, D.; Buy, C.; Cadonati, L.; Cagnoli, G.; Cain, J.; Calderón Bustillo, J.; Calloni, E.; Camp, J. B.; Campsie, P.; Cannon, K. C.; Canuel, B.; Cao, J.; Capano, C. D.; Carbognani, F.; Carbone, L.; Caride, S.; Castaldi, G.; Caudill, S.; Cavaglià, M.; Cavalier, F.; Cavalieri, R.; Celerier, C.; Cella, G.; Cepeda, C.; Cesarini, E.; Chakraborty, R.; Chalermsongsak, T.; Chamberlin, S. J.; Chao, S.; Charlton, P.; Chassande-Mottin, E.; Chen, X.; Chen, Y.; Chincarini, A.; Chiummo, A.; Cho, H. S.; Cho, M.; Chow, J. H.; Christensen, N.; Chu, Q.; Chua, S. S. Y.; Chung, S.; Ciani, G.; Clara, F.; Clark, D. E.; Clark, J. A.; Clayton, J. H.; Cleva, F.; Coccia, E.; Cohadon, P.-F.; Colla, A.; Collette, C.; Colombini, M.; Cominsky, L.; Constancio, M.; Conte, A.; Cook, D.; Corbitt, T. R.; Cornish, N.; Corsi, A.; Costa, C. A.; Coughlin, M. W.; Coulon, J.-P.; Countryman, S.; Couvares, P.; Coward, D. M.; Cowart, M. J.; Coyne, D. C.; Coyne, R.; Craig, K.; Creighton, J. D. E.; Croce, R. P.; Crowder, S. G.; Cumming, A.; Cunningham, L.; Cuoco, E.; Cutler, C.; Dahl, K.; Dal Canton, T.; Damjanic, M.; Danilishin, S. L.; D'Antonio, S.; Danzmann, K.; Dattilo, V.; Daveloza, H.; Davier, M.; Davies, G. S.; Daw, E. J.; Day, R.; Dayanga, T.; DeBra, D.; Debreczeni, G.; Degallaix, J.; Deléglise, S.; Del Pozzo, W.; Del Pozzo, W.; Denker, T.; Dent, T.; Dereli, H.; Dergachev, V.; De Rosa, R.; DeRosa, R. T.; DeSalvo, R.; Dhurandhar, S.; Díaz, M.; Dickson, J.; Di Fiore, L.; Di Lieto, A.; Di Palma, I.; Di Virgilio, A.; Dolique, V.; Dominguez, E.; Donovan, F.; Dooley, K. L.; Doravari, S.; Douglas, R.; Downes, T. P.; Drago, M.; Drever, R. W. P.; Driggers, J. C.; Du, Z.; Ducrot, M.; Dwyer, S.; Eberle, T.; Edo, T.; Edwards, M.; Effler, A.; Eggenstein, H.-B.; Ehrens, P.; Eichholz, J.; Eikenberry, S. S.; Endrőczi, G.; Essick, R.; Etzel, T.; Evans, M.; Evans, T.; Factourovich, M.; Fafone, V.; Fairhurst, S.; Fan, X.; Fang, Q.; Farinon, S.; Farr, B.; Farr, W. M.; Favata, M.; Fazi, D.; Fehrmann, H.; Fejer, M. M.; Feldbaum, D.; Feroz, F.; Ferrante, I.; Ferreira, E. C.; Ferrini, F.; Fidecaro, F.; Finn, L. S.; Fiori, I.; Fisher, R. P.; Flaminio, R.; Fotopoulos, N.; Fournier, J.-D.; Franco, S.; Frasca, S.; Frasconi, F.; Frede, M.; Frei, Z.; Freise, A.; Frey, R.; Fricke, T. T.; Fritschel, P.; Frolov, V. V.; Fulda, P.; Fyffe, M.; Gair, J. R.; Gammaitoni, L.; Gaonkar, S.; Garufi, F.; Gehrels, N.; Gemme, G.; Gendre, B.; Genin, E.; Gennai, A.; Ghosh, S.; Giaime, J. A.; Giardina, K. D.; Giazotto, A.; Gill, C.; Gleason, J.; Goetz, E.; Goetz, R.; Gondan, L.; González, G.; Gordon, N.; Gorodetsky, M. L.; Gossan, S.; Goßler, S.; Gouaty, R.; Gräf, C.; Graff, P. B.; Granata, M.; Grant, A.; Gras, S.; Gray, C.; Greenhalgh, R. J. S.; Gretarsson, A. M.; Groot, P.; Grote, H.; Grover, K.; Grunewald, S.; Guidi, G. M.; Guido, C. J.; Gushwa, K.; Gustafson, E. K.; Gustafson, R.; Ha, J.; Hall, E. D.; Hamilton, W.; Hammer, D.; Hammond, G.; Hanke, M.; Hanks, J.; Hanna, C.; Hannam, M. D.; Hanson, J.; Haris, K.; Harms, J.; Harry, G. M.; Harry, I. W.; Harstad, E. D.; Hart, M.; Hartman, M. T.; Haster, C.-J.; Haughian, K.; Heidmann, A.; Heintze, M.; Heitmann, H.; Hello, P.; Hemming, G.; Hendry, M.; Heng, I. S.; Heptonstall, A. W.; Heurs, M.; Hewitson, M.; Hild, S.; Hoak, D.; Hodge, K. A.; Hofman, D.; Holt, K.; Hopkins, P.; Horrom, T.; Hoske, D.; Hosken, D. J.; Hough, J.; Howell, E. J.; Hu, Y.; Huerta, E.; Hughey, B.; Husa, S.; Huttner, S. H.; Huynh, M.; Huynh-Dinh, T.; Idrisy, A.; Ingram, D. R.; Inta, R.; Islas, G.; Isogai, T.; Ivanov, A.; Iyer, B. R.; Izumi, K.; Jacobson, M.; Jang, H.; Jaranowski, P.; Ji, Y.; Jiménez-Forteza, F.; Johnson, W. W.; Jones, D. I.; Jones, G.; Jones, R.; Jonker, R. J. G.; Ju, L.; Kalmus, P.; Kalogera, V.; Kandhasamy, S.; Kang, G.; Kanner, J. B.; Karlen, J.; Kasprzack, M.; Katsavounidis, E.; Katzman, W.; Kaufer, H.; Kaufer, S.; Kaur, T.; Kawabe, K.; Kawazoe, F.; Kéfélian, F.; Keiser, G. M.; Keitel, D.; Kelley, D. B.; Kells, W.; Keppel, D. G.; Khalaidovski, A.; Khalili, F. Y.; Khazanov, E. A.; Kim, C.; Kim, K.; Kim, N. G.; Kim, N.; Kim, S.; Kim, Y.-M.; King, E. J.; King, P. J.; Kinzel, D. L.; Kissel, J. S.; Klimenko, S.; Kline, J.; Koehlenbeck, S.; Kokeyama, K.; Kondrashov, V.; Koranda, S.; Korth, W. Z.; Kowalska, I.; Kozak, D. B.; Kringel, V.; Krishnan, B.; Królak, A.; Kuehn, G.; Kumar, A.; Kumar, D. Nanda; Kumar, P.; Kumar, R.; Kuo, L.; Kutynia, A.; Lam, P. K.; Landry, M.; Lantz, B.; Larson, S.; Lasky, P. D.; Lazzaro, C.; Leaci, P.; Leavey, S.; Lebigot, E. O.; Lee, C. H.; Lee, H. K.; Lee, H. M.; Lee, J.; Lee, P. J.; Leonardi, M.; Leong, J. R.; Le Roux, A.; Leroy, N.; Letendre, N.; Levin, Y.; Levine, B.; Lewis, J.; Li, T. G. F.; Libbrecht, K.; Libson, A.; Lin, A. C.; Littenberg, T. B.; Lockerbie, N. A.; Lockett, V.; Lodhia, D.; Loew, K.; Logue, J.; Lombardi, A. L.; Lopez, E.; Lorenzini, M.; Loriette, V.; Lormand, M.; Losurdo, G.; Lough, J.; Lubinski, M. J.; Lück, H.; Lundgren, A. P.; Ma, Y.; Macdonald, E. P.; MacDonald, T.; Machenschalk, B.; MacInnis, M.; Macleod, D. M.; Magaña-Sandoval, F.; Magee, R.; Mageswaran, M.; Maglione, C.; Mailand, K.; Majorana, E.; Maksimovic, I.; Malvezzi, V.; Man, N.; Manca, G. M.; Mandel, I.; Mandic, V.; Mangano, V.; Mangini, N. M.; Mansell, G.; Mantovani, M.; Marchesoni, F.; Marion, F.; Márka, S.; Márka, Z.; Markosyan, A.; Maros, E.; Marque, J.; Martelli, F.; Martin, I. W.; Martin, R. M.; Martinelli, L.; Martynov, D.; Marx, J. N.; Mason, K.; Masserot, A.; Massinger, T. J.; Matichard, F.; Matone, L.; Mavalvala, N.; May, G.; Mazumder, N.; Mazzolo, G.; McCarthy, R.; McClelland, D. E.; McGuire, S. C.; McIntyre, G.; McIver, J.; McLin, K.; Meacher, D.; Meadors, G. D.; Mehmet, M.; Meidam, J.; Meinders, M.; Melatos, A.; Mendell, G.; Mercer, R. A.; Meshkov, S.; Messenger, C.; Meyer, A.; Meyer, M. S.; Meyers, P. M.; Mezzani, F.; Miao, H.; Michel, C.; Mikhailov, E. E.; Milano, L.; Miller, J.; Minenkov, Y.; Mingarelli, C. M. F.; Mishra, C.; Mitra, S.; Mitrofanov, V. P.; Mitselmakher, G.; Mittleman, R.; Moe, B.; Moggi, A.; Mohan, M.; Mohapatra, S. R. P.; Moraru, D.; Moreno, G.; Morgado, N.; Morriss, S. R.; Mossavi, K.; Mours, B.; Mow-Lowry, C. M.; Mueller, C. L.; Mueller, G.; Mukherjee, S.; Mullavey, A.; Munch, J.; Murphy, D.; Murray, P. G.; Mytidis, A.; Nagy, M. F.; Nardecchia, I.; Naticchioni, L.; Nayak, R. K.; Necula, V.; Nelemans, G.; Neri, I.; Neri, M.; Newton, G.; Nguyen, T.; Nielsen, A. B.; Nissanke, S.; Nitz, A. H.; Nocera, F.; Nolting, D.; Normandin, M. E. N.; Nuttall, L. K.; Ochsner, E.; O'Dell, J.; Oelker, E.; Oh, J. J.; Oh, S. H.; Ohme, F.; Omar, S.; Oppermann, P.; Oram, R.; O'Reilly, B.; Ortega, W.; O'Shaughnessy, R.; Osthelder, C.; Ottaway, D. J.; Ottens, R. S.; Overmier, H.; Owen, B. J.; Padilla, C.; Pai, A.; Palashov, O.; Palomba, C.; Pan, H.; Pan, Y.; Pankow, C.; Paoletti, F.; Papa, M. A.; Paris, H.; Pasqualetti, A.; Passaquieti, R.; Passuello, D.; Patel, P.; Pedraza, M.; Pele, A.; Penn, S.; Perreca, A.; Phelps, M.; Pichot, M.; Pickenpack, M.; Piergiovanni, F.; Pierro, V.; Pinard, L.; Pinto, I. M.; Pitkin, M.; Poeld, J.; Poggiani, R.; Poteomkin, A.; Powell, J.; Prasad, J.; Predoi, V.; Premachandra, S.; Prestegard, T.; Price, L. R.; Prijatelj, M.; Privitera, S.; Prodi, G. A.; Prokhorov, L.; Puncken, O.; Punturo, M.; Puppo, P.; Pürrer, M.; Qin, J.; Quetschke, V.; Quintero, E.; Quitzow-James, R.; Raab, F. J.; Rabeling, D. S.; Rácz, I.; Radkins, H.; Raffai, P.; Raja, S.; Rajalakshmi, G.; Rakhmanov, M.; Ramet, C.; Ramirez, K.; Rapagnani, P.; Raymond, V.; Razzano, M.; Re, V.; Recchia, S.; Reed, C. M.; Regimbau, T.; Reid, S.; Reitze, D. H.; Reula, O.; Rhoades, E.; Ricci, F.; Riesen, R.; Riles, K.; Robertson, N. A.; Robinet, F.; Rocchi, A.; Roddy, S. B.; Rogstad, S.; Rolland, L.; Rollins, J. G.; Romano, R.; Romanov, G.; Romie, J. H.; Rosińska, D.; Rowan, S.; Rüdiger, A.; Ruggi, P.; Ryan, K.; Salemi, F.; Sammut, L.; Sandberg, V.; Sanders, J. R.; Sankar, S.; Sannibale, V.; Santiago-Prieto, I.; Saracco, E.; Sassolas, B.; Sathyaprakash, B. S.; Saulson, P. R.; Savage, R.; Scheuer, J.; Schilling, R.; Schilman, M.; Schmidt, P.; Schnabel, R.; Schofield, R. M. S.; Schreiber, E.; Schuette, D.; Schutz, B. F.; Scott, J.; Scott, S. M.; Sellers, D.; Sengupta, A. S.; Sentenac, D.; Sequino, V.; Sergeev, A.; Shaddock, D. A.; Shah, S.; Shahriar, M. S.; Shaltev, M.; Shao, Z.; Shapiro, B.; Shawhan, P.; Shoemaker, D. H.; Sidery, T. L.; Siellez, K.; Siemens, X.; Sigg, D.; Simakov, D.; Singer, A.; Singer, L.; Singh, R.; Sintes, A. M.; Slagmolen, B. J. J.; Slutsky, J.; Smith, J. R.; Smith, M. R.; Smith, R. J. E.; Smith-Lefebvre, N. D.; Son, E. J.; Sorazu, B.; Souradeep, T.; Staley, A.; Stebbins, J.; Steinke, M.; Steinlechner, J.; Steinlechner, S.; Stephens, B. C.; Steplewski, S.; Stevenson, S.; Stone, R.; Stops, D.; Strain, K. A.; Straniero, N.; Strigin, S.; Sturani, R.; Stuver, A. L.; Summerscales, T. Z.; Susmithan, S.; Sutton, P. J.; Swinkels, B.; Tacca, M.; Talukder, D.; Tanner, D. B.; Tao, J.; Tarabrin, S. P.; Taylor, R.; Tellez, G.; Thirugnanasambandam, M. P.; Thomas, M.; Thomas, P.; Thorne, K. A.; Thorne, K. S.; Thrane, E.; Tiwari, V.; Tokmakov, K. V.; Tomlinson, C.; Tonelli, M.; Torres, C. V.; Torrie, C. I.; Travasso, F.; Traylor, G.; Trias, M.; Tse, M.; Tshilumba, D.; Tuennermann, H.; Ugolini, D.; Unnikrishnan, C. S.; Urban, A. L.; Usman, S. A.; Vahlbruch, H.; Vajente, G.; Valdes, G.; Vallisneri, M.; van Beuzekom, M.; van den Brand, J. F. J.; Van Den Broeck, C.; van der Sluys, M. V.; van Heijningen, J.; van Veggel, A. A.; Vass, S.; Vasúth, M.; Vaulin, R.; Vecchio, A.; Vedovato, G.; Veitch, J.; Veitch, P. J.; Venkateswara, K.; Verkindt, D.; Vetrano, F.; Viceré, A.; Vincent-Finley, R.; Vinet, J.-Y.; Vitale, S.; Vo, T.; Vocca, H.; Vorvick, C.; Vousden, W. D.; Vyachanin, S. P.; Wade, A. R.; Wade, L.; Wade, M.; Walker, M.; Wallace, L.; Walsh, S.; Wang, M.; Wang, X.; Ward, R. L.; Was, M.; Weaver, B.; Wei, L.-W.; Weinert, M.; Weinstein, A. J.; Weiss, R.; Welborn, T.; Wen, L.; Wessels, P.; West, M.; Westphal, T.; Wette, K.; Whelan, J. T.; White, D. J.; Whiting, B. F.; Wiesner, K.; Wilkinson, C.; Williams, K.; Williams, L.; Williams, R.; Williams, T. D.; Williamson, A. R.; Willis, J. L.; Willke, B.; Wimmer, M.; Winkler, W.; Wipf, C. C.; Wiseman, A. G.; Wittel, H.; Woan, G.; Wolovick, N.; Worden, J.; Wu, Y.; Yablon, J.; Yakushin, I.; Yam, W.; Yamamoto, H.; Yancey, C. C.; Yang, H.; Yoshida, S.; Yvert, M.; ZadroŻny, A.; Zanolin, M.; Zendri, J.-P.; Zhang, Fan; Zhang, L.; Zhao, C.; Zhu, H.; Zhu, X. J.; Zucker, M. E.; Zuraw, S.; Zweizig, J.; LIGO Scientific Collaboration; Virgo Collaboration

2014-06-01

In this paper we report on a search for short-duration gravitational wave bursts in the frequency range 64 Hz-1792 Hz associated with gamma-ray bursts (GRBs), using data from GEO 600 and one of the LIGO or Virgo detectors. We introduce the method of a linear search grid to analyze GRB events with large sky localization uncertainties, for example the localizations provided by the Fermi Gamma-ray Burst Monitor (GBM). Coherent searches for gravitational waves (GWs) can be computationally intensive when the GRB sky position is not well localized, due to the corrections required for the difference in arrival time between detectors. Using a linear search grid we are able to reduce the computational cost of the analysis by a factor of O(10) for GBM events. Furthermore, we demonstrate that our analysis pipeline can improve upon the sky localization of GRBs detected by the GBM, if a high-frequency GW signal is observed in coincidence. We use the method of the linear grid in a search for GWs associated with 129 GRBs observed satellite-based gamma-ray experiments between 2006 and 2011. The GRBs in our sample had not been previously analyzed for GW counterparts. A fraction of our GRB events are analyzed using data from GEO 600 while the detector was using squeezed-light states to improve its sensitivity; this is the first search for GWs using data from a squeezed-light interferometric observatory. We find no evidence for GW signals, either with any individual GRB in this sample or with the population as a whole. For each GRB we place lower bounds on the distance to the progenitor, under an assumption of a fixed GW emission energy of 10-2M⊙c2, with a median exclusion distance of 0.8 Mpc for emission at 500 Hz and 0.3 Mpc at 1 kHz. The reduced computational cost associated with a linear search grid will enable rapid searches for GWs associated with Fermi GBM events once the advanced LIGO and Virgo detectors begin operation.

Methods and Results of a Search for Gravitational Waves Associated with Gamma-Ray Bursts Using the GEO 600, LIGO, and Virgo Detectors

NASA Technical Reports Server (NTRS)

Aasi, J.; Abbott, B. P.; Abbott, R.; Abbott, T.; Abernathy, M. R.; Acernese, F.; Ackley, K.; Adams, C.; Adams, T.; Blackburn, Lindy L.;

Dimethyl sulfoxide (DMSO) as a potential contrast agent for brain tumors.

PubMed

Delgado-Goñi, T; Martín-Sitjar, J; Simões, R V; Acosta, M; Lope-Piedrafita, S; Arús, C

2013-02-01

Dimethyl sulfoxide (DMSO) is commonly used in preclinical studies of animal models of high-grade glioma as a solvent for chemotherapeutic agents. A strong DMSO signal was detected by single-voxel MRS in the brain of three C57BL/6 control mice during a pilot study of DMSO tolerance after intragastric administration. This led us to investigate the accumulation and wash-out kinetics of DMSO in both normal brain parenchyma (n=3 control mice) by single-voxel MRS, and in 12 GL261 glioblastomas (GBMs) by single-voxel MRS (n=3) and MRSI (n=9). DMSO accumulated differently in each tissue type, reaching its highest concentration in tumors: 6.18 ± 0.85 µmol/g water, 1.5-fold higher than in control mouse brain (p<0.05). A faster wash-out was detected in normal brain parenchyma with respect to GBM tissue: half-lives of 2.06 ± 0.58 and 4.57 ± 1.15 h, respectively. MRSI maps of time-course DMSO changes revealed clear hotspots of differential spatial accumulation in GL261 tumors. Additional MRSI studies with four mice bearing oligodendrogliomas (ODs) revealed similar results as in GBM tumors. The lack of T(1) contrast enhancement post-gadolinium (gadopentetate dimeglumine, Gd-DTPA) in control mouse brain and mice with ODs suggested that DMSO was fully able to cross the intact blood-brain barrier in both normal brain parenchyma and in low-grade tumors. Our results indicate a potential role for DMSO as a contrast agent for brain tumor detection, even in those tumors 'invisible' to standard gadolinium-enhanced MRI, and possibly for monitoring heterogeneities associated with progression or with therapeutic response. Copyright © 2012 John Wiley & Sons, Ltd.

A practical review of prognostic correlations of molecular biomarkers in glioblastoma.

PubMed

Karsy, Michael; Neil, Jayson A; Guan, Jian; Mahan, Mark A; Mark, Mahan A; Colman, Howard; Jensen, Randy L

2015-03-01

Despite extensive efforts in research and therapeutics, achieving longer survival for patients with glioblastoma (GBM) remains a formidable challenge. Furthermore, because of rapid advances in the scientific understanding of GBM, communication with patients regarding the explanations and implications of genetic and molecular markers can be difficult. Understanding the important biomarkers that play a role in GBM pathogenesis may also help clinicians in educating patients about prognosis, potential clinical trials, and monitoring response to treatments. This article aims to provide an up-to-date review that can be discussed with patients regarding common molecular markers, namely O-6-methylguanine-DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q. The importance of the distinction between a prognostic and a predictive biomarker as well as clinical trials regarding these markers and their relevance to clinical practice are discussed.

The impact of hyperglycemia on survival in glioblastoma: A systematic review and meta-analysis.

PubMed

Lu, Victor M; Goyal, Anshit; Vaughan, Lachlin S; McDonald, Kerrie L

2018-07-01

In the management of glioblastoma (GBM), there is a considerable predisposition to hyperglycemia due to significant integration of corticosteroid therapy to treat predictable clinical sequelae following diagnosis and treatment. The aim of this study was to quantify effect of hyperglycemia during the management of GBM on overall survival (OS). Searches of seven electronic databases from inception to January 2018 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 1475 articles identified for screening. Prognostic hazard ratios (HRs) derived from multivariate regression analysis were extracted, and analyzed using meta-analysis of proportions and linear regression. Six observational studies reporting prognostic HRs in 10 cohorts were included. They described 1481 GBM diagnoses, all surveyed for hyperglycemia during management. Hyperglycemia was found to confer a statistically significant poorer OS outcome (HR, 1.671; p < 0.001). This trend and its significance was not modified by study year, size or proportion of pre-diagnostic diabetes mellitus. Hyperglycemia in GBM is an independent poor prognostic factor for OS. Heterogeneity in clinical course limits inter-study comparability. Future, prospective, randomized studies will validate the findings of this study, and ascertain the potential benefit of more rigorous monitoring for hyperglycemia and glycemic control. Copyright © 2018 Elsevier B.V. All rights reserved.

Monitoring of Tumor Growth with [(18)F]-FET PET in a Mouse Model of Glioblastoma: SUV Measurements and Volumetric Approaches.

PubMed

Holzgreve, Adrien; Brendel, Matthias; Gu, Song; Carlsen, Janette; Mille, Erik; Böning, Guido; Mastrella, Giorgia; Unterrainer, Marcus; Gildehaus, Franz J; Rominger, Axel; Bartenstein, Peter; Kälin, Roland E; Glass, Rainer; Albert, Nathalie L

2016-01-01

Noninvasive tumor growth monitoring is of particular interest for the evaluation of experimental glioma therapies. This study investigates the potential of positron emission tomography (PET) using O-(2-(18)F-fluoroethyl)-L-tyrosine ([(18)F]-FET) to determine tumor growth in a murine glioblastoma (GBM) model-including estimation of the biological tumor volume (BTV), which has hitherto not been investigated in the pre-clinical context. Fifteen GBM-bearing mice (GL261) and six control mice (shams) were investigated during 5 weeks by PET followed by autoradiographic and histological assessments. [(18)F]-FET PET was quantitated by calculation of maximum and mean standardized uptake values within a universal volume-of-interest (VOI) corrected for healthy background (SUVmax/BG, SUVmean/BG). A partial volume effect correction (PVEC) was applied in comparison to ex vivo autoradiography. BTVs obtained by predefined thresholds for VOI definition (SUV/BG: ≥1.4; ≥1.6; ≥1.8; ≥2.0) were compared to the histologically assessed tumor volume (n = 8). Finally, individual "optimal" thresholds for BTV definition best reflecting the histology were determined. In GBM mice SUVmax/BG and SUVmean/BG clearly increased with time, however at high inter-animal variability. No relevant [(18)F]-FET uptake was observed in shams. PVEC recovered signal loss of SUVmean/BG assessment in relation to autoradiography. BTV as estimated by predefined thresholds strongly differed from the histology volume. Strikingly, the individual "optimal" thresholds for BTV assessment correlated highly with SUVmax/BG (ρ = 0.97, p < 0.001), allowing SUVmax/BG-based calculation of individual thresholds. The method was verified by a subsequent validation study (n = 15, ρ = 0.88, p < 0.01) leading to extensively higher agreement of BTV estimations when compared to histology in contrast to predefined thresholds. [(18)F]-FET PET with standard SUV measurements is feasible for glioma imaging in the GBM mouse model. PVEC is beneficial to improve accuracy of [(18)F]-FET PET SUV quantification. Although SUVmax/BG and SUVmean/BG increase during the disease course, these parameters do not correlate with the respective tumor size. For the first time, we propose a histology-verified method allowing appropriate individual BTV estimation for volumetric in vivo monitoring of tumor growth with [(18)F]-FET PET and show that standardized thresholds from routine clinical practice seem to be inappropriate for BTV estimation in the GBM mouse model.

Demographic variation in incidence of adult glioma by subtype, United States, 1992-2007.

PubMed

Dubrow, Robert; Darefsky, Amy S

2011-07-29

We hypothesized that race/ethnic group, sex, age, and/or calendar period variation in adult glioma incidence differs between the two broad subtypes of glioblastoma (GBM) and non-GBM. Primary GBM, which constitute 90-95% of GBM, differ from non-GBM with respect to a number of molecular characteristics, providing a molecular rationale for these two broad glioma subtypes. We utilized data from the Surveillance, Epidemiology, and End Results Program for 1992-2007, ages 30-69 years. We compared 15,088 GBM cases with 9,252 non-GBM cases. We used Poisson regression to calculate adjusted rate ratios and 95% confidence intervals. The GBM incidence rate increased proportionally with the 4th power of age, whereas the non-GBM rate increased proportionally with the square root of age. For each subtype, compared to non-Hispanic Whites, the incidence rate among Blacks, Asians/Pacific Islanders, and American Indians/Alaskan Natives was substantially lower (one-fourth to one-half for GBM; about two-fifths for non-GBM). Secondary to this primary effect, race/ethnic group variation in incidence was significantly less for non-GBM than for GBM. For each subtype, the incidence rate was higher for males than for females, with the male/female rate ratio being significantly higher for GBM (1.6) than for non-GBM (1.4). We observed significant calendar period trends of increasing incidence for GBM and decreasing incidence for non-GBM. For the two subtypes combined, we observed a 3% decrease in incidence between 1992-1995 and 2004-2007. The substantial difference in age effect between GBM and non-GBM suggests a fundamental difference in the genesis of primary GBM (the driver of GBM incidence) versus non-GBM. However, the commonalities between GBM and non-GBM with respect to race/ethnic group and sex variation, more notable than the somewhat subtle, albeit statistically significant, differences, suggest that within the context of a fundamental difference, some aspects of the complex process of gliomagenesis are shared by these subtypes as well. The increasing calendar period trend of GBM incidence coupled with the decreasing trend of non-GBM incidence may at least partly be due to a secular trend in diagnostic fashion, as opposed to real changes in incidence of these subtypes.

Glioblastoma progression is assisted by induction of immunosuppressive function of pericytes through interaction with tumor cells

PubMed Central

Valdor, Rut; García-Bernal, David; Bueno, Carlos; Ródenas, Mónica; Moraleda, José M.; Macian, Fernando; Martínez, Salvador

2017-01-01

The establishment of immune tolerance during Glioblastoma Multiforme (GBM) progression, is characterized by high levels expression of anti-inflammatory cytokines, which suppress the function of tumor assocciated myeloid cells, and the activation and expansion of tumor antigen specific T cells. However, the mechanisms underlying the failed anti-tumor immune response around the blood vessels during GBM, are poorly understood. The consequences of possible interactions between cancer cells and the perivascular compartment might affect the tumor growth. In this work we show for the first time that GBM cells induce immunomodulatory changes in pericytes in a cell interaction-dependent manner, acquiring an immunosuppresive function that possibly assists the evasion of the anti-tumor immune response and consequently participates in tumor growth promotion. Expression of high levels of anti-inflammatory cytokines was detected in vitro and in vivo in brain pericytes that interacted with GBM cells (GBC-PC). Furthermore, reduction of surface expression of co-stimulatory molecules and major histocompatibility complex molecules in GBC-PC correlated with a failure of antigen presentation to T cells and the acquisition of the ability to supress T cell responses. In vivo, orthotopic xenotransplant of human glioblastoma in an immunocompetent mouse model showed significant GBM cell proliferation and tumor growth after the establishment of interspecific immunotolerance that followed GMB interaction with pericytes. PMID:28978142

¹H MRS characterization of neurochemical profiles in orthotopic mouse models of human brain tumors.

PubMed

Hulsey, Keith M; Mashimo, Tomoyuki; Banerjee, Abhishek; Soesbe, Todd C; Spence, Jeffrey S; Vemireddy, Vamsidhara; Maher, Elizabeth A; Bachoo, Robert M; Choi, Changho

2015-01-01

Glioblastoma (GBM), the most common primary brain tumor, is resistant to currently available treatments. The development of mouse models of human GBM has provided a tool for studying mechanisms involved in tumor initiation and growth as well as a platform for preclinical investigation of new drugs. In this study we used (1) H MR spectroscopy to study the neurochemical profile of a human orthotopic tumor (HOT) mouse model of human GBM. The goal of this study was to evaluate differences in metabolite concentrations in the GBM HOT mice when compared with normal mouse brain in order to determine if MRS could reliably differentiate tumor from normal brain. A TE =19 ms PRESS sequence at 9.4 T was used for measuring metabolite levels in 12 GBM mice and 8 healthy mice. Levels for 12 metabolites and for lipids/macromolecules at 0.9 ppm and at 1.3 ppm were reliably detected in all mouse spectra. The tumors had significantly lower concentrations of total creatine, GABA, glutamate, total N-acetylaspartate, aspartate, lipids/macromolecules at 0.9 ppm, and lipids/macromolecules at 1.3 ppm than did the brains of normal mice. The concentrations of glycine and lactate, however, were significantly higher in tumors than in normal brain. Copyright © 2014 John Wiley & Sons, Ltd.

A cytoplasmic long noncoding RNA LINC00470 as a new AKT activator to mediate glioblastoma cell autophagy.

PubMed

Liu, Changhong; Zhang, Yan; She, Xiaoling; Fan, Li; Li, Peiyao; Feng, Jianbo; Fu, Haijuan; Liu, Qing; Liu, Qiang; Zhao, Chunhua; Sun, Yingnan; Wu, Minghua

2018-06-04

Despite the overwhelming number of investigations on AKT, little is known about lncRNA on AKT regulation, especially in GBM cells. RNA-binding protein immunoprecipitation assay (RIP) and RNA pulldown were used to confirm the binding of LINC00470 and fused in sarcoma (FUS). Confocal imaging, co-immunoprecipitation (Co-IP) and GST pulldown assays were used to detect the interaction between FUS and AKT. EdU assay, CCK-8 assay, and intracranial xenograft assays were performed to demonstrate the effect of LINC00470 on the malignant phenotype of GBM cells. RT-qPCR and Western blotting were performed to test the effect of LINC00470 on AKT and pAKT. In this study, we demonstrated that LINC00470 was a positive regulator for AKT activation in GBM. LINC00470 bound to FUS and AKT to form a ternary complex, anchoring FUS in the cytoplasm to increase AKT activity. Higher pAKT activated by LINC00470 inhibited ubiquitination of HK1, which affected glycolysis, and inhibited cell autophagy. Furthermore, higher LINC00470 expression was associated with GBM tumorigenesis and poor patient prognosis. Our findings revealed a noncanonical AKT activation signaling pathway, i.e., LINC00470 directly interacts with FUS, serving as an AKT activator to promote GBM progression. LINC00470 has an important referential significance to evaluate the prognosis of patients.

Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue.

PubMed

Krolicki, Leszek; Bruchertseifer, Frank; Kunikowska, Jolanta; Koziara, Henryk; Królicki, Bartosz; Jakuciński, Maciej; Pawlak, Dariusz; Apostolidis, Christos; Mirzadeh, Saed; Rola, Rafał; Merlo, Adrian; Morgenstern, Alfred

2018-04-30

Glioblastoma multiforme (GBM), the most common malignant brain tumor, mainly manifests as a primary de novo and less frequently as a secondary glial neoplasm. GBM has been demonstrated to overexpress the NK-1 receptor and substance P can be used as a ligand for targeted therapy. Alpha emitters, e.g. 213 Bi, that deposit their high energy within a short range allow the selective irradiation of tumor cells while sparing adjacent neuronal structures. Among 50 glioma patients of different subtypes that have to date been treated with targeted alpha therapy at the Medical University Warsaw, we report here the data on nine patients with secondary GBM. Following surgery, chemo- and radiotherapy, recurrent GBM was treated by intracavitary injection of 1-6 doses of 0.9-2.3 GBq 213 Bi- DOTA-[Thi 8 ,Met(O 2 ) 11 ]-substance P ( 213 Bi-DOTA-SP) in 2-month intervals. 68 Ga-DOTA-[Thi 8 ,Met(O 2 ) 11 ]-substance P ( 68 Ga-DOTA-SP) was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI. Treatment with activities ranging from 1.4 to 9.7 (median 5.8) GBq 213 Bi- DOTA-SP was well tolerated with only mild transient adverse reactions, mainly headaches due to a transient perfocal edema reaction. The median progression free survival and overall survival time following the initiation of alpha therapy was 5.8 and 16.4 months, respectively. The median overall survival time from the first diagnosis was 52.3 months. Two out of nine patients are still alive 39 and 51 months, respectively, after the initiation of the therapy. Targeted alpha therapy of secondary GBM with 213 Bi-DOTA-SP is safe and well tolerated and may evolve as a promising novel therapeutic option for secondary GBM.

Response assessment of bevacizumab therapy in GBM with integrated 11C-MET-PET/MRI: a feasibility study.

PubMed

Deuschl, Cornelius; Moenninghoff, Christoph; Goericke, Sophia; Kirchner, Julian; Köppen, Susanne; Binse, Ina; Poeppel, Thorsten D; Quick, Harald H; Forsting, Michael; Umutlu, Lale; Herrmann, Ken; Hense, Joerg; Schlamann, Marc

2017-08-01

The objective of this study was to evaluate the potential of integrated 11C-MET PET/MR for response assessment of relapsed glioblastoma (GBM) receiving bevacizumab treatment. Eleven consecutive patients with relapsed GBM were enrolled for an integrated 11C-MET PET/MRI at baseline and at follow-up. Treatment response for MRI was evaluated according to Response Assessment in Neuro-oncology (RANO) criteria and integrated 11C-MET PET was assessed by the T/N ratio. MRI showed no patient with complete response (CR), six of 11 patients with PR, four of 11 patients with SD, and one of 11 patients with progressive disease (PD). PET revealed metabolic response in five of the six patients with partial response (PR) and in two of the four patients with stable disease (SD), whereas metabolic non-response was detected in one of the six patients with PR, in two of the four patients with SD, and in the one patient with PD. Morphological imaging was predictive for PFS and OS when response was defined as CR, PR, SD, and non-response as PD. Metabolic imaging was predictive when using T/N ratio reduction of >25 as discriminator. Based on the morphologic and metabolic findings of this study a proposal for applying integrated PET/MRI for treatment response in relapsed GBM was developed, which was significantly predictive for PFS and OS (P = 0.010 respectively 0,029, log). This study demonstrates the potential of integrated 11C-MET-PET/MRI for response assessment of GBM and the utility of combined assessment of morphologic and metabolic information with the proposal for assessing relapsed GBM.

Systemic approaches identify a garlic-derived chemical, Z-ajoene, as a glioblastoma multiforme cancer stem cell-specific targeting agent.

PubMed

Jung, Yuchae; Park, Heejoo; Zhao, Hui-Yuan; Jeon, Raok; Ryu, Jae-Ha; Kim, Woo-Young

2014-07-01

Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFβ signaling pathways are key mediators of Z-ajoene's action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs.

Orotracheal administration of contrast agents: a new protocol for brain tumor targeting.

PubMed

Bianchi, Andrea; Moncelet, Damien; Lux, François; Plissonneau, Marie; Rizzitelli, Silvia; Ribot, Emeline Julie; Tassali, Nawal; Bouchaud, Véronique; Tillement, Olivier; Voisin, Pierre; Crémillieux, Yannick

2015-06-01

The development of new non-invasive diagnostic and therapeutic approaches is of paramount importance in order to improve the outcome of patients with glioblastoma (GBM). In this work we investigated a completely non-invasive pre-clinical protocol to effectively target and detect brain tumors through the orotracheal route, using ultra-small nanoparticles (USRPs) and MRI. A mouse model of GBM was developed. In vivo MRI acquisitions were performed before and after intravenous or orotracheal administration of the nanoparticles to identify and segment the tumor. The accumulation of the nanoparticles in neoplastic lesions was assessed ex vivo through fluorescence microscopy. Before the administration of contrast agents, MR images allowed the identification of the presence of abnormal brain tissue in 73% of animals. After orotracheal or intravenous administration of USRPs, in all the mice an excellent co-localization of the position of the tumor with MRI and histology was observed. The elimination time of the USRPs from the tumor after the orotracheal administration was approximately 70% longer compared with intravenous injection. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify and longitudinally monitor the development of GBMs. The absence of ionizing radiation and high resolution of MRI, along with the complete non-invasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge, this is the first time that the advantages of a needle-free orotracheal administration route have been demonstrated for the investigation of the pathomorphological changes due to GBMs. Copyright © 2015 John Wiley & Sons, Ltd.

Space-Borne Observations of Intense Gamma-Ray Flashes (TGFs) Above Thunderstorms

NASA Technical Reports Server (NTRS)

Fishman, Gerald J.

2011-01-01

Intense millisecond flashes of MeV photons have been observed with space-borne detectors. These terrestrial gamma-ray flashes (TGFs) were discovered with the Burst and Transient Source Experiment (BATSE) aboard the Compton Gamma- Ray Observatory (CGRO) in the early 1990s. They are now being observed with several other instruments, including the Gamma-ray Burst Monitor (GBM) detectors on the Fermi Gamma-ray Space Telescope. Although Fermi-GBM was designed and optimized for the observation of cosmic gamma-ray bursts (GRBs), it has unprecedented capabilities for these TGF observations. On several occasions, intense beams of high-energy electrons and positrons have been observed at the geomagnetic conjugate points of TGFs.

Serum antibody-negative Goodpasture syndrome with delta granule pool storage deficiency and eosinophilia.

PubMed

Kussman, Ashleigh; Gohara, Amira

2012-12-01

Goodpasture syndrome is a rare, life-threatening autoimmune disease characterized by a triad of rapidly progressive glomerulonephritis, a hemorrhagic pulmonary condition and the presence of anti-glomerular basement membrane (anti-GBM) antibodies. The antibodies initiate destruction of the kidney glomeruli, resulting in a focal necrotizing glomerulitis, which may progress rapidly to renal failure. Autoantibody-mediated damage of alveolar basement membranes leads to diffuse pulmonary hemorrhage, which in some cases may be severe enough to cause respiratory failure. Many clinicians use a variety of assays to detect serum anti-GBM antibodies; however, these tests may be falsely negative in up to 15% of patients with Goodpasture syndrome. Here, we report an unusual case of a 40-year-old man with clinical evidence of Goodpasture syndrome, a negative anti-GBM antibody serum result, eosinophilia and delta granule pool storage deficiency. After a 14-day hospital stay and extensive workup, as well as treatment with antibiotics, steroids and ventilator support for respiratory failure, the patient continued to deteriorate and entered multisystem organ failure. The family decided to withdraw ventilator support, and the patient expired. Immunofluorescence testing for anti-GBM autoantibodies on lung and kidney tissues during an autopsy confirmed the diagnosis of Goodpasture syndrome.

Fermi and Swift Gamma-Ray Burst Afterglow Population Studies

NASA Technical Reports Server (NTRS)

Racusin, Judith L.; Oates, S. R.; Schady, P.; Burrows, D. N.; dePasquale, M.; Donato, D.; Gehrels, N.; Koch, S.; McEnery, J.; Piran, T.;

The Fermi-LAT detection of magnetar-like pulsar PSR J1846-0258 at high-energy gamma-rays

NASA Astrophysics Data System (ADS)

Kuiper, L.; Hermsen, W.; Dekker, A.

2018-03-01

We report the detection of the pulsed signal of the radio-quiet magnetar-like pulsar PSR J1846-0258 in the high-energy γ-ray data of the Fermi Large Area Telescope (Fermi LAT). We produced phase-coherent timing models exploiting RXTE PCA and Swift XRT monitoring data for the post- (magnetar-like) outburst period from 2007 August 28 to 2016 September 4, with independent verification using INTEGRAL ISGRI and Fermi GBM data. Phase-folding barycentric arrival times of selected Fermi LAT events from PSR J1846-0258 resulted in a 4.2σ detection (30-100 MeV) of a broad pulse consistent in shape and aligned in phase with the profiles that we measured with Swift XRT (2.5-10 keV), INTEGRAL ISGRI (20-150 keV), and Fermi GBM (20-300 keV). The pulsed flux (30-100 MeV) is (3.91 ± 0.97) × 10-9 photons cm-2 s-1 MeV-1. Declining significances of the INTEGRAL ISGRI 20-150 keV pulse profiles suggest fading of the pulsed hard X-ray emission during the post-outburst epochs. We revisited with greatly improved statistics the timing and spectral characteristics of PSR B1509-58 as measured with the Fermi LAT. The broad-band pulsed emission spectra (from 2 keV up to GeV energies) of PSR J1846-0258 and PSR B1509-58 can be accurately described with similarly curved shapes, with maximum luminosities at 3.5 ± 1.1 MeV (PSR J1846-0258) and 2.23 ± 0.11 MeV (PSR B1509-58). We discuss possible explanations for observational differences between Fermi LAT detected pulsars that reach maximum luminosities at GeV energies, like the second magnetar-like pulsar PSR J1119-6127, and pulsars with maximum luminosities at MeV energies, which might be due to geometric differences rather than exotic physics in high-B fields.

Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain

PubMed Central

van der Vos, Kristan E.; Abels, Erik R.; Zhang, Xuan; Lai, Charles; Carrizosa, Esteban; Oakley, Derek; Prabhakar, Shilpa; Mardini, Osama; Crommentuijn, Matheus H. W.; Skog, Johan; Krichevsky, Anna M.; Stemmer-Rachamimov, Anat; Mempel, Thorsten R.; El Khoury, Joseph; Hickman, Suzanne E.; Breakefield, Xandra O.

2016-01-01

Background To understand the ability of gliomas to manipulate their microenvironment, we visualized the transfer of vesicles and the effects of tumor-released extracellular RNA on the phenotype of microglia in culture and in vivo. Methods Extracellular vesicles (EVs) released from primary human glioblastoma (GBM) cells were isolated and microRNAs (miRNAs) were analyzed. Primary mouse microglia were exposed to GBM-EVs, and their uptake and effect on proliferation and levels of specific miRNAs, mRNAs, and proteins were analyzed. For in vivo analysis, mouse glioma cells were implanted in the brains of mice, and EV release and uptake by microglia and monocytes/macrophages were monitored by intravital 2-photon microscopy, immunohistochemistry, and fluorescence activated cell sorting analysis, as well as RNA and protein levels. Results Microglia avidly took up GBM-EVs, leading to increased proliferation and shifting of their cytokine profile toward immune suppression. High levels of miR-451/miR-21 in GBM-EVs were transferred to microglia with a decrease in the miR-451/miR-21 target c-Myc mRNA. In in vivo analysis, we directly visualized release of EVs from glioma cells and their uptake by microglia and monocytes/macrophages in brain. Dissociated microglia and monocytes/macrophages from tumor-bearing brains revealed increased levels of miR-21 and reduced levels of c-Myc mRNA. Conclusions Intravital microscopy confirms the release of EVs from gliomas and their uptake into microglia and monocytes/macrophages within the brain. Our studies also support functional effects of GBM-released EVs following uptake into microglia, associated in part with increased miRNA levels, decreased target mRNAs, and encoded proteins, presumably as a means for the tumor to manipulate its environs. PMID:26433199

Anti-glomerular basement membrane (anti-GBM) disease accompanied by vasculitis that was not positive for antineutrophil cytoplasmic antibodies to myeloperoxidase and proteinase 3: a report of two cases and the incidence of anti-GBM disease at one institution.

PubMed

Nakabayashi, Kimimasa; Fujioka, Yasunori; Arimura, Yoshihiro; Fukuoka, Toshihito; Marumo, Tomohumi; Umino, Michiru; Kamiya, Yasushi; Okai, Takahiro; Tsurumaki, Shigeru; Nagasawa, Toshihiko; Yamada, Akira

2011-08-01

Anti-glomerular basement membrane (anti-GBM) disease is thought to be distinct from vasculitis. In contrast, there have been several papers suggesting the presence of angiitis in cases that were positive for anti-GBM antibody (Ab), as well as for either myeloperoxidase (MPO)- or proteinase 3 (PR3)-anti-neutrophil cytoplasmic antibody (ANCA) (Group I). We experienced four patients who had anti-GBM Abs, but not MPO- and PR3-ANCA (Group II), and two of these patients were found to have vasculitis. Therefore, we performed an in-depth study on these two patients. The patients with anti-GBM disease were isolated from 578 cases whose renal tissues were examined, and they were categorized into two groups. We have already published the data about Group I. We then proceeded to study two vasculitic patients in Group II clinically, pathologically, and serologically. The anti-GBM Ab and ANCA levels were detected by enzyme-linked immunosorbent assays. Renal specimens were studied by routine staining as well as immunohistochemical investigations of CD31 and type IV collagen. The total number of patients with anti-GBM disease was 7 (7/578 = 1.2%), with 3 patients belonging to Group I and 4 patients belonging to Group II. Two patients in Group II were diagnosed to have vasculitis, but the remaining 2 patients did not. One vasculitic patient was complicated by pulmonary hemorrhage, while the other vasculitic patient displayed peripheral neuropathy as well as a small cavity lesion in the lung. The latter patient was found to be positive for perinuclear (p)-ANCA, but not for any other ANCA subsets. The renal pathology in the two vasculitic patients showed crescentic glomerulonephritis (CSGN) and immunoglobulin (Ig) G linear deposits along the glomerular capillary loops. The former patient showed fibrinoid angiitis in an afferent arteriole as well as peritubular capillaritis. The latter patient demonstrated peritubular capillaritis. These peritubular capillaritides were diagnosed by the loss of CD31 and type IV collagen staining, the blurred appearance of peritubular capillary walls by periodic acid-Schiff staining, and the pericapillary infiltration of inflammatory cells. The incidence of anti-GBM disease was very low, and our patients were categorized into two groups (Groups I and II) based on whether or not they were positive for MPO- or PR3-ANCA. Two patients in Group II were found to have vasculitis. According to our results, we concluded that the anti-GBM disease of Group II could also be associated with vasculitis.

Irradiation induces glioblastoma cell senescence and senescence-associated secretory phenotype.

PubMed

Jeon, Hee-Young; Kim, Jun-Kyum; Ham, Seok Won; Oh, Se-Yeong; Kim, Jaebong; Park, Jae-Bong; Lee, Jae-Yong; Kim, Sung-Chan; Kim, Hyunggee

2016-05-01

Glioblastoma multiforme (GBM) is one of the most aggressive and fatal primary brain tumors in humans. The standard therapy for the treatment of GBM is surgical resection, followed by radiotherapy and/or chemotherapy. However, the frequency of tumor recurrence in GBM patients is very high, and the survival rate remains poor. Delineating the mechanisms of GBM recurrence is essential for therapeutic advances. Here, we demonstrate that irradiation rendered 17-20 % of GBM cells dead, but resulted in 60-80 % of GBM cells growth-arrested with increases in senescence markers, such as senescence-associated beta-galactosidase-positive cells, H3K9me3-positive cells, and p53-p21(CIP1)-positive cells. Moreover, irradiation induced expression of senescence-associated secretory phenotype (SASP) mRNAs and NFκB transcriptional activity in GBM cells. Strikingly, compared to injection of non-irradiated GBM cells into immune-deficient mice, the co-injection of irradiated and non-irradiated GBM cells resulted in faster growth of tumors with the histological features of human GBM. Taken together, our findings suggest that the increases in senescent cells and SASP in GBM cells after irradiation is likely one of main reasons for tumor recurrence in post-radiotherapy GBM patients.

SU-F-R-17: Advancing Glioblastoma Multiforme (GBM) Recurrence Detection with MRI Image Texture Feature Extraction and Machine Learning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, V; Ruan, D; Nguyen, D

Purpose: To test the potential of early Glioblastoma Multiforme (GBM) recurrence detection utilizing image texture pattern analysis in serial MR images post primary treatment intervention. Methods: MR image-sets of six time points prior to the confirmed recurrence diagnosis of a GBM patient were included in this study, with each time point containing T1 pre-contrast, T1 post-contrast, T2-Flair, and T2-TSE images. Eight Gray-level co-occurrence matrix (GLCM) texture features including Contrast, Correlation, Dissimilarity, Energy, Entropy, Homogeneity, Sum-Average, and Variance were calculated from all images, resulting in a total of 32 features at each time point. A confirmed recurrent volume was contoured, alongmore » with an adjacent non-recurrent region-of-interest (ROI) and both volumes were propagated to all prior time points via deformable image registration. A support vector machine (SVM) with radial-basis-function kernels was trained on the latest time point prior to the confirmed recurrence to construct a model for recurrence classification. The SVM model was then applied to all prior time points and the volumes classified as recurrence were obtained. Results: An increase in classified volume was observed over time as expected. The size of classified recurrence maintained at a stable level of approximately 0.1 cm{sup 3} up to 272 days prior to confirmation. Noticeable volume increase to 0.44 cm{sup 3} was demonstrated at 96 days prior, followed by significant increase to 1.57 cm{sup 3} at 42 days prior. Visualization of the classified volume shows the merging of recurrence-susceptible region as the volume change became noticeable. Conclusion: Image texture pattern analysis in serial MR images appears to be sensitive to detecting the recurrent GBM a long time before the recurrence is confirmed by a radiologist. The early detection may improve the efficacy of targeted intervention including radiosurgery. More patient cases will be included to create a generalizable classification model applicable to a larger patient cohort. NIH R43CA183390 and R01CA188300.NSF Graduate Research Fellowship DGE-1144087.« less

Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway.

PubMed

Mu, Qingchun; Wang, Lijun; Yu, Fengbo; Gao, Haijun; Lei, Ting; Li, Peiwen; Liu, Pengfei; Zheng, Xu; Hu, Xitong; Chen, Yong; Jiang, Zhenfeng; Sayari, Arash J; Shen, Jia; Huang, Haiyan

2015-01-01

Glioblastomas multiforme (GBM) are the most frequently occurring malignant brain cancers. Treatment for GBM consists of surgical resection and subsequent adjuvant radiation therapy and chemotherapy. Despite this, GBM patient survival is limited to 12-15 months, and researchers are continually trying to develop improved therapy options. Insulin-like growth factor 2 mRNA-binding protein 2 (Imp2) is known to be upregulated in many cancers and is known to regulate the signaling activity of insulin-like growth factor 2 (IGF2). However, relatively little is known about its role in malignant development of GBM. In this study, we first found Imp2 is upregulated in GBM tissues by using clinical samples and public database search. Studies with loss and gain of Imp2 expression in in vitro GBM cell culture system demonstrated the role of Imp2 in promoting GBM cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT). Additionally, our results show that Imp2 regulates the activity of IGF2, which further activates PI3K/Akt signaling, thereby to promote GBM malignancy. Inhibition of Imp2 was also found to sensitize GBM to temozolomide treatment. These observations add to the current knowledge of GBM biology, and may prove useful in development of more effective GBM therapy.

Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway

PubMed Central

Mu, Qingchun; Wang, Lijun; Yu, Fengbo; Gao, Haijun; Lei, Ting; Li, Peiwen; Liu, Pengfei; Zheng, Xu; Hu, Xitong; Chen, Yong; Jiang, Zhenfeng; Sayari, Arash J; Shen, Jia; Huang, Haiyan

2015-01-01

Glioblastomas multiforme (GBM) are the most frequently occurring malignant brain cancers. Treatment for GBM consists of surgical resection and subsequent adjuvant radiation therapy and chemotherapy. Despite this, GBM patient survival is limited to 12–15 months, and researchers are continually trying to develop improved therapy options. Insulin-like growth factor 2 mRNA-binding protein 2 (Imp2) is known to be upregulated in many cancers and is known to regulate the signaling activity of insulin-like growth factor 2 (IGF2). However, relatively little is known about its role in malignant development of GBM. In this study, we first found Imp2 is upregulated in GBM tissues by using clinical samples and public database search. Studies with loss and gain of Imp2 expression in in vitro GBM cell culture system demonstrated the role of Imp2 in promoting GBM cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT). Additionally, our results show that Imp2 regulates the activity of IGF2, which further activates PI3K/Akt signaling, thereby to promote GBM malignancy. Inhibition of Imp2 was also found to sensitize GBM to temozolomide treatment. These observations add to the current knowledge of GBM biology, and may prove useful in development of more effective GBM therapy. PMID:25719943

The Fermi Science Support Center Data Servers and Archive

NASA Astrophysics Data System (ADS)

Reustle, Alexander; Fermi Science Support Center

2018-01-01

The Fermi Science Support Center (FSSC) provides the scientific community with access to Fermi data and other products. The Gamma-Ray Burst Monitor (GBM) data is stored at NASA's High Energy Astrophysics Science Archive Research Center (HEASARC) and is accessible through their searchable Browse web interface. The Large Area Telescope (LAT) data is distributed through a custom FSSC interface where users can request all photons detected from a region on the sky over a specified time and energy range. Through its website the FSSC also provides planning and scheduling products, such as long and short term observing timelines, spacecraft position and attitude histories, and exposure maps. We present an overview of the different data products provided by the FSSC, how they can be accessed, and statistics on the archive usage since launch.

Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma

PubMed Central

Lin, Chin-Hsing Annie; Rhodes, Christopher T.; Lin, ChenWei; Phillips, Joanna J.; Berger, Mitchel S.

2017-01-01

ABSTRACT Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. While efforts to identify genes responsible for GBM have revealed mutations and aberrant gene expression associated with distinct types of GBM, patients with GBM are often diagnosed and classified based on MRI features. Therefore, we seek to identify molecular representatives in parallel with MRI classification for group I and group II primary GBM associated with the subventricular zone (SVZ). As group I and II GBM contain stem-like signature, we compared gene expression profiles between these 2 groups of primary GBM and endogenous neural stem progenitor cells to reveal dysregulation of cell cycle, chromatin status, cellular morphogenesis, and signaling pathways in these 2 types of MRI-classified GBM. In the absence of IDH mutation, several genes associated with metabolism are differentially expressed in these subtypes of primary GBM, implicating metabolic reprogramming occurs in tumor microenvironment. Furthermore, histone lysine methyltransferase EZH2 was upregulated while histone lysine demethylases KDM2 and KDM4 were downregulated in both group I and II primary GBM. Lastly, we identified 9 common genes across large data sets of gene expression profiles among MRI-classified group I/II GBM, a large cohort of GBM subtypes from TCGA, and glioma stem cells by unsupervised clustering comparison. These commonly upregulated genes have known functions in cell cycle, centromere assembly, chromosome segregation, and mitotic progression. Our findings highlight altered expression of genes important in chromosome integrity across all GBM, suggesting a common mechanism of disrupted fidelity of chromosome structure in GBM. PMID:28278055

Glioblastoma entities express subtle differences in molecular composition and response to treatment

PubMed Central

Balça-Silva, Joana; Matias, Diana; Do Carmo, Anália; Dubois, Luiz Gustavo; Gonçalves, Ana Cristina; Girão, Henrique; Silva Canedo, Nathalie Henriques; Correia, Ana Helena; De Souza, Jorge Marcondes; Sarmento-Ribeiro, Ana Bela; Lopes, Maria Celeste; Moura-Neto, Vivaldo

2017-01-01

Glioblastoma (GBM) is a grade IV astrocytoma. GBM patients show resistance to chemotherapy such as temozolomide (TMZ), the gold standard treatment. In order to simulate the molecular mechanisms behind the different chemotherapeutic responses in GBM patients we compared the cellular heterogeneity and chemotherapeutic resistance mechanisms in different GBM cell lines. We isolated and characterized a human GBM cell line obtained from a GBM patient, named GBM11. We studied the GBM11 behaviour when treated with Tamoxifen (TMX) that, among other functions, is a protein kinase C (PKC) inhibitor, alone and in combination with TMZ in comparison with the responses of U87 and U118 human GBM cell lines. We evaluated the cell death, cell cycle arrest and cell proliferation, mainly through PKC expression, by flow cytometry and western blot analysis and, ultimately, cell migration capability and F-actin filament disorganization by fluorescence microscopy. We demonstrated that the constitutive activation of p-PKC seems to be one of the main metabolic implicated on GBM malignancy. Despite of its higher resistance, possibly due to the overexpression of P-glycoprotein and stem-like cell markers, GBM11 cells presented a subtle different chemotherapeutic response compared to U87 and U118 cells. The GBM11, U87, U118 cell lines show subtle molecular differences, which clearly indicate the characterization of GBM heterogeneity, one of the main reasons for tumor resistance. The adding of cellular heterogeneity in molecular behaviour constitutes a step closer in the understanding of resistant molecular mechanisms in GBM, and can circumvents the eventual impaired therapy. PMID:28714013

GLAST: Exploring Nature's Highest Energy Processes with the Gamma-ray Large Area Space Telescope

NASA Technical Reports Server (NTRS)

Digel, Seth; Myers, J. D.; White, Nicholas E. (Technical Monitor)

2001-01-01

The Gamma-ray Large Area Space Telescope (GLAST) is an international and multi-agency space mission that will study the cosmos in the energy range 10 keV-300 GeV. Several successful exploratory missions in gamma-ray astronomy led to the Energetic Gamma Ray Experiment Telescope (EGRET) instrument on the Compton Gamma Ray Observatory (CGRO). Launched in 1991, EGRET made the first complete survey of the sky in the 30 MeV-10 GeV range. EGRET showed the high-energy gamma-ray sky to be surprisingly dynamic and diverse, with sources ranging from the sun and moon to massive black holes at large redshifts. Most of the gamma-ray sources detected by EGRET remain unidentified. In light of the discoveries with EGRET, the great potential of the next generation gamma-ray telescope can be appreciated. GLAST will have an imaging gamma-ray telescope vastly more capable than instruments flown previously, as well as a secondary instrument to augment the study of gamma-ray bursts. The main instrument, the Large Area Telescope (LAT), will have superior area, angular resolution, field of view, and deadtime that together will provide a factor of 30 or more advance in sensitivity, as well as provide capability for study of transient phenomena. The GLAST Burst Monitor (GBM) will have a field of view several times larger than the LAT and will provide spectral coverage of gamma-ray bursts that extends from the lower limit of the LAT down to 10 keV. The basic parameters of the GBM are compared to those of the Burst and Transient Source Experiment (BATSE) instrument on CGRO in Table 1-2. With the LAT and GBM, GLAST will be a flexible observatory for investigating the great range of astrophysical phenomena best studied in high-energy gamma rays. NASA plans to launch GLAST in late 2005.

Serum antibody-negative Goodpasture syndrome with delta granule pool storage deficiency and eosinophilia

PubMed Central

Kussman, Ashleigh; Gohara, Amira

2012-01-01

Goodpasture syndrome is a rare, life-threatening autoimmune disease characterized by a triad of rapidly progressive glomerulonephritis, a hemorrhagic pulmonary condition and the presence of anti-glomerular basement membrane (anti-GBM) antibodies. The antibodies initiate destruction of the kidney glomeruli, resulting in a focal necrotizing glomerulitis, which may progress rapidly to renal failure. Autoantibody-mediated damage of alveolar basement membranes leads to diffuse pulmonary hemorrhage, which in some cases may be severe enough to cause respiratory failure. Many clinicians use a variety of assays to detect serum anti-GBM antibodies; however, these tests may be falsely negative in up to 15% of patients with Goodpasture syndrome. Here, we report an unusual case of a 40-year-old man with clinical evidence of Goodpasture syndrome, a negative anti-GBM antibody serum result, eosinophilia and delta granule pool storage deficiency. After a 14-day hospital stay and extensive workup, as well as treatment with antibiotics, steroids and ventilator support for respiratory failure, the patient continued to deteriorate and entered multisystem organ failure. The family decided to withdraw ventilator support, and the patient expired. Immunofluorescence testing for anti-GBM autoantibodies on lung and kidney tissues during an autopsy confirmed the diagnosis of Goodpasture syndrome. PMID:26069804

Biomimetic strategies for the glioblastoma microenvironment

NASA Astrophysics Data System (ADS)

Cha, Junghwa; Kim, Pilnam

2017-12-01

Glioblastoma multiforme (GBM) is a devastating type of tumor with high mortality, caused by extensive infiltration into adjacent tissue and rapid recurrence. Most therapies for GBM have focused on the cytotoxicity, and have not targeted GBM spread. However, there have been numerous attempts to improve therapy by addressing GBM invasion, through understanding and mimicking its behavior using three-dimensional (3D) experimental models. Compared with two-dimensional models and in vivo animal models, 3D GBM models can capture the invasive motility of glioma cells within a 3D environment comprising many cellular and non-cellular components. Based on tissue engineering techniques, GBM invasion has been investigated within a biologically relevant environment, from biophysical and biochemical perspectives, to clarify the pro-invasive factors of GBM. This review discusses the recent progress in techniques for modeling the microenvironments of GBM tissue and suggests future directions with respect to recreating the GBM microenvironment and preclinical applications.

¹⁸F-Fluoromisonidazole positron emission tomography may differentiate glioblastoma multiforme from less malignant gliomas.

PubMed

Hirata, Kenji; Terasaka, Shunsuke; Shiga, Tohru; Hattori, Naoya; Magota, Keiichi; Kobayashi, Hiroyuki; Yamaguchi, Shigeru; Houkin, Kiyohiro; Tanaka, Shinya; Kuge, Yuji; Tamaki, Nagara

2012-05-01

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and its prognosis is significantly poorer than those of less malignant gliomas. Pathologically, necrosis is one of the most important characteristics that differentiate GBM from lower grade gliomas; therefore, we hypothesized that (18)F fluoromisonidazole (FMISO), a radiotracer for hypoxia imaging, accumulates in GBM but not in lower grade gliomas. We aimed to evaluate the diagnostic value of FMISO positron emission tomography (PET) for the differential diagnosis of GBM from lower grade gliomas. This prospective study included 23 patients with pathologically confirmed gliomas. All of the patients underwent FMISO PET and (18)F-fluorodeoxyglucose (FDG) PET within a week. FMISO images were acquired 4 h after intravenous administration of 400 MBq of FMISO. Tracer uptake in the tumor was visually assessed. Lesion to normal tissue ratios and FMISO uptake volume were calculated. Of the 23 glioma patients, 14 were diagnosed as having GBM (grade IV glioma in the 2007 WHO classification), and the others were diagnosed as having non-GBM (5 grade III and 4 grade II). In visual assessment, all GBM patients showed FMISO uptake in the tumor greater than that in the surrounding brain tissues, whereas all the non-GBM patients showed FMISO uptake in the tumor equal to that in the surrounding brain tissues (p ≤ 0.001). One GBM patient was excluded from FDG PET study because of hyperglycemia. All GBM patients and three of the nine (33%) non-GBM patients showed FDG uptake greater than or equal to that in the gray matter. The sensitivity and specificity for diagnosing GBM were 100 and 100% for FMISO, and 100 and 66% for FDG, respectively. The lesion to cerebellum ratio of FMISO uptake was higher in GBM patients (2.74 ± 0.60, range 1.71-3.81) than in non-GBM patients (1.22 ± 0.06, range 1.09-1.29, p ≤ 0.001) with no overlap between the groups. The lesion to gray matter ratio of FDG was also higher in GBM patients (1.46 ± 0.75, range 0.91-3.79) than in non-GBM patients (1.07 ± 0.62, range 0.66-2.95, p ≤ 0.05); however, overlap of the ranges did not allow clear differentiation between GBM and non-GBM. The uptake volume of FMISO was larger in GBM (27.18 ± 10.46%, range 14.02-46.67%) than in non-GBM (6.07 ± 2.50%, range 2.12-9.22%, p ≤ 0.001). These preliminary data suggest that FMISO PET may distinguish GBM from lower grade gliomas.

Atypical nuclear localization of VIP receptors in glioma cell lines and patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barbarin, Alice; Séité, Paule; Godet, Julie

Highlights: • The VIP receptor VPAC1 contains a putative NLS signal. • VPAC1 is predominantly nuclear in GBM cell lines but not VPAC2. • Non-nuclear VPAC1/2 protein expression is correlated with glioma grade. • Nuclear VPAC1 is observed in 50% of stage IV glioma (GBM). - Abstract: An increasing number of G protein-coupled receptors, like receptors for vasoactive intestinal peptide (VIP), are found in cell nucleus. As VIP receptors are involved in the regulation of glioma cell proliferation and migration, we investigated the expression and the nuclear localization of the VIP receptors VPAC1 and VPAC2 in this cancer. First, bymore » applying Western blot and immunofluorescence detection in three human glioblastoma (GBM) cell lines, we observed a strong nuclear staining for the VPAC1 receptor and a weak nuclear VPAC2 receptor staining. Second, immunohistochemical staining of VPAC1 and VPAC2 on tissue microarrays (TMA) showed that the two receptors were expressed in normal brain and glioma tissues. Expression in the non-nuclear compartment of the two receptors significantly increased with the grade of the tumors. Analysis of nuclear staining revealed a significant increase of VPAC1 staining with glioma grade, with up to 50% of GBM displaying strong VPAC1 nuclear staining, whereas nuclear VPAC2 staining remained marginal. The increase in VPAC receptor expression with glioma grades and the enhanced nuclear localization of the VPAC1 receptors in GBM might be of importance for glioma progression.« less

An Event Observed as a Terrestrial Gamma-ray Flash (TGF) and a Terrestrial Electron Beam (TEB) by Fermi GBM

NASA Astrophysics Data System (ADS)

Stanbro, M.; Briggs, M. S.; Cramer, E.; Dwyer, J. R.; Roberts, O.

2017-12-01

Terrestrial Gamma-ray Flashes (TGFs) are sub-ms, intense flashes of gamma-rays. They are due to the acceleration of electrons with relativistic energies in thunderstorms that emit gamma-rays via bremsstrahlung. When these photons reach the upper atmosphere, they can produce secondary electrons and positrons that escape the atmosphere and propagate along the Earth's magnetic field line. Space instruments can detect these charged particles, known as Terrestrial Electron Beams (TEBs), after traveling thousands of kilometers from the thunderstorm. We present an event that was observed by the Fermi Gamma-ray Burst Monitor (GBM) as both a TGF and a TEB. To our knowledge this is the first such event that has ever been observed. We interpret the first pulse as a TGF with a duration of 0.2 ms. After 0.5 ms a second pulse is seen with a duration of 2 ms that we interpret as a TEB. Confirming this interpretation, a third pulse is seen 90 ms later, which is understood as a TEB magnetic mirror pulse. The World Wide Lightning Location Network (WWLLN) and the Earth Networks Total Lightning Network (ENTLN) detected a sferic, under the spacecraft footprint and within the southern magnetic footprint that is simultaneous with the first pulse. Along with the sferic, this unique observation allows us for the first time to test TGF and TEB models for the same event. We present Monte Carlo simulations of the first two pulses, including pitch angles for electrons and positrons, to see if the models can consistently describe the TGF/TEB spectra and time profiles originating from the same source.

Fermi and Swift Gamma-Ray Burst Afterglow Population Studies

NASA Technical Reports Server (NTRS)

Racusin, J. L.; Oates, S. R.; Schady, P.; Burrows, D. N.; de Pasquale, M.; Donato, D.; Gehrels, N.; Koch, S.; McEnery, J.; Piran, T.;

Fermi and Swift Gamma-Ray Burst Afterglow Population Studies

NASA Technical Reports Server (NTRS)

Racusin, Judith I.

2011-01-01

The new and extreme population of GRBs detected by Fermi-LAT shows several new features in high energy gamma-rays that are providing interesting and unexpected clues into GRB prompt and afterglow emission mechanisms. Over the last 6 years, it has been Swift that has provided the robust data set of UV/optical and X-ray afterglow observations that opened many windows into components of GRB emission structure. The relationship between the LAT GRBs and the well studied, fainter, less energetic GRBs detected by Swift-BAT is only beginning to be explored by multi-wavelength studies. We explore the large sample of GRBs detected by BAT only, BAT and Fermi-GBM, and GBM and LAT, focusing on these samples separately in order to search for statistically significant differences between the populations, using only those GRBs with measured redshifts in order to physically characterize these objects. We disentangle which differences are instrumental selection effects versus intrinsic properties, in order to better understand the nature of the special characteristics of the LAT bursts.

Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging.

PubMed

Salphati, Laurent; Shahidi-Latham, Sheerin; Quiason, Cristine; Barck, Kai; Nishimura, Merry; Alicke, Bruno; Pang, Jodie; Carano, Richard A; Olivero, Alan G; Phillips, Heidi S

2014-07-01

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and the limited available treatment options have not meaningfully impacted patient survival in the past decades. Such poor outcomes can be at least partly attributed to the inability of most drugs tested to cross the blood-brain barrier and reach all areas of the glioma. The objectives of these studies were to visualize and compare by matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry the brain and tumor distribution of the phosphatidylinositol 3-kinase (PI3K) inhibitors pictilisib (GDC-0941, 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine) and GNE-317 [5-(6-(3-methoxyoxetan-3-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine] in U87 and GS2 orthotopic models of GBM, models that exhibit differing blood-brain barrier characteristics. Following administration to tumor-bearing mice, pictilisib was readily detected within tumors of the contrast-enhancing U87 model whereas it was not located in tumors of the nonenhancing GS2 model. In both GBM models, pictilisib was not detected in the healthy brain. In contrast, GNE-317 was uniformly distributed throughout the brain in the U87 and GS2 models. MALDI imaging revealed also that the pictilisib signal varied regionally by up to 6-fold within the U87 tumors whereas GNE-317 intratumor levels were more homogeneous. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analyses of the nontumored half of the brain showed pictilisib had brain-to-plasma ratios lower than 0.03 whereas they were greater than 1 for GNE-317, in agreement with their brain penetration properties. These results in orthotopic models representing either the contrast-enhancing or invasive areas of GBM clearly demonstrate the need for whole-brain distribution to potentially achieve long-term efficacy in GBM. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Detection of p53 mutations in proliferating vascular cells in glioblastoma multiforme.

PubMed

Kawasoe, Takuma; Takeshima, Hideo; Yamashita, Shinji; Mizuguchi, Sohei; Fukushima, Tsuyoshi; Yokogami, Kiyotaka; Yamasaki, Kouji

2015-02-01

Glioblastoma multiforme (GBM), one of the most aggressive tumors in humans, is highly angiogenic. However, treatment with the angiogenesis inhibitor bevacizumab has not significantly prolonged overall patient survival times. GBM resistance to angiogenesis inhibitors is attributed to multiple interacting mechanisms. Although mesenchymal transition via glioma stem-like cells has attracted attention, it is considered a poor biomarker. There is no simple method for differentiating tumor-derived and reactive vascular cells from normal cells. The authors attempted to detect the mesenchymal transition of tumor cells by means of p53 and isocitrate dehydrogenase 1 (IDH1) immunohistochemistry. Using antibody against p53 and IDH1 R132H, the authors immunohistochemically analyzed GBM tissue from patients who had undergone surgery at the University of Miyazaki Hospital during August 2005-December 2011. They focused on microvascular proliferation with a p53-positive ratio exceeding 50%. They compared TP53 mutations in original tumor tissues and in p53-positive and p53-negative microvascular proliferation cells collected by laser microdissection. Among 61 enrolled GBM patients, the first screening step (immunostaining) identified 46 GBMs as p53 positive, 3 of which manifested areas of prominent p53-positive microvascular proliferation (>50%). Histologically, areas of p53-positive microvascular proliferation tended to be clustered, and they coexisted with areas of p53-negative microvascular proliferation. Both types of microvascular proliferation cells were clearly separated from original tumor cells by glial fibrillary acidic protein, epidermal growth factor receptor, and low-/high-molecular-weight cytokeratin. DNA sequencing analysis disclosed that p53-positive microvascular proliferation cells exhibited TP53 mutations identical to those observed in the original tumor; p53-negative microvascular proliferation cells contained a normal allele. Although immunostaining indicated that 3 (2 primary and 1 secondary) of the 61 GBMs were positive for IDH1, no tumors contained microvascular proliferation cells positive for IDH1 R132H. Some microvascular proliferation clusters in GBM result from mesenchymal transition. The identification of useful markers might reveal this phenomenon as an infrequent event in GBMs.

Towards precision medicine-based therapies for glioblastoma: interrogating human disease genomics and mouse phenotypes.

PubMed

Chen, Yang; Gao, Zhen; Wang, Bingcheng; Xu, Rong

2016-08-22

Glioblastoma (GBM) is the most common and aggressive brain tumors. It has poor prognosis even with optimal radio- and chemo-therapies. Since GBM is highly heterogeneous, drugs that target on specific molecular profiles of individual tumors may achieve maximized efficacy. Currently, the Cancer Genome Atlas (TCGA) projects have identified hundreds of GBM-associated genes. We develop a drug repositioning approach combining disease genomics and mouse phenotype data towards predicting targeted therapies for GBM. We first identified disease specific mouse phenotypes using the most recently discovered GBM genes. Then we systematically searched all FDA-approved drugs for candidates that share similar mouse phenotype profiles with GBM. We evaluated the ranks for approved and novel GBM drugs, and compared with an existing approach, which also use the mouse phenotype data but not the disease genomics data. We achieved significantly higher ranks for the approved and novel GBM drugs than the earlier approach. For all positive examples of GBM drugs, we achieved a median rank of 9.2 45.6 of the top predictions have been demonstrated effective in inhibiting the growth of human GBM cells. We developed a computational drug repositioning approach based on both genomic and phenotypic data. Our approach prioritized existing GBM drugs and outperformed a recent approach. Overall, our approach shows potential in discovering new targeted therapies for GBM.

MUC4 modulates human glioblastoma cell proliferation and invasion by upregulating EGFR expression.

PubMed

Li, Weihua; Wu, Chunming; Yao, Yiqun; Dong, Bin; Wei, Zhenqing; Lv, Xiupeng; Zhang, Jian; Xu, Yinghui

2014-04-30

Glioblastoma (GBM), the most common primary brain tumor, is the leading cause of deaths related to tumors in the central nervous system. The prognosis of GBM patients is currently poor, and the mechanisms underlying GBM genesis remain unclear. The expression of MUC4, a high-molecular-weight and highly glycosylated protein, has been studied in many cancers. However, information on MUC4 expression in GBM is limited. In this study, we found that MUC4 was overexpressed in GBM cell lines and tissues. The proliferation and invasive potential of GBM cells were significantly increased by the ectopic expression of MUC4. By contrast, RNA interference targeting MUC4 in GBM cells significantly decreased the proliferation and invasive potential of GBM cells. We also found that the expression of epidermal growth factor receptor (EGFR) was modulated by MUC4. EGFR inhibition by siRNA reversed the MUC4-induced proliferation and invasion. These results indicated that MUC4 expression in GBM was important in GBM cell proliferation and invasion, which may be partly associated with EGFR overexpression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A Large-Scale RNAi Screen Identifies SGK1 as a Key Survival Kinase for GBM Stem Cells.

PubMed

Kulkarni, Shreya; Goel-Bhattacharya, Surbhi; Sengupta, Sejuti; Cochran, Brent H

2018-01-01

Glioblastoma multiforme (GBM) is the most common type of primary malignant brain cancer and has a very poor prognosis. A subpopulation of cells known as GBM stem-like cells (GBM-SC) have the capacity to initiate and sustain tumor growth and possess molecular characteristics similar to the parental tumor. GBM-SCs are known to be enriched in hypoxic niches and may contribute to therapeutic resistance. Therefore, to identify genetic determinants important for the proliferation and survival of GBM stem cells, an unbiased pooled shRNA screen of 10,000 genes was conducted under normoxic as well as hypoxic conditions. A number of essential genes were identified that are required for GBM-SC growth, under either or both oxygen conditions, in two different GBM-SC lines. Interestingly, only about a third of the essential genes were common to both cell lines. The oxygen environment significantly impacts the cellular genetic dependencies as 30% of the genes required under hypoxia were not required under normoxic conditions. In addition to identifying essential genes already implicated in GBM such as CDK4, KIF11 , and RAN , the screen also identified new genes that have not been previously implicated in GBM stem cell biology. The importance of the serum and glucocorticoid-regulated kinase 1 (SGK1) for cellular survival was validated in multiple patient-derived GBM stem cell lines using shRNA, CRISPR, and pharmacologic inhibitors. However, SGK1 depletion and inhibition has little effect on traditional serum grown glioma lines and on differentiated GBM-SCs indicating its specific importance in GBM stem cell survival. Implications: This study identifies genes required for the growth and survival of GBM stem cells under both normoxic and hypoxic conditions and finds SGK1 as a novel potential drug target for GBM. Mol Cancer Res; 16(1); 103-14. ©2017 AACR . ©2017 American Association for Cancer Research.

Swift XRT Observation of 1E 1841-045

NASA Astrophysics Data System (ADS)

Archibald, Robert; Scholz, Paul; Kaspi, Victoria

2013-09-01

We report on Swift XRT observations made following an X-ray/soft gamma-ray burst detected by Fermi-GBM on 13 September 2013 (GCNs 15245, 15228) from the direction of magnetar 1E 1841-045 in the supernova remnant Kes 73. As part of an ongoing monitoring campaign of 1E 1841-045, as well as several other magnetars with the Swift XRT, we observed the source on 16 September 2013 for 4.4 ks. We detect no significant change in the X-ray flux relative to pre-burst epochs: we measure an absorbed 2-10 keV flux of 2.48^(+0.07)_(-0.09) E-11 ergs/s/cm^2 for the 16 September 2013 observation, compared with an average of 2.484^(+0.006)_(-0.06) E-11 ergs/s/cm^2 for observations for the 2 years prior, or 2.39^(+0.10)_(-0.17) E-11 ergs/s/cm^2 for the prior observation on 24 August, 2013.

Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).

PubMed

Elkamhawy, Ahmed; Viswanath, Ambily Nath Indu; Pae, Ae Nim; Kim, Hyeon Young; Heo, Jin-Chul; Park, Woo-Kyu; Lee, Chong-Ock; Yang, Heekyoung; Kim, Kang Ho; Nam, Do-Hyun; Seol, Ho Jun; Cho, Heeyeong; Roh, Eun Joo

2015-10-20

Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Strategies of Mesenchymal Invasion of Patient-derived Brain Tumors: Microenvironmental Adaptation.

PubMed

Cha, Junghwa; Kang, Seok-Gu; Kim, Pilnam

2016-04-25

The high mortality in glioblastoma multiforme (GBM) patients is primarily caused by extensive infiltration into adjacent tissue and subsequent rapid recurrence. There are no clear therapeutic strategies that target the infiltrative subpopulation of GBM mass. Using mesenchymal mode of invasion, the GBM is known to widely infiltrate by interacting with various unique components within brain microenvironment such as hyaluronic acid (HA)-rich matrix and white matter tracts. However, it is unclear how these GBM microenvironments influence the strategies of mesenchymal invasion. We hypothesize that GBM has different strategies to facilitate such invasion through adaptation to their local microenvironment. Using our in vitro biomimetic microenvironment platform for three-dimensional GBM tumorspheres (TSs), we found that the strategies of GBM invasion were predominantly regulated by the HA-rich ECM microenvironment, showing marked phenotypic changes in the presence of HA, which were mainly mediated by HA synthase (HAS). Interestingly, after inhibition of the HAS gene, GBM switched their invasion strategies to a focal adhesion (FA)-mediated invasion. These results demonstrate that the microenvironmental adaptation allowed a flexible invasion strategy for GBM. Using our model, we suggest a new inhibitory pathway for targeting infiltrative GBM and propose an importance of multi-target therapy for GBM, which underwent microenvironmental adaptation.

Fermi Observations of GRB 090510: A Short Hard Gamma-Ray Burst with an Additional, Hard Power-Law Component from 10 keV to GeV Energies

DOE PAGES

Ackermann, M.; Asano, K.; Atwood, W. B.; ...

2010-05-27

We present detailed observations of the bright short-hard gamma-ray burst GRB 090510 made with the Gamma-ray Burst Monitor (GBM) and Large Area Telescope (LAT) on board the Fermi observatory. GRB 090510 is the first burst detected by the LAT that shows strong evidence for a deviation from a Band spectral fitting function during the prompt emission phase. The time-integrated spectrum is fit by the sum of a Band function with E peak = 3.9 ± 0.3 MeV, which is the highest yet measured, and a hard power-law component with photon index –1.62 ± 0.03 that dominates the emission below ≈20more » keV and above ≈100 MeV. The onset of the high-energy spectral component appears to be delayed by ~0.1 s with respect to the onset of a component well fit with a single Band function. A faint GBM pulse and a LAT photon are detected 0.5 s before the main pulse. During the prompt phase, the LAT detected a photon with energy 30.5 +5.8 –2.6 GeV, the highest ever measured from a short GRB. Observation of this photon sets a minimum bulk outflow Lorentz factor, Γ≳ 1200, using simple γγ opacity arguments for this GRB at redshift z = 0.903 and a variability timescale on the order of tens of ms for the ≈100 keV-few MeV flux. Stricter high confidence estimates imply Γ ≳ 1000 and still require that the outflows powering short GRBs are at least as highly relativistic as those of long-duration GRBs. Finally, implications of the temporal behavior and power-law shape of the additional component on synchrotron/synchrotron self-Compton, external-shock synchrotron, and hadronic models are considered.« less

PKCδ activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling

PubMed Central

Kang, Seok-Gu; Kim, Rae-Kwon; Cui, Yan-Hong; Lee, Hae-June; Kim, Min-Jung; Lee, Jae-Seong; Kim, In-Gyu; Suh, Yongjoon; Lee, Su-Jae

2016-01-01

Poor prognosis of glioblastoma (GBM) is attributable to the propensity of tumor cells to infiltrate into the brain parenchyma. Protein kinase C (PKC) isozymes are highly expressed or aberrantly activated in GBM. However, how this signaling node translates to GBM cell invasiveness remains unknown. Here, we report that among PKC isoforms, PKCδ is strongly associated with infiltration of GBM cells. Notably, PKCδ enhanced Tyr418 phosphorylation of the non-receptor tyrosine kinase SRC, which in turn activated STAT3 and subsequent NOTCH2 signaling, ultimately leading to GBM cell invasiveness. Furthermore, we showed that PKCδ was aberrantly activated in GBM cells by c-MET, a receptor tyrosine kinase hyperactivated in GBM. In agreement, inhibition either component in the c-MET/PKCδ/SRC/STAT3 signaling axis effectively blocked the NOTCH2 signaling and invasiveness of GBM cells. Taken together, our findings shed a light on the signaling mechanisms behind the constitutive activation of PKCδ signaling in GBM. PMID:26700818

Identification of a Druggable Pathway Controlling Glioblastoma Invasiveness.

PubMed

Pencheva, Nora; de Gooijer, Mark C; Vis, Daniel J; Wessels, Lodewyk F A; Würdinger, Tom; van Tellingen, Olaf; Bernards, René

2017-07-05

Diffuse and uncontrollable brain invasion is a hallmark of glioblastoma (GBM), but its mechanism is understood poorly. We developed a 3D ex vivo organotypic model to study GBM invasion. We demonstrate that invading GBM cells upregulate a network of extracellular matrix (ECM) components, including multiple collagens, whose expression correlates strongly with grade and clinical outcome. We identify interferon regulatory factor 3 (IRF3) as a transcriptional repressor of ECM factors and show that IRF3 acts as a suppressor of GBM invasion. Therapeutic activation of IRF3 by inhibiting casein kinase 2 (CK2)-a negative regulator of IRF3-downregulated the expression of ECM factors and suppressed GBM invasion in ex vivo and in vivo models across a panel of patient-derived GBM cell lines representative of the main molecular GBM subtypes. Our data provide mechanistic insight into the invasive capacity of GBM tumors and identify a potential therapy to inhibit GBM invasion. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.

PubMed

Binder, Zev A; Wilson, Kelli M; Salmasi, Vafi; Orr, Brent A; Eberhart, Charles G; Siu, I-Mei; Lim, Michael; Weingart, Jon D; Quinones-Hinojosa, Alfredo; Bettegowda, Chetan; Kassam, Amin B; Olivi, Alessandro; Brem, Henry; Riggins, Gregory J; Gallia, Gary L

2016-01-01

Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants. Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling. Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors. We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study.

NG2 expression in glioblastoma identifies an actively proliferating population with an aggressive molecular signature

PubMed Central

Al-Mayhani, M. Talal F.; Grenfell, Richard; Narita, Masashi; Piccirillo, Sara; Kenney-Herbert, Emma; Fawcett, James W.; Collins, V. Peter; Ichimura, Koichi; Watts, Colin

2011-01-01

Glioblastoma multiforme (GBM) is the most common type of primary brain tumor and a highly malignant and heterogeneous cancer. Current conventional therapies fail to eradicate or curb GBM cell growth. Hence, exploring the cellular and molecular basis of GBM cell growth is vital to develop novel therapeutic approaches. Neuroglia (NG)-2 is a transmembrane proteoglycan expressed by NG2+ progenitors and is strongly linked to cell proliferation in the normal brain. By using NG2 as a biomarker we identify a GBM cell population (GBM NG2+ cells) with robust proliferative, clonogenic, and tumorigenic capacity. We show that a significant proportion (mean 83%) of cells proliferating in the tumor mass express NG2 and that over 50% of GBM NG2+ cells are proliferating. Compared with the GBM NG2− cells from the same tumor, the GBM of NG2+ cells overexpress genes associated with aggressive tumorigenicity, including overexpression of Mitosis and Cell Cycling Module genes (e.g., MELK, CDC, MCM, E2F), which have been previously shown to correlate with poor survival in GBM. We also show that the coexpression pattern of NG2 with other glial progenitor markers in GBM does not recapitulate that described in the normal brain. The expression of NG2 by such an aggressive and actively cycling GBM population combined with its location on the cell surface identifies this cell population as a potential therapeutic target in a subset of patients with GBM. PMID:21798846

CXCR4 expression varies significantly among different subtypes of glioblastoma multiforme (GBM) and its low expression or hypermethylation might predict favorable overall survival.

PubMed

Ma, Xinlong; Shang, Feng; Zhu, Weidong; Lin, Qingtang

2017-09-01

CXCR4 is an oncogene in glioblastoma multiforme (GBM) but the mechanism of its dysregulation and its prognostic value in GBM have not been fully understood. Bioinformatic analysis was performed by using R2 and the UCSC Xena browser based on data from GSE16011 in GEO datasets and in GBM cohort in TCGA database (TCGA-GBM). Kaplan Meier curves of overall survival (OS) were generated to assess the association between CXCR4 expression/methylation and OS in patients with GBM. GBM patients with high CXCR4 expression had significantly worse 5 and 10 yrs OS (p < 0.05). Across different GBM subtypes, there was an inverse relationship between overall DNA methylation and CXCR4 expression. CXCR4 expression was significantly lower in CpG island methylation phenotype (CIMP) group than in non CIMP group. Log rank test results showed that patients with high CXCR4 methylation (first tertile) had significantly better 5 yrs OS (p = 0.038). CXCR4 expression is regulated by DNA methylation in GBM and its low expression or hypermethylation might indicate favorable OS in GBM patients.

Selective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma

PubMed Central

Sareddy, Gangadhara R.; Li, Xiaonan; Liu, Jinyou; Viswanadhapalli, Suryavathi; Garcia, Lauren; Gruslova, Aleksandra; Cavazos, David; Garcia, Mike; Strom, Anders M.; Gustafsson, Jan-Ake; Tekmal, Rajeshwar Rao; Brenner, Andrew; Vadlamudi, Ratna K.

2016-01-01

Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERβ, a second receptor for estrogen, targeting ERβ with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERβ agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERβ agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM. PMID:27126081

Influence of trap design on capture of female grape berry moth (lepidoptera: tortricidae) with a kairomone Lure

USDA-ARS?s Scientific Manuscript database

Oil-coated clear panel traps baited with a host plant-based kairomone lure are effective in monitoring female grape berry moth (GBM), Paralobesia viteana (Clemens) (Lepidoptera:Tortricidae), but servicing these traps in a vineyard is cumbersome. In this study, we compared the performance of six diff...

New Results on High Energy Cosmic Ray Electrons Observed with Fermi LAT and Their Implications on the Models of Pulsars

NASA Technical Reports Server (NTRS)

Moiseev, Alexander

2010-01-01

This viewgraph presentation describes, in detail, the Fermi Large Area Telescope (LAT) and GLAST Burst Monitor (GBM). Observations made from the June 11, 2008 launch and a discussion of observations made of high energy cosmic ray electrons is also presented.

Hard X-ray Variations in the Crab Nebula

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Cherry, M. L.; Case, G. L.; Baumgartner, W. H.; Beklen, E.; Bhat, P. N.; Briggs, M. S.; Camero-Arranz, A.; Chaplin, V.; Connaughton, V.;

Hard X-ray Variations in the Crab Nebula

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Cherry, M. L.; Case, G. L.; Baumgarter, W. H.; Beklen, E.; Bhat, P. N.; Briggs, M. S.; Camero-Arranz, A.; Chaplin, V.; Connaughton, V.;

Hard X-ray Variations in the Crab Nebula

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Cherry, M. L.; Case, G. L.; Baumgartner, W. H.; Beklen, E.; Bhat, P. N.; Briggs, M. S.; Camero-Arranz, A.; Connaughton, V.; Finger, M. H.;

Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models.

PubMed

Cen, Ling; Carlson, Brett L; Pokorny, Jenny L; Mladek, Ann C; Grogan, Patrick T; Schroeder, Mark A; Decker, Paul A; Anderson, S Keith; Giannini, Caterina; Wu, Wenting; Ballman, Karla V; Kitange, Gaspar J; Sarkaria, Jann N

2013-06-01

Temozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear. The efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model. Protracted TMZ therapy (TMZ daily M-F, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O(6)-DNA methylguanine-methyltransferase (MGMT) promoter hypermethylated lines (GBM12) and none of the 3 MGMT unmethylated lines, while standard therapy (TMZ daily M-F, 1 wk every 4) provided superior survival to the placebo-treated group in 2 of 3 MGMT unmethylated lines (GBM14 and GBM43) and none of the methylated lines. In comparing GBM12, GBM14, and GBM43 intracranial specimens, both GBM14 and GBM43 mice treated with protracted TMZ had a significant elevation in MGMT levels compared with placebo. Similarly, high MGMT was found in a second model of acquired TMZ resistance in GBM14 flank xenografts, and resistance was reversed in vitro by treatment with the MGMT inhibitor O(6)-benzylguanine, demonstrating a mechanistic link between MGMT overexpression and TMZ resistance in this line. Additionally, in an analysis of gene expression data, comparison of parental and TMZ-resistant GBM14 demonstrated enrichment of functional ontologies for cell cycle control within the S, G2, and M phases of the cell cycle and DNA damage checkpoints. Across the 7 tumor models studied, there was no consistent difference between protracted and standard TMZ regimens. The efficacy of protracted TMZ regimens may be limited in a subset of MGMT unmethylated tumors by induction of MGMT expression.

P08.14 In situ detection of hypoxia inducible factor 2 alpha in malignant gliomas

PubMed Central

Renfrow, J. J.; Strowd, R. E.; Huang, Y.; Herpai, D.; Mott, R. T.; Wong, T.; Lesser, G. J.; Debinski, W.

2017-01-01

Abstract Introduction: Direct intratumoral measurements confirm that necrosis and hypoxia are fundamental features of the pathobiology of glioblastoma (GBM). Tumor cells adapt to hypoxia through up regulation of hypoxia inducible factors (HIFs), a conserved family of transcription factors. Of the HIFs, HIF-2 alpha (HIF-2α) appears to be expressed in GBM tumor cells (not neural progenitors) and drives adaptation to prolonged (>24 hour) hypoxia. Targeting HIFs is an attractive cancer treatment strategy given that tumor hypoxia is a constant environmental cue driving genetic instability, cell migration, angiogenesis, and chemoradiation resistance. GBM, a tumor uniformly characterized by an intratumoral hypoxic environment, is a prime candidate for HIF therapeutic targeting but specific drugs were not available. PT2385 is a novel, first-in-class, HIF-2α inhibitor which recently entered clinical trials for renal carcinoma. PT2385 is orally administered and is small, lipophilic with a brain:plasma ratio of 0.9 in rats. To establish HIF-2α as a therapeutic target in GBM, we investigated in situ expression of HIF-2α protein in tissue samples from the Wake Forest Brain Tumor Center of Excellence Brain Tumor Bank. Methods: 22 formalin-fixed, paraffin-embedded glioma samples (grade II-IV) were analyzed for HIF-2α expression using immunohistochemistry. After rehydration, endogenous peroxidase was blocked, epitopes were retrieved using a microwaved Tris EDTA pH 9.0 solution, non-specific epitopes were blocked, and HIF-2α antibody (Santa Cruz, sc-13596) was added. A horseradish peroxidase conjugated anti-mouse antibody was then added followed by detection chromagen. An inverted bright field microscope captured images and representative samples were digitally scanned. Localization and quantification of HIF-2α was independently verified by a neuropathologist. Results: There was no detectable HIF-2α expression in the four Grade II and two Grade III gliomas studied. Of the 16 GBMs (Grade IV), HIF-2α was expressed in 13 (81%). HIF-2α was highly expressed in seven specimens (>10% cells positive), intermediate in six specimens (<10% of cells positive), and minimal to none in three specimens. Staining was specific to both tumor cells and occasionally monocytic cells (based on morphology). It was noted that HIF-2α was frequently present in perivascular and perinecrotic regions. Conclusions: HIF-2α expression is found in the majority of GBM specimens, but is absent in low-grade gliomas. Immunohistochemistry demonstrated a range of HIF-2α abundance along with regional staining patterns, clustered in perivascular and perinecrotic niches. HIF-2α appears to correlate with increasing malignancy grade. This is the first in situ description of HIF-2α in gliomas and further studies are in progress for preclinical in vitro and in vivo testing of PT2385, a first-in-class HIF-2α targeted agent, in GBM.

Glioblastoma with oligodendroglioma component (GBM-O): molecular genetic and clinical characteristics.

PubMed

Appin, Christina L; Gao, Jingjing; Chisolm, Candace; Torian, Mike; Alexis, Dianne; Vincentelli, Cristina; Schniederjan, Matthew J; Hadjipanayis, Costas; Olson, Jeffrey J; Hunter, Stephen; Hao, Chunhai; Brat, Daniel J

2013-07-01

Glioblastoma (GBM) is an aggressive primary brain tumor with an average survival of approximately 1 year. A recently recognized subtype, glioblastoma with oligodendroglioma component (GBM-O), was designated by the World Health Organization (WHO) in 2007. We investigated GBM-Os for their clinical and molecular characteristics as compared to other forms of GBM. Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation-specific polymerase chain reaction (PCR). GBM-Os accounted for 11.9% of all GBMs. GBM-Os arose in younger patients compared to other forms of GBMs (50.7 years vs. 58.7 years, respectively), were more frequently secondary neoplasms, had a higher frequency of IDH1 mutations and had a lower frequency of PTEN deletions. Survival was longer in patients with GBM-Os compared to those with other GBMs, with median survivals of 16.2 and 8.1 months, respectively. Most of the survival advantage for GBM-O appeared to be associated with a younger age at presentation. Among patients with GBM-O, younger age at presentation and 1p deletion were most significant in conferring prolonged survival. Thus, GBM-O represents a subset of GBMs with distinctive morphologic, clinical and molecular characteristics. © 2013 The Authors; Brain Pathology © 2013 International Society of Neuropathology.

A Large-scale Search for Evidence of Quasi-periodic Pulsations in Solar Flares

NASA Astrophysics Data System (ADS)

Inglis, A. R.; Ireland, J.; Dennis, B. R.; Hayes, L.; Gallagher, P.

2016-12-01

The nature of quasi-periodic pulsations (QPP) in solar flares is poorly constrained, and critically the general prevalence of such signals in solar flares is unknown. Therefore, we perform a large-scale search for evidence of signals consistent with QPP in solar flares, focusing on the 1-300 s timescale. We analyze 675 M- and X-class flares observed by the Geostationary Operational Environmental Satellite (GOES) series in 1-8 Å soft X-rays between 2011 February 1 and 2015 December 31. Additionally, over the same era we analyze Fermi/Gamma-ray Burst Monitor (GBM) 15-25 keV X-ray data for each of these flares associated with a Fermi/GBM solar flare trigger, a total of 261 events. Using a model comparison method, we determine whether there is evidence for a substantial enhancement in the Fourier power spectrum that may be consistent with a QPP signature, based on three tested models; a power-law plus a constant, a broken power-law plus constant, and a power-law-plus-constant with an additional QPP signature component. From this, we determine that ˜30% of GOES events and ˜8% of Fermi/GBM events show strong signatures consistent with classical interpretations of QPP. For the remaining events either two or more tested models cannot be strongly distinguished from each other, or the events are well-described by single power-law or broken power-law Fourier power spectra. For both instruments, a preferred characteristic timescale of ˜5-30 s was found in the QPP-like events, with no dependence on flare magnitude in either GOES or GBM data. We also show that individual events in the sample show similar characteristic timescales in both GBM and GOES data sets. We discuss the implications of these results for our understanding of solar flares and possible QPP mechanisms.

A Large-Scale Search for Evidence of Quasi-Periodic Pulsations in Solar Flares

NASA Technical Reports Server (NTRS)

Inglis, A. R.; Ireland, J.; Dennis, B. R..; Hayes, L.; Gallagher, P.

2016-01-01

The nature of quasi-periodic pulsations (QPP) in solar flares is poorly constrained, and critically the general prevalence of such signals in solar flares is unknown. Therefore, we perform a large-scale search for evidence of signals consistent with QPP in solar flares, focusing on the 1300 s timescale. We analyze 675 M- and X-class flares observed by the Geostationary Operational Environmental Satellite (GOES) series in 18 soft X-rays between 2011 February 1 and 2015 December 31. Additionally, over the same era we analyze Fermi/Gamma-ray Burst Monitor (GBM) 1525 keV X-ray data for each of these flares associated with a Fermi/GBM solar flare trigger, a total of 261 events. Using a model comparison method, we determine whether there is evidence for a substantial enhancement in the Fourier power spectrum that may be consistent with a QPP signature, based on three tested models; a power-law plus a constant, a broken power-law plus constant, and a power-law-plus-constant with an additional QPP signature component. From this, we determine that approx. 30% of GOES events and approx. 8% of Fermi/GBM events show strong signatures consistent with classical interpretations of QPP. For the remaining events either two or more tested models cannot be strongly distinguished from each other, or the events are well-described by single power-law or broken power-law Fourier power spectra. For both instruments, a preferred characteristic time-scale of approx. 5-30 s was found in the QPP-like events, with no dependence on flare magnitude in either GOES or GBM data. We also show that individual events in the sample show similar characteristic time-scales in both GBM and GOES data sets. We discuss the implications of these results for our understanding of solar flares and possible QPP mechanisms.

A LARGE-SCALE SEARCH FOR EVIDENCE OF QUASI-PERIODIC PULSATIONS IN SOLAR FLARES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inglis, A. R.; Ireland, J.; Dennis, B. R.

The nature of quasi-periodic pulsations (QPP) in solar flares is poorly constrained, and critically the general prevalence of such signals in solar flares is unknown. Therefore, we perform a large-scale search for evidence of signals consistent with QPP in solar flares, focusing on the 1–300 s timescale. We analyze 675 M- and X-class flares observed by the Geostationary Operational Environmental Satellite (GOES) series in 1–8 Å soft X-rays between 2011 February 1 and 2015 December 31. Additionally, over the same era we analyze Fermi /Gamma-ray Burst Monitor (GBM) 15–25 keV X-ray data for each of these flares associated with amore » Fermi /GBM solar flare trigger, a total of 261 events. Using a model comparison method, we determine whether there is evidence for a substantial enhancement in the Fourier power spectrum that may be consistent with a QPP signature, based on three tested models; a power-law plus a constant, a broken power-law plus constant, and a power-law-plus-constant with an additional QPP signature component. From this, we determine that ∼30% of GOES events and ∼8% of Fermi /GBM events show strong signatures consistent with classical interpretations of QPP. For the remaining events either two or more tested models cannot be strongly distinguished from each other, or the events are well-described by single power-law or broken power-law Fourier power spectra. For both instruments, a preferred characteristic timescale of ∼5–30 s was found in the QPP-like events, with no dependence on flare magnitude in either GOES or GBM data. We also show that individual events in the sample show similar characteristic timescales in both GBM and GOES data sets. We discuss the implications of these results for our understanding of solar flares and possible QPP mechanisms.« less

NFκB inhibitors induce cell death in glioblastomas.

PubMed

Zanotto-Filho, Alfeu; Braganhol, Elizandra; Schröder, Rafael; de Souza, Luís Henrique T; Dalmolin, Rodrigo J S; Pasquali, Matheus A Bittencourt; Gelain, Daniel Pens; Battastini, Ana Maria Oliveira; Moreira, José Cláudio Fonseca

2011-02-01

Identification of novel target pathways in glioblastoma (GBM) remains critical due to poor prognosis, inefficient therapies and recurrence associated with these tumors. In this work, we evaluated the role of nuclear-factor-kappa-B (NFκB) in the growth of GBM cells, and the potential of NFκB inhibitors as antiglioma agents. NFκB pathway was found overstimulated in GBM cell lines and in tumor specimens compared to normal astrocytes and healthy brain tissues, respectively. Treatment of a panel of established GBM cell lines (U138MG, U87, U373 and C6) with pharmacological NFκB inhibitors (BAY117082, parthenolide, MG132, curcumin and arsenic trioxide) and NFκB-p65 siRNA markedly decreased the viability of GBMs as compared to inhibitors of other signaling pathways such as MAPKs (ERK, JNK and p38), PKC, EGFR and PI3K/Akt. In addition, NFκB inhibitors presented a low toxicity to normal astrocytes, indicating selectivity to cancerous cells. In GBMs, mitochondrial dysfunction (membrane depolarization, bcl-xL downregulation and cytochrome c release) and arrest in the G2/M phase were observed at the early steps of NFκB inhibitors treatment. These events preceded sub-G1 detection, apoptotic body formation and caspase-3 activation. Also, NFκB was found overstimulated in cisplatin-resistant C6 cells, and treatment of GBMs with NFκB inhibitors overcame cisplatin resistance besides potentiating the effects of the chemotherapeutics, cisplatin and doxorubicin. These findings support NFκB as a potential target to cell death induction in GBMs, and that the NFκB inhibitors may be considered for in vivo testing on animal models and possibly on GBM therapy. Copyright © 2010 Elsevier Inc. All rights reserved.

MRI to MGMT: predicting methylation status in glioblastoma patients using convolutional recurrent neural networks

PubMed Central

Han, Lichy; Kamdar, Maulik R.

2017-01-01

Glioblastoma Multiforme (GBM), a malignant brain tumor, is among the most lethal of all cancers. Temozolomide is the primary chemotherapy treatment for patients diagnosed with GBM. The methylation status of the promoter or the enhancer regions of the O6− methylguanine methyltransferase (MGMT) gene may impact the efficacy and sensitivity of temozolomide, and hence may affect overall patient survival. Microscopic genetic changes may manifest as macroscopic morphological changes in the brain tumors that can be detected using magnetic resonance imaging (MRI), which can serve as noninvasive biomarkers for determining methylation of MGMT regulatory regions. In this research, we use a compendium of brain MRI scans of GBM patients collected from The Cancer Imaging Archive (TCIA) combined with methylation data from The Cancer Genome Atlas (TCGA) to predict the methylation state of the MGMT regulatory regions in these patients. Our approach relies on a bi-directional convolutional recurrent neural network architecture (CRNN) that leverages the spatial aspects of these 3-dimensional MRI scans. Our CRNN obtains an accuracy of 67% on the validation data and 62% on the test data, with precision and recall both at 67%, suggesting the existence of MRI features that may complement existing markers for GBM patient stratification and prognosis. We have additionally presented our model via a novel neural network visualization platform, which we have developed to improve interpretability of deep learning MRI-based classification models. PMID:29218894

Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide

PubMed Central

Murphy, Susan F; Varghese, Robin T; Lamouille, Samy; Guo, Sujuan; Pridham, Kevin J; Kanabur, Pratik; Osimani, Alyssa M; Sharma, Shaan; Jourdan, Jane; Rodgers, Cara M; Simonds, Gary R; Gourdie, Robert G; Sheng, Zhi

2015-01-01

Resistance of glioblastoma (GBM) to the front-line chemotherapeutic agent temozolomide (TMZ) continues to challenge GBM treatment efforts. The repair of TMZ-induced DNA damage by O-6-methylguanine-DNA methyltransferase (MGMT) confers one mechanism of TMZ resistance. Paradoxically, MGMT-deficient GBM patients survive longer despite still developing resistance to TMZ. Recent studies indicate that the gap junction protein connexin 43 (Cx43) renders GBM cells resistant to TMZ through its carboxyl terminus (CT). In this study, we report insights into how Cx43 promotes TMZ resistance. Cx43 levels were inversely correlated with TMZ sensitivity of GBM cells, including GBM stem cells. Moreover, Cx43 levels inversely correlated with patient survival, including as observed in MGMT-deficient GBM patients. Addition of the C-terminal peptide mimetic αCT1, a selective inhibitor of Cx43 channels, sensitized human MGMT-deficient and TMZ-resistant GBM cells to TMZ treatment. Moreover, combining αCT1 with TMZ blocked AKT/mTOR signaling, induced autophagy and apoptosis in TMZ-resistant GBM cells. Our findings suggest that Cx43 may offer a biomarker to predict the survival of patients with MGMT-independent TMZ resistance, and that combining a Cx43 inhibitor with TMZ could enhance therapeutic responses in GBM and perhaps other TMZ-resistant cancers. PMID:26542214

BIRC3 is a biomarker of mesenchymal habitat of glioblastoma, and a mediator of survival adaptation in hypoxia-driven glioblastoma habitats.

PubMed

Wang, Dapeng; Berglund, Anders E; Kenchappa, Rajappa S; MacAulay, Robert J; Mulé, James J; Etame, Arnold B

2017-08-24

Tumor hypoxia is an established facilitator of survival adaptation and mesenchymal transformation in glioblastoma (GBM). The underlying mechanisms that direct hypoxia-mediated survival in GBM habitats are unclear. We previously identified BIRC3 as a mediator of therapeutic resistance in GBM to standard temozolomide (TMZ) chemotherapy and radiotherapy (RT). Here we report that BIRC3 is a biomarker of the hypoxia-mediated adaptive mesenchymal phenotype of GBM. Specifically, in the TCGA dataset elevated BIRC3 gene expression was identified as a superior and selective biomarker of mesenchymal GBM versus neural, proneural and classical subtypes. Further, BIRC3 protein was highly expressed in the tumor cell niches compared to the perivascular niche across multiple regions in GBM patient tissue microarrays. Tumor hypoxia was found to mechanistically induce BIRC3 expression through HIF1-alpha signaling in GBM cells. Moreover, in human GBM xenografts robust BIRC3 expression was noted within hypoxic regions of the tumor. Importantly, selective inhibition of BIRC3 reversed therapeutic resistance of GBM cells to RT in hypoxic microenvironments through enhanced activation of caspases. Collectively, we have uncovered a novel role for BIRC3 as a targetable biomarker and mediator of hypoxia-driven habitats in GBM.

Liposomal TriCurin, A Synergistic Combination of Curcumin, Epicatechin Gallate and Resveratrol, Repolarizes Tumor-Associated Microglia/Macrophages, and Eliminates Glioblastoma (GBM) and GBM Stem Cells.

PubMed

Mukherjee, Sumit; Baidoo, Juliet N E; Sampat, Samay; Mancuso, Andrew; David, Lovena; Cohen, Leah S; Zhou, Shuiqin; Banerjee, Probal

2018-01-18

Glioblastoma (GBM) is a deadly brain tumor with a current mean survival of 12-15 months. Despite being a potent anti-cancer agent, the turmeric ingredient curcumin (C) has limited anti-tumor efficacy in vivo due to its low bioavailability. We have reported earlier a strategy involving the use two other polyphenols, epicatechin gallate (E) from green tea and resveratrol (R) from red grapes at a unique, synergistic molar ratio with C (C:E:R: 4:1:12.5, termed TriCurin) to achieve superior potency against HPV+ tumors than C alone at C:E:R (μM): 32:8:100 (termed 32 μM+ TriCurin). We have now prepared liposomal TriCurin (TrLp) and demonstrated that TrLp boosts activated p53 in cultured GL261 mouse GBM cells to trigger apoptosis of GBM and GBM stem cells in vitro. TrLp administration into mice yielded a stable plasma concentration of 210 nM C for 60 min, which, though sub-lethal for cultured GL261 cells, was able to cause repolarization of M2-like tumor (GBM)-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells. The intratumor presence of such tumoricidal immune cells was associated with concomitant suppression of tumor-load, and apoptosis of GBM and GBM stem cells. Thus, TrLp is a potential onco-immunotherapeutic agent against GBM tumors.

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the genemore » expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. - Highlights: • Gene expression signarue in long-term survived GBM patients are identified from Gene Expression Omnibus database. • Repaglinide is identified as a survival-related drug for GBM via drug repositioning in CMap. • Repaglinide effectively kills GBM cells, inhibits GBM cell migration and increases survival of mice bearing orthotopic glioma. • Repaglinide reduces Bcl-2, Beclin-1 and PD-L1 in GBM tissues.« less

Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients.

PubMed

Figueroa, Javier M; Skog, Johan; Akers, Johnny; Li, Hongying; Komotar, Ricardo; Jensen, Randy; Ringel, Florian; Yang, Isaac; Kalkanis, Steven; Thompson, Reid; LoGuidice, Lori; Berghoff, Emily; Parsa, Andrew; Liau, Linda; Curry, William; Cahill, Daniel; Bettegowda, Chetan; Lang, Frederick F; Chiocca, E Antonio; Henson, John; Kim, Ryan; Breakefield, Xandra; Chen, Clark; Messer, Karen; Hochberg, Fred; Carter, Bob S

2017-10-19

RNAs within extracellular vesicles (EVs) have potential as diagnostic biomarkers for patients with cancer and are identified in a variety of biofluids. Glioblastomas (GBMs) release EVs containing RNA into cerebrospinal fluid (CSF). Here we describe a multi-institutional study of RNA extracted from CSF-derived EVs of GBM patients to detect the presence of tumor-associated amplifications and mutations in epidermal growth factor receptor (EGFR). CSF and matching tumor tissue were obtained from patients undergoing resection of GBMs. We determined wild-type (wt)EGFR DNA copy number amplification, as well as wtEGFR and EGFR variant (v)III RNA expression in tumor samples. We also characterized wtEGFR and EGFRvIII RNA expression in CSF-derived EVs. EGFRvIII-positive tumors had significantly greater wtEGFR DNA amplification (P = 0.02) and RNA expression (P = 0.03), and EGFRvIII-positive CSF-derived EVs had significantly more wtEGFR RNA expression (P = 0.004). EGFRvIII was detected in CSF-derived EVs for 14 of the 23 EGFRvIII tissue-positive GBM patients. Conversely, only one of the 48 EGFRvIII tissue-negative patients had the EGFRvIII mutation detected in their CSF-derived EVs. These results yield a sensitivity of 61% and a specificity of 98% for the utility of CSF-derived EVs to detect an EGFRvIII-positive GBM. Our results demonstrate CSF-derived EVs contain RNA signatures reflective of the underlying molecular genetic status of GBMs in terms of wtEGFR expression and EGFRvIII status. The high specificity of the CSF-derived EV diagnostic test gives us an accurate determination of positive EGFRvIII tumor status and is essentially a less invasive "liquid biopsy" that might direct mutation-specific therapies for GBMs. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

FoxM1 Promotes Stemness and Radio-Resistance of Glioblastoma by Regulating the Master Stem Cell Regulator Sox2

PubMed Central

Kim, Dong Geon; Cho, Hee Jin; Kim, Yeonghwan; Rheey, Jinguen; Shin, Kayoung; Seo, Yun Jee; Choi, Yeon-Sook; Lee, Jung-Il; Lee, Jeongwu; Joo, Kyeung Min; Nam, Do-Hyun

2015-01-01

Glioblastoma (GBM) is the most aggressive and most lethal brain tumor. As current standard therapy consisting of surgery and chemo-irradiation provides limited benefit for GBM patients, novel therapeutic options are urgently required. Forkhead box M1 (FoxM1) transcription factor is an oncogenic regulator that promotes the proliferation, survival, and treatment resistance of various human cancers. The roles of FoxM1 in GBM remain incompletely understood, due in part to pleotropic nature of the FoxM1 pathway. Here, we show the roles of FoxM1 in GBM stem cell maintenance and radioresistance. ShRNA-mediated FoxM1 inhibition significantly impeded clonogenic growth and survival of patient-derived primary GBM cells with marked downregulation of Sox2, a master regulator of stem cell phenotype. Ectopic expression of Sox2 partially rescued FoxM1 inhibition-mediated effects. Conversely, FoxM1 overexpression upregulated Sox2 expression and promoted clonogenic growth of GBM cells. These data, with a direct binding of FoxM1 in the Sox2 promoter region in GBM cells, suggest that FoxM1 regulates stemness of primary GBM cells via Sox2. We also found significant increases in FoxM1 and Sox2 expression in GBM cells after irradiation both in vitro and in vivo orthotopic tumor models. Notably, genetic or a small-molecule FoxM1 inhibitor-mediated FoxM1 targeting significantly sensitized GBM cells to irradiation, accompanying with Sox2 downregulation. Finally, FoxM1 inhibition combined with irradiation in a patient GBM-derived orthotopic model significantly impeded tumor growth and prolonged the survival of tumor bearing mice. Taken together, these results indicate that the FoxM1-Sox2 signaling axis promotes clonogenic growth and radiation resistance of GBM, and suggest that FoxM1 targeting combined with irradiation is a potentially effective therapeutic approach for GBM. PMID:26444992

FoxM1 Promotes Stemness and Radio-Resistance of Glioblastoma by Regulating the Master Stem Cell Regulator Sox2.

PubMed

Lee, Yeri; Kim, Kang Ho; Kim, Dong Geon; Cho, Hee Jin; Kim, Yeonghwan; Rheey, Jinguen; Shin, Kayoung; Seo, Yun Jee; Choi, Yeon-Sook; Lee, Jung-Il; Lee, Jeongwu; Joo, Kyeung Min; Nam, Do-Hyun

2015-01-01

Glioblastoma (GBM) is the most aggressive and most lethal brain tumor. As current standard therapy consisting of surgery and chemo-irradiation provides limited benefit for GBM patients, novel therapeutic options are urgently required. Forkhead box M1 (FoxM1) transcription factor is an oncogenic regulator that promotes the proliferation, survival, and treatment resistance of various human cancers. The roles of FoxM1 in GBM remain incompletely understood, due in part to pleotropic nature of the FoxM1 pathway. Here, we show the roles of FoxM1 in GBM stem cell maintenance and radioresistance. ShRNA-mediated FoxM1 inhibition significantly impeded clonogenic growth and survival of patient-derived primary GBM cells with marked downregulation of Sox2, a master regulator of stem cell phenotype. Ectopic expression of Sox2 partially rescued FoxM1 inhibition-mediated effects. Conversely, FoxM1 overexpression upregulated Sox2 expression and promoted clonogenic growth of GBM cells. These data, with a direct binding of FoxM1 in the Sox2 promoter region in GBM cells, suggest that FoxM1 regulates stemness of primary GBM cells via Sox2. We also found significant increases in FoxM1 and Sox2 expression in GBM cells after irradiation both in vitro and in vivo orthotopic tumor models. Notably, genetic or a small-molecule FoxM1 inhibitor-mediated FoxM1 targeting significantly sensitized GBM cells to irradiation, accompanying with Sox2 downregulation. Finally, FoxM1 inhibition combined with irradiation in a patient GBM-derived orthotopic model significantly impeded tumor growth and prolonged the survival of tumor bearing mice. Taken together, these results indicate that the FoxM1-Sox2 signaling axis promotes clonogenic growth and radiation resistance of GBM, and suggest that FoxM1 targeting combined with irradiation is a potentially effective therapeutic approach for GBM.

microRNA-598 inhibits cell proliferation and invasion of glioblastoma by directly targeting metastasis associated in colon cancer-1.

PubMed

Wang, Ning; Zhang, Yang; Liang, Huaxin

2018-02-14

The dysregulation of microRNAs (miRNAs) expression is closely related with tumorigenesis and tumour development in glioblastoma (GBM). In this study, we found that miRNA-598 (miR-598) expression was significantly downregulated in GBM tissues and cell lines. Restoring miR-598 expression inhibited cell proliferation and invasion in GBM. Moreover, we validated that metastasis associated in colon cancer-1 (MACC1) is a novel target of miR-598 in GBM. Recovered MACC1 expression reversed the inhibitory effects of miR-598 overexpression on GBM cells. In addition, miR-598 overexpression suppressed the Met/AKT pathway activation in GBM. Our results provided compelling evidence that miR-598 serves tumour suppressive roles in GBM and that its anti-oncogenic effects are mediated chiefly through the direct suppression of MACC1 expression and regulation of the Met/AKT signalling pathway. Therefore, miR-598 is a potential target in the treatment of GBM.

Discovery of cell surface vimentin targeting mAb for direct disruption of GBM tumor initiating cells.

PubMed

Noh, Hyangsoon; Yan, Jun; Hong, Sungguan; Kong, Ling-Yuan; Gabrusiewicz, Konrad; Xia, Xueqing; Heimberger, Amy B; Li, Shulin

2016-11-01

Intracellular vimentin overexpression has been associated with epithelial-mesenchymal transition, metastasis, invasion, and proliferation, but cell surface vimentin (CSV) is less understood. Furthermore, it remains unknown whether CSV can serve as a therapeutic target in CSV-expressing tumor cells. We found that CSV was present on glioblastoma multiforme (GBM) cancer stem cells and that CSV expression was associated with spheroid formation in those cells. A newly developed monoclonal antibody against CSV, 86C, specifically and significantly induced apoptosis and inhibited spheroid formation in GBM cells in vitro. The addition of 86C to GBM cells in vitro also led to rapid internalization of vimentin and decreased GBM cell viability. These findings were associated with an increase in caspase-3 activity, indicating activation of apoptosis. Finally, treatment with 86C inhibited GBM progression in vivo. In conclusion, CSV-expressing GBM cells have properties of tumor initiating cells, and targeting CSV with the monoclonal antibody 86C is a promising approach in the treatment of GBM.

Characteristics of NLDN-Reported Radio Frequency Emissions Associated with Terrestrial Gamma-ray Flashes

NASA Astrophysics Data System (ADS)

Mailyan, B. G.; Nag, A.; Murphy, M. J.; Briggs, M. S.; Dwyer, J. R.; Cramer, E.; Stanbro, M.; Roberts, O. J.; Rassoul, H.

2017-12-01

Electric and magnetic field signals in the radio frequency range associated with Terrestrial Gamma-ray Flashes (TGFs) have become important measurements for studying this high-energy atmospheric phenomenon. These signals can be used to geolocate the source of TGFs, but they also provide insights into the TGF production mechanism, and the relationship between particle fluxes and lightning. In this study, we analyze 32 TGFs detected by the Fermi Gamma-ray Burst Monitor (GBM) occurring in 2014-2016 in conjunction with data from the U.S. National Lightning Detection Network (NLDN). We examine the characteristics of magnetic field waveforms measured by NLDN sensors for 48 pulses occurring within 5 ms of the peak-time of the gamma-ray photon flux. The -3 dB bandwidth of the NLDN sensors are from about 400 Hz to 400 KHz. For 15 (out of 32) TGFs, the associated NLDN pulse occurred almost simultaneously with (that is, within 300 μs of) the TGF. It is possible that these near-simultaneous low frequency magnetic field pulses were produced by relativistic electron beams. The median time interval between the beginning of these near-simultaneous NLDN pulses and the peak-times of the TGF flux is 38 μs. 3 out of 16 ( 19%) of these pulses had negative initial polarity. The absolute value of NLDN-estimated peak currents, which can be viewed as a quantity proportional to the peak magnetic radiation field of these pulses, ranges from 17 kA to 166 kA, with the median being 32 kA. Twelve pulses had peak currents less than 50 kA. Additionally, we will compare the characteristics of GBM-reported gamma-ray signatures of the two categories of TGFs, those with a near-simultaneous NLDN-detected pulse and those with no such pulse (but with other pulses detected by the NLDN occurring within 5 ms of the TGF). Also, one of the TGFs occurred within the coverage region of the Kennedy Space Center Lightning Mapping Array (LMA). We will examine in detail the LMA, NLDN, and NEXRAD radar data for this TGF.

Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation

PubMed Central

Jha, Prerana; Pia Patric, Irene Rosita; Shukla, Sudhanshu; Pathak, Pankaj; Pal, Jagriti; Sharma, Vikas; Thinagararanjan, Sivaarumugam; Santosh, Vani; Suri, Vaishali; Sharma, Mehar Chand; Arivazhagan, Arimappamagan; Suri, Ashish; Gupta, Deepak; Somasundaram, Kumaravel; Sarkar, Chitra

2014-01-01

Background Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways. Methods Genome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine–phosphate–guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done. Results Distinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine–phosphate–guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment. Conclusions Our study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation–specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and needs further evaluation. PMID:24997139

Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma

PubMed Central

Sun, Jingchun; Gong, Xue; Purow, Benjamin; Zhao, Zhongming

2012-01-01

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers. PMID:22829753

Long term variability of Cygnus X-1. V. State definitions with all sky monitors

NASA Astrophysics Data System (ADS)

Grinberg, V.; Hell, N.; Pottschmidt, K.; Böck, M.; Nowak, M. A.; Rodriguez, J.; Bodaghee, A.; Cadolle Bel, M.; Case, G. L.; Hanke, M.; Kühnel, M.; Markoff, S. B.; Pooley, G. G.; Rothschild, R. E.; Tomsick, J. A.; Wilson-Hodge, C. A.; Wilms, J.

2013-06-01

We present a scheme for determining the spectral state of the canonical black hole Cyg X-1 using data from previous and current X-ray all sky monitors (RXTE-ASM, Swift-BAT, MAXI, and Fermi-GBM). Determinations of the hard/intermediate and soft state agree to better than 10% between different monitors, facilitating the determination of the state and its context for any observation of the source, potentially over the lifetimes of different individual monitors. A separation of the hard and the intermediate states, which strongly differ in their spectral shape and short-term timing behavior, is only possible when data in the soft X-rays (<5 keV) are available. A statistical analysis of the states confirms the different activity patterns of the source (e.g., month- to year-long hard-state periods or phases during which numerous transitions occur). It also shows that the hard and soft states are stable, with the probability of Cyg X-1 remaining in a given state for at least one week to be larger than 85% in the hard state and larger than 75% in the soft state. Intermediate states are short lived, with a 50% probability that the source leaves the intermediate state within three days. Reliable detection of these potentially short-lived events is only possible with monitor data that have a time resolution better than 1 d.

High Energy Cosmic Electrons: Messengers from Nearby Cosmic Ray Sources or Dark Matter?

NASA Technical Reports Server (NTRS)

Moiseev, Alexander

2011-01-01

This slide presentation reviews the recent discoveries by the Large Area Telescope (LAT) and the Gamma-ray Burst Monitor (GBM) on board the Fermi Gamma-Ray Telescope in reference to high energy cosmic electrons, and whether their source is cosmic rays or dark matter. Specific interest is devoted to Cosmic Ray electrons anisotropy,

Influence of trap design on upwind flight behavior and capture of female grape berry moth (Lepidoptera: Tortricidea) with a kairomone lure

USDA-ARS?s Scientific Manuscript database

Oil-coated clear panel traps baited with a host plant-based kairomone lure are effective in monitoring female grape berry moth (GBM), Paralobesia viteana (Clemens) (Lepidoptera:Tortricidae), but servicing these traps in a vineyard is cumbersome. In this study, we compared the performance of differen...

A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways

PubMed Central

Huang, Tianzhi; Alvarez, Angel A.; Pangeni, Rajendra P.; M. Horbinski, Craig; Lu, Songjian; Kim, Sung-Hak; James, C. David; J. Raizer, Jeffery; A. Kessler, John; Brenann, Cameron W.; Sulman, Erik P.; Finocchiaro, Gaetano; Tan, Ming; Nishikawa, Ryo; Lu, Xinghua; Nakano, Ichiro; Hu, Bo; Cheng, Shi-Yuan

2016-01-01

Molecularly defined subclassification is associated with phenotypic malignancy of glioblastoma (GBM). However, current understanding of the molecular basis of subclass conversion that is often involved in GBM recurrence remain rudimentary at best. Here we report that canonical Wnt signalling that is active in proneural (PN) but inactive in mesenchymal (MES) GBM, along with miR-125b and miR-20b that are expressed at high levels in PN compared with MES GBM, comprise a regulatory circuit involving TCF4-miR-125b/miR-20b-FZD6. FZD6 acts as a negative regulator of this circuit by activating CaMKII–TAK1–NLK signalling, which, in turn, attenuates Wnt pathway activity while promoting STAT3 and NF-κB signalling that are important regulators of the MES-associated phenotype. These findings are confirmed by targeting differentially enriched pathways in PN versus MES GBM that results in inhibition of distinct GBM subtypes. Correlative expressions of the components of this circuit are prognostic relevant for clinical GBM. Our findings provide insights for understanding GBM pathogenesis and for improving treatment of GBM. PMID:27698350

MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma

PubMed Central

McIntyre, Alan; Smith, Stuart

2017-01-01

Glioblastoma (GBM) is the most aggressive and common malignant brain tumour in adults. A well-known hallmark of GMB and many other tumours is aerobic glycolysis. MicroRNAs (miRNAs) are a class of short nonprotein coding sequences that exert posttranscriptional controls on gene expression and represent critical regulators of aerobic glycolysis in GBM. In GBM, miRNAs regulate the expression of glycolytic genes directly and via the regulation of metabolism-associated tumour suppressors and oncogenic signalling pathways. This review aims to establish links between miRNAs expression levels, the expression of GBM glycolytic regulatory genes, and the malignant progression and prognosis of GBM. In this review, the involvement of 25 miRNAs in the regulation of glycolytic metabolism of GBM is discussed. Seven of these miRNAs have been shown to regulate glycolytic metabolism in other tumour types. Further eight miRNAs, which are differentially expressed in GBM, have also been reported to regulate glycolytic metabolism in other cancer types. Thus, these miRNAs could serve as potential glycolytic regulators in GBM but will require functional validation. As such, the characterisation of these molecular and metabolic signatures in GBM can facilitate a better understanding of the molecular pathogenesis of this disease. PMID:28804724

The Role of Hypoxia in Glioblastoma Invasion

PubMed Central

Monteiro, Ana Rita; Pilkington, Geoffrey J.

2017-01-01

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient’s median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression. PMID:29165393

Development of Advanced Technologies for Complete Genomic and Proteomic Characterization of Quantized Human Tumor Cells

DTIC Science & Technology

2014-07-01

establishment of Glioblastoma ( GBM ) cell lines from GBM patient’s tumor samples and quantized cell populations of each of the parental GBM cell lines, we... GBM patients are now well established and from the basis of the molecular characterization of the tumor development and signatures presented by these...analysis of these quantized cell sub populations and have begun to assemble the protein signatures of GBM tumors underpinned by the comprehensive

The Accuracy of GBM GRB Localizations

NASA Astrophysics Data System (ADS)

Briggs, Michael Stephen; Connaughton, V.; Meegan, C.; Hurley, K.

2010-03-01

We report an study of the accuracy of GBM GRB localizations, analyzing three types of localizations: those produced automatically by the GBM Flight Software on board GBM, those produced automatically with ground software in near real time, and localizations produced with human guidance. The two types of automatic locations are distributed in near real-time via GCN Notices; the human-guided locations are distributed on timescale of many minutes or hours using GCN Circulars. This work uses a Bayesian analysis that models the distribution of the GBM total location error by comparing GBM locations to more accurate locations obtained with other instruments. Reference locations are obtained from Swift, Super-AGILE, the LAT, and with the IPN. We model the GBM total location errors as having systematic errors in addition to the statistical errors and use the Bayesian analysis to constrain the systematic errors.

A unique evolution of the kidney phenotype in a patient with autosomal recessive Alport syndrome.

PubMed

Vischini, Gisella; Kapp, Meghan E; Wheeler, Ferrin C; Hopp, Laszlo; Fogo, Agnes B

2018-03-09

Alport syndrome is due to mutations in one of the genes encoding (α3,4,5) type IV collagen resulting in defective type IV collagen, a key component of the glomerular basement membrane (GBM). The GBM is initially thin, and with ongoing remodeling, develops a thickened basket-woven appearance. We report a unique case of a 9-year-old boy who was biopsied for hematuria and proteinuria, diagnosed as IgA nephropathy, with normal GBM appearance and thickness. Due to a family history of hematuria and chronic kidney disease, he subsequently underwent genetic evaluation and a mutation of α3 type IV collagen (COL4A3) was detected. Additional studies of the initial biopsy demonstrated abnormal type IV collagen immunostaining. A repeat biopsy 4years later showed characteristic glomerular basement membrane morphology of Alport syndrome, and scarring consistent with sequelae of IgA nephropathy. This is the first description of this unusual transition from an initial normal appearance of the glomerular basement membrane to the classic Alport phenotype. Copyright © 2018. Published by Elsevier Inc.

Apparent diffusion coefficient in glioblastoma with PNET-like components, a GBM variant.

PubMed

Ali, Saad; Joseph, Nancy M; Perry, Arie; Barajas, Ramon F; Cha, Soonmee

2014-09-01

Glioblastoma (GBM) with primitive neuroectodermal tumor (PNET)-like (GBM-PNET) components is a rare variant of GBM. Recent studies describe PNET-like clinical behavior in these patients-with significantly increased propensity for CSF dissemination and a benefit of "PNET-like" chemotherapy. The imaging appearance of GBM-PNET is not well-described and given areas of marked cellularity in the PNET components one might expect significantly reduced diffusion on MRI. The purpose of this study is to quantitatively evaluate the diffusion characteristics in GBM-PNET and compare them with conventional GBMs. Nine patients with surgical specimens yielding GBM-PNET were identified from the UCSF Pathology files. MR images of these patients were reviewed retrospectively. DWI (diffusion-weighted imaging) sequences were analyzed with multiple regions of interests placed within the tumor, and ADC (apparent diffusion coefficient) values were measured. Results were compared to previously published ADC values in pathology-proven conventional GBM cases from our institution. Reduced ADC was seen in GBM-PNET (mean 581 × 10(-6) mm(2)/s, range 338-817) compared to previously published mean of 1,030 × 10(-6) mm(2)/s in the enhancing components of conventional GBMs. We report substantially reduced ADC values in GBM-PNETs compared to conventional GBMs. If demonstrated in a larger sample, when areas of marked reduced diffusion are seen in a suspected GBM, MRI may appropriately direct tissue sampling and can advocate a thorough search for PNET-like components on histopathology. These patients may have a higher chance of developing CSF dissemination and may benefit from "PNET-like" platinum-based chemotherapy.

Detection of Endotoxin Contamination of Graphene Based Materials Using the TNF-α Expression Test and Guidelines for Endotoxin-Free Graphene Oxide Production

PubMed Central

Del Rio-Castillo, Antonio E.; Newman, Leon; Vázquez, Ester; Kostarelos, Kostas; Wick, Peter; Fadeel, Bengt

2016-01-01

Nanomaterials may be contaminated with bacterial endotoxin during production and handling, which may confound toxicological testing of these materials, not least when assessing for immunotoxicity. In the present study, we evaluated the conventional Limulus amebocyte lysate (LAL) assay for endotoxin detection in graphene based material (GBM) samples, including graphene oxide (GO) and few-layered graphene (FLG). Our results showed that some GO samples interfered with various formats of the LAL assay. To overcome this problem, we developed a TNF-α expression test (TET) using primary human monocyte-derived macrophages incubated in the presence or absence of the endotoxin inhibitor, polymyxin B sulfate, and found that this assay, performed with non-cytotoxic doses of the GBM samples, enabled unequivocal detection of endotoxin with a sensitivity that is comparable to the LAL assay. FLG also triggered TNF-α production in the presence of the LPS inhibitor, pointing to an intrinsic pro-inflammatory effect. Finally, we present guidelines for the preparation of endotoxin-free GO, validated by using the TET. PMID:27880838

Detection of Endotoxin Contamination of Graphene Based Materials Using the TNF-α Expression Test and Guidelines for Endotoxin-Free Graphene Oxide Production.

PubMed

Mukherjee, Sourav P; Lozano, Neus; Kucki, Melanie; Del Rio-Castillo, Antonio E; Newman, Leon; Vázquez, Ester; Kostarelos, Kostas; Wick, Peter; Fadeel, Bengt

2016-01-01

Nanomaterials may be contaminated with bacterial endotoxin during production and handling, which may confound toxicological testing of these materials, not least when assessing for immunotoxicity. In the present study, we evaluated the conventional Limulus amebocyte lysate (LAL) assay for endotoxin detection in graphene based material (GBM) samples, including graphene oxide (GO) and few-layered graphene (FLG). Our results showed that some GO samples interfered with various formats of the LAL assay. To overcome this problem, we developed a TNF-α expression test (TET) using primary human monocyte-derived macrophages incubated in the presence or absence of the endotoxin inhibitor, polymyxin B sulfate, and found that this assay, performed with non-cytotoxic doses of the GBM samples, enabled unequivocal detection of endotoxin with a sensitivity that is comparable to the LAL assay. FLG also triggered TNF-α production in the presence of the LPS inhibitor, pointing to an intrinsic pro-inflammatory effect. Finally, we present guidelines for the preparation of endotoxin-free GO, validated by using the TET.

Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells.

PubMed

Farace, Cristiano; Oliver, Jaime Antonio; Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

2015-01-01

The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities of SLRP in response to CSC enrichment, simultaneously acquiring TMZ resistance, cellular heterogeneity, and a quiescent phenotype, suggesting a novel pivotal role for SLRP in drug resistance and cell plasticity of CSC-like, allowing cell survival and ECM/niche modulation potential.

Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells

PubMed Central

Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

2015-01-01

The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell–microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities of SLRP in response to CSC enrichment, simultaneously acquiring TMZ resistance, cellular heterogeneity, and a quiescent phenotype, suggesting a novel pivotal role for SLRP in drug resistance and cell plasticity of CSC-like, allowing cell survival and ECM/niche modulation potential. PMID:26230845

Nuclear factor one B (NFIB) encodes a subtype-specific tumour suppressor in glioblastoma

PubMed Central

Stringer, Brett W.; Bunt, Jens; Day, Bryan W.; Barry, Guy; Jamieson, Paul R.; Ensbey, Kathleen S.; Bruce, Zara C.; Goasdoué, Kate; Vidal, Hélène; Charmsaz, Sara; Smith, Fiona M.; Cooper, Leanne T.; Piper, Michael

2016-01-01

Glioblastoma (GBM) is an essentially incurable and rapidly fatal cancer, with few markers predicting a favourable prognosis. Here we report that the transcription factor NFIB is associated with significantly improved survival in GBM. NFIB expression correlates inversely with astrocytoma grade and is lowest in mesenchymal GBM. Ectopic expression of NFIB in low-passage, patient-derived classical and mesenchymal subtype GBM cells inhibits tumourigenesis. Ectopic NFIB expression activated phospho-STAT3 signalling only in classical and mesenchymal GBM cells, suggesting a mechanism through which NFIB may exert its context-dependent tumour suppressor activity. Finally, NFIB expression can be induced in GBM cells by drug treatment with beneficial effects. PMID:27083054

Rituximab for the treatment of refractory simultaneous anti-glomerular basement membrane (anti-GBM) and membranous nephropathy.

PubMed

Bandak, Ghassan; Jones, Bruce A; Li, Jian; Yee, Jerry; Umanath, Kausik

2014-02-01

Antibody-mediated anti-glomerular basement membrane (anti-GBM) disease occurs rarely in the presence of another B-cell disorder, membranous nephropathy. The coexistence of these two autoimmune disorders would be anticipated to require differing, specific therapies targeted to each disease process. We describe a case of concomitant membranous nephropathy and anti-GBM disease in which conventional therapy, including steroids, plasmapheresis and cyclophosphamide, failed to attenuate the anti-GBM disease, yet responded to an alternative treatment of rituximab. This B-cell directed, monoclonal, chimeric antibody treatment substantially reduced anti-GBM antibody titers and led to discontinuation of plasmapheresis, while maintaining the remission of membranous nephropathy and anti-GBM disease.

A search for Fermi bursts associated with supernovae and their frequency of occurrence

NASA Astrophysics Data System (ADS)

Kovacevic, M.; Izzo, L.; Wang, Y.; Muccino, M.; Della Valle, M.; Amati, L.; Barbarino, C.; Enderli, M.; Pisani, G. B.; Li, L.

2014-09-01

Context. Observations suggest that most long duration gamma-ray bursts (GRBs) are connected with broad-line supernovae Ib/c, (SNe-Ibc). The presence of GRB-SNe is revealed by rebrightenings emerging from the optical GRB afterglow 10-15 days, in the rest-frame of the source, after the prompt GRB emission. Aims: Fermi/GBM has a field of view (FoV) about 6.5 times larger than the FoV of Swift, therefore we expect that a number of GRB-SN connections have been missed because of lack of optical and X-ray instruments on board of Fermi, which are essential for revealing SNe associated with GRBs. This has motivated our search in the Fermi catalog for possible GRB-SN events. Methods: The search for possible GRB-SN associations follows two requirements: (1) SNe should fall inside the Fermi/GBM error box of the considered long GRB, and (2) this GRB should occur within 20 days before the SN event. Results: We have found five cases within z< 0.2 fulfilling the above reported requirements. One of them, GRB 130702A-SN 2013dx, was already known to have a GRB-SN association. We have analyzed the remaining four cases and we have concluded that three of them are, very likely, just random coincidences due to the Fermi/GBM large error box associated with each GRB detection. We found one GRB possibly associated with a SN 1998bw-like source, GRB 120121B/SN 2012ba. Conclusions: The very low redshift of GRB 120121B/SN 2012ba (z = 0.017) implies a low isotropic energy of this burst (Eiso = 1.39 × 1048) erg. We then compute the rate of Fermi low-luminosity GRBs connected with SNe to be ρ0,b ≤ 770 Gpc-3 yr-1. We estimate that Fermi/GBM could detect 1-4 GRBs-SNe within z ≤ 0.2 in the next 4 years.

Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of U251MG human glioma cells in a mouse xenograft model.

PubMed

Ji, Xiang-Jun; Chen, Sui-Hua; Zhu, Lin; Pan, Hao; Zhou, Yuan; Li, Wei; You, Wan-Chun; Gao, Chao-Chao; Zhu, Jian-Hong; Jiang, Kuan; Wang, Han-Dong

2013-07-01

NF-E2-related factor 2 (Nrf2) is a pivotal transcription factor of cellular responses to oxidative stress and recent evidence suggests that Nrf2 plays an important role in cancer pathobiology. However, the underlying mechanism has yet to be elucidated, particularly in glioma. In the present study, we investigated the role of Nrf2 in the clinical prognosis, cell proliferation and tumor growth of human glioblastoma multiforme (GBM). We detected overexpression of Nrf2 protein levels in GBM compared to normal brain tissues. Notably, higher protein levels of Nrf2 were significantly associated with poorer overall survival and 1-year survival for GBM patients. Furthermore, we constructed the plasmid Si-Nrf2 and transduced it into U251MG cells to downregulate the expression of Nrf2 and established stable Nrf2 knockdown cells. The downregulation of Nrf2 suppressed cell proliferation in vitro and tumor growth in mouse xenograft models. We performed immunohistochemistry staining to detect the protein levels of Nrf2, Ki-67, caspase-3 and CD31 in the xenograft tumors and found that the expression levels of Nrf2 and Ki-67 were much lower in the Si-Nrf2 group compared to the Si-control group. In addition, the number of caspase-3-positive cells was significantly increased in the Si-Nrf2 group. By analysis of microvessel density (MVD) assessed by CD31, the MVD value in the Si-Nrf2 group decreased significantly compared to the Si-control group. These findings indicate that the knockdown of Nrf2 may suppress tumor growth by inhibiting cell proliferation, increasing cell apoptosis and inhibiting angiogenesis. These results highlight the potential of Nrf2 as a candidate molecular target to control GBM cell proliferation and tumor growth.

Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress

PubMed Central

Suzuki, Kenshi; Gerelchuluun, Ariungerel; Hong, Zhengshan; Sun, Lue; Zenkoh, Junko; Moritake, Takashi; Tsuboi, Koji

2013-01-01

Background Refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance. We investigated the radiosensitizing effects of celecoxib on GBM cell lines under both normoxic and hypoxic conditions. Methods Two human GBM cell lines, U87MG and U251MG, and a mouse GBM cell line, GL261, were treated with celecoxib or γ-irradiation either alone or in combination under normoxic and hypoxic conditions. Radiosensitizing effects were analyzed by clonogenic survival assays and cell growth assays and by assessing apoptosis and autophagy. Expression of apoptosis-, autophagy-, and endoplasmic reticulum (ER) stress–related genes was analyzed by immunoblotting. Results Celecoxib significantly enhanced the radiosensitivity of GBM cells under both normoxic and hypoxic conditions. In addition, combined treatment with celecoxib and γ-irradiation induced marked autophagy, particularly in hypoxic cells. The mechanism underlying the radiosensitizing effect of celecoxib was determined to be ER stress loading on GBM cells. Conclusion Celecoxib enhances the radiosensitivity of GBM cells by a mechanism that is different from cyclooxygenase-2 inhibition. Our results indicate that celecoxib may be a promising radiosensitizing drug for clinical use in patients with GBM. PMID:23658321

Anti-Epidermal Growth Factor Receptor Gene Therapy for Glioblastoma

PubMed Central

Hicks, Martin J.; Chiuchiolo, Maria J.; Ballon, Douglas; Dyke, Jonathan P.; Aronowitz, Eric; Funato, Kosuke; Tabar, Viviane; Havlicek, David; Fan, Fan; Sondhi, Dolan; Kaminsky, Stephen M.; Crystal, Ronald G.

2016-01-01

Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh.10 gene transfer vector. The data demonstrates that single, local delivery of an anti-EGFR antibody by an AAVrh.10 vector coding for cetuximab (AAVrh.10Cetmab) reduces GBM tumor growth and increases survival in xenograft mouse models of a human GBM EGFR-expressing cell line and patient-derived GBM. AAVrh10.CetMab-treated mice displayed a reduction in cachexia, a significant decrease in tumor volume and a prolonged survival following therapy. Adeno-associated-directed delivery of a gene encoding a therapeutic anti-EGFR monoclonal antibody may be an effective strategy to treat GBM. PMID:27711187

Qualitative examination of enacted stigma towards gay and bisexual men and related health outcomes in Tajikistan, Central Asia.

PubMed

Ibragimov, Umedjon; Wong, Frank Y

2018-05-01

Gay and bisexual men (GBM) in Tajikistan are an extremely stigmatised group at high risk for sexually transmitted infections and HIV. However, there is a paucity of research on how and in what way stigma affects their lives. We conducted a qualitative study to examine the impact of stigma on GBM's lives in Tajikistan, focusing on stigma enactors, settings, factors affecting vulnerability of GBM and health consequences. Eight individual in-depth interviews and 3 focus-group discussions with 13 participants (N   =   21) from GBM community were conducted in two cities of Tajikistan. Results reveal that police frequently engage in blackmail and perpetrate sexual and physical violence against GBM. Service providers often discriminate against GBM limiting their access to health and legal services. Exposure to stigma results in chronic stress affecting mental health of GBM. Fear of disclosure, low social cohesion, absence of prominent opinion leaders and activists reduce resilience of GBM community to stigma. State-sanctioned violations of human rights of marginalised populations and lack of effective legal protection mechanisms have enabled widespread harassment of GBM. These findings warrant further research on stigma leading to the development of culturally adapted and tailored multilevel structural interventions, including broad legal and policy reforms.

Association between RTEL1, PHLDB1, and TREH Polymorphisms and Glioblastoma Risk: A Case-Control Study

PubMed Central

Yang, Bo; Heng, Liang; Du, Shuli; Yang, Hua; Jin, Tianbo; Lang, Hongjuan; Li, Shanqu

2015-01-01

Background Glioblastoma (GBM) is a highly invasive, aggressive, and incurable brain tumor. Genetic factors play important roles in GBM risk. The aim of this study was to elucidate the influence of gene polymorphism on GBM susceptibility. Material/Methods In this case-control study, we included 72 GBM patients and 320 healthy controls to analyze the association between 29 single-nucleotide polymorphisms and GBM cancer risk in the Chinese Han population. The single-nucleotide polymorphisms were determined by Sequenom MassARRAY RS1000 and statistical analysis was performed using SPSS software and SNPStats software. Results Using the χ2 test, we found that rs2297440 and rs6010620 in RTEL1 increased risk of GBM. In the recessive model, we also found that the genotypes “CC” of rs2297440 and “GG” of rs6010620 in RTEL1 significantly increased GBM risk. The variant TT genotype of TREH rs17748 and the variant TT genotype of PHLDB1 rs498872 decreased GBM risk in the recessive model. We also found that the TREH rs17748 variant C allele showed an increased risk in males in the dominant model. Conclusions Our results suggest a significant association between the RETL1, TREH, and PHLDB1 genes and GBM development in the Han Chinese population. PMID:26156397

Association between RTEL1, PHLDB1, and TREH Polymorphisms and Glioblastoma Risk: A Case-Control Study.

PubMed

Yang, Bo; Heng, Liang; Du, Shuli; Yang, Hua; Jin, Tianbo; Lang, Hongjun; Li, Shanqu

2015-07-09

Glioblastoma (GBM) is a highly invasive, aggressive, and incurable brain tumor. Genetic factors play important roles in GBM risk. The aim of this study was to elucidate the influence of gene polymorphism on GBM susceptibility. In this case-control study, we included 72 GBM patients and 320 healthy controls to analyze the association between 29 single-nucleotide polymorphisms and GBM cancer risk in the Chinese Han population. The single-nucleotide polymorphisms were determined by Sequenom MassARRAY RS1000 and statistical analysis was performed using SPSS software and SNPStats software. Using the χ(2) test, we found that rs2297440 and rs6010620 in RTEL1 increased risk of GBM. In the recessive model, we also found that the genotypes "CC" of rs2297440 and "GG" of rs6010620 in RTEL1 significantly increased GBM risk. The variant TT genotype of TREH rs17748 and the variant TT genotype of PHLDB1 rs498872 decreased GBM risk in the recessive model. We also found that the TREH rs17748 variant C allele showed an increased risk in males in the dominant model. Our results suggest a significant association between the RETL1, TREH, and PHLDB1 genes and GBM development in the Han Chinese population.

Long non-coding RNA CASP5 promotes the malignant phenotypes of human glioblastoma multiforme.

PubMed

Zhou, Yali; Dai, Wei; Wang, Handong; Pan, Hao; Wang, Qiang

2018-06-12

Long non-coding RNAs (lncRNAs) have been demonstrated to be intensively involved in the development of various carcinomas, including glioblastoma multiforme (GBM). However, only a few of them have been well characterized. LncRNA CASP5 have been found to be up-regulated in GBM tissues compared with normal tissues in a microarray-based lncRNA profiling study. In the present study, we further explored the biological role of lncRNA CASP5 in GBM. We examined the expression level of lncRNA CASP5 in GBM tissues as well as GBM cell lines. CCK-8 assay, flow cytometric analysis, western blotting, orthotopic GBM model as well as transwell assay were performed to investigate the biological role of CASP5. We observed that lncRNA CASP5 was highly expressed in GBM tissues and cell lines. Knockdown of CASP5 greatly inhibited GBM proliferation and resulted in G1 cell cycle arrest along with higher apoptosis ratios in vitro and in vivo, while overexpression led to the opposite phenomenon. Furthermore, the migration and invasion ability of GBM cells were significantly decreased after CASP5 down-regulation, while increased migration and invasion can be observed after CASP5 up-regulation. We demonstrate for the first time the potential oncogenic role of lncRNA CASP5 which may be helpful for identifying novel therapeutic targets in GBM. Copyright © 2018 Elsevier Inc. All rights reserved.

Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

PubMed Central

Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

2009-01-01

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

Impact of oligodendroglial component in glioblastoma (GBM-O): Is the outcome favourable than glioblastoma?

PubMed

Goda, Jayant S; Lewis, Shirley; Agarwal, Aditi; Epari, Sridhar; Churi, Shraddha; Padmavati, A; Gupta, Tejpal; Shetty, Prakash; Moiyadi, Aliasgar; Jalali, Rakesh

2015-08-01

Prognosis of patients with glioblastoma with oligodendroglial component (GBM-O) is not well defined. We report our experience of patients of GBM-O treated at our center. Between January 2007 and August 2013, out of 817 consecutive patients with glioblastoma (GBM), 74 patients with GBM-O were identified in our prospectively maintained database. An experienced neuropathologist revaluated the histopathology of all these 74 patients and the diagnosis of GBM-O was eventually confirmed in 57 patients. Patients were uniformly treated with maximal safe resection followed by focal radiotherapy with concurrent and adjuvant temozolamide (TMZ). At a median follow up of 16 months, median overall survival (OS) and progression free survival (PFS) of the entire cohort was 23 months and 13 months respectively. Near total excision was performed in 30/57 (52.6%). On univariate analysis, age < 50 years was a significant favourable prognostic factor for OS (p = 0.009) and PFS (p = 0.017), while patients with near total resection had a significantly better PFS (p = 0.017), patients who completed a minimum of 6 cycles of adjuvant TMZ had significantly better OS (p = 0.000) and PFS (p = 0.003). On multivariate analysis, none of the above factors were significant except for patient who had completed a minimum of 6 cycles of TMZ (OS; p = 0.000 & PFS; p = 0.015). A comparative analysis of GBM-O patients with a similarly treated cohort of 105 GBM patients during the same period revealed significantly better median OS in favour of GBM-O (p = 0.01). Our experience suggests patients with GBM-O have a more favourable clinical outcome as compared to GBM. Copyright © 2015 Elsevier B.V. All rights reserved.

Presence of stromal cells in a bioengineered tumor microenvironment alters glioblastoma migration and response to STAT3 inhibition

PubMed Central

Voytik-Harbin, Sherry L.; Sarkaria, Jann N.; Pollok, Karen E.; Fishel, Melissa L.; Rickus, Jenna L.

2018-01-01

Despite the increasingly recognized importance of the tumor microenvironment (TME) as a regulator of tumor progression, only few in vitro models have been developed to systematically study the effects of TME on tumor behavior in a controlled manner. Here we developed a three-dimensional (3D) in vitro model that recapitulates the physical and compositional characteristics of Glioblastoma (GBM) extracellular matrix (ECM) and incorporates brain stromal cells such as astrocytes and endothelial cell precursors. The model was used to evaluate the effect of TME components on migration and survival of various patient-derived GBM cell lines (GBM10, GBM43 and GBAM1) in the context of STAT3 inhibition. Migration analysis of GBM within the 3D in vitro model demonstrated that the presence of astrocytes significantly increases the migration of GBM, while presence of endothelial precursors has varied effects on the migration of different GBM cell lines. Given the role of the tumor microenvironment as a regulator of STAT3 activity, we tested the effect of the STAT3 inhibitor SH-4-54 on GBM migration and survival. SH-4-54 inhibited STAT3 activity and reduced 3D migration and survival of GBM43 but had no effect on GBM10. SH-4-54 treatment drastically reduced the viability of the stem-like line GBAM1 in liquid culture, but its effect lessened in presence of a 3D ECM and stromal cells. Our results highlight the interplay between the ECM and stromal cells in the microenvironment with the cancer cells and indicate that the impact of these relationships may differ for GBM cells of varying genetic and clinical histories. PMID:29566069

Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data.

PubMed

Lee, Sang Y; Zhu, Junjia; Salzberg, Anna C; Zhang, Bo; Liu, Dajiang J; Muscat, Joshua E; Langan, Sara T; Connor, James R

2017-01-01

Human hemochromatosis protein (HFE) is involved in iron metabolism. Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers. Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM). However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied. To expand our finding in a larger sample, and to identify other HFE SNV, we analyzed the frequency of somatic SNV in HFE gene and its relationship to survival in GBM patients using The Cancer Genome Atlas (TCGA) GBM (Caucasian only) database. We found 9 SNVs with increased frequency in blood normal of TCGA GBM patients compared to the 1000Genome. Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene. The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119-0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474-0.1159) HFE polymorphisms than 1000Genome. The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients. In addition, there was no difference in the survival of male/female GBM patients based on HFE genotype. There was no correlation between HFE expression and survival. In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients' survival in the TCGA data set of GBM.

Coexistence of Anti-Glomerular Basement Membrane Glomerulonephritis and Membranous Nephropathy in a Female Patient with Preserved Renal Function.

PubMed

Ogawara, Aoi; Harada, Makoto; Ichikawa, Tohru; Fujii, Kazuaki; Ehara, Takashi; Kobayashi, Mamoru

2017-12-01

Renal prognosis for anti-glomerular basement membrane (GBM) glomerulonephritis is poor. The greater the amount of anti-GBM antibody binding the antigen (type IV collagen of the glomerular basement membrane), the greater the number of crescents that develop in glomeruli, resulting in progression of renal impairment. Immunofluorescence staining reveals linear IgG depositions on glomerular capillary walls. Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in middle-aged to elderly patients. Immune complex is deposited in the sub-epithelial space of the glomerulus resulting in the development of a membranous lesion. Immunofluorescence staining reveals granular IgG depositions on glomerular capillary walls. Coexisting anti-GBM glomerulonephritis and MN are rare and, here we report a case of coexisting anti-GBM glomerulonephritis and MN with preserved renal function. There are some cases of coexisting anti-GBM glomerulonephritis and MN do not show severely decreased renal function. A 76-year-old Japanese woman presented with nephrotic syndrome, microscopic hematuria, and was positive for anti-GBM antibody. Kidney biopsy revealed linear and granular IgG depositions in glomerular capillary walls, crescent formations, and electron-dense deposits in the sub-epithelial space. She was diagnosed with anti-GBM glomerulonephritis and MN. Steroid and cyclosporine therapy achieved complete remission, and kidney function was preserved. In conclusion, coexisting anti-GBM glomerulonephritis and MN can have preserved renal function. IgG subclass of deposited anti-GBM antibody may be associated with the severity of anti-GBM glomerulonephritis. In addition, in the case of nephrotic syndrome with hematuria, we should consider the possibility of coexisting anti-GBM glomerulonephritis and MN.

Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes

PubMed Central

Liu, Che; Clark, Paul A.; Kuo, John S.

2017-01-01

ABSTRACT Glioblastoma multiforme (GBM) is the most common brain tumor in adults. Human cytomegalovirus (HCMV) genomes are present in GBM tumors, yielding hope that antiviral treatments could prove therapeutic and improve the poor prognosis of GBM patients. We discovered that GBM cells infected in vitro with HCMV display properties of cancer stem cells. HCMV-infected GBM cells grow more slowly than mock-infected controls, demonstrate a higher capacity for self-renewal determined by a sphere formation assay, and display resistance to the chemotherapeutic drug temozolomide. Our data suggest that HCMV, while present in only a minority of the cells within a tumor, could contribute to the pathogenesis of GBMs by promoting or prolonging stem cell-like phenotypes, thereby perpetuating tumors in the face of chemotherapy. Importantly, we show that temozolomide sensitivity is restored by the antiviral drug ganciclovir, indicating a potential mechanism underlying the positive effects observed in GBM patients treated with antiviral therapy. IMPORTANCE A role for HCMV in GBMs remains controversial for several reasons. Some studies find HCMV in GBM tumors, while others do not. Few cells within a GBM may harbor HCMV, making it unclear how the virus could be contributing to the tumor phenotype without infecting every cell. Finally, HCMV does not overtly transform cells in vitro. However, tumors induced by other viruses can be treated with antiviral remedies, and initial results indicate that this may be true for anti-HCMV therapies and GBMs. With such a poor prognosis for GBM patients, any potential new intervention deserves exploration. Our work here describes an evidence-based model for how HCMV could contribute to GBM biology while infecting very few cells and without transforming them. It also illuminates why anti-HCMV treatments may be beneficial to GBM patients. Our observations provide blueprints for future in vitro studies examining how HCMV manipulates stem cell-specific pathways and future clinical studies of anti-HCMV measures as GBM therapeutics. PMID:28656174

Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation.

PubMed

Jha, Prerana; Pia Patric, Irene Rosita; Shukla, Sudhanshu; Pathak, Pankaj; Pal, Jagriti; Sharma, Vikas; Thinagararanjan, Sivaarumugam; Santosh, Vani; Suri, Vaishali; Sharma, Mehar Chand; Arivazhagan, Arimappamagan; Suri, Ashish; Gupta, Deepak; Somasundaram, Kumaravel; Sarkar, Chitra

2014-12-01

Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways. Genome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done. Distinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine-phosphate-guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment. Our study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation-specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and needs further evaluation. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Liposomal temozolomide drug delivery using convection enhanced delivery.

PubMed

Nordling-David, Mirjam M; Yaffe, Roni; Guez, David; Meirow, Hadar; Last, David; Grad, Etty; Salomon, Sharona; Sharabi, Shirley; Levi-Kalisman, Yael; Golomb, Gershon; Mardor, Yael

2017-09-10

Even though some progress in diagnosis and treatment has been made over the years, there is still no definitive treatment available for Glioblastoma multiforme (GBM). Convection-enhanced delivery (CED), a continuous infusion-mediated pressure gradient via intracranial catheters, studied in clinical trials, enables in situ drug concentrations several orders of magnitude greater than those achieved by systemic administration. We hypothesized that the currently limited efficacy of CED could be enhanced by a liposomal formulation, thus achieving enhanced drug localization to the tumor site with minimal toxicity. We hereby describe a novel approach for treating GBM by CED of liposomes containing the known chemotherapeutic agent, temozolomide (TMZ). A new technique for encapsulating TMZ in hydrophilic (PEGylated) liposomes, characterized by nano-size (121nm), low polydispersity index (<0.13) and with near-neutral charge (-ʒ,0.2mV), has been developed. Co-infusion of PEGylated Gd-DTPA liposomes and TMZ-liposomes by CED in GBM bearing rats, resulted in enhanced tumor detection with longer residence time than free Gd-DTPA. Treatment of GBM-bearing rats with either TMZ solution or TMZ-liposomes resulted in greater tumor inhibition and significantly higher survival. However, the longer survival and smaller tumor volumes exhibited by TMZ liposomal treatment in comparison to TMZ in solution were insignificant (p<0.053); and only significantly lower edema volumes were observed. Thus, there are no clear-cut advantages to use a liposomal delivery system of TMZ via CED over a drug solution. Copyright © 2017 Elsevier B.V. All rights reserved.

Brain Tumor’s Radioresistance: The Neighborhood Helps | Center for Cancer Research

Cancer.gov

Glioblastoma (GBM) is the most common and most aggressive form of brain cancer. The primary treatment for GBM is radiation therapy. Unfortunately, while some patients initially respond, the vast majority of GBM patients fail radiotherapy, and the tumor usually grows back within two years. To gain a better understanding of the biological basis for GBM resistance to radiation, researchers initially studied GBM cell lines in vitro. In recent years, the focus has been on so-called tumor stem-like cells (TSCs), which are thought to be responsible for driving and maintaining tumor growth. To the researchers’ surprise, TSCs grown in vitro did not have the same ability to resist radiation as TSCs in the GBM tumors.

Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma.

PubMed

Liu, Weiwen; Song, Xian-Lu; Zhao, Shan-Chao; He, Minyi; Wang, Hai; Chen, Ziyang; Xiang, Wei; Yi, Guozhong; Qi, Songtao; Liu, Yawei

2018-01-01

Dapivirine is one of reverse transcriptase inhibitors (RTIs). It is the prototype of diarylpyrimidines (DAPY), formerly known as TMC120 or DAPY R147681 (IUPAC name: 4- [[4-(2, 4, 6-trimethylphenyl) amino]-2-pyrimidinyl] amino]-benzonitrile; CAS no.244767-67-7). The purpose of this study is to investigate the antitumor activity of dapivirine, one of the RTIs, on U87 glioblastoma (GBM) cells in vitro and in vivo . U87 GBM cells were cultured and treated with or without dapivirine. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis was analyzed by flow cytometry; cell migration was evaluated by Boyden Chamber assay; Western blotting was performed to detect proteins related to apoptosis, epithelial-to-mesenchymal transition and autophagy. PathScan intracellular signaling array kit was used to detect important and well-characterized signaling molecules. Tumor xenograft model in nude mice was used to evaluate the antitumorigenic effect in vivo . Dapivirine weakened proliferation of glioma cells and induced the apoptosis of U87 glioblastoma cells. Furthermore, dapivirine regulated autophagy and induced Akt, Bad and SAPK/JNK activations. Moreover, the inhibition of glioma cell growth by dapivirine was also observed in nude mice in vivo . In summary, in our study dapivirine exposure induces stress, resulting in JNK and PI3K/Akt pathway activation through diminished inhibition of the apoptosis and autophagy cascade in U87 GBM cells, which inhibits cell growth in vitro and in vivo .

Detection of immune deposits in glomeruli: the masking effect on antigenicity of formalin in the presence of proteins.

PubMed

Hed, J; Eneström, S

1981-01-01

Formalin is known to mask the antigenicity of immune deposits in glomeruli but not of surface immunoglobulins of isolated lymphocytes. We have shown in mice with experimental passive anti-GBM glomerulonephritis that formalin masks the antigenicity of GBM-bound immunoglobulins only if the tissue is fixed before sectioning. The presence of a high concentration of normal bovine serum during fixation of cryostat sections masks the antigenicity of immune deposits, whereas formalin alone has no obvious effect. The same results were obtained with human immunoglobulins (IgG, IgM and IgA) bound to tissue sections. Protease treatment with pepsin and trypsin restored the ability of the immunoglobulins to be stained. The masking effect seems to be due to extensive cross-linking of environmental proteins which prevents fluorescent conjugates reaching their antigens. Methods for detecting immunoglobulins in tissues must, therefore, take into consideration the influence of fixatives not only on epitopes but also on the environment in which the antigenic determinants are localised.

The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme.

PubMed

Zhu, Haihao; Woolfenden, Steve; Bronson, Roderick T; Jaffer, Zahara M; Barluenga, Sofia; Winssinger, Nicolas; Rubenstein, Allan E; Chen, Ruihong; Charest, Al

2010-09-01

Glioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently shown that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of which are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that shows improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment.

Electrospun nanofibrous scaffolds increase the efficacy of stem cell-mediated therapy of surgically resected glioblastoma

PubMed Central

Bagó, Juli R.; Pegna, Guillaume J.; Okolie, Onyi; Mohiti-Asli, Mahsa; Loboa, Elizabeth G.; Hingtgen, Shawn D.

2017-01-01

Engineered stem cell (SC)-based therapy holds enormous promise for treating the incurable brain cancer glioblastoma (GBM). Retaining the cytotoxic SCs in the surgical cavity after GBM resection is one of the greatest challenges to this approach. Here, we describe a biocompatible electrospun nanofibrous scaffold (bENS) implant capable of delivering and retaining tumor-homing cytotoxic stem cells that suppress recurrence of post-surgical GBM. As a new approach to GBM therapy, we created poly(l-lactic acid) (PLA) bENS bearing drug-releasing human mesenchymal stem cells (hMSCs). We discovered that bENS-based implant increased hMSC retention in the surgical cavity 5-fold and prolonged persistence 3-fold compared to standard direct injection using our mouse model of GBM surgical resection/recurrence. Time-lapse imaging showed cytotoxic hMSC/bENS treatment killed co-cultured human GBM cells, and allowed hMSCs to rapidly migrate off the scaffolds as they homed to GBMs. In vivo, bENS loaded with hMSCs releasing the anti-tumor protein TRAIL (bENSsTR) reduced the volume of established GBM xenografts 3-fold. Mimicking clinical GBM patient therapy, lining the post-operative GBM surgical cavity with bENSsTR implants inhibited the re-growth of residual GBM foci 2.3-fold and prolonged post-surgical median survival from 13.5 to 31 days in mice. These results suggest that nanofibrous-based SC therapies could be an innovative new approach to improve the outcomes of patients suffering from terminal brain cancer. PMID:27016620

Long-term outcome of anti-glomerular basement membrane antibody disease treated with immunoadsorption.

PubMed

Biesenbach, Peter; Kain, Renate; Derfler, Kurt; Perkmann, Thomas; Soleiman, Afschin; Benharkou, Alexandra; Druml, Wilfred; Rees, Andrew; Säemann, Marcus D

2014-01-01

Anti-glomerular basement membrane (GBM) antibody disease may lead to acute crescentic glomerulonephritis with poor renal prognosis. Current therapy favours plasma exchange (PE) for removal of pathogenic antibodies. Immunoadsorption (IAS) is superior to PE regarding efficiency of antibody-removal and safety. Apart from anecdotal data, there is no systemic analysis of the long-term effects of IAS on anti-GBM-disease and antibody kinetics. To examine the long-term effect of high-frequency IAS combined with standard immunosuppression on patient and renal survival in patients with anti-GBM-disease and to quantify antibody removal and kinetics through IAS. Retrospective review of patients treated with IAS for anti-GBM-antibody disease confirmed by biopsy and/or anti-GBM-antibodies. University Hospital of Vienna, Austria. 10 patients with anti-GBM-disease treated with IAS. Patient and renal survival, renal histology, anti-GBM-antibodies. Anti-GBM-antibodies were reduced by the first 9 IAS treatments (mean number of 23) to negative levels in all patients. Renal survival was 40% at diagnosis, 70% after the end of IAS, 63% after one year and 50% at the end of observation (mean 84 months, range 9 to 186). Dialysis dependency was successfully reversed in three of six patients. Patient survival was 90% at the end of observation. IAS efficiently eliminates anti-GBM-antibodies suggesting non-inferiority to PE with regard to renal and patient survival. Hence IAS should be considered as a valuable treatment option for anti-GBM-disease, especially in patients presenting with a high percentage of crescents and dialysis dependency due to an unusual high proportion of responders.

MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway

PubMed Central

Yang, Chuan He; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Häcker, Hans; Yue, Junming; Cheng, Jinjun; Boop, Frederick A.; Pfeffer, Lawrence M.

2017-01-01

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro, and inhibited GBM tumorigenesis in vivo. Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro, and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway. PMID:29348882

MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway.

PubMed

Yang, Chuan He; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Häcker, Hans; Yue, Junming; Cheng, Jinjun; Boop, Frederick A; Pfeffer, Lawrence M

2017-12-22

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro , and inhibited GBM tumorigenesis in vivo . Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro , and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway.

Annexin 2A sustains glioblastoma cell dissemination and proliferation

PubMed Central

Maule, Francesca; Bresolin, Silvia; Rampazzo, Elena; Boso, Daniele; Puppa, Alessandro Della; Esposito, Giovanni; Porcù, Elena; Mitola, Stefania; Lombardi, Giuseppe; Accordi, Benedetta; Tumino, Manuela; Basso, Giuseppe; Persano, Luca

2016-01-01

Glioblastoma (GBM) is the most devastating tumor of the brain, characterized by an almost inevitable tendency to recur after intensive treatments and a fatal prognosis. Indeed, despite recent technical improvements in GBM surgery, the complete eradication of cancer cell disseminated outside the tumor mass still remains a crucial issue for glioma patients management. In this context, Annexin 2A (ANXA2) is a phospholipid-binding protein expressed in a variety of cell types, whose expression has been recently associated with cell dissemination and metastasis in many cancer types, thus making ANXA2 an attractive putative regulator of cell invasion also in GBM. Here we show that ANXA2 is over-expressed in GBM and positively correlates with tumor aggressiveness and patient survival. In particular, we associate the expression of ANXA2 to a mesenchymal and metastatic phenotype of GBM tumors. Moreover, we functionally characterized the effects exerted by ANXA2 inhibition in primary GBM cultures, demonstrating its ability to sustain cell migration, matrix invasion, cytoskeletal remodeling and proliferation. Finally, we were able to generate an ANXA2-dependent gene signature with a significant prognostic potential in different cohorts of solid tumor patients, including GBM. In conclusion, we demonstrate that ANXA2 acts at multiple levels in determining the disseminating and aggressive behaviour of GBM cells, thus proving its potential as a possible target and strong prognostic factor in the future management of GBM patients. PMID:27429043

Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture

PubMed Central

Deng, Liting; Ng, Lindsay; Ozawa, Tatsuya

2017-01-01

Evidence suggests that the nonpsychotropic cannabis-derived compound, cannabidiol (CBD), has antineoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM). DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM. Here we studied the antiproliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine, or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures. This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system toxicity. We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells. Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells. Cotreatment regimens combining CBD and DNA-damaging agents produced synergistic antiproliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs. Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells. Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little to no therapeutic window when considering NPCs. PMID:27821713

LncRNA and mRNA expression profiles of glioblastoma multiforme (GBM) reveal the potential roles of lncRNAs in GBM pathogenesis.

PubMed

Li, Qi; Jia, Hongmei; Li, Haowen; Dong, Chengya; Wang, Yajie; Zou, Zhongmei

2016-11-01

Glioblastoma multiforme (GBM) is the most common brain malignancy. Long non-coding RNAs (lncRNAs) are aberrantly expressed in many cancers and are involved in their cell proliferation, apoptosis, angiogenesis, and invasion. The functional roles of lncRNAs in GBM are less known. We analyzed a cohort of exon microarray datasets from The Cancer Genome Atlas. The differently expressed lncRNAs and mRNA were subjected to construct lncRNA-mRNA co-expression network. Probable functions for lncRNAs were predicted according to lncRNA-mRNA network and genomic adjacency by GO and pathway analysis. The expression of lncRNAs and mRNAs in GBM tissues versus normal brain tissues was examined by quantitative reverse transcription polymerase chain reaction. The 398 lncRNAs and 1995 mRNAs were identified as distinctively expressed in GBM. Probable functional roles for 98 lncRNAs were involved in 30 pathways and 32 gene functions related to tumorigenesis, development, and metastasis. The identified sets of key lncRNAs specific to GBM were subsequently verified by experiment in GBM tissues. Our reports predict the biological functions of a multitude of lncRNAs in GBM that could be potential diagnostic and prognostic biomarkers as well as therapeutic targets. Moreover, our research provides a road map for the identification and analysis of lncRNAs in tumors.

USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance

PubMed Central

Lee, Jin-Ku; Chang, Nakho; Yoon, Yeup; Yang, Heekyoung; Cho, Heejin; Kim, Eunhee; Shin, Yongjae; Kang, Wonyoung; Oh, Young Taek; Mun, Gyeong In; Joo, Kyeung Min; Nam, Do-Hyun; Lee, Jeongwu

2016-01-01

Background Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. Methods We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. Results USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. Conclusion USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM. PMID:26032834

Identification of radiation responsive genes and transcriptome profiling via complete RNA sequencing in a stable radioresistant U87 glioblastoma model.

PubMed

Doan, Ninh B; Nguyen, Ha S; Alhajala, Hisham S; Jaber, Basem; Al-Gizawiy, Mona M; Ahn, Eun-Young Erin; Mueller, Wade M; Chitambar, Christopher R; Mirza, Shama P; Schmainda, Kathleen M

2018-05-04

The absence of major progress in the treatment of glioblastoma (GBM) is partly attributable to our poor understanding of both GBM tumor biology and the acquirement of treatment resistance in recurrent GBMs. Recurrent GBMs are characterized by their resistance to radiation. In this study, we used an established stable U87 radioresistant GBM model and total RNA sequencing to shed light on global mRNA expression changes following irradiation. We identified many genes, the expressions of which were altered in our radioresistant GBM model, that have never before been reported to be associated with the development of radioresistant GBM and should be concertedly further investigated to understand their roles in radioresistance. These genes were enriched in various biological processes such as inflammatory response, cell migration, positive regulation of epithelial to mesenchymal transition, angiogenesis, apoptosis, positive regulation of T-cell migration, positive regulation of macrophage chemotaxis, T-cell antigen processing and presentation, and microglial cell activation involved in immune response genes. These findings furnish crucial information for elucidating the molecular mechanisms associated with radioresistance in GBM. Therapeutically, with the global alterations of multiple biological pathways observed in irradiated GBM cells, an effective GBM therapy may require a cocktail carrying multiple agents targeting multiple implicated pathways in order to have a chance at making a substantial impact on improving the overall GBM survival.

MicroRNA‑518b functions as a tumor suppressor in glioblastoma by targeting PDGFRB.

PubMed

Xu, Xiaolong; Zhang, Fenglin; Chen, Xianzhen; Ying, Qi

2017-10-01

Glioblastoma (GBM) is the most common and aggressive type of primary human brain tumor in China. Dysregulated microRNA (miRNA/miR) expression has been hypothesized to serve a role in the tumorigenesis and progression of human GBM. To explore the potential mechanisms affecting GBM tumorigenesis, the function of miR‑518b in regulating GBM cell proliferation and angiogenesis was examined in vitro by CCK‑8 and tube formation assay and in vivo by xenograft assay. The present study demonstrated that the expression of miR‑518b was downregulated in GBM tissues and in GBM cell lines (U87 and U251). In addition, the expression levels of miR‑518b were highly associated with tumor size, World Health Organization grade and prognosis. Furthermore, overexpression of miR‑518b suppressed GBM cell proliferation and angiogenesis, and induced GBM cell apoptosis in vitro and in vivo. Overexpression of miR‑518b also inhibited the expression of platelet‑derived growth factor receptor β (PDGFRB), and the present study confirmed that the 3' untranslated region (3'UTR) of PDGFRB was a direct target of miR‑518b. In conclusion, to the best of our knowledge, the present study is the first to present evidence suggesting that miR‑518b may serve as a potential marker and target in GBM treatment.

MicroRNA-518b functions as a tumor suppressor in glioblastoma by targeting PDGFRB

PubMed Central

Xu, Xiaolong; Zhang, Fenglin; Chen, Xianzhen; Ying, Qi

2017-01-01

Glioblastoma (GBM) is the most common and aggressive type of primary human brain tumor in China. Dysregulated microRNA (miRNA/miR) expression has been hypothesized to serve a role in the tumorigenesis and progression of human GBM. To explore the potential mechanisms affecting GBM tumorigenesis, the function of miR-518b in regulating GBM cell proliferation and angiogenesis was examined in vitro by CCK-8 and tube formation assay and in vivo by xenograft assay. The present study demonstrated that the expression of miR-518b was downregulated in GBM tissues and in GBM cell lines (U87 and U251). In addition, the expression levels of miR-518b were highly associated with tumor size, World Health Organization grade and prognosis. Furthermore, overexpression of miR-518b suppressed GBM cell proliferation and angiogenesis, and induced GBM cell apoptosis in vitro and in vivo. Overexpression of miR-518b also inhibited the expression of platelet-derived growth factor receptor β (PDGFRB), and the present study confirmed that the 3′ untranslated region (3′UTR) of PDGFRB was a direct target of miR-518b. In conclusion, to the best of our knowledge, the present study is the first to present evidence suggesting that miR-518b may serve as a potential marker and target in GBM treatment. PMID:28849154

Repression of Septin9 and Septin2 suppresses tumor growth of human glioblastoma cells.

PubMed

Xu, Dongchao; Liu, Ajuan; Wang, Xuan; Chen, Yidan; Shen, Yunyun; Tan, Zhou; Qiu, Mengsheng

2018-05-01

Glioblastoma (GBM) is the most common primary malignancy of the central nervous system (CNS) with <10% 5-year survival rate. The growth and invasion of GBM cells into normal brain make the resection and treatment difficult. A better understanding of the biology of GBM cells is crucial to the targeted therapies for the disease. In this study, we identified Septin9 (SEPT9) and Septin2 (SEPT2) as GBM-related genes through integrated multi-omics analysis across independent transcriptomic and proteomic studies. Further studies revealed that expression of SEPT9 and SEPT2 was elevated in glioma tissues and cell lines (A172, U87-MG). Knockdown of SEPT9 and SEPT2 in A172/U87-MG was able to inhibit GBM cell proliferation and arrest cell cycle progression in the S phase in a synergistic mechanism. Moreover, suppression of SEPT9 and SEPT2 decreased the GBM cell invasive capability and significantly impaired the growth of glioma xenografts in nude mice. Furthermore, the decrease in GBM cell growth caused by SEPT9 and SEPT2 RNAi appears to involve two parallel signaling pathway including the p53/p21 axis and MEK/ERK activation. Together, our integration of multi-omics analysis has revealed previously unrecognized synergistic role of SEPT9 and SEPT2 in GBM, and provided novel insights into the targeted therapy of GBM.

Brain Tumor’s Radioresistance: The Neighborhood Helps | Center for Cancer Research

Cancer.gov

Glioblastoma (GBM) is the most common and most aggressive form of brain cancer. The primary treatment for GBM is radiation therapy. Unfortunately, while some patients initially respond, the vast majority of GBM patients fail radiotherapy, and the tumor usually grows back within two years. To gain a better understanding of the biological basis for GBM resistance to radiation,

Statistical Properties of SGR J1550-5418 Bursts

NASA Technical Reports Server (NTRS)

Gorgone, Nicholas M.

2010-01-01

Magnetars are slowly rotating neutron stars with extreme magnetic fields, over 10(exp 15) Gauss. Only few have been discovered in the last 30 years. These sources are dormant most of their lifetimes and become randomly active emitting multiple soft gamma-ray bursts. We present here our results on the temporal analysis of 300 bursts from Soft Gamma Repeater SGR J1550-5418 recorded with the Gamma-ray Burst Monitor (GBM) onboard the Fermi Observatory during its activation on January 22-29, 2009. We employed an un-triggered burst search in the energy range 8-100keV to collect all events from the source, besides the ones that triggered GBM. For the entire sample of bursts we determined their durations, rise and decay times. We study here the statistical properties of these characteristics and discuss how these may help us better understand the physical characteristics of the magnetar model.

Early presentation of primary glioblastoma.

PubMed

Faguer, R; Tanguy, J-Y; Rousseau, A; Clavreul, A; Menei, P

2014-08-01

Clinical and neuroimaging findings of glioblastomas (GBM) at an early stage have rarely been described and those tumors are most probably under-diagnosed. Furthermore, their genetic alterations, to our knowledge, have never been previously reported. We report the clinical as well as neuroimaging findings of four early cases of patients with GBM. In our series, early stage GBM occurred at a mean age of 57 years. All patients had seizures as their first symptom. In all early stages, MRI showed a hyperintense signal on T2-weighted sequences and an enhancement on GdE-T1WI sequences. A hyperintense signal on diffusion sequences with a low ADC value was also found. These early observed occurrences of GBM developed rapidly and presented the MRI characteristics of classic GBM within a few weeks. The GBM size was multiplied by 32 in one month. Immunohistochemical analysis indicated the de novo nature of these tumors, i.e. absence of mutant IDH1 R132H protein expression, which is a diagnostic marker of low-grade diffuse glioma and secondary GBM. A better knowledge of early GBM presentation would allow a more suitable management of the patients and may improve their prognosis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Dysregulated miR-671-5p / CDR1-AS / CDR1 / VSNL1 axis is involved in glioblastoma multiforme.

PubMed

Barbagallo, Davide; Condorelli, Angelo; Ragusa, Marco; Salito, Loredana; Sammito, Mariangela; Banelli, Barbara; Caltabiano, Rosario; Barbagallo, Giuseppe; Zappalà, Agata; Battaglia, Rosalia; Cirnigliaro, Matilde; Lanzafame, Salvatore; Vasquez, Enrico; Parenti, Rosalba; Cicirata, Federico; Di Pietro, Cinzia; Romani, Massimo; Purrello, Michele

2016-01-26

MiR-671-5p is encoded by a gene localized at 7q36.1, a region amplified in human glioblastoma multiforme (GBM), the most malignant brain cancer. To investigate whether expression of miR-671-5p were altered in GBM, we analyzed biopsies from a cohort of forty-five GBM patients and from five GBM cell lines. Our data show significant overexpression of miR-671-5p in both biopsies and cell lines. By exploiting specific miRNA mimics and inhibitors, we demonstrated that miR-671-5p overexpression significantly increases migration and to a less extent proliferation rates of GBM cells. Through a combined in silico and in vitro approach, we identified CDR1-AS, CDR1, VSNL1 as downstream miR-671-5p targets in GBM. Expression of these genes significantly decreased both in GBM biopsies and cell lines and negatively correlated with that of miR-671-5p. Based on our data, we propose that the axis miR-671-5p / CDR1-AS / CDR1 / VSNL1 is functionally altered in GBM cells and is involved in the modification of their biopathological profile.

An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway

PubMed Central

Guo, Deliang; Reinitz, Felicia; Youssef, Mary; Hong, Cynthia; Nathanson, David; Akhavan, David; Kuga, Daisuke; Amzajerdi, Ali Nael; Soto, Horacio; Zhu, Shaojun; Babic, Ivan; Tanaka, Kazuhiro; Dang, Julie; Iwanami, Akio; Gini, Beatrice; DeJesus, Jason; Lisiero, Dominique D.; Huang, Tiffany T.; Prins, Robert M.; Wen, Patrick Y.; Robins, H. Ian; Prados, Michael D.; DeAngelis, Lisa M.; Mellinghoff, Ingo K.; Mehta, Minesh P.; James, C. David; Chakravarti, Arnab; Cloughesy, Timothy F.; Tontonoz, Peter; Mischel, Paul S.

2011-01-01

Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. EGFR mutations (EGFRvIII) and PI3K hyperactivation are common in GBM, promoting tumor growth and survival, including through SREBP-1-dependent-lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. Here, studies in GBM cell lines, xenograft models and GBM clinical samples, including from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1-dependent tumor survival pathway through the LDL receptor. Targeting LDLR with the Liver X Receptor (LXR) agonist GW3965 caused IDOL (Inducible Degrader Of LDLR)-mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results demonstrate that EGFRvIII can promote tumor survival through PI3K-SREBP-1 dependent up-regulation of LDLR, and suggest a role for LXR agonists in the treatment of GBM patients. PMID:22059152

Blockade of the SNARE Protein Syntaxin 1 Inhibits Glioblastoma Tumor Growth

PubMed Central

Ulloa, Fausto; Gonzàlez-Juncà, Alba; Meffre, Delphine; Barrecheguren, Pablo José; Martínez-Mármol, Ramón; Pazos, Irene; Olivé, Núria; Cotrufo, Tiziana; Seoane, Joan; Soriano, Eduardo

2015-01-01

Glioblastoma (GBM) is the most prevalent adult brain tumor, with virtually no cure, and with a median overall survival of 15 months from diagnosis despite of the treatment. SNARE proteins mediate membrane fusion events in cells and are essential for many cellular processes including exocytosis and neurotransmission, intracellular trafficking and cell migration. Here we show that the blockade of the SNARE protein Syntaxin 1 (Stx1) function impairs GBM cell proliferation. We show that Stx1 loss-of-function in GBM cells, through ShRNA lentiviral transduction, a Stx1 dominant negative and botulinum toxins, dramatically reduces the growth of GBM after grafting U373 cells into the brain of immune compromised mice. Interestingly, Stx1 role on GBM progression may not be restricted just to cell proliferation since the blockade of Stx1 also reduces in vitro GBM cell invasiveness suggesting a role in several processes relevant for tumor progression. Altogether, our findings indicate that the blockade of SNARE proteins may represent a novel therapeutic tool against GBM. PMID:25803850

MicroRNA-137 inhibits growth of glioblastoma through EGFR suppression

PubMed Central

Zhang, Zhenxing; Song, Xiaofeng; Tian, He; Miao, Ye; Feng, Xu; Li, Yang; Wang, Honglei

2017-01-01

Aberrant expression of certain microRNAs (miRNAs) has been shown to contribute to the development of Glioblastoma multiforme (GBM). However, the involvement of miR-137 in the carcinogenesis of GBM has not been reported. Here, we showed that miR-137 levels in GBM tissues were significantly lower than the paired normal brain tissue in patients’ specimens. Moreover, low miR-137 levels in GBM tissue were associated with poor prognosis. In vitro, overexpression of miR-137 decreased GBM cell growth and increased cell apoptosis, while depletion of miR-137 enhanced cell growth and decreased cell apoptosis. Combined bioinformatics analysis and dual luciferase reporter assay showed that miR-137 may target the 3’-UTR of the epidermal growth factor receptor (EGFR) to reduce its protein translation, resulting in suppression of EGFR signaling in GBM cells. Together, our data suggest that reduction in miR-137 levels in GBM tissues may increase cell growth and decrease cell apoptosis, possibly through suppression of EGFR. PMID:28386374

Search for High-energy Neutrinos from Binary Neutron Star Merger GW170817 with ANTARES, IceCube, and the Pierre Auger Observatory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albert, A.; André, M.; Anghinolfi, M.

The Advanced LIGO and Advanced Virgo observatories recently discovered gravitational waves from a binary neutron star inspiral. A short gamma-ray burst (GRB) that followed the merger of this binary was also recorded by the Fermi Gamma-ray Burst Monitor (Fermi-GBM), and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory (INTEGRAL), indicating particle acceleration by the source. The precise location of the event was determined by optical detections of emission following the merger. We searched for high-energy neutrinos from the merger in the GeV–EeV energy range using the Antares, IceCube, and Pierre Auger Observatories. No neutrinos directionally coincidentmore » with the source were detected within ±500 s around the merger time. Additionally, no MeV neutrino burst signal was detected coincident with the merger. We further carried out an extended search in the direction of the source for high-energy neutrinos within the 14 day period following the merger, but found no evidence of emission. We used these results to probe dissipation mechanisms in relativistic outflows driven by the binary neutron star merger. The non-detection is consistent with model predictions of short GRBs observed at a large off-axis angle.« less

Search for High-energy Neutrinos from Binary Neutron Star Merger GW170817 with ANTARES, IceCube, and the Pierre Auger Observatory

DOE PAGES

Albert, A.; André, M.; Anghinolfi, M.; ...

2017-11-29

The Advanced LIGO and Advanced Virgo observatories recently discovered gravitational waves from a binary neutron star inspiral. A short gamma-ray burst (GRB) that followed the merger of this binary was also recorded by the Fermi Gamma-ray Burst Monitor (Fermi-GBM), and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory (INTEGRAL), indicating particle acceleration by the source. The precise location of the event was determined by optical detections of emission following the merger. We searched for high-energy neutrinos from the merger in the GeV–EeV energy range using the Antares, IceCube, and Pierre Auger Observatories. No neutrinos directionally coincidentmore » with the source were detected within ±500 s around the merger time. Additionally, no MeV neutrino burst signal was detected coincident with the merger. We further carried out an extended search in the direction of the source for high-energy neutrinos within the 14 day period following the merger, but found no evidence of emission. We used these results to probe dissipation mechanisms in relativistic outflows driven by the binary neutron star merger. The non-detection is consistent with model predictions of short GRBs observed at a large off-axis angle.« less

Search for High-energy Neutrinos from Binary Neutron Star Merger GW170817 with ANTARES, IceCube, and the Pierre Auger Observatory

NASA Astrophysics Data System (ADS)

Albert, A.; André, M.; Anghinolfi, M.; Ardid, M.; Aubert, J.-J.; Aublin, J.; Avgitas, T.; Baret, B.; Barrios-Martí, J.; Basa, S.; Belhorma, B.; Bertin, V.; Biagi, S.; Bormuth, R.; Bourret, S.; Bouwhuis, M. C.; Brânzaş, H.; Bruijn, R.; Brunner, J.; Busto, J.; Capone, A.; Caramete, L.; Carr, J.; Celli, S.; Cherkaoui El Moursli, R.; Chiarusi, T.; Circella, M.; Coelho, J. A. B.; Coleiro, A.; Coniglione, R.; Costantini, H.; Coyle, P.; Creusot, A.; Díaz, A. F.; Deschamps, A.; De Bonis, G.; Distefano, C.; Di Palma, I.; Domi, A.; Donzaud, C.; Dornic, D.; Drouhin, D.; Eberl, T.; El Bojaddaini, I.; El Khayati, N.; Elsässer, D.; Enzenhöfer, A.; Ettahiri, A.; Fassi, F.; Felis, I.; Fusco, L. A.; Gay, P.; Giordano, V.; Glotin, H.; Grégoire, T.; Ruiz, R. Gracia; Graf, K.; Hallmann, S.; van Haren, H.; Heijboer, A. J.; Hello, Y.; Hernández-Rey, J. J.; Hößl, J.; Hofestädt, J.; Illuminati, G.; James, C. W.; de Jong, M.; Jongen, M.; Kadler, M.; Kalekin, O.; Katz, U.; Kießling, D.; Kouchner, A.; Kreter, M.; Kreykenbohm, I.; Kulikovskiy, V.; Lachaud, C.; Lahmann, R.; Lefèvre, D.; Leonora, E.; Lotze, M.; Loucatos, S.; Marcelin, M.; Margiotta, A.; Marinelli, A.; Martínez-Mora, J. A.; Mele, R.; Melis, K.; Michael, T.; Migliozzi, P.; Moussa, A.; Navas, S.; Nezri, E.; Organokov, M.; Păvălaş, G. E.; Pellegrino, C.; Perrina, C.; Piattelli, P.; Popa, V.; Pradier, T.; Quinn, L.; Racca, C.; Riccobene, G.; Sánchez-Losa, A.; Saldaña, M.; Salvadori, I.; Samtleben, D. F. E.; Sanguineti, M.; Sapienza, P.; Schüssler, F.; Sieger, C.; Spurio, M.; Stolarczyk, Th.; Taiuti, M.; Tayalati, Y.; Trovato, A.; Turpin, D.; Tönnis, C.; Vallage, B.; Van Elewyck, V.; Versari, F.; Vivolo, D.; Vizzoca, A.; Wilms, J.; Zornoza, J. D.; Zúñiga, J.; ANTARES Collaboration; Aartsen, M. G.; Ackermann, M.; Adams, J.; Aguilar, J. A.; Ahlers, M.; Ahrens, M.; Samarai, I. Al; Altmann, D.; Andeen, K.; Anderson, T.; Ansseau, I.; Anton, G.; Argüelles, C.; Auffenberg, J.; Axani, S.; Bagherpour, H.; Bai, X.; Barron, J. P.; Barwick, S. W.; Baum, V.; Bay, R.; Beatty, J. J.; Becker Tjus, J.; Becker, K.-H.; BenZvi, S.; Berley, D.; Bernardini, E.; Besson, D. Z.; Binder, G.; Bindig, D.; Blaufuss, E.; Blot, S.; Bohm, C.; Börner, M.; Bos, F.; Bose, D.; Böser, S.; Botner, O.; Bourbeau, E.; Bourbeau, J.; Bradascio, F.; Braun, J.; Brayeur, L.; Brenzke, M.; Bretz, H.-P.; Bron, S.; Brostean-Kaiser, J.; Burgman, A.; Carver, T.; Casey, J.; Casier, M.; Cheung, E.; Chirkin, D.; Christov, A.; Clark, K.; Classen, L.; Coenders, S.; Collin, G. H.; Conrad, J. M.; Cowen, D. F.; Cross, R.; Day, M.; de André, J. P. A. M.; De Clercq, C.; DeLaunay, J. J.; Dembinski, H.; De Ridder, S.; Desiati, P.; de Vries, K. D.; de Wasseige, G.; de With, M.; DeYoung, T.; Díaz-Vélez, J. C.; di Lorenzo, V.; Dujmovic, H.; Dumm, J. P.; Dunkman, M.; Dvorak, E.; Eberhardt, B.; Ehrhardt, T.; Eichmann, B.; Eller, P.; Evenson, P. A.; Fahey, S.; Fazely, A. R.; Felde, J.; Filimonov, K.; Finley, C.; Flis, S.; Franckowiak, A.; Friedman, E.; Fuchs, T.; Gaisser, T. K.; Gallagher, J.; Gerhardt, L.; Ghorbani, K.; Giang, W.; Glauch, T.; Glüsenkamp, T.; Goldschmidt, A.; Gonzalez, J. G.; Grant, D.; Griffith, Z.; Haack, C.; Hallgren, A.; Halzen, F.; Hanson, K.; Hebecker, D.; Heereman, D.; Helbing, K.; Hellauer, R.; Hickford, S.; Hignight, J.; Hill, G. C.; Hoffman, K. D.; Hoffmann, R.; Hokanson-Fasig, B.; Hoshina, K.; Huang, F.; Huber, M.; Hultqvist, K.; Hünnefeld, M.; In, S.; Ishihara, A.; Jacobi, E.; Japaridze, G. S.; Jeong, M.; Jero, K.; Jones, B. J. P.; Kalaczynski, P.; Kang, W.; Kappes, A.; Karg, T.; Karle, A.; Katz, U.; Kauer, M.; Keivani, A.; Kelley, J. L.; Kheirandish, A.; Kim, J.; Kim, M.; Kintscher, T.; Kiryluk, J.; Kittler, T.; Klein, S. R.; Kohnen, G.; Koirala, R.; Kolanoski, H.; Köpke, L.; Kopper, C.; Kopper, S.; Koschinsky, J. P.; Koskinen, D. J.; Kowalski, M.; Krings, K.; Kroll, M.; Krückl, G.; Kunnen, J.; Kunwar, S.; Kurahashi, N.; Kuwabara, T.; Kyriacou, A.; Labare, M.; Lanfranchi, J. L.; Larson, M. J.; Lauber, F.; Lesiak-Bzdak, M.; Leuermann, M.; Liu, Q. R.; Lu, L.; Lünemann, J.; Luszczak, W.; Madsen, J.; Maggi, G.; Mahn, K. B. M.; Mancina, S.; Maruyama, R.; Mase, K.; Maunu, R.; McNally, F.; Meagher, K.; Medici, M.; Meier, M.; Menne, T.; Merino, G.; Meures, T.; Miarecki, S.; Micallef, J.; Momenté, G.; Montaruli, T.; Moore, R. W.; Moulai, M.; Nahnhauer, R.; Nakarmi, P.; Naumann, U.; Neer, G.; Niederhausen, H.; Nowicki, S. C.; Nygren, D. R.; Obertacke Pollmann, A.; Olivas, A.; O’Murchadha, A.; Palczewski, T.; Pandya, H.; Pankova, D. V.; Peiffer, P.; Pepper, J. A.; Pérez de los Heros, C.; Pieloth, D.; Pinat, E.; Plum, M.; Pranav, D.; Price, P. B.; Przybylski, G. 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J.; Favata, M.; Fays, M.; Fee, C.; Fehrmann, H.; Feicht, J.; Fejer, M. M.; Fernandez-Galiana, A.; Ferrante, I.; Ferreira, E. C.; Ferrini, F.; Fidecaro, F.; Finstad, D.; Fiori, I.; Fiorucci, D.; Fishbach, M.; Fisher, R. P.; Fitz-Axen, M.; Flaminio, R.; Fletcher, M.; Fong, H.; Font, J. A.; Forsyth, P. W. F.; Forsyth, S. S.; Fournier, J.-D.; Frasca, S.; Frasconi, F.; Frei, Z.; Freise, A.; Frey, R.; Frey, V.; Fries, E. M.; Fritschel, P.; Frolov, V. V.; Fulda, P.; Fyffe, M.; Gabbard, H.; Gadre, B. U.; Gaebel, S. M.; Gair, J. R.; Gammaitoni, L.; Ganija, M. R.; Gaonkar, S. G.; Garcia-Quiros, C.; Garufi, F.; Gateley, B.; Gaudio, S.; Gaur, G.; Gayathri, V.; Gehrels, N.; Gemme, G.; Genin, E.; Gennai, A.; George, D.; George, J.; Gergely, L.; Germain, V.; Ghonge, S.; Ghosh, Abhirup; Ghosh, Archisman; Ghosh, S.; Giaime, J. A.; Giardina, K. D.; Giazotto, A.; Gill, K.; Glover, L.; Goetz, E.; Goetz, R.; Gomes, S.; Goncharov, B.; González, G.; Gonzalez Castro, J. M.; Gopakumar, A.; Gorodetsky, M. L.; Gossan, S. E.; Gosselin, M.; Gouaty, R.; Grado, A.; Graef, C.; Granata, M.; Grant, A.; Gras, S.; Gray, C.; Greco, G.; Green, A. C.; Gretarsson, E. M.; Groot, P.; Grote, H.; Grunewald, S.; Gruning, P.; Guidi, G. M.; Guo, X.; Gupta, A.; Gupta, M. K.; Gushwa, K. E.; Gustafson, E. K.; Gustafson, R.; Halim, O.; Hall, B. R.; Hall, E. D.; Hamilton, E. Z.; Hammond, G.; Haney, M.; Hanke, M. M.; Hanks, J.; Hanna, C.; Hannam, M. D.; Hannuksela, O. A.; Hanson, J.; Hardwick, T.; Harms, J.; Harry, G. M.; Harry, I. W.; Hart, M. J.; Haster, C.-J.; Haughian, K.; Healy, J.; Heidmann, A.; Heintze, M. C.; Heitmann, H.; Hello, P.; Hemming, G.; Hendry, M.; Heng, I. S.; Hennig, J.; Heptonstall, A. W.; Heurs, M.; Hild, S.; Hinderer, T.; Hoak, D.; Hofman, D.; Holt, K.; Holz, D. E.; Hopkins, P.; Horst, C.; Hough, J.; Houston, E. A.; Howell, E. J.; Hreibi, A.; Hu, Y. M.; Huerta, E. A.; Huet, D.; Hughey, B.; Husa, S.; Huttner, S. H.; Huynh-Dinh, T.; Indik, N.; Inta, R.; Intini, G.; Isa, H. N.; Isac, J.-M.; Isi, M.; Iyer, B. R.; Izumi, K.; Jacqmin, T.; Jani, K.; Jaranowski, P.; Jawahar, S.; Jiménez-Forteza, F.; Johnson, W. W.; Jones, D. I.; Jones, R.; Jonker, R. J. G.; Ju, L.; Junker, J.; Kalaghatgi, C. V.; Kalogera, V.; Kamai, B.; Kandhasamy, S.; Kang, G.; Kanner, J. B.; Kapadia, S. J.; Karki, S.; Karvinen, K. S.; Kasprzack, M.; Katolik, M.; Katsavounidis, E.; Katzman, W.; Kaufer, S.; Kawabe, K.; Kéfélian, F.; Keitel, D.; Kemball, A. J.; Kennedy, R.; Kent, C.; Key, J. S.; Khalili, F. Y.; Khan, I.; Khan, S.; Khan, Z.; Khazanov, E. A.; Kijbunchoo, N.; Kim, Chunglee; Kim, J. C.; Kim, K.; Kim, W.; Kim, W. S.; Kim, Y.-M.; Kimbrell, S. J.; King, E. J.; King, P. J.; Kinley-Hanlon, M.; Kirchhoff, R.; Kissel, J. S.; Kleybolte, L.; Klimenko, S.; Knowles, T. D.; Koch, P.; Koehlenbeck, S. M.; Koley, S.; Kondrashov, V.; Kontos, A.; Korobko, M.; Korth, W. Z.; Kowalska, I.; Kozak, D. B.; Krämer, C.; Kringel, V.; Krishnan, B.; Królak, A.; Kuehn, G.; Kumar, P.; Kumar, R.; Kumar, S.; Kuo, L.; Kutynia, A.; Kwang, S.; Lackey, B. D.; Lai, K. H.; Landry, M.; Lang, R. N.; Lange, J.; Lantz, B.; Lanza, R. K.; Lartaux-Vollard, A.; Lasky, P. D.; Laxen, M.; Lazzarini, A.; Lazzaro, C.; Leaci, P.; Leavey, S.; Lee, C. H.; Lee, H. K.; Lee, H. M.; Lee, H. W.; Lee, K.; Lehmann, J.; Lenon, A.; Leonardi, M.; Leroy, N.; Letendre, N.; Levin, Y.; Li, T. G. F.; Linker, S. D.; Littenberg, T. B.; Liu, J.; Lo, R. K. L.; Lockerbie, N. A.; London, L. T.; Lord, J. E.; Lorenzini, M.; Loriette, V.; Lormand, M.; Losurdo, G.; Lough, J. D.; Lousto, C. O.; Lovelace, G.; Lück, H.; Lumaca, D.; Lundgren, A. P.; Lynch, R.; Ma, Y.; Macas, R.; Macfoy, S.; Machenschalk, B.; MacInnis, M.; Macleod, D. M.; Magaña Hernandez, I.; Magaña-Sandoval, F.; Magaña Zertuche, L.; Magee, R. M.; Majorana, E.; Maksimovic, I.; Man, N.; Mandic, V.; Mangano, V.; Mansell, G. L.; Manske, M.; Mantovani, M.; Marchesoni, F.; Marion, F.; Márka, S.; Márka, Z.; Markakis, C.; Markosyan, A. S.; Markowitz, A.; Maros, E.; Marquina, A.; Martelli, F.; Martellini, L.; Martin, I. W.; Martin, R. M.; Martynov, D. V.; Mason, K.; Massera, E.; Masserot, A.; Massinger, T. J.; Masso-Reid, M.; Mastrogiovanni, S.; Matas, A.; Matichard, F.; Matone, L.; Mavalvala, N.; Mazumder, N.; McCarthy, R.; McClelland, D. E.; McCormick, S.; McCuller, L.; McGuire, S. C.; McIntyre, G.; McIver, J.; McManus, D. J.; McNeill, L.; McRae, T.; McWilliams, S. T.; Meacher, D.; Meadors, G. D.; Mehmet, M.; Meidam, J.; Mejuto-Villa, E.; Melatos, A.; Mendell, G.; Mercer, R. A.; Merilh, E. L.; Merzougui, M.; Meshkov, S.; Messenger, C.; Messick, C.; Metzdorff, R.; Meyers, P. M.; Miao, H.; Michel, C.; Middleton, H.; Mikhailov, E. E.; Milano, L.; Miller, A. L.; Miller, B. B.; Miller, J.; Millhouse, M.; Milovich-Goff, M. C.; Minazzoli, O.; Minenkov, Y.; Ming, J.; Mishra, C.; Mitra, S.; Mitrofanov, V. P.; Mitselmakher, G.; Mittleman, R.; Moffa, D.; Moggi, A.; Mogushi, K.; Mohan, M.; Mohapatra, S. R. P.; Montani, M.; Moore, C. J.; Moraru, D.; Moreno, G.; Morriss, S. R.; Mours, B.; Mow-Lowry, C. M.; Mueller, G.; Muir, A. W.; Mukherjee, Arunava; Mukherjee, D.; Mukherjee, S.; Mukund, N.; Mullavey, A.; Munch, J.; Muñiz, E. A.; Muratore, M.; Murray, P. G.; Napier, K.; Nardecchia, I.; Naticchioni, L.; Nayak, R. K.; Neilson, J.; Nelemans, G.; Nelson, T. J. N.; Nery, M.; Neunzert, A.; Nevin, L.; Newport, J. M.; Newton, G.; Ng, K. K. Y.; Nguyen, T. T.; Nichols, D.; Nielsen, A. B.; Nissanke, S.; Nitz, A.; Noack, A.; Nocera, F.; Nolting, D.; North, C.; Nuttall, L. K.; Oberling, J.; O’Dea, G. D.; Ogin, G. H.; Oh, J. J.; Oh, S. H.; Ohme, F.; Okada, M. A.; Oliver, M.; Oppermann, P.; Oram, Richard J.; O’Reilly, B.; Ormiston, R.; Ortega, L. F.; O’Shaughnessy, R.; Ossokine, S.; Ottaway, D. J.; Overmier, H.; Owen, B. J.; Pace, A. E.; Page, J.; Page, M. A.; Pai, A.; Pai, S. A.; Palamos, J. R.; Palashov, O.; Palomba, C.; Pal-Singh, A.; Pan, Howard; Pan, Huang-Wei; Pang, B.; Pang, P. T. H.; Pankow, C.; Pannarale, F.; Pant, B. C.; Paoletti, F.; Paoli, A.; Papa, M. A.; Parida, A.; Parker, W.; Pascucci, D.; Pasqualetti, A.; Passaquieti, R.; Passuello, D.; Patil, M.; Patricelli, B.; Pearlstone, B. L.; Pedraza, M.; Pedurand, R.; Pekowsky, L.; Pele, A.; Penn, S.; Perez, C. J.; Perreca, A.; Perri, L. M.; Pfeiffer, H. P.; Phelps, M.; Piccinni, O. J.; Pichot, M.; Piergiovanni, F.; Pierro, V.; Pillant, G.; Pinard, L.; Pinto, I. M.; Pirello, M.; Pitkin, M.; Poe, M.; Poggiani, R.; Popolizio, P.; Porter, E. K.; Post, A.; Powell, J.; Prasad, J.; Pratt, J. W. W.; Pratten, G.; Predoi, V.; Prestegard, T.; Prijatelj, M.; Principe, M.; Privitera, S.; Prodi, G. A.; Prokhorov, L. G.; Puncken, O.; Punturo, M.; Puppo, P.; Pürrer, M.; Qi, H.; Quetschke, V.; Quintero, E. A.; Quitzow-James, R.; Raab, F. J.; Rabeling, D. S.; Radkins, H.; Raffai, P.; Raja, S.; Rajan, C.; Rajbhandari, B.; Rakhmanov, M.; Ramirez, K. E.; Ramos-Buades, A.; Rapagnani, P.; Raymond, V.; Razzano, M.; Read, J.; Regimbau, T.; Rei, L.; Reid, S.; Reitze, D. H.; Ren, W.; Reyes, S. D.; Ricci, F.; Ricker, P. M.; Rieger, S.; Riles, K.; Rizzo, M.; Robertson, N. A.; Robie, R.; Robinet, F.; Rocchi, A.; Rolland, L.; Rollins, J. G.; Roma, V. J.; Romano, R.; Romel, C. L.; Romie, J. H.; Rosińska, D.; Ross, M. P.; Rowan, S.; Rüdiger, A.; Ruggi, P.; Rutins, G.; Ryan, K.; Sachdev, S.; Sadecki, T.; Sadeghian, L.; Sakellariadou, M.; Salconi, L.; Saleem, M.; Salemi, F.; Samajdar, A.; Sammut, L.; Sampson, L. M.; Sanchez, E. J.; Sanchez, L. E.; Sanchis-Gual, N.; Sandberg, V.; Sanders, J. R.; Sassolas, B.; Saulson, P. R.; Sauter, O.; Savage, R. L.; Sawadsky, A.; Schale, P.; Scheel, M.; Scheuer, J.; Schmidt, J.; Schmidt, P.; Schnabel, R.; Schofield, R. M. S.; Schönbeck, A.; Schreiber, E.; Schuette, D.; Schulte, B. W.; Schutz, B. F.; Schwalbe, S. G.; Scott, J.; Scott, S. M.; Seidel, E.; Sellers, D.; Sengupta, A. S.; Sentenac, D.; Sequino, V.; Sergeev, A.; Shaddock, D. A.; Shaffer, T. J.; Shah, A. A.; Shahriar, M. S.; Shaner, M. B.; Shao, L.; Shapiro, B.; Shawhan, P.; Sheperd, A.; Shoemaker, D. H.; Shoemaker, D. M.; Siellez, K.; Siemens, X.; Sieniawska, M.; Sigg, D.; Silva, A. D.; Singer, L. P.; Singh, A.; Singhal, A.; Sintes, A. M.; Slagmolen, B. J. J.; Smith, B.; Smith, J. R.; Smith, R. J. E.; Somala, S.; Son, E. J.; Sonnenberg, J. A.; Sorazu, B.; Sorrentino, F.; Souradeep, T.; Spencer, A. P.; Srivastava, A. K.; Staats, K.; Staley, A.; Steinke, M.; Steinlechner, J.; Steinlechner, S.; Steinmeyer, D.; Stevenson, S. P.; Stone, R.; Stops, D. J.; Strain, K. A.; Stratta, G.; Strigin, S. E.; Strunk, A.; Sturani, R.; Stuver, A. L.; Summerscales, T. Z.; Sun, L.; Sunil, S.; Suresh, J.; Sutton, P. J.; Swinkels, B. L.; Szczepańczyk, M. J.; Tacca, M.; Tait, S. C.; Talbot, C.; Talukder, D.; Tanner, D. B.; Tápai, M.; Taracchini, A.; Tasson, J. D.; Taylor, J. A.; Taylor, R.; Tewari, S. V.; Theeg, T.; Thies, F.; Thomas, E. G.; Thomas, M.; Thomas, P.; Thorne, K. A.; Thrane, E.; Tiwari, S.; Tiwari, V.; Tokmakov, K. V.; Toland, K.; Tonelli, M.; Tornasi, Z.; Torres-Forné, A.; Torrie, C. I.; Töyrä, D.; Travasso, F.; Traylor, G.; Trinastic, J.; Tringali, M. C.; Trozzo, L.; Tsang, K. W.; Tse, M.; Tso, R.; Tsukada, L.; Tsuna, D.; Tuyenbayev, D.; Ueno, K.; Ugolini, D.; Unnikrishnan, C. S.; Urban, A. L.; Usman, S. A.; Vahlbruch, H.; Vajente, G.; Valdes, G.; van Bakel, N.; van Beuzekom, M.; van den Brand, J. F. J.; Van Den Broeck, C.; Vander-Hyde, D. C.; van der Schaaf, L.; van Heijningen, J. V.; van Veggel, A. A.; Vardaro, M.; Varma, V.; Vass, S.; Vasúth, M.; Vecchio, A.; Vedovato, G.; Veitch, J.; Veitch, P. J.; Venkateswara, K.; Venugopalan, G.; Verkindt, D.; Vetrano, F.; Viceré, A.; Viets, A. D.; Vinciguerra, S.; Vine, D. J.; Vinet, J.-Y.; Vitale, S.; Vo, T.; Vocca, H.; Vorvick, C.; Vyatchanin, S. P.; Wade, A. R.; Wade, L. E.; Wade, M.; Walet, R.; Walker, M.; Wallace, L.; Walsh, S.; Wang, G.; Wang, H.; Wang, J. Z.; Wang, W. H.; Wang, Y. F.; Ward, R. L.; Warner, J.; Was, M.; Watchi, J.; Weaver, B.; Wei, L.-W.; Weinert, M.; Weinstein, A. J.; Weiss, R.; Wen, L.; Wessel, E. K.; Weßels, P.; Westerweck, J.; Westphal, T.; Wette, K.; Whelan, J. T.; Whiting, B. F.; Whittle, C.; Wilken, D.; Williams, D.; Williams, R. D.; Williamson, A. R.; Willis, J. L.; Willke, B.; Wimmer, M. H.; Winkler, W.; Wipf, C. C.; Wittel, H.; Woan, G.; Woehler, J.; Wofford, J.; Wong, K. W. K.; Worden, J.; Wright, J. L.; Wu, D. S.; Wysocki, D. M.; Xiao, S.; Yamamoto, H.; Yancey, C. C.; Yang, L.; Yap, M. J.; Yazback, M.; Yu, Hang; Yu, Haocun; Yvert, M.; Zadrożny, A.; Zanolin, M.; Zelenova, T.; Zendri, J.-P.; Zevin, M.; Zhang, L.; Zhang, M.; Zhang, T.; Zhang, Y.-H.; Zhao, C.; Zhou, M.; Zhou, Z.; Zhu, S. J.; Zhu, X. J.; Zucker, M. E.; Zweizig, J.; LIGO Scientific Collaboration; Virgo Collaboration

2017-12-01

The Advanced LIGO and Advanced Virgo observatories recently discovered gravitational waves from a binary neutron star inspiral. A short gamma-ray burst (GRB) that followed the merger of this binary was also recorded by the Fermi Gamma-ray Burst Monitor (Fermi-GBM), and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory (INTEGRAL), indicating particle acceleration by the source. The precise location of the event was determined by optical detections of emission following the merger. We searched for high-energy neutrinos from the merger in the GeV–EeV energy range using the ANTARES, IceCube, and Pierre Auger Observatories. No neutrinos directionally coincident with the source were detected within ±500 s around the merger time. Additionally, no MeV neutrino burst signal was detected coincident with the merger. We further carried out an extended search in the direction of the source for high-energy neutrinos within the 14 day period following the merger, but found no evidence of emission. We used these results to probe dissipation mechanisms in relativistic outflows driven by the binary neutron star merger. The non-detection is consistent with model predictions of short GRBs observed at a large off-axis angle.

Nucleotide sequence of wild-type hepatitis A virus GBM in comparison with two cell culture-adapted variants.

PubMed Central

Graff, J; Normann, A; Feinstone, S M; Flehmig, B

1994-01-01

In order to study cell tropism and attenuation of hepatitis A virus (HAV), the genome of HAV wild-type GBM and two cell culture-adapted variants, GBM/FRhK and GBM/HFS, were cloned and sequenced after amplification by reverse transcriptase-PCR. During virus cultivation, the HAV variant GBM/FRhK had a strict host range for FRhK-4 cells, in contrast to GBM/HFS, which can be grown in HFS and FRhK-4 cells. The HAV variant GBM/HFS was shown to be attenuated when inoculated into chimpanzees (B. Flehmig, R. F. Mauler, G. Noll, E. Weinmann, and J. P. Gregerson, p. 87-90, in A. Zuckerman, ed., Viral Hepatitis and Liver Disease, 1988). On the basis of this biological background, the comparison of the nucleotide sequences of these three HAV GBM variants should elucidate differences which may be of importance for cell tropism and attenuation. The comparison of the genome between the GBM wild type and HAV wild types HM175 (J. I. Cohen, J. R. Ticehurst, R. H. Purcell, A. Buckler-White, and B. M. Baroudy, J. Virol. 61:50-59, 1987) and HAV-LA (R. Najarian, O. Caput, W. Gee, S. J. Potter, A. Renard, J. Merryweather, G. Van Nest, and D. Dina, Proc. Natl. Acad. Sci. USA 82:2627-2631, 1985) showed a 92 to 96.3% identity, whereas the identity was 99.3 to 99.6% between the GBM variants. Nucleotide differences between the wild-type and the cell culture-adapted variants, which were identical in both cell culture-adapted GBM variants, were localized in the 5' noncoding region; in 2B, 3B, and 3D; and in the 3' noncoding region. Our result concerning the 2B/2C region confirms a mutation at position 3889 (C-->T, alanine to valine), which had been shown to be of importance for cell culture adaptation (S. U. Emerson, C. McRill, B. Rosenblum, S. M. Feinstone, and R. H. Purcell, J. Virol. 65:4882-4886, 1991; S. U. Emerson, Y. K. Huang, C. McRill, M. Lewis, and R. H. Purcell, J. Virol. 66:650-654, 1992), whereas other mutations differ from published HAV sequence data and may be cell specific. Further comparison of the two cell culture-adapted GBM variants showed cell-specific mutations resulting in deletions of six amino acids in the VP1 region and three amino acids in the 3A region of the GBM variant GBM/FRhK. PMID:8254770

Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways.

PubMed

Bijangi-Vishehsaraei, Khadijeh; Reza Saadatzadeh, M; Wang, Haiyan; Nguyen, Angie; Kamocka, Malgorzata M; Cai, Wenjing; Cohen-Gadol, Aaron A; Halum, Stacey L; Sarkaria, Jann N; Pollok, Karen E; Safa, Ahmad R

2017-12-01

OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

PubMed Central

Favero, F.; McGranahan, N.; Salm, M.; Birkbak, N. J.; Sanborn, J. Z.; Benz, S. C.; Becq, J.; Peden, J. F.; Kingsbury, Z.; Grocok, R. J.; Humphray, S.; Bentley, D.; Spencer-Dene, B.; Gutteridge, A.; Brada, M.; Roger, S.; Dietrich, P.-Y.; Forshew, T.; Gerlinger, M.; Rowan, A.; Stamp, G.; Eklund, A. C.; Szallasi, Z.; Swanton, C.

2015-01-01

Background Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. Methods We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. Results We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. Conclusion This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success. PMID:25732040

Gene expression profiling of anti-GBM glomerulonephritis model: the role of NF-kappaB in immune complex kidney disease.

PubMed

Kim, Ju Han; Ha, Il Soo; Hwang, Chang-Il; Lee, Young-Ju; Kim, Jihoon; Yang, Seung-Hee; Kim, Yon Su; Cao, Yun Anna; Choi, Sangdun; Park, Woong-Yang

2004-11-01

Immune complexes may cause an irreversible onset of chronic renal disease. Most patients with chronic renal disease undergo a final common pathway, marked by glomerulosclerosis and interstitial fibrosis. We attempted to draw a molecular map of anti-glomerular basement membrane (GBM) glomerulonephritis in mice using oligonucleotide microarray technology. Kidneys were harvested at days 1, 3, 7, 11, and 16 after inducing glomerulonephritis by using anti-GBM antibody. In parallel with examining the biochemical and histologic changes, gene expression profiles were acquired against five pooled control kidneys. Gene expression levels were cross-validated by either reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, or immunohistochemistry. Pathologic changes in anti-GBM glomerulonephritis were confirmed in both BALB/c and C57BL/6 strains. Among the 13,680 spotted 65mer oligonucleotides, 1112 genes showing significant temporal patterns by permutation analysis of variance (ANOVA) with multiple testing correction [false discovery ratio (FDR) < 0.05] were chosen for cluster analysis. From the expression profile, acute inflammatory reactions characterized by the elevation of various cytokines, including interleukin (IL)-1 and IL-6, were identified within 3 days of disease onset. After 7 days, tissue remodeling response was prominent with highly induced extracellular-matrix (ECM) genes. Although cytokines related to lymphocyte activation were not detected, monocyte or mesangial cell proliferation-related genes were increased. Tumor necrosis factor-alpha (TNF-alpha) and nuclear factor-kappaB (NF-kappaB) pathway were consistently activated along the entire disease progression, inducing various target genes like complement 3, IL-1b, IL-6, Traf1, and Saa1. We made a large-scale gene expression time table for mouse anti-GBM glomerulonephritis model, providing a comprehensive overview on the mechanism governing the initiation and the progression of inflammatory renal disease.

Development of a Function-Blocking Antibody Against Fibulin-3 as a Targeted Reagent for Glioblastoma.

PubMed

Nandhu, Mohan S; Behera, Prajna; Bhaskaran, Vivek; Longo, Sharon L; Barrera-Arenas, Lina M; Sengupta, Sadhak; Rodriguez-Gil, Diego J; Chiocca, E Antonio; Viapiano, Mariano S

2018-02-15

Purpose: We sought a novel approach against glioblastomas (GBM) focused on targeting signaling molecules localized in the tumor extracellular matrix (ECM). We investigated fibulin-3, a glycoprotein that forms the ECM scaffold of GBMs and promotes tumor progression by driving Notch and NFκB signaling. Experimental Design: We used deletion constructs to identify a key signaling motif of fibulin-3. An mAb (mAb428.2) was generated against this epitope and extensively validated for specific detection of human fibulin-3. mAb428.2 was tested in cultures to measure its inhibitory effect on fibulin-3 signaling. Nude mice carrying subcutaneous and intracranial GBM xenografts were treated with the maximum achievable dose of mAb428.2 to measure target engagement and antitumor efficacy. Results: We identified a critical 23-amino acid sequence of fibulin-3 that activates its signaling mechanisms. mAb428.2 binds to that epitope with nanomolar affinity and blocks the ability of fibulin-3 to activate ADAM17, Notch, and NFκB signaling in GBM cells. mAb428.2 treatment of subcutaneous GBM xenografts inhibited fibulin-3, increased tumor cell apoptosis, and enhanced the infiltration of inflammatory macrophages. The antibody reduced tumor growth and extended survival of mice carrying GBMs as well as other fibulin-3-expressing tumors. Locally infused mAb428.2 showed efficacy against intracranial GBMs, increasing tumor apoptosis and reducing tumor invasion and vascularization, which are enhanced by fibulin-3. Conclusions: To our knowledge, this is the first rationally developed, function-blocking antibody against an ECM target in GBM. Our results offer a proof of principle for using "anti-ECM" strategies toward more efficient targeted therapies for malignant glioma. Clin Cancer Res; 24(4); 821-33. ©2017 AACR . ©2017 American Association for Cancer Research.

Opposing roles of PGD2 in GBM.

PubMed

Ferreira, Matthew Thomas; Gomes, Renata Nascimento; Panagopoulos, Alexandros Theodoros; de Almeida, Fernando Gonçalves; Veiga, José Carlos Esteves; Colquhoun, Alison

2018-01-01

The World Health Organization classifies glioblastoma (GBM) as a grade IV astrocytoma. Despite the advances in chemotherapy, surgery, and radiation treatments that improve a patient's length of survival, the overall trajectory of the disease remains unchanged. GBM cells produce significant levels of various types of bioactive lipids. Prostaglandin D 2 (PGD 2 ) influences both pro- and anti-tumorigenic activities in the cell; however, its role in GBM is unclear. Therefore, this study aimed to identify the impact of PGD 2 on GBM cell activities in vitro. First we looked to identify the presence of the PGD 2 synthesis pathway through RT-PCR, immunohistochemistry, and HPLC-MS/MS in three GBM cell lines. Then, to observe PGD 2 's effects on cell count and apoptosis/mitosis (Hoechst 33342 stain), and migration (Transwell Assay), the cells were treated in vitro with physiological (<1μM) and/or supraphysiological (>1μM) concentrations of PGD 2 over 72h. HPLC-MS/MS was used to identify the lipid composition of patients with either Grade II/III gliomas or GBM. We identified the presence of endogenous PGD 2 with its corresponding enzymes and receptors. Exogenous PGD 2 both increased cell count (<1μM) and decreased cell count (10μM) in a concentration-dependent manner. There were no significant effects on apoptosis. A significant decrease in mitotic activity was seen only in U251MG, and a significant increase was seen in migration with 5μM PGD 2 treatments. A very significant increase of PGD 2 was seen from Grade II/III gliomas to GBM. Our study demonstrates that prostaglandin D 2 possesses a dynamic, concentration-dependent effect in GBM cell activities. The increase of PGD 2 production in GBM patients suggests a pro-tumorigenic role of PGD 2 in glioma growth and invasion. Therefore, prostaglandin signaling in GBM requires further investigation to identify new targets for more effective therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data

PubMed Central

Zhang, Bo; Liu, Dajiang J.; Muscat, Joshua E.; Langan, Sara T.; Connor, James R.

2017-01-01

Human hemochromatosis protein (HFE) is involved in iron metabolism. Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers. Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM). However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied. To expand our finding in a larger sample, and to identify other HFE SNV, we analyzed the frequency of somatic SNV in HFE gene and its relationship to survival in GBM patients using The Cancer Genome Atlas (TCGA) GBM (Caucasian only) database. We found 9 SNVs with increased frequency in blood normal of TCGA GBM patients compared to the 1000Genome. Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene. The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119–0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474–0.1159) HFE polymorphisms than 1000Genome. The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients. In addition, there was no difference in the survival of male/female GBM patients based on HFE genotype. There was no correlation between HFE expression and survival. In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients’ survival in the TCGA data set of GBM. PMID:28358914

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models

PubMed Central

Pohling, Christoph; Natarajan, Arutselvan; Witney, Timothy H.; Kaur, Jasdeep; Xu, Lingyun; Gowrishankar, Gayatri; D’Souza, Aloma L; Murty, Surya; Schick, Sophie; Chen, Liyin; Wu, Nicholas; Khaw, Phoo; Mischel, Paul; Abbasi, Taher; Usmani, Shahabuddin; Mallick, Parag

2017-01-01

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O’Neill (J Neurooncol 107: 359–364, 2012). An extract from the winter cherry plant (Withania somnifera), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985–1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3–5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 μM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 μM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM. PMID:26650066

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models.

PubMed

Chang, Edwin; Pohling, Christoph; Natarajan, Arutselvan; Witney, Timothy H; Kaur, Jasdeep; Xu, Lingyun; Gowrishankar, Gayatri; D'Souza, Aloma L; Murty, Surya; Schick, Sophie; Chen, Liyin; Wu, Nicholas; Khaw, Phoo; Mischel, Paul; Abbasi, Taher; Usmani, Shahabuddin; Mallick, Parag; Gambhir, Sanjiv S

2016-01-01

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O'Neill (J Neurooncol 107: 359-364, 2012). An extract from the winter cherry plant (Withania somnifera ), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985-1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3-5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 µM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 µM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM.

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment.

PubMed

Würth, Roberto; Bajetto, Adriana; Harrison, Jeffrey K; Barbieri, Federica; Florio, Tullio

2014-01-01

Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem-like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4-CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine-based drugs.

Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I.

PubMed

Sippel, Trisha R; White, Jason; Nag, Kamalika; Tsvankin, Vadim; Klaassen, Marci; Kleinschmidt-DeMasters, B K; Waziri, Allen

2011-11-15

The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM. Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation. We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b(+) cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients.

Fibrin matrices enhance the transplant and efficacy of cytotoxic stem cell therapy for post-surgical cancer

PubMed Central

Bagó, Juli R.; Pegna, Guillaume J.; Okolie, Onyi; Hingtgen, Shawn D.

2016-01-01

Tumor-homing cytotoxic stem cell (SC) therapy is a promising new approach for treating the incurable brain cancer glioblastoma (GBM). However, problems of retaining cytotoxic SCs within the post-surgical GBM resection cavity are likely to significantly limit the clinical utility of this strategy. Here, we describe a new fibrin-based transplant approach capable of increasing cytotoxic SC retention and persistence within the resection cavity, yet remaining permissive to tumoritropic migration. This fibrin-based transplant can effectively treat both solid and post-surgical human GBM in mice. Using our murine model of image-guided model of GBM resection, we discovered that suspending human mesenchymal stem cells (hMSCS) in a fibrin matrix increased initial retention in the surgical resection cavity 2-fold and prolonged persistence in the cavity 3-fold compared to conventional delivery strategies. Time-lapse motion analysis revealed that cytotoxic hMSCs in the fibrin matrix remain tumoritropic, rapidly migrating from the fibrin matrix to co-localize with cultured human GBM cells. We encapsulated hMSCs releasing the cytotoxic agent TRAIL (hMSC-sTR) in fibrin, and found hMSC-sTR/fibrin therapy reduced the viability of multiple 3-D human GBM spheroids and regressed established human GBM xenografts 3-fold in 11 days. Mimicking clinical therapy of surgically resected GBM, intra-cavity seeding of therapeutic hMSC-sTR encapsulated in fibrin reduced post-surgical GBM volumes 6-fold, increased time to recurrence 4-fold, and prolonged median survival from 15 to 36 days compared to control-treated animals. Fibrin-based SC therapy could represent a clinically compatible, viable treatment to suppress recurrence of post-surgical GBM and other lethal cancer types. PMID:26803410

BET bromodomain proteins are required for glioblastoma cell proliferation.

PubMed

Pastori, Chiara; Daniel, Mark; Penas, Clara; Volmar, Claude-Henry; Johnstone, Andrea L; Brothers, Shaun P; Graham, Regina M; Allen, Bryce; Sarkaria, Jann N; Komotar, Ricardo J; Wahlestedt, Claes; Ayad, Nagi G

2014-04-01

Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine-acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I-BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I-BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors.

NF-κB-Induced IL-6 Ensures STAT3 Activation and Tumor Aggressiveness in Glioblastoma

PubMed Central

McFarland, Braden C.; Hong, Suk W.; Rajbhandari, Rajani; Twitty, George B.; Gray, G. Kenneth; Yu, Hao; Benveniste, Etty N.; Nozell, Susan E.

2013-01-01

Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance. In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo. We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness. PMID:24244348

BET bromodomain proteins are required for glioblastoma cell proliferation

PubMed Central

Pastori, Chiara; Daniel, Mark; Penas, Clara; Volmar, Claude-Henry; Johnstone, Andrea L; Brothers, Shaun P; Graham, Regina M; Allen, Bryce; Sarkaria, Jann N; Komotar, Ricardo J; Wahlestedt, Claes; Ayad, Nagi G

2014-01-01

Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine-acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I-BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I-BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors. PMID:24496381

Selective coexpression of VEGF receptor 2 in EGFRvIII-positive glioblastoma cells prevents cellular senescence and contributes to their aggressive nature.

PubMed

Jones, Karra A; Gilder, Andrew S; Lam, Michael S; Du, Na; Banki, Michael A; Merati, Aran; Pizzo, Donald P; VandenBerg, Scott R; Gonias, Steven L

2016-05-01

In glioblastoma (GBM), the gene for epidermal growth factor receptor (EGFR) is frequently amplified. EGFR mutations also are common, including a truncation mutation that yields a constitutively active variant called EGFR variant (v)III. EGFRvIII-positive GBM progresses rapidly; however, the reason for this is not clear because the activity of EGFRvIII is attenuated compared with EGF-ligated wild-type EGFR. We hypothesized that EGFRvIII-expressing GBM cells selectively express other oncogenic receptors that support tumor progression. Mining of The Cancer Genome Atlas prompted us to test whether GBM cells in culture, which express EGFRvIII, selectively express vascular endothelial growth factor receptor (VEGFR)2. We also studied human GBM propagated as xenografts. We then applied multiple approaches to test the effects of VEGFR2 on GBM cell growth, apoptosis, and cellular senescence. In human GBM, EGFR overexpression and EGFRvIII positivity were associated with increased VEGFR2 expression. In GBM cells in culture, EGFRvIII-initiated cell signaling increased expression of VEGFR2, which prevented cellular senescence and promoted cell cycle progression. The VEGFR-selective tyrosine kinase inhibitor cediranib decreased tumor DNA synthesis, increased staining for senescence-associated β-galactosidase, reduced retinoblastoma phosphorylation, and increased p27(Kip1), all markers of cellular senescence. Similar results were obtained when VEGFR2 was silenced. VEGFR2 expression by GBM cells supports cell cycle progression and prevents cellular senescence. Coexpression of VEGFR2 by GBM cells in which EGFR signaling is activated may contribute to the aggressive nature of these cells. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

NF-κB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma.

PubMed

McFarland, Braden C; Hong, Suk W; Rajbhandari, Rajani; Twitty, George B; Gray, G Kenneth; Yu, Hao; Benveniste, Etty N; Nozell, Susan E

2013-01-01

Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance. In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo. We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness.

The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma.

PubMed

Pokorny, Jenny L; Calligaris, David; Gupta, Shiv K; Iyekegbe, Dennis O; Mueller, Dustin; Bakken, Katrina K; Carlson, Brett L; Schroeder, Mark A; Evans, Debra L; Lou, Zhenkun; Decker, Paul A; Eckel-Passow, Jeanette E; Pucci, Vincenzo; Ma, Bennett; Shumway, Stuart D; Elmquist, William F; Agar, Nathalie Y R; Sarkaria, Jann N

2015-04-15

Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in glioblastoma multiforme (GBM) xenograft models alone and in combination with radiation and/or temozolomide. In vitro MK-1775 efficacy alone and in combination with temozolomide, and the impact on DNA damage, was analyzed by Western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI)-MS imaging. GBM22 (IC50 = 68 nmol/L) was significantly more sensitive to MK-1775 compared with five other GBM xenograft lines, including GBM6 (IC50 >300 nmol/L), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with temozolomide in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with temozolomide, whereas in a flank model of GBM22, MK-1775 exhibited both single-agent and combinatorial activity with temozolomide. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared with heterotopic GBM22 tumors. Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM. ©2015 American Association for Cancer Research.

The efficacy of the Wee1 inhibitor MK-1775 combined with temozolomide is limited by heterogeneous distribution across the blood-brain barrier in glioblastoma

PubMed Central

Pokorny, Jenny L.; Calligaris, David; Gupta, Shiv K.; Iyekegbe, Dennis O.; Mueller, Dustin; Bakken, Katrina K.; Carlson, Brett L.; Schroeder, Mark A.; Evans, Debra L.; Lou, Zhenkun; Decker, Paul A.; Eckel-Passow, Jeanette E.; Pucci, Vincenzo; Ma, Bennett; Shumway, Stuart D.; Elmquist, William; Agar, Nathalie Y.; Sarkaria, Jann N.

2015-01-01

Purpose Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in GBM xenograft models alone and in combination with radiation and/or temozolomide (TMZ). Experimental design In vitro MK-1775 efficacy alone and in combination with TMZ, and the impact on DNA damage was analyzed by western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI) -MS imaging. Results GBM22 (IC50 = 68 nM) was significantly more sensitive to MK-1775 compared to 5 other GBM xenograft lines including GBM6 (IC50 >300 nM), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with TMZ in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with TMZ, while in a flank model of GBM22, MK-1775 exhibited both single agent and combinatorial activity with TMZ. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared to heterotopic GBM22 tumors. Conclusions Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM. PMID:25609063

Comparison of clinical outcomes and genomic characteristics of single focus and multifocal glioblastoma

PubMed Central

Paulsson, Anna K.; Holmes, Jordan A.; Peiffer, Ann M.; Miller, Lance D.; Liu, Wennuan; Xu, Jianfeng; Hinson, William H.; Lesser, Glenn J.; Laxton, Adrian W.; Tatter, Stephen B.; Debinski, Waldemar

2014-01-01

We investigate the differences in molecular signature and clinical outcomes between multiple lesion glioblastoma (GBM) and single focus GBM in the modern treatment era. Between August 2000 and May 2010, 161 patients with GBM were treated with modern radiotherapy techniques. Of this group, 33 were considered to have multiple lesion GBM (25 multifocal and 8 multicentric). Patterns of failure, time to progression and overall survival were compared based on whether the tumor was considered a single focus or multiple lesion GBM. Genomic groupings and methylation status were also investigated as a possible predictor of multifocality in a cohort of 41 patients with available tissue for analysis. There was no statistically significant difference in overall survival (p < 0.3) between the multiple lesion tumors (8.2 months) and single focus GBM (11 months). Progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p = 0.02). For patients with single focus, multifocal and multicentric GBM, 81, 76 and 88 % of treatment failures occurred in the 60 Gy volume (p < 0.5), while 54, 72, and 38 % of treatment failures occurred in the 46 Gy volume (p < 0.4). Out of field failures were rare in both single focus and multiple foci GBM (7 vs 3 %). Genomic groupings and methylation status were not found to predict for multifocality. Patterns of failure, survival and genomic signatures for multiple lesion GBM do not appreciably differ when compared to single focus tumors. PMID:24990827

Basement Membrane Defects in Genetic Kidney Diseases

PubMed Central

Chew, Christine; Lennon, Rachel

2018-01-01

The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. The characteristics of specific matrix isoforms such as laminin-521 (α5β2γ1) and the α3α4α5 chain of type IV collagen are essential for the formation of a mature GBM and the restricted tissue distribution of these isoforms makes the GBM a unique structure. Detailed investigation of the GBM has been driven by the identification of inherited abnormalities in matrix proteins and the need to understand pathogenic mechanisms causing severe glomerular disease. A well-described hereditary GBM disease is Alport syndrome, associated with a progressive glomerular disease, hearing loss, and lens defects due to mutations in the genes COL4A3, COL4A4, or COL4A5. Other proteins associated with inherited diseases of the GBM include laminin β2 in Pierson syndrome and LMX1B in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell–matrix signaling pathways affected in glomerular disease. This review will address current knowledge of GBM-associated abnormalities and related signaling pathways, as well as discussing the advances toward disease-targeted therapies for patients with glomerular disease. PMID:29435440

Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture.

PubMed

Deng, Liting; Ng, Lindsay; Ozawa, Tatsuya; Stella, Nephi

2017-01-01

Evidence suggests that the nonpsychotropic cannabis-derived compound, cannabidiol (CBD), has antineoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM). DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM. Here we studied the antiproliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine, or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures. This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system toxicity. We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells. Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells. Cotreatment regimens combining CBD and DNA-damaging agents produced synergistic antiproliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs. Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells. Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little to no therapeutic window when considering NPCs. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

miR-139-5p suppresses cancer cell migration and invasion through targeting ZEB1 and ZEB2 in GBM.

PubMed

Yue, Sihai; Wang, Lihua; Zhang, Hui; Min, Youhui; Lou, Yongli; Sun, Hongshan; Jiang, Yu; Zhang, Wenjin; Liang, Aming; Guo, Yongkun; Chen, Ping; Lv, Guowei; Wang, Liuxiang; Zong, Qinghua; Li, Yong

2015-09-01

Invasion and migration of glioblastoma multiforme (GBM) is a multistep process and an important phenotype that causes this disease to invade surrounding tissues in the brain. Recent studies have highlighted that miRNAs play a pivotal role in controlling GBM cell plasticity. In this report, we used wound healing and transwell assays to identify a novel role of miR-139-5p in inhibition of GBM cell migration and invasion. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-139-5p inhibited expression of ZEB1 and ZEB2, which are master regulators of tumor metastasis. MiR-139-5p specifically interacts with the 3'-UTR regions of ZEB1 and ZEB2, attenuating their expression in GBM cells. To corroborate this finding, we rescued ZEB1 and ZEB2 expression and found partial but significant increases in miR-139-5p-suppressed invasion of GBM cells. The biological relevance of our study was validated by analyzing levels of miR-139-5p in GBM tissue. We found that its expression significantly downregulated compared to normal tissue and shorter overall survival rates in patients with lower miR-139-5p expression. These results confirm that miR-139-5p suppresses GBM migration and invasion and highlight its potential as a biomarker and therapeutic target for treating GBM.

miR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal.

PubMed

Lulli, Valentina; Buccarelli, Mariachiara; Martini, Maurizio; Signore, Michele; Biffoni, Mauro; Giannetti, Stefano; Morgante, Liliana; Marziali, Giovanna; Ilari, Ramona; Pagliuca, Alfredo; Larocca, Luigi Maria; De Maria, Ruggero; Pallini, Roberto; Ricci-Vitiani, Lucia

2015-11-10

Glioblastoma multiforme (GBM) is the most common and fatal malignant adult primary brain tumor. Currently, the overall prognosis for GBM patients remains poor despite advances in neurosurgery and adjuvant treatments. MicroRNAs (miRNAs) contribute to the pathogenesis of various types of tumor, including GBM. In this study we analyzed the expression of a panel of miRNAs, which are known to be differentially expressed by the brain and GBM tumor, in a collection of patient-derived GBM stem-like cells (GSCs). Notably, the average expression level of miR-135b, was the most downregulated compared to its normal counterpart, suggesting a potential role as anti-oncogene.Restoration of miR-135b in GSCs significantly decreased proliferation, migration and clonogenic abilities. More importantly, miR-135b restoration was able to significantly reduce brain infiltration in mouse models of GBM obtained by intracerebral injection of GSC lines. We identified ADAM12 and confirmed SMAD5 and GSK3β as miR-135b targets and potential mediators of its effects. The whole transcriptome analysis ascertained that the expression of miR-135b downmodulated additional genes driving key pathways in GBM survival and infiltration capabilities.Our results identify a critical role of miR-135b in the regulation of GBM development, suggesting that miR-135b might act as a tumor-suppressor factor and thus providing a potential candidate for the treatment of GBM patients.

Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma

PubMed Central

Shen, Y; Wang, Y; Sheng, K; Fei, X; Guo, Q; Larner, J; Kong, X; Qiu, Y; Mi, J

2011-01-01

Increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma multiforme (GBM). This study aims to determine if serine/threonine phosphatase (protein phosphatase 6 (PP6)) is a molecular target for GBM radiosensitization treatment. The GBM orthotopic xenograft mice model was used in this study. Our data demonstrated that the protein level of PP6 catalytic subunit (PP6c) was upregulated in the GBM tissue from about 50% patients compared with the surrounding tissue or control tissue. Both the in vitro survival fraction of GBM cells and the patient survival time were highly correlated or inversely correlated with PP6c expression (R2=0.755 and −0.707, respectively). We also found that siRNA knockdown of PP6c reduced DNA-dependent protein kinase (DNA-PK) activity in three different GBM cell lines, increasing their sensitivity to radiation. In the orthotopic mice model, the overexpression of PP6c in GBM U87 cells attenuated the effect of radiation treatment, and reduced the survival time of mice compared with the control mice, while the PP6c knocking-down improved the effect of radiation treatment, and increased the survival time of mice. These findings demonstrate that PP6 regulates the sensitivity of GBM cells to radiation, and suggest small molecules disrupting or inhibiting PP6 association with DNA-PK is a potential radiosensitizer for GBM. PMID:22158480

Ischemic stroke and intracranial hemorrhage in patients with recurrent glioblastoma multiforme, treated with bevacizumab.

PubMed

Auer, Timo A; Renovanz, Mirjam; Marini, Federico; Brockmann, Marc A; Tanyildizi, Yasemin

2017-07-01

Bevacizumab (BVZ), a monoclonal antibody directed against vascular endothelial growth factor (VEGF), has been suspected to increase the incidence of ischemic stroke (IS) and intracranial hemorrhage (ICH) in GBM patients. Intracranial vascular events, such as IS and ICH, were retrospectively analyzed in 364 MRI scans of 82 patients with recurrent GBM (1st/2nd/3rd relapse). Out of these 82 patients, 40 were treated with BVZ (178 scans) in addition to basic treatment, whereas 42 patients matching for age and gender received basic treatment (186 scans). Distribution of typical vascular risk factors between both groups was analyzed retrospectively. In seven out of 82 patients (8%) vascular events were detected in MRI. Four vascular events were recorded in the BVZ-group (3 IS and 1 ICH), and 3 vascular events were found in the Control-group (1 IS and 2 ICH; p > 0.05 between both groups). Likewise, vascular risk factors (arterial hypertension, diabetes mellitus, obesity, former vascular event, hyperlipidemia, tobacco consumption and/or hypercholesterolemia) did not differ significantly between both groups. BVZ treatment does not seem to be associated with an increased risk for vascular events in patients with GBM in recurrence.

Evaluation of Concurrent Radiation, Temozolomide and ABT-888 Treatment Followed by Maintenance Therapy with Temozolomide and ABT-888 in a Genetically Engineered Glioblastoma Mouse Model.

PubMed

Lemasson, Benjamin; Wang, Hanxiao; Galbán, Stefanie; Li, Yinghua; Zhu, Yuan; Heist, Kevin A; Tsein, Christina; Chenevert, Thomas L; Rehemtulla, Alnawaz; Galbán, Craig J; Holland, Eric C; Ross, Brian D

2016-02-01

Despite the use of ionizing radiation (IR) and temozolomide (TMZ), outcome for glioblastoma (GBM) patients remains dismal. Poly (ADP-ribose) polymerase (PARP) is important in repair pathways for IR-induced DNA damage and TMZ-induced alkylation at N7-methylguanine and N3-methyldenine. However, optimized protocols for administration of PARP inhibitors have not been delineated. In this study, the PARP inhibitor ABT-888 was evaluated in combination with and compared to current standard-of-care in a genetically engineered mouse GBM model. Results demonstrated that concomitant TMZ/IR/ABT-888 with adjuvant TMZ/ABT-888 was more effective in inducing apoptosis and reducing proliferation with significant tumor growth delay and improved overall survival over concomitant TMZ/IR with adjuvant TMZ. Diffusion-weighted MRI, an early translatable response biomarker detected changes in tumors reflecting response at 1 day post TMZ/IR/ABT-888 treatment. This study provides strong scientific rationale for the development of an optimized dosing regimen for a PARP inhibitor with TMZ/IR for upfront treatment of GBM. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

GRAVITATIONAL-WAVE OBSERVATIONS MAY CONSTRAIN GAMMA-RAY BURST MODELS: THE CASE OF GW150914–GBM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veres, P.; Preece, R. D.; Goldstein, A.

The possible short gamma-ray burst (GRB) observed by Fermi /GBM in coincidence with the first gravitational-wave (GW) detection offers new ways to test GRB prompt emission models. GW observations provide previously inaccessible physical parameters for the black hole central engine such as its horizon radius and rotation parameter. Using a minimum jet launching radius from the Advanced LIGO measurement of GW 150914, we calculate photospheric and internal shock models and find that they are marginally inconsistent with the GBM data, but cannot be definitely ruled out. Dissipative photosphere models, however, have no problem explaining the observations. Based on the peakmore » energy and the observed flux, we find that the external shock model gives a natural explanation, suggesting a low interstellar density (∼10{sup −3} cm{sup −3}) and a high Lorentz factor (∼2000). We only speculate on the exact nature of the system producing the gamma-rays, and study the parameter space of a generic Blandford–Znajek model. If future joint observations confirm the GW–short-GRB association we can provide similar but more detailed tests for prompt emission models.« less

DEspR roles in tumor vasculo-angiogenesis, invasiveness, CSC-survival and anoikis resistance: a 'common receptor coordinator' paradigm.

PubMed

Herrera, Victoria L; Decano, Julius L; Tan, Glaiza A; Moran, Ann M; Pasion, Khristine A; Matsubara, Yuichi; Ruiz-Opazo, Nelson

2014-01-01

A priori, a common receptor induced in tumor microvessels, cancer cells and cancer stem-like cells (CSCs) that is involved in tumor angiogenesis, invasiveness, and CSC anoikis resistance and survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show that functional analysis of the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports the putative common receptor paradigm in pancreatic ductal adenocarcinoma (PDAC) and glioblastoma (GBM) selected for their invasiveness, CD133+CSCs, and polar angiogenic features. Unlike normal tissue, DEspR is detected in PDAC and GBM microvessels, tumor cells, and CSCs isolated from PDAC-Panc1 and GBM-U87 cells. DEspR-inhibition decreased angiogenesis, invasiveness, CSC-survival and anoikis resistance in vitro, and decreased Panc1-CSC and U87-CSC xenograft tumor growth, vasculo-angiogenesis and invasiveness in nude(nu/nu) rats, suggesting that DEspR activation would coordinate these tumor progression events. As an accessible, cell-surface 'common receptor coordinator', DEspR-inhibition defines a novel targeted-therapy paradigm for pancreatic cancer and glioblastoma.

DEspR Roles in Tumor Vasculo-Angiogenesis, Invasiveness, CSC-Survival and Anoikis Resistance: A ‘Common Receptor Coordinator’ Paradigm

PubMed Central

Herrera, Victoria L.; Decano, Julius L.; Tan, Glaiza A.; Moran, Ann M.; Pasion, Khristine A.; Matsubara, Yuichi; Ruiz-Opazo, Nelson

2014-01-01

A priori, a common receptor induced in tumor microvessels, cancer cells and cancer stem-like cells (CSCs) that is involved in tumor angiogenesis, invasiveness, and CSC anoikis resistance and survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show that functional analysis of the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports the putative common receptor paradigm in pancreatic ductal adenocarcinoma (PDAC) and glioblastoma (GBM) selected for their invasiveness, CD133+CSCs, and polar angiogenic features. Unlike normal tissue, DEspR is detected in PDAC and GBM microvessels, tumor cells, and CSCs isolated from PDAC-Panc1 and GBM-U87 cells. DEspR-inhibition decreased angiogenesis, invasiveness, CSC-survival and anoikis resistance in vitro, and decreased Panc1-CSC and U87-CSC xenograft tumor growth, vasculo-angiogenesis and invasiveness in nudenu/nu rats, suggesting that DEspR activation would coordinate these tumor progression events. As an accessible, cell-surface ‘common receptor coordinator’, DEspR-inhibition defines a novel targeted-therapy paradigm for pancreatic cancer and glioblastoma. PMID:24465725

The Effects of Nanotexturing Microfluidic Platforms to Isolate Brain Tumor Cells

NASA Astrophysics Data System (ADS)

Islam, Muhymin; Sajid, Adeel; Kim, Young-Tae; Iqbal, Samir M.

2015-03-01

Detection of tumor cells in the early stages of disease requires sensitive and selective approaches. Nanotextured polydimethylsiloxane (PDMS) substrates were implemented to detect metastatic human glioblastoma (hGBM) cells. RNA aptamers that were specific to epidermal growth factor receptors (EGFR) were used to functionalize the substrates. EGFR is known to be overexpressed on many cancer cells including hGBM. Nanotextured PDMS was prepared by micro reactive ion etching. PDMS surfaces became hydrophilic uponnanotexturing. Nanotextured substrates were incubated in tumor cell solution and density of captured cells was determined. Nanotextured PDMS provided >300% cell capture compared to plain PDMS due to increased effective surface area of roughened substrates at nanoscale as well as mire focal points for cell adhesion. Next, aptamer functionalized nanotextured PDMS was incorporated in microfluidic device to detect tumor cells at different flow velocities. The shear stress introduced by the flow pressure and heterogeneity of the EGFR overexpression on cell membranes of the tumor cells had significant impact on the cell capture efficiency of aptamer anchored nanotextured microfluidic devices. Eventually tumor cells were detected from the mixture of white blood cells at an efficiency of 73% using the microfluidic device. The interplay of binding energies and surface energies was major factor in this system. Support Acknowledged from NSF through ECCS-1407990.

PRMT5 as a druggable target for glioblastoma therapy.

PubMed

Banasavadi-Siddegowda, Yeshavanth Kumar; Welker, Alessandra M; An, Min; Yang, Xiaozhi; Zhou, Wei; Shi, Guqin; Imitola, Jaime; Li, Chenglong; Hsu, Sigmund; Wang, Jiang; Phelps, Mitch; Zhang, Jianying; Beattie, Christine E; Baiocchi, Robert; Kaur, Balveen

2018-05-18

In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (GBM) patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogeneous tumor cell population. Protein arginine methyltransferase 5 (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of 4 novel PRMT5 inhibitors in the treatment of GBM. Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence. In vitro and in vivo studies revealed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state. In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.

Temozolomide-induced increase of tumorigenicity can be diminished by targeting of mitochondria in in vitro models of patient individual glioblastoma

PubMed Central

Walther, Madlin; Schneider, Björn; Linnebacher, Michael; Classen, Carl Friedrich

2018-01-01

Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor with a dismal prognosis. Development of resistance towards cytostatic drugs like the GBM standard drug temozolomide is a severe problem in GBM treatment. One potential source of GBM relapse could be so called cancer stem like cells (CSCs). These represent an undifferentiated subpopulation of cells with high potential for tumor initiation. Furthermore, it has been shown that differentiated GBM cells can regain CSC properties when exposed to continuous temozolomide treatment in vitro. In this study, treatment of several primary GBM cell lines with clinically relevant doses of temozolomide increased their tumorigenicity as determined by colony formation assays in soft agar. Increased tumorigenicity is a known property of CSCs. Hence, therapy options that specifically target CSCs are under investigation. CSCs appear to be particularly dependent on mitochondria biogenesis which may represent a useful target for CSC elimination. Toxicity towards mitochondria is a known side effect of several antibiotics. Thus, addition of antibiotics like doxycycline may represent a useful tool to inhibit CSCs in GBM. Here, we show that combining temozolomide treatment of primary GBM cells with doxycycline could counteract the increase of tumorigenicity induced by temozolomide treatment. PMID:29352318

SOX4 inhibits GBM cell growth and induces G0/G1 cell cycle arrest through Akt-p53 axis.

PubMed

Zhang, Jing; Jiang, Huawei; Shao, Jiaofang; Mao, Ruifang; Liu, Jie; Ma, Yingying; Fang, Xuefeng; Zhao, Na; Zheng, Shu; Lin, Biaoyang

2014-11-01

SOX4 is a transcription factor required for tissue development and differentiation in vertebrates. Overexpression of SOX4 has been reported in many cancers including glioblastoma multiforme (GBM), however, the underlying mechanism of actions has not been studied. In this study, we investigated the role of SOX4 in GBM. Kaplan-Meier analysis was performed to assess the association between SOX4 expression levels and survival times in primary GBM samples. Cre/lox P system was used to generate gain or loss of SOX4 in GBM cells, and microarray analysis uncovered the regulation network of SOX4 in GBM cells. High SOX4 expression was significantly associated with good prognosis of primary GBMs. SOX4 inhibited the growth of GBM cell line LN229, A172G and U87MG, partly via the activation of p53-p21 signaling and down-regulation of phosphorylated AKT1. Gene expression profiling and subsequent gene ontology analysis showed that SOX4 influenced several key pathways including the Wnt/ beta-catenin and TGF-beta signaling pathways. Our study found that SOX4 acts as a tumor suppressor in GBM cells by induce cell cycle arrest and inhibiting cell growth.

Dysregulated miR-671-5p / CDR1-AS / CDR1 / VSNL1 axis is involved in glioblastoma multiforme

PubMed Central

Salito, Loredana; Sammito, Mariangela; Banelli, Barbara; Caltabiano, Rosario; Barbagallo, Giuseppe; Zappalà, Agata; Battaglia, Rosalia; Cirnigliaro, Matilde; Lanzafame, Salvatore; Vasquez, Enrico; Parenti, Rosalba; Cicirata, Federico; Di Pietro, Cinzia; Romani, Massimo; Purrello, Michele

2016-01-01

MiR-671-5p is encoded by a gene localized at 7q36.1, a region amplified in human glioblastoma multiforme (GBM), the most malignant brain cancer. To investigate whether expression of miR-671-5p were altered in GBM, we analyzed biopsies from a cohort of forty-five GBM patients and from five GBM cell lines. Our data show significant overexpression of miR-671-5p in both biopsies and cell lines. By exploiting specific miRNA mimics and inhibitors, we demonstrated that miR-671-5p overexpression significantly increases migration and to a less extent proliferation rates of GBM cells. Through a combined in silico and in vitro approach, we identified CDR1-AS, CDR1, VSNL1 as downstream miR-671-5p targets in GBM. Expression of these genes significantly decreased both in GBM biopsies and cell lines and negatively correlated with that of miR-671-5p. Based on our data, we propose that the axis miR-671-5p / CDR1-AS / CDR1 / VSNL1 is functionally altered in GBM cells and is involved in the modification of their biopathological profile. PMID:26683098

Parecoxib inhibits glioblastoma cell proliferation, migration and invasion by upregulating miRNA-29c.

PubMed

Li, Lin-Yong; Xiao, Jie; Liu, Qiang; Xia, Kun

2017-03-15

Glioblastoma (GBM) is one of the most lethal brain cancers worldwide, and there is an urgent need for development of novel therapeutic approaches. Parecoxib is a well-known cyclooxygenase-2 (COX-2) inhibitor, and had already been developed for postoperative analgesia with high efficacy and low adverse reaction. A recent study has suggested that parecoxib potently enhances immunotherapeutic efficacy of GBM, but its effects on GBM growth, migration and invasion have not previously been studied. In the present study, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and BrdU (5-bromo-2-deoxyuridine) incorporation assays were used to evaluate the cell proliferation of GBM cells. Wound-healing and transwell assays were preformed to analyze GBM cell migration and invasion, respectively. The results suggested that parecoxib inhibits cell proliferation, migration and invasion of GBM cells in a dose-dependent manner. RT-qPCR (real-time quantitative PCR) analysis demonstrated that miRNA-29c can be significantly induced by parecoxib. Furthermore, our data suggests that a miRNA-29c inhibitor can significantly attenuate parecoxib's effect on proliferation, migration and invasion of GBM. In conclusion, the present study suggests that parecoxib inhibits GBM cell proliferation, migration and invasion by upregulating miRNA-29c. © 2017. Published by The Company of Biologists Ltd.

Parecoxib inhibits glioblastoma cell proliferation, migration and invasion by upregulating miRNA-29c

PubMed Central

Li, Lin-Yong; Xiao, Jie; Liu, Qiang

2017-01-01

ABSTRACT Glioblastoma (GBM) is one of the most lethal brain cancers worldwide, and there is an urgent need for development of novel therapeutic approaches. Parecoxib is a well-known cyclooxygenase-2 (COX-2) inhibitor, and had already been developed for postoperative analgesia with high efficacy and low adverse reaction. A recent study has suggested that parecoxib potently enhances immunotherapeutic efficacy of GBM, but its effects on GBM growth, migration and invasion have not previously been studied. In the present study, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and BrdU (5-bromo-2-deoxyuridine) incorporation assays were used to evaluate the cell proliferation of GBM cells. Wound-healing and transwell assays were preformed to analyze GBM cell migration and invasion, respectively. The results suggested that parecoxib inhibits cell proliferation, migration and invasion of GBM cells in a dose-dependent manner. RT-qPCR (real-time quantitative PCR) analysis demonstrated that miRNA-29c can be significantly induced by parecoxib. Furthermore, our data suggests that a miRNA-29c inhibitor can significantly attenuate parecoxib's effect on proliferation, migration and invasion of GBM. In conclusion, the present study suggests that parecoxib inhibits GBM cell proliferation, migration and invasion by upregulating miRNA-29c. PMID:27895048

Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, C.-J.; Hsu, C.-C.; Department of Surgery, Chi-Mei Medical Center, Taipei, Taiwan

2009-03-06

CD133-expressing glioma cells play a critical role in tumor recovery after treatment and are resistant to radiotherapy. Herein, we demonstrated that glioblastoma-derived CD133-positive cells (GBM-CD133{sup +}) are capable of self-renewal and express high levels of embryonic stem cell genes and SirT1 compared to GBM-CD133{sup -} cells. To evaluate the role of SirT1 in GBM-CD133{sup +}, we used a lentiviral vector expressing shRNA to knock-down SirT1 expression (sh-SirT1) in GBM-CD133{sup +}. Silencing of SirT1 significantly enhanced the sensitivity of GBM-CD133{sup +} to radiation and increased the level of radiation-mediated apoptosis. Importantly, knock-down of SirT1 increased the effectiveness of radiotherapy in themore » inhibition of tumor growth in nude mice transplanted with GBM-CD133{sup +}. Kaplan-Meier survival analysis indicated that the mean survival rate of GBM-CD133{sup +} mice treated with radiotherapy was significantly improved by Sh-SirT1 as well. In sum, these results suggest that SirT1 is a potential target for increasing the sensitivity of GBM and glioblastoma-associated cancer stem cells to radiotherapy.« less

EGFR gene overexpression retained in an invasive xenograft model by solid orthotopic transplantation of human glioblastoma multiforme into nude mice.

PubMed

Yi, Diao; Hua, Tian Xin; Lin, Huang Yan

2011-03-01

Orthotopic xenograft animal model from human glioblastoma multiforme (GBM) cell lines often do not recapitulate an extremely important aspect of invasive growth and epidermal growth factor receptor (EGFR) gene overexpression of human GBM. We developed an orthotopic xenograft model by solid transplantation of human GBM into the brain of nude mouse. The orthotopic xenografts sharing the same histopathological features with their original human GBMs were highly invasive and retained the overexpression of EGFR gene. The murine orthotopic GBM models constitute a valuable in vivo system for preclinical studies to test novel therapies for human GBM.

The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes.

PubMed

Xing, Fan; Luan, Yizhao; Cai, Jing; Wu, Sihan; Mai, Jialuo; Gu, Jiayu; Zhang, Haipeng; Li, Kai; Lin, Yuan; Xiao, Xiao; Liang, Jiankai; Li, Yuan; Chen, Wenli; Tan, Yaqian; Sheng, Longxiang; Lu, Bingzheng; Lu, Wanjun; Gao, Mingshi; Qiu, Pengxin; Su, Xingwen; Yin, Wei; Hu, Jun; Chen, Zhongping; Sai, Ke; Wang, Jing; Chen, Furong; Chen, Yinsheng; Zhu, Shida; Liu, Dongbing; Cheng, Shiyuan; Xie, Zhi; Zhu, Wenbo; Yan, Guangmei

2017-01-10

Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Methylation-mediated silencing of microRNA-211 promotes cell growth and epithelial to mesenchymal transition through activation of the AKT/β-catenin pathway in GBM.

PubMed

Li, Weidong; Miao, Xiaobo; Liu, Lingling; Zhang, Yue; Jin, Xuejun; Luo, Xiaojun; Gao, Hai; Deng, Xubin

2017-04-11

Aberrant expression of miR-211 has frequently been reported in cancer studies; however, its role in glioblastoma multiforme (GBM) has not been examined in detail. We investigated the function and the underlying mechanism of miR-211 in GBM. We revealed that miR-211 was downregulated in GBM tissues and cell lines. Restoration of miR-211 inhibited GBM cell growth and invasion both in vitro and in vivo. The epithelial to mesenchymal transition (EMT) phenotype was reversed when miR-211 expression was restored. HMGA2 was identified as a down-stream target of miR-211. MiR-211 had an inhibitory effect on AKT/β-catenin signaling, which was reversed by HMGA2 overexpression or miR-211 restoration. In addition, miR-211 was transcriptionally repressed by EZH2-induced H3K27 trimethylation and promoter methylation. Overall, our findings revealed miR-211 as a tumor suppressor in GBM and mir-211 may be a potential therapeutic target for GBM patients.

Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation

PubMed Central

Blake, Sophia M; Stricker, Stefan H; Halavach, Hanna; Poetsch, Anna R; Cresswell, George; Kelly, Gavin; Kanu, Nnennaya; Marino, Silvia; Luscombe, Nicholas M; Pollard, Steven M; Behrens, Axel

2016-01-01

Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors. DOI: http://dx.doi.org/10.7554/eLife.08711.001 PMID:26984279

Downregulation of β-arrestin 1 suppresses glioblastoma cell malignant progression vis inhibition of Src signaling.

PubMed

Lan, Tian; Wang, Haoran; Zhang, Zhihua; Zhang, Mingshan; Qu, Yanming; Zhao, Zitong; Fan, Xinyi; Zhan, Qimin; Song, Yongmei; Yu, Chunjiang

2017-08-01

Glioblastoma multiforme (GBM) is one of the most common brain malignancies worldwide and is typically associated with a dismal prognosis, yet the mechanisms underlying its aggressiveness remain unclear. Here, we revealed that β-arrestin 1 was overexpressed in GBM and contributed to poorer outcome. Knockdown of β-arrestin 1 suppressed the proliferation, invasiveness and glycolysis of GBM cells, and also enhanced temozolomide efficacy. Further, we discovered that knockdown of β-arrestin 1 decreased the activity of Src, and suppression of Src signaling was critically involved in β-arrestin 1 silencing-mediated suppression of GBM malignancies. Finally, we investigated the effect of β-arrestin 1 knockdown on the tumor growth and survival of xenograft models, and found that shβ-arrestin 1 apparently inhibited GBM growth in vivo and resulted in better survival of mice. Taken together, our findings suggest that knockdown of β-arrestin 1 can suppress GBM cell proliferation, invasion and glycolysis by inhibiting Src signaling. Thus, targeting β-arrestin 1 may be a potential therapeutic strategy for GBM treatment. Copyright © 2017. Published by Elsevier Inc.

The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes.

PubMed

Xie, Yuan; Bergström, Tobias; Jiang, Yiwen; Johansson, Patrik; Marinescu, Voichita Dana; Lindberg, Nanna; Segerman, Anna; Wicher, Grzegorz; Niklasson, Mia; Baskaran, Sathishkumar; Sreedharan, Smitha; Everlien, Isabelle; Kastemar, Marianne; Hermansson, Annika; Elfineh, Lioudmila; Libard, Sylwia; Holland, Eric Charles; Hesselager, Göran; Alafuzoff, Irina; Westermark, Bengt; Nelander, Sven; Forsberg-Nilsson, Karin; Uhrbom, Lene

2015-10-01

Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma

PubMed Central

Cruickshanks, Nichola; Zhang, Ying; Yuan, Fang; Pahuski, Mary; Gibert, Myron; Abounader, Roger

2017-01-01

Glioblastoma (GBM) is a lethal brain tumor with dismal prognosis. Current therapeutic options, consisting of surgery, chemotherapy and radiation, have only served to marginally increase patient survival. Receptor tyrosine kinases (RTKs) are dysregulated in approximately 90% of GBM; attributed to this, research has focused on inhibiting RTKs as a novel and effective therapy for GBM. Overexpression of RTK mesenchymal epithelial transition (MET), and its ligand, hepatocyte growth factor (HGF), in GBM highlights a promising new therapeutic target. This review will discuss the role of MET in cell cycle regulation, cell proliferation, evasion of apoptosis, cell migration and invasion, angiogenesis and therapeutic resistance in GBM. It will also discuss the modes of deregulation of HGF/MET and their regulation by microRNAs. As the HGF/MET pathway is a vital regulator of multiple pro-survival pathways, efforts and strategies for its exploitation for GBM therapy are also described. PMID:28696366

Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma

PubMed Central

Shinsato, Yoshinari; Furukawa, Tatsuhiko; Yunoue, Shunji; Yonezawa, Hajime; Minami, Kentarou; Nishizawa, Yukihiko; Ikeda, Ryuji; Kawahara, Kohichi; Yamamoto, Masatatsu; Hirano, Hirofumi; Tokimura, Hiroshi; Arita, Kazunori

2013-01-01

Although there is a relationship between DNA repair deficiency and temozolomide (TMZ) resistance in glioblastoma (GBM), it remains unclear which molecule is associated with GBM recurrence. We isolated three TMZ-resistant human GBM cell lines and examined the expression of O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) components. We used immunohistochemical analysis to compare MutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2) and MGMT expression in primary and recurrent GBM specimens obtained from GBM patients during TMZ treatment. We found a reduction in MLH1 expression and a subsequent reduction in PMS2 protein levels in TMZ-resistant cells. Furthermore, MLH1 or PMS2 knockdown confered TMZ resistance. In recurrent GBM tumours, the expression of MLH1 and PMS2 was reduced when compared to primary tumours. PMID:24259277

Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma.

PubMed

Shinsato, Yoshinari; Furukawa, Tatsuhiko; Yunoue, Shunji; Yonezawa, Hajime; Minami, Kentarou; Nishizawa, Yukihiko; Ikeda, Ryuji; Kawahara, Kohichi; Yamamoto, Masatatsu; Hirano, Hirofumi; Tokimura, Hiroshi; Arita, Kazunori

2013-12-01

Although there is a relationship between DNA repair deficiency and temozolomide (TMZ) resistance in glioblastoma (GBM), it remains unclear which molecule is associated with GBM recurrence. We isolated three TMZ-resistant human GBM cell lines and examined the expression of O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) components. We used immunohistochemical analysis to compare MutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2) and MGMT expression in primary and recurrent GBM specimens obtained from GBM patients during TMZ treatment. We found a reduction in MLH1 expression and a subsequent reduction in PMS2 protein levels in TMZ-resistant cells. Furthermore, MLH1 or PMS2 knockdown confered TMZ resistance. In recurrent GBM tumours, the expression of MLH1 and PMS2 was reduced when compared to primary tumours.

Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma.

PubMed

Luedi, Markus M; Singh, Sanjay K; Mosley, Jennifer C; Hassan, Islam S A; Hatami, Masumeh; Gumin, Joy; Andereggen, Lukas; Sulman, Erik P; Lang, Frederick F; Stueber, Frank; Fuller, Gregory N; Colen, Rivka R; Zinn, Pascal O

2018-01-12

OBJECTIVE Dexamethasone, a known regulator of mesenchymal programming in glioblastoma (GBM), is routinely used to manage edema in GBM patients. Dexamethasone also activates the expression of genes, such as CEBPB, in GBM stem cells (GSCs). However, the drug's impact on invasion, proliferation, and angiogenesis in GBM remains unclear. To determine whether dexamethasone induces invasion, proliferation, and angiogenesis in GBM, the authors investigated the drug's impact in vitro, in vivo, and in clinical information derived from The Cancer Genome Atlas (TCGA) cohort. METHODS Expression profiles of patients from the TCGA cohort with mesenchymal GBM (n = 155) were compared with patients with proneural GBM by comparative marker selection. To obtain robust data, GSCs with IDH1 wild-type (GSC3) and with IDH1 mutant (GSC6) status were exposed to dexamethasone in vitro and in vivo and analyzed for invasion (Boyden chamber, human-specific nucleolin), proliferation (Ki-67), and angiogenesis (CD31). Ex vivo tumor cells from dexamethasone-treated and control mice were isolated by fluorescence activated cell sorting and profiled using Affymetrix chips for mRNA (HTA 2.0) and microRNAs (miRNA 4.0). A pathway analysis was performed to identify a dexamethasone-regulated gene signature, and its relationship with overall survival (OS) was assessed using Kaplan-Meier analysis in the entire GBM TCGA cohort (n = 520). RESULTS The mesenchymal subgroup, when compared with the proneural subgroup, had significant upregulation of a dexamethasone-regulated gene network, as well as canonical pathways of proliferation, invasion, and angiogenesis. Dexamethasone-treated GSC3 demonstrated a significant increase in invasion, both in vitro and in vivo, whereas GSC6 demonstrated a modest increase. Furthermore, dexamethasone treatment of both GSC3 and GSC6 lines resulted in significantly elevated cell proliferation and angiogenesis in vivo. Patients with mesenchymal GBM had significant upregulation of dexamethasone-regulated pathways when compared with patients with proneural GBM. A prognostic (p = 0.0007) 33-gene signature was derived from the ex vivo expression profile analyses and used to dichotomize the entire TCGA cohort by high (median OS 12.65 months) or low (median OS 14.91 months) dexamethasone signature. CONCLUSIONS The authors present evidence that furthers the understanding of the complex effects of dexamethasone on biological characteristics of GBM. The results suggest that the drug increases invasion, proliferation, and angiogenesis in human GSC-derived orthotopic tumors, potentially worsening GBM patients' prognoses. The authors believe that careful investigation is needed to determine how to minimize these deleterious dexamethasone-associated side effects in GBM.

When a Standard Candle Flickers: Hard X-Ray Variations in the Crab Nebula

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen A.; Cherry, M. L.; Case, G. L.; Baumgartner, W. H.; Beklen, E.; Bhat, P. N.; Briggs, M. S.; Camaro-Arranz, A.; Connaughton, V.; Diehl, R.;

When a Standard Candle Flickers: Hard X-ray Variations in the Crab Nebula

NASA Technical Reports Server (NTRS)

Wilson-Hodge, Colleen; Cherry, Michael L.; Case, Gary L.; Baumgartner, Wayne H.; Beklen, Elif; Bhat, Narayana P.; Briggs, Michael S.; Buehler, Rolf; Camero-Arranz, Ascension; Connaughton, Valerie;

The IPV-GBM scale: a new scale to measure intimate partner violence among gay and bisexual men.

PubMed

Stephenson, Rob; Finneran, Catherine

2013-01-01

The paper describes the creation of a new scale to measure intimate partner violence (IPV) among gay and bisexual men. Seven focus group discussions were held with gay and bisexual men, focusing on defining intimate partner violence: 30 forms of IPV were identified. A venue-recruited sample of 912 gay and bisexual men was surveyed, examining definitional understanding and recent experiences of each of the 30 forms of IPV. Participants were also asked questions from the CDC definition of intimate partner violence and the short-form of the Conflicts Tactics Scale (CTS2S). Factor analysis of responses to the definitional questions was used to create the IPV-GBM scale, and the prevalence of intimate partner violence was compared with that identified by the CDC and CTS2S measures of intimate partner violence. A 23-item scale, with 5 unique domains, was created, with strong internal reliability (Cronbach Alpha >.90). The IPV-GBM scale mirrored both the CDC and CTS2S definitions of intimate partner violence, but contained additional domains such as controlling violence, monitoring behaviors, emotional violence, and HIV-related violence. The new scale identified a significantly higher prevalence of IPV than either of the more commonly used measures. The results presented here provide encouraging evidence for a new, more accurate measure of intimate partner violence among gay and bisexual men in the U.S.

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas.

PubMed

Miranda-Gonçalves, Vera; Granja, Sara; Martinho, Olga; Honavar, Mrinalini; Pojo, Marta; Costa, Bruno M; Pires, Manuel M; Pinheiro, Célia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Reis, Rui M; Baltazar, Fátima

2016-07-19

Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular. Expression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions. Hypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX. Hypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM.

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

PubMed Central

Miranda-Gonçalves, Vera; Granja, Sara; Martinho, Olga; Honavar, Mrinalini; Pojo, Marta; Costa, Bruno M.; Pires, Manuel M.; Pinheiro, Célia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Reis, Rui M.; Baltazar, Fátima

2016-01-01

Background Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular. Methods Expression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions. Results Hypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX. Conclusion Hypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM. PMID:27331625

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells.

PubMed

Tivnan, Amanda; Heilinger, Tatjana; Ramsey, Joanne M; O'Connor, Gemma; Pokorny, Jenny L; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Boyd, Andrew W; Kim, Ella L; Lode, Holger N; Cryan, Sally-Ann; Prehn, Jochen H M

2017-03-07

Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer.

GBM heterogeneity characterization by radiomic analysis of phenotype anatomical planes

NASA Astrophysics Data System (ADS)

Chaddad, Ahmad; Desrosiers, Christian; Toews, Matthew

2016-03-01

Glioblastoma multiforme (GBM) is the most common malignant primary tumor of the central nervous system, characterized among other traits by rapid metastatis. Three tissue phenotypes closely associated with GBMs, namely, necrosis (N), contrast enhancement (CE), and edema/invasion (E), exhibit characteristic patterns of texture heterogeneity in magnetic resonance images (MRI). In this study, we propose a novel model to characterize GBM tissue phenotypes using gray level co-occurrence matrices (GLCM) in three anatomical planes. The GLCM encodes local image patches in terms of informative, orientation-invariant texture descriptors, which are used here to sub-classify GBM tissue phenotypes. Experiments demonstrate the model on MRI data of 41 GBM patients, obtained from the cancer genome atlas (TCGA). Intensity-based automatic image registration is applied to align corresponding pairs of fixed T1˗weighted (T1˗WI) post-contrast and fluid attenuated inversion recovery (FLAIR) images. GBM tissue regions are then segmented using the 3D Slicer tool. Texture features are computed from 12 quantifier functions operating on GLCM descriptors, that are generated from MRI intensities within segmented GBM tissue regions. Various classifier models are used to evaluate the effectiveness of texture features for discriminating between GBM phenotypes. Results based on T1-WI scans showed a phenotype classification accuracy of over 88.14%, a sensitivity of 85.37% and a specificity of 96.1%, using the linear discriminant analysis (LDA) classifier. This model has the potential to provide important characteristics of tumors, which can be used for the sub-classification of GBM phenotypes.

USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance.

PubMed

Lee, Jin-Ku; Chang, Nakho; Yoon, Yeup; Yang, Heekyoung; Cho, Heejin; Kim, Eunhee; Shin, Yongjae; Kang, Wonyoung; Oh, Young Taek; Mun, Gyeong In; Joo, Kyeung Min; Nam, Do-Hyun; Lee, Jeongwu

2016-01-01

Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Farewell to GBM-O: Genomic and transcriptomic profiling of glioblastoma with oligodendroglioma component reveals distinct molecular subgroups.

PubMed

Hinrichs, Benjamin H; Newman, Scott; Appin, Christina L; Dunn, William; Cooper, Lee; Pauly, Rini; Kowalski, Jeanne; Rossi, Michael R; Brat, Daniel J

2016-01-13

Glioblastoma with oligodendroglioma component (GBM-O) was recognized as a histologic pattern of glioblastoma (GBM) by the World Health Organization (WHO) in 2007 and is distinguished by the presence of oligodendroglioma-like differentiation. To better understand the genetic underpinnings of this morphologic entity, we performed a genome-wide, integrated copy number, mutational and transcriptomic analysis of eight (seven primary, primary secondary) cases. Three GBM-O samples had IDH1 (p.R132H) mutations; two of these also demonstrated 1p/19q co-deletion and had a proneural transcriptional profile, a molecular signature characteristic of oligodendroglioma. The additional IDH1 mutant tumor lacked 1p/19q co-deletion, harbored a TP53 mutation, and overall, demonstrated features most consistent with IDH mutant (secondary) GBM. Finally, five tumors were IDH wild-type (IDHwt) and had chromosome seven gains, chromosome 10 losses, and homozygous 9p deletions (CDKN2A), alterations typical of IDHwt (primary) GBM. IDHwt GBM-Os also demonstrated EGFR and PDGFRA amplifications, which correlated with classical and proneural expression subtypes, respectively. Our findings demonstrate that GBM-O is composed of three discrete molecular subgroups with characteristic mutations, copy number alterations and gene expression patterns. Despite displaying areas that morphologically resemble oligodendroglioma, the current results indicate that morphologically defined GBM-O does not correspond to a particular genetic signature, but rather represents a collection of genetically dissimilar entities. Ancillary testing, especially for IDH and 1p/19q, should be used for determining these molecular subtypes.

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

PubMed Central

Tivnan, Amanda; Heilinger, Tatjana; Ramsey, Joanne M; O’Connor, Gemma; Pokorny, Jenny L; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Boyd, Andrew W; Kim, Ella L; Lode, Holger N; Cryan, Sally-Ann; Prehn, Jochen H.M

2017-01-01

Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer. PMID:28178667

Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma.

PubMed

Crommentuijn, Matheus H W; Maguire, Casey A; Niers, Johanna M; Vandertop, W Peter; Badr, Christian E; Würdinger, Thomas; Tannous, Bakhos A

2016-04-01

Glioblastoma (GBM) is the most common malignant brain tumor in adults. We designed an adeno-associated virus (AAV) vector for intracranial delivery of secreted, soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) to GBM tumors in mice and combined it with the TRAIL-sensitizing cardiac glycoside, lanatoside C (lan C). We applied this combined therapy to two different GBM models using human U87 glioma cells and primary patient-derived GBM neural spheres in culture and in orthotopic GBM xenograft models in mice. In U87 cells, conditioned medium from AAV2-sTRAIL expressing cells combined with lan C induced 80% cell death. Similarly, lan C sensitized primary GBM spheres to sTRAIL causing over 90% cell death. In mice bearing intracranial U87 tumors treated with AAVrh.8-sTRAIL, administration of lan C caused a decrease in tumor-associated Fluc signal, while tumor size increased within days of stopping the treatment. Another round of lan C treatment re-sensitized GBM tumor to sTRAIL-induced cell death. AAVrh.8-sTRAIL treatment alone and combined with lanatoside C resulted in a significant decrease in tumor growth and longer survival of mice bearing orthotopic invasive GBM brain tumors. In summary, AAV-sTRAIL combined with lanatoside C induced cell death in U87 glioma cells and patient-derived GBM neural spheres in culture and in vivo leading to an increased in overall mice survival. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors

PubMed Central

Singh, Melissa M.; Manton, Christa A.; Bhat, Krishna P.; Tsai, Wen-Wei; Aldape, Kenneth; Barton, Michelle C.; Chandra, Joya

2011-01-01

Glioblastoma multiforme (GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despite innovative therapies for the treatment of GBM, there has been no significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations are of considerable interest as targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDACs) have been developed and tested in GBM with moderate success. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histone methylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examine the effects of simultaneously inhibiting HDACs and LSD1 as a potential combination therapy. We evaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDACs. LSD1 was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDACs was achieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis was significantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover, pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combination with HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normal human astrocytes. Taken together, these results indicate that LSD1 and HDACs cooperate to regulate key pathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combined use of LSD1 and HDAC inhibitors as a therapeutic approach for GBM. PMID:21653597

TCGA Workshop: Genomics and Biology of Glioblastoma Multiforme (GBM) - TCGA

Cancer.gov

The National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) held a workshop entitled, “Genomics and Biology of Glioblastoma Multiforme (GBM),” to review the initial GBM data from the TCGA pilot project.

Glioblastoma, a brief review of history, molecular genetics, animal models and novel therapeutic strategies.

PubMed

Agnihotri, Sameer; Burrell, Kelly E; Wolf, Amparo; Jalali, Sharzhad; Hawkins, Cynthia; Rutka, James T; Zadeh, Gelareh

2013-02-01

Glioblastoma (GBM) is the most common and lethal primary brain tumor. Over the past few years tremendous genomic and proteomic characterization along with robust animal models of GBM have provided invaluable data that show that "GBM", although histologically indistinguishable from one another, are comprised of molecularly heterogenous diseases. In addition, robust pre-clinical models and a better understanding of the core pathways disrupted in GBM are providing a renewed optimism for novel strategies targeting these devastating tumors. Here, we summarize a brief history of the disease, our current molecular knowledge, lessons from animal models and emerging concepts of angiogenesis, invasion, and metabolism in GBM that may lend themselves to therapeutic targeting.

Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma

PubMed Central

Liu, Weiwen; Song, Xian-lu; Zhao, Shan-chao; He, Minyi; Wang, Hai; Chen, Ziyang; Xiang, Wei; Yi, Guozhong; Qi, Songtao; Liu, Yawei

2018-01-01

Ethnopharmacological relevance: Dapivirine is one of reverse transcriptase inhibitors (RTIs). It is the prototype of diarylpyrimidines (DAPY), formerly known as TMC120 or DAPY R147681 (IUPAC name: 4- [[4-(2, 4, 6-trimethylphenyl) amino]-2-pyrimidinyl] amino]-benzonitrile; CAS no.244767-67-7). Aim: The purpose of this study is to investigate the antitumor activity of dapivirine, one of the RTIs, on U87 glioblastoma (GBM) cells in vitro and in vivo. Materials and Methods: U87 GBM cells were cultured and treated with or without dapivirine. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis was analyzed by flow cytometry; cell migration was evaluated by Boyden Chamber assay; Western blotting was performed to detect proteins related to apoptosis, epithelial-to-mesenchymal transition and autophagy. PathScan intracellular signaling array kit was used to detect important and well-characterized signaling molecules. Tumor xenograft model in nude mice was used to evaluate the antitumorigenic effect in vivo. Results: Dapivirine weakened proliferation of glioma cells and induced the apoptosis of U87 glioblastoma cells. Furthermore, dapivirine regulated autophagy and induced Akt, Bad and SAPK/JNK activations. Moreover, the inhibition of glioma cell growth by dapivirine was also observed in nude mice in vivo. Conclusion: In summary, in our study dapivirine exposure induces stress, resulting in JNK and PI3K/Akt pathway activation through diminished inhibition of the apoptosis and autophagy cascade in U87 GBM cells, which inhibits cell growth in vitro and in vivo. PMID:29290776

Tumour cell dormancy as a contributor to the reduced survival of GBM patients who received standard therapy.

PubMed

Tong, Luqing; Yi, Li; Liu, Peidong; Abeysekera, Iruni Roshanie; Hai, Long; Li, Tao; Tao, Zhennan; Ma, Haiwen; Xie, Yang; Huang, Yubao; Yu, Shengping; Li, Jiabo; Yuan, Feng; Yang, Xuejun

2018-07-01

Glioblastoma multiforme (GBM) is a fatal cancer with varying life expectancy, even for patients undergoing the same standard therapy. Identification of differentially expressed genes in GBM patients with different survival rates may benefit the development of effective therapeutic strategies. In the present study, key pathways and genes correlated with survival in GBM patients were screened with bioinformatic analysis. Included in the study were 136 eligible patients who had undertaken surgical resection of GBM followed by temozolomide (TMZ) chemoradiation and long-term therapy with TMZ. A total of 383 differentially expressed genes (DEGs) related to GBM survival were identified. Gene Ontology and pathway enrichment analysis as well as hub gene screening and module analysis were performed. As expected, angiogenesis and migration of GBM cells were closely correlated with a poor prognosis. Importantly, the results also indicated that cell dormancy was an essential contributor to the reduced survival of GBM patients. Given the lack of specific targeted genes and pathways known to be involved in tumour cell dormancy, we proposed enriched candidate genes related to the negative regulation of cell proliferation, signalling pathways regulating pluripotency of stem cells and neuroactive ligand-receptor interaction, and 3 hub genes (FTH1, GRM1 and DDIT3). Maintaining persistent cell dormancy or preventing tumour cells from entering dormancy during chemoradiation should be a promising therapeutic strategy.

Towards the Personalized Treatment of Glioblastoma: Integrating Patient-Specific Clinical Data in a Continuous Mechanical Model

PubMed Central

Faggiano, Elena; Boffano, Carlo; Acerbi, Francesco; Ciarletta, Pasquale

2015-01-01

Glioblastoma multiforme (GBM) is the most aggressive and malignant among brain tumors. In addition to uncontrolled proliferation and genetic instability, GBM is characterized by a diffuse infiltration, developing long protrusions that penetrate deeply along the fibers of the white matter. These features, combined with the underestimation of the invading GBM area by available imaging techniques, make a definitive treatment of GBM particularly difficult. A multidisciplinary approach combining mathematical, clinical and radiological data has the potential to foster our understanding of GBM evolution in every single patient throughout his/her oncological history, in order to target therapeutic weapons in a patient-specific manner. In this work, we propose a continuous mechanical model and we perform numerical simulations of GBM invasion combining the main mechano-biological characteristics of GBM with the micro-structural information extracted from radiological images, i.e. by elaborating patient-specific Diffusion Tensor Imaging (DTI) data. The numerical simulations highlight the influence of the different biological parameters on tumor progression and they demonstrate the fundamental importance of including anisotropic and heterogeneous patient-specific DTI data in order to obtain a more accurate prediction of GBM evolution. The results of the proposed mathematical model have the potential to provide a relevant benefit for clinicians involved in the treatment of this particularly aggressive disease and, more importantly, they might drive progress towards improving tumor control and patient’s prognosis. PMID:26186462

Novel Therapy for Glioblastoma Multiforme by Restoring LRRC4 in Tumor Cells: LRRC4 Inhibits Tumor-Infitrating Regulatory T Cells by Cytokine and Programmed Cell Death 1-Containing Exosomes

PubMed Central

Li, Peiyao; Feng, Jianbo; Liu, Yang; Liu, Qiang; Fan, Li; Liu, Qing; She, Xiaoling; Liu, Changhong; Liu, Tao; Zhao, Chunhua; Wang, Wei; Li, Guiyuan; Wu, Minghua

2017-01-01

Glioblastoma multiforme (GBM) is a heterogeneous malignant brain tumor, the pathological incidence of which induces the accumulation of tumor-infiltrating lymphocytes (TILs). As a tumor suppressor gene, LRRC4 is absent in GBM cells. Here, we report that the recovery of LRRC4 in GBM cells inhibited the infiltration of tumor-infiltrating regulatory T cells (Ti-Treg), promoted the expansion of tumor-infiltrating effector T (Ti-Teff) cells and CD4+CCR4+ T cells, and enhanced the chemotaxis of CD4+CCR4+ T cells in the GBM immune microenvironment. LRRC4 was not transferred into TILs from GBM cells through exosomes but mainly exerted its inhibiting function on Ti-Treg cell expansion by directly promoting cytokine secretion. GBM cell-derived exosomes (cytokine-free and programmed cell death 1 containing) also contributed to the modulation of LRRC4 on Ti-Treg, Ti-Teff, and CD4+CCR4+ T cells. In GBM cells, LRRC4 directly bound to phosphoinositide-dependent protein kinase 1 (PDPK1), phosphorylated IKKβser181, facilitated NF-κB activation, and promoted the secretion of interleukin-6 (IL-6), CCL2, and interferon gamma. In addition, HSP90 was required to maintain the interaction between LRRC4 and PDPK1. However, the inhibition of Ti-Treg cell expansion and promotion of CD4+CCR4+ T cell chemotaxis by LRRC4 could be blocked by anti-IL-6 antibody or anti-CCL2 antibody, respectively. miR-101 is a suppressor gene in GBM. Our previous studies have shown that EZH2, EED, and DNMT3A are direct targets of miR-101. Here, we showed that miR-101 reversed the hypermethylation of the LRRC4 promoter and induced the re-expression of LRRC4 in GBM cells by directly targeting EZH2, EED, and DNMT3A. Our results reveal a novel mechanism underlying GBM microenvironment and provide a new therapeutic strategy using re-expression of LRRC4 in GBM cells to create a permissive intratumoral environment. PMID:29312296

Proteolysis breaks tolerance toward intact α345(IV) collagen, eliciting novel anti-GBM autoantibodies specific for α345NC1 hexamers

PubMed Central

Olaru, Florina; Wang, Xu-Ping; Luo, Wentian; Ge, Linna; Miner, Jeffrey H; Kleinau, Sandra; Geiger, Xochiquetzal J.; Wasiluk, Andrew; Heidet, Laurence; Kitching, A. Richard; Borza, Dorin-Bogdan

2012-01-01

Goodpasture disease is an autoimmune kidney disease mediated by autoAbs against NC1 monomers of α3(IV) collagen that bind to the glomerular basement membrane (GBM), usually causing rapidly progressive glomerulonephritis. We identified a novel type of human IgG4-restricted anti-GBM autoAbs associated with mild non-progressive glomerulonephritis, which specifically targeted α345NC1 hexamers but not α3NC1 monomers. The mechanisms eliciting these anti-GBM autoAbs were investigated in mouse models recapitulating this phenotype. Wild type and FcγRIIB−/− mice immunized with autologous murine GBM NC1 hexamers produced mouse IgG1-restricted autoAbs specific for α345NC1 hexamers, which bound to the GBM in vivo but did not cause glomerulonephritis. In these mice, intact collagen IV from murine GBM was not immunogenic. However, in Col4a3−/− Alport mice, both intact collagen IV and NC1 hexamers from murine GBM elicited IgG antibodies specific for α3α4α5NC1 hexamers, which were not subclass restricted. As heterologous antigen in COL4A3-humanized mice, murine GBM NC1 hexamers elicited mouse IgG1, IgG2a and IgG2b autoAbs specific for α345NC1 hexamers and induced anti-GBM Ab glomerulonephritis. These findings indicate that tolerance toward autologous intact α3α4α5(IV) collagen is established in hosts expressing this antigen, even though autoreactive B cells specific for α345NC1 hexamers are not purged from their repertoire. Proteolysis selectively breaches this tolerance by generating autoimmunogenic α3α4α5NC1 hexamers. This provides a mechanism eliciting autoAbs specific for α345NC1 hexamers, which are restricted to non-inflammatory IgG subclasses and non-nephritogenic. In Alport syndrome, lack of tolerance toward α3α4α5(IV) collagen promotes production of alloantibodies to α345NC1 hexamers, including pro-inflammatory IgG subclasses which mediate post-transplant anti-GBM nephritis. PMID:23303673

Diagnostic and prognostic value of preoperative combined GFAP, IGFBP-2, and YKL-40 plasma levels in patients with glioblastoma.

PubMed

Gállego Pérez-Larraya, Jaime; Paris, Sophie; Idbaih, Ahmed; Dehais, Caroline; Laigle-Donadey, Florence; Navarro, Soledad; Capelle, Laurent; Mokhtari, Karima; Marie, Yannick; Sanson, Marc; Hoang-Xuan, Khê; Delattre, Jean-Yves; Mallet, Alain

2014-12-15

Circulating proteins released by tumor cells have recently been investigated as potential single surrogate biomarkers for glioblastoma multiforme (GBM). The aim of the current hypothesis-generating study was to evaluate the diagnostic and prognostic role of preoperative insulin-like growth factor-binding protein 2 (IGFBP-2), chitinase-3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) plasma levels in patients with GBM, both as single markers and as a combined profile. Plasma samples from 111 patients with GBM and a subset of 40 patients with nonglial brain tumors were obtained preoperatively. Plasma from 99 healthy controls was also analyzed. IGFBP-2, YKL-40, and GFAP levels were determined using enzyme-linked immunoadsorbent assay tests. Their association with histological and radiological variables was assessed. Circulating levels of all 3 proteins were found to be significantly higher in patients with GBM compared with healthy controls (P < .01). Only YKL-40 and GFAP were found to demonstrate significant differences between patients with GBM and nonglial brain tumors (P = .04). GFAP was undetectable (<0.02 ng/mL) in all patients without GBM. A receiver operating characteristic analysis accounting for a 2-step diagnostic procedure including the 3 biomarkers afforded an area under the curve of 0.77 for differentiating patients with GBM from those with nonglial brain tumors. There was a significant correlation between tumor volume and plasma IGFBP-2 level (Spearman Rho correlation coefficient, 0.22; P = .025) and GFAP (Spearman Rho correlation coefficient, 0.36; P < .001) among patients with GBM. Preoperative plasma IGFBP-2 levels were found to be independently associated with worse overall survival among patients with GBM (hazard ratio, 1.3; P = .05). A combined profile of preoperative IGFBP-2, GFAP, and YKL-40 plasma levels could serve as an additional diagnostic tool for patients with inoperable brain lesions suggestive of GBM. In addition, IGFBP-2 levels appear to constitute an independent prognostic factor in patients with GBM. © 2014 American Cancer Society.

Association of Gallbladder Mucocele Histologic Diagnosis with Selected Drug Use in Dogs: A Matched Case-Control Study.

PubMed

Gookin, J L; Correa, M T; Peters, A; Malueg, A; Mathews, K G; Cullen, J; Seiler, G

2015-01-01

The cause of gallbladder mucocele (GBM) formation in dogs currently is unknown. Many available drugs represent a newer generation of xenobiotics that may predispose dogs to GBM formation. To determine if there is an association between the histologic diagnosis of GBM in dogs and administration of selected drugs. Eighty-one dogs with a histologic diagnosis of GBM and 162 breed, age, and admission date-matched control dogs from a single referral institution. Medical records of dogs with GBM and control dogs from 2001 to 2011 were reviewed. Owner verification of drug history was sought by a standard questionnaire. Reported use of heartworm, flea, and tick preventatives as well as nonsteroidal anti-inflammatory drugs, analgesics, corticosteroids, or medications for treatment of osteoarthritis was recorded. Dogs with GBM were 2.2 times as likely to have had reported use of thyroxine (as a proxy for the diagnosis of hypothyroidism) as control dogs (95% confidence interval [CI], 0.949-5.051), 3.6 times as likely to have had reported treatment for Cushing's disease (95% CI, 1.228-10.612), and 2.3 times as likely to have had reported use of products containing imidacloprid (95% CI, 1.094-4.723). Analysis of a data subset containing only Shetland sheepdogs (23 GBM and 46 control) indicated that Shetland sheepdogs with GBM formation were 9.3 times as likely to have had reported use of imidacloprid as were control Shetland sheepdogs (95% CI, 1.103-78.239). This study provides evidence for an association between selected drug use and GBM formation in dogs. A larger epidemiologic study of Shetland sheepdogs with GBM formation and exposure to imidacloprid is warranted. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress GBM Tumor Growth.

PubMed

Lee, Jaehyun; Shin, Yong Jae; Lee, Kyoungmin; Cho, Hee Jin; Sa, Jason K; Lee, Sang-Yun; Kim, Seok-Hyung; Lee, Jeongwu; Yoon, Yeup; Nam, Do-Hyun

2017-11-10

Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression. We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3A mRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo. By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell-line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment. In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.

Anisotropic smoothing regularization (AnSR) in Thirion's Demons registration evaluates brain MRI tissue changes post-laser ablation.

PubMed

Hwuang, Eileen; Danish, Shabbar; Rusu, Mirabela; Sparks, Rachel; Toth, Robert; Madabhushi, Anant

2013-01-01

MRI-guided laser-induced interstitial thermal therapy (LITT) is a form of laser ablation and a potential alternative to craniotomy in treating glioblastoma multiforme (GBM) and epilepsy patients, but its effectiveness has yet to be fully evaluated. One way of assessing short-term treatment of LITT is by evaluating changes in post-treatment MRI as a measure of response. Alignment of pre- and post-LITT MRI in GBM and epilepsy patients via nonrigid registration is necessary to detect subtle localized treatment changes on imaging, which can then be correlated with patient outcome. A popular deformable registration scheme in the context of brain imaging is Thirion's Demons algorithm, but its flexibility often introduces artifacts without physical significance, which has conventionally been corrected by Gaussian smoothing of the deformation field. In order to prevent such artifacts, we instead present the Anisotropic smoothing regularizer (AnSR) which utilizes edge-detection and denoising within the Demons framework to regularize the deformation field at each iteration of the registration more aggressively in regions of homogeneously oriented displacements while simultaneously regularizing less aggressively in areas containing heterogeneous local deformation and tissue interfaces. In contrast, the conventional Gaussian smoothing regularizer (GaSR) uniformly averages over the entire deformation field, without carefully accounting for transitions across tissue boundaries and local displacements in the deformation field. In this work we employ AnSR within the Demons algorithm and perform pairwise registration on 2D synthetic brain MRI with and without noise after inducing a deformation that models shrinkage of the target region expected from LITT. We also applied Demons with AnSR for registering clinical T1-weighted MRI for one epilepsy and one GBM patient pre- and post-LITT. Our results demonstrate that by maintaining select displacements in the deformation field, AnSR outperforms both GaSR and no regularizer (NoR) in terms of normalized sum of squared differences (NSSD) with values such as 0.743, 0.807, and 1.000, respectively, for GBM.

Personalized regulation of glioblastoma cancer stem cells based on biomedical technologies: From theory to experiment (Review).

PubMed

Bryukhovetskiy, Igor; Ponomarenko, Arina; Lyakhova, Irina; Zaitsev, Sergey; Zayats, Yulia; Korneyko, Maria; Eliseikina, Marina; Mischenko, Polina; Shevchenko, Valerie; Shanker Sharma, Hari; Sharma, Aruna; Khotimchenko, Yuri

2018-08-01

Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. GBM represents >50% of primary tumors of the nervous system and ~20% of intracranial neoplasms. Standard treatment involves surgery, radiation and chemotherapy. However, the prognosis of GBM is usually poor, with a median survival of 15 months. Resistance of GBM to treatment can be explained by the presence of cancer stem cells (CSCs) among the GBM cell population. At present, there are no effective therapeutic strategies for the elimination of CSCs. The present review examined the nature of human GBM therapeutic resistance and attempted to systematize and put forward novel approaches for a personalized therapy of GBM that not only destroys tumor tissue, but also regulates cellular signaling and the morphogenetic properties of CSCs. The CSCs are considered to be an informationally accessible living system, and the CSC proteome should be used as a target for therapy directed at suppressing clonal selection mechanisms and CSC generation, destroying CSC hierarchy, and disrupting the interaction of CSCs with their microenvironment and extracellular matrix. These objectives can be achieved through the use of biomedical cellular products.

Investigating a signature of temozolomide resistance in GBM cell lines using metabolomics.

PubMed

St-Coeur, Patrick-Denis; Poitras, Julie J; Cuperlovic-Culf, Miroslava; Touaibia, Mohamed; Morin, Pier

2015-10-01

Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Current therapeutic approach to treat this malignancy involves a combination of surgery, radiotherapy and chemotherapy with temozolomide. Numerous mechanisms contributing to inherent and acquired resistance to this chemotherapeutic agent have been identified and can lead to treatment failure. This study undertook a metabolomics-based approach to characterize the metabolic profiles observed in temozolomide-sensitive and temozolomide-resistant GBM cell lines as well as in a small sub-set of primary GBM tumors. This approach was also utilized to explore the metabolic changes modulated upon cell treatment with temozolomide and lomeguatrib, an MGMT inhibitor with temozolomide-sensitizing potential. Metabolites previously explored for their potential role in chemoresistance including glucose, citrate and isocitrate demonstrated elevated levels in temozolomide-resistant GBM cells. In addition, a signature of metabolites comprising alanine, choline, creatine and phosphorylcholine was identified as up-regulated in sensitive GBM cell line across different treatments. These results present the metabolic profiles associated with temozolomide response in selected GBM models and propose interesting leads that could be leveraged for the development of therapeutic or diagnostic tools to impact temozolomide response in GBMs.

Development of Advanced Technologies for Complete Genomic and Proteomic Characterization of Quantized Human Tumor Cells

DTIC Science & Technology

2014-07-01

13. SUPPLEMENTARY NOTES 14. ABSTRACT With the establishment of Glioblastoma ( GBM ) cell lines from GBM patient’s tumor samples and quantized cell...populations of each of the parental GBM cell lines, we have completed most of our major aims of this project. We will continue in our efforts in the...signatures. Whole genome sequencing from two families of GBM patients are now well established and from the basis of the molecular characterization of

Anti-nucleosome antibodies complexed to nucleosomal antigens show anti-DNA reactivity and bind to rat glomerular basement membrane in vivo.

PubMed Central

Kramers, C; Hylkema, M N; van Bruggen, M C; van de Lagemaat, R; Dijkman, H B; Assmann, K J; Smeenk, R J; Berden, J H

1994-01-01

Histones can mediate the binding of DNA and anti-DNA to the glomerular basement membrane (GBM). In ELISA histone/DNA/anti-DNA complexes are able to bind to heparan sulfate (HS), an intrinsic constituent of the GBM. We questioned whether histone containing immune complexes are able to bind to the GBM, and if so, whether the ligand in the GBM is HS. Monoclonal antibodies (mAbs) complexed to nucleosomal antigens and noncomplexed mAbs were isolated from culture supernatants of four IgG anti-nuclear mAbs. All noncomplexed mAbs showed strong anti-nucleosome reactivity in ELISA. One of them showed in addition anti-DNA reactivity in noncomplexed form. The other three mAbs only showed anti-DNA reactivity when they were complexed to nucleosomal antigens. After renal perfusion a fine granular binding of complexed mAbs to the glomerular capillary wall and activation of complement was observed in immunofluorescence, whereas noncomplexed mAbs did not bind. Immuno-electron microscopy showed binding of complexes to the whole width of the GBM. When HS in the GBM was removed by renal heparinase perfusion the binding of complexed mAb decreased, but did not disappear completely. We conclude that anti-nucleosome mAbs, which do not bind DNA, become DNA reactive once complexed to nucleosomal antigens. These complexed mAbs can bind to the GBM. The binding ligand in the GBM is partly, but not solely, HS. Binding to the GBM of immune complexes containing nucleosomal material might be an important event in the pathogenesis of lupus nephritis. Images PMID:8040312

GM-CSF production by glioblastoma cells has a functional role in eosinophil survival, activation and growth factor production for enhanced tumor cell proliferation

PubMed Central

Curran, Colleen S.; Evans, Michael D.; Bertics, Paul J.

2011-01-01

Medicinal interventions of limited efficacy are currently available for the treatment of glioblastoma multiforme (GBM), the most common and lethal primary brain tumor in adults. The eosinophil is a pivotal immune cell in the pathobiology of atopic disease that is also found to accumulate in certain tumor tissues. Inverse associations between atopy and GBM risk suggest that the eosinophil may play a functional role in certain tumor immune responses. To assess the potential interactions between eosinophils and GBM, human primary blood eosinophils were cultured with two separate human GBM-derived cell lines (A172, U87-MG) or conditioned media generated in the presence or absence of TNF-α. Results revealed differential eosinophil adhesion and increased survival in response to co-culture with GBM cell lines. Eosinophil responses to GBM cell line-conditioned media included increased survival, activation, CD11b expression and S100A9 release. Addition of GM-CSF neutralizing antibodies to GBM cell cultures or conditioned media reduced eosinophil adhesion, survival and activation, linking tumor cell-derived GM-CSF to the functions of eosinophils in the tumor microenvironment. Dexamethasone, which has been reported to inhibit eosinophil recruitment and shrink GBM lesions on contrast enhanced scans, reduced the production of tumor cell-derived GM-CSF. Furthermore, culture of GBM cells in eosinophil-conditioned media increased tumor cell viability, and generation of eosinophil-conditioned media in the presence of GM-CSF enhanced the effect. These data support the idea of a paracrine loop between GM-CSF producing tumors and eosinophil-derived growth factors in tumor promotion/progression. PMID:21705618

GBM secretome induces transient transformation of human neural precursor cells.

PubMed

Venugopal, Chitra; Wang, X Simon; Manoranjan, Branavan; McFarlane, Nicole; Nolte, Sara; Li, Meredith; Murty, Naresh; Siu, K W Michael; Singh, Sheila K

2012-09-01

Glioblastoma (GBM) is the most aggressive primary brain tumor in humans, with a uniformly poor prognosis. The tumor microenvironment is composed of both supportive cellular substrates and exogenous factors. We hypothesize that exogenous factors secreted by brain tumor initiating cells (BTICs) could predispose normal neural precursor cells (NPCs) to transformation. When NPCs are grown in GBM-conditioned media, and designated as "tumor-conditioned NPCs" (tcNPCs), they become highly proliferative and exhibit increased stem cell self-renewal, or the unique ability of stem cells to asymmetrically generate another stem cell and a daughter cell. tcNPCs also show an increased transcript level of stem cell markers such as CD133 and ALDH and growth factor receptors such as VEGFR1, VEGFR2, EGFR and PDGFRα. Media analysis by ELISA of GBM-conditioned media reveals an elevated secretion of growth factors such as EGF, VEGF and PDGF-AA when compared to normal neural stem cell-conditioned media. We also demonstrate that tcNPCs require prolonged or continuous exposure to the GBM secretome in vitro to retain GBM BTIC characteristics. Our in vivo studies reveal that tcNPCs are unable to form tumors, confirming that irreversible transformation events may require sustained or prolonged presence of the GBM secretome. Analysis of GBM-conditioned media by mass spectrometry reveals the presence of secreted proteins Chitinase-3-like 1 (CHI3L1) and H2A histone family member H2AX. Collectively, our data suggest that GBM-secreted factors are capable of transiently altering normal NPCs, although for retention of the transformed phenotype, sustained or prolonged secretome exposure or additional transformation events are likely necessary.

Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome.

PubMed

Lin, Meei-Hua; Miller, Joseph B; Kikkawa, Yamato; Suleiman, Hani Y; Tryggvason, Karl; Hodges, Bradley L; Miner, Jeffrey H

2018-05-01

Background Laminin α 5 β 2 γ 1 (LM-521) is a major component of the GBM. Mutations in LAMB2 that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of Lamb2 mutant mice and restore glomerular permselectivity. Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2 -/- pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture. Results Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM. Conclusions These studies show that GBM composition and function can be altered in vivo via vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired. Copyright © 2018 by the American Society of Nephrology.

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin.

PubMed

Kim, Eui Hyun; Lee, Ji-Hyun; Oh, Yoonjee; Koh, Ilkyoo; Shim, Jin-Kyoung; Park, Junseong; Choi, Junjeong; Yun, Mijin; Jeon, Jeong Yong; Huh, Yong Min; Chang, Jong Hee; Kim, Sun Ho; Kim, Kyung-Sup; Cheong, Jae-Ho; Kim, Pilnam; Kang, Seok-Gu

2017-02-01

Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness- and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival

PubMed Central

Herzog, Susann; Fink, Matthias Alexander; Weitmann, Kerstin; Friedel, Claudius; Hadlich, Stefan; Langner, Sönke; Kindermann, Katharina; Holm, Tobias; Böhm, Andreas; Eskilsson, Eskil; Miletic, Hrvoje; Hildner, Markus; Fritsch, Michael; Vogelgesang, Silke; Havemann, Christoph; Ritter, Christoph Alexander; Meyer zu Schwabedissen, Henriette Elisabeth; Rauch, Bernhard; Hoffmann, Wolfgang; Kroemer, Heyo Klaus; Schroeder, Henry; Bien-Möller, Sandra

2015-01-01

Background The current therapy for glioblastoma multiforme (GBM), the most aggressive and common primary brain tumor of adults, involves surgery and a combined radiochemotherapy that controls tumor progression only for a limited time window. Therefore, the identification of new molecular targets is highly necessary. Inhibition of kinases has become a standard of clinical oncology, and thus the oncogenic kinase Pim1 might represent a promising target for improvement of GBM therapy. Methods Expression of Pim1 and associated signaling molecules was analyzed in human GBM samples, and the potential role of this kinase in patients' prognosis was evaluated. Furthermore, we analyzed the in vivo role of Pim1 in GBM cell growth in an orthotopic mouse model and examined the consequences of Pim1 inhibition in vitro to clarify underlying pathways. Results In comparison with normal brain, a strong upregulation of Pim1 was demonstrated in human GBM samples. Notably, patients with short overall survival showed a significantly higher Pim1 expression compared with GBM patients who lived longer than the median. In vitro experiments with GBM cells and analysis of patients' GBM samples suggest that Pim1 regulation is dependent on epidermal growth factor receptor. Furthermore, inhibition of Pim1 resulted in reduced cell viability accompanied by decreased cell numbers and increased apoptotic cells, as seen by elevated subG1 cell contents and caspase-3 and -9 activation, as well as modulation of several cell cycle or apoptosis regulatory proteins. Conclusions Altogether, Pim1 could be a novel therapeutic target, which should be further analyzed to improve the outcome of patients with aggressive GBM. PMID:25155357

Epithelial and Pseudoepithelial Differentiation in Glioblastoma and Gliosarcoma: A Comparative Morphologic and Molecular Genetic Study

PubMed Central

Scheithauer, Bernd W.; Giannini, Caterina; Bryant, Sandra C.; Jenkins, Robert B.

2008-01-01

Background Glioblastomas exhibit a remarkable tendency to morphologic diversity. Although rare, pseudoepithelial components (adenoid or epithelioid) or true epithelial differentiation may occur and poses a significant diagnostic challenge. Methods H&E slides were reviewed and immunohistochemistry and fluorescence in situ hybridization were performed. Results The patients included 38 males and 20 females. Median age at diagnosis was 57 years (IQR, 50 to 67), and median overall survival was 7 months (IQR, 4 to 11). “Adenoid” glioblastomas (A-GBM) predominated (48%). True epithelial glioblastomas (TE-GBM) were next most frequent based on morphology and immunohistochemistry (35%), followed by epithelioid glioblastomas (E-GBM) (17%). Overall 25 (43%) tumors featured a sarcomatous component. Molecular cytogenetic abnormalities identified by FISH in A-GBM, EGBM and TE-GBM respectively included p16 deletion/-9 (60%, 71%, 64%); chromosome 10 loss (40%, 63%, 57%), chromosome 7 gain without EGFR amplification (70%, 38%, 40%), EGFR amplification (10%, 50%, 27%), PTEN deletion (10%, 25%,29%), PDGFRA amplification (10%, 25%, 0%), and RB1 deletion/-13q (50%, 0%, 14%). Abnormalities identified by IHC included p21 immunonegativity (60%, 25%, 93%), that was most frequent in TE-GBM (p=0.008), strong diffuse p53 staining (29%, 29%, 41%), strong membranous staining for EGFR (21%, 63%, 19%) most frequent in E-GBM (p=0.03), and an increased frequency of p27 immunonegativity in gliosarcomas (15% negative, 85% focal) compared to tumors without sarcoma (38% strongly positive)(p=0.009). Conclusion Pseudoepithelial and true epithelial morphology are rare phenomena in GBM and may be associated with a similar poor prognosis. These tumors demonstrate proportions of molecular genetic abnormalities varying somewhat from conventional GBM. PMID:18816605

The novel agent phospho-glycerol-ibuprofen-amide (MDC-330) inhibits glioblastoma growth in mice: an effect mediated by cyclin D1

PubMed Central

Bartels, Lauren E.; Mattheolabakis, George; Vaeth, Brandon M.; LaComb, Joseph F.; Wang, Ruixue; Zhi, Jizu; Komninou, Despina; Rigas, Basil; Mackenzie, Gerardo G.

2016-01-01

Given that glioblastoma multiforme (GBM) is associated with poor prognosis, new agents are urgently needed. We developed phospho-glycerol-ibuprofen-amide (PGIA), a novel ibuprofen derivative, and evaluated its safety and efficacy in preclinical models of GBM, and its mechanism of action using human GBM cells and animal tumor models. Furthermore, we explored whether formulating PGIA in polymeric nanoparticles could enhance its levels in the brain. PGIA was 3.7- to 5.1-fold more potent than ibuprofen in suppressing the growth of human GBM cell lines. PGIA 0.75× IC50 inhibited cell proliferation by 91 and 87% in human LN-229 and U87-MG GBM cells, respectively, and induced strong G1/S arrest. In vivo, compared with control, PGIA reduced U118-MG and U87-MG xenograft growth by 77 and 56%, respectively (P < 0.05), and was >2-fold more efficacious than ibuprofen. Normal human astrocytes were resistant to PGIA, indicating selectivity. Mechanistically, PGIA reduced cyclin D1 levels in a time- and concentration-dependent manner in GBM cells and in xenografts. PGIA induced cyclin D1 degradation via the proteasome pathway and induced dephosphorylation of GSK3β, which was required for cyclin D1 turnover. Furthermore, cyclin D1 overexpression rescued GBM cells from the cell growth inhibition by PGIA. Moreover, the formulation of PGIA in poly-(l)-lactic acid poly(ethylene glycol) polymeric nanoparticles improved its pharmacokinetics in mice, delivering PGIA to the brain. PGIA displays strong efficacy against GBM, crosses the blood-brain barrier when properly formulated, reaching the target tissue, and establishes cyclin D1 as an important molecular target. Thus, PGIA merits further evaluation as a potential therapeutic option for GBM. PMID:26905586

Glioblastoma recurrence correlates with NLGN3 levels.

PubMed

Liu, Rui; Qin, Xing-Ping; Zhuang, Yang; Zhang, Ya; Liao, Hua-Bao; Tang, Jun-Chun; Pan, Meng-Xian; Zeng, Fei-Fei; Lei, Yang; Lei, Rui-Xue; Wang, Shu; Liu, An-Chun; Chen, Juan; Zhang, Zhi-Feng; Zhao, Dan; Wu, Song-Lin; Liu, Ren-Zhong; Wang, Ze-Fen; Wan, Qi

2018-05-18

Glioblastoma (GBM) is the most aggressive glioma in the brain. Recurrence of GBM is almost inevitable within a short term after tumor resection. In a retrospective study of 386 cases of GBM collected between 2013 and 2016, we found that recurrence of GBM mainly occurs in the deep brain regions, including the basal ganglia, thalamus, and corpus callosum. But the mechanism underlying this phenomenon is not clear. Previous studies suggest that neuroligin-3 (NLGN3) is necessary for GBM growth. Our results show that the levels of NLGN3 in the cortex are higher than those in the deep regions in a normal human brain, and similar patterns are also found in a normal mouse brain. In contrast, NLGN3 levels in the deep brain regions of GBM patients are high. We also show that an increase in NLGN3 concentration promotes the growth of U251 cells and U87-MG cells. Respective use of the cortex neuron culture medium (C-NCM) and basal ganglia neuron culture medium (BG-NCM) with DMEM to cultivate U251, U87-MG and GBM cells isolated from patients, we found that these cells grew faster after treatment with C-NCM and BG-NCM in which the cells treated with C-NCM grew faster than the ones treated with BG-NCM group. Inhibition of NLGN3 release by ADAM10i prevents NCM-induced cell growth. Together, this study suggests that increased levels of NLGN3 in the deep brain region under the GBM pathological circumstances may contribute to GBM recurrence in the basal ganglia, thalamus, and corpus callosum. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors.

PubMed

Ahmed, Nabil; Salsman, Vita S; Kew, Yvonne; Shaffer, Donald; Powell, Suzanne; Zhang, Yi J; Grossman, Robert G; Heslop, Helen E; Gottschalk, Stephen

2010-01-15

Glioblastoma multiforme (GBM) is the most aggressive human primary brain tumor and is currently incurable. Immunotherapies have the potential to target GBM stem cells, which are resistant to conventional therapies. Human epidermal growth factor receptor 2 (HER2) is a validated immunotherapy target, and we determined if HER2-specific T cells can be generated from GBM patients that will target autologous HER2-positive GBMs and their CD133-positive stem cell compartment. HER2-specific T cells from 10 consecutive GBM patients were generated by transduction with a retroviral vector encoding a HER2-specific chimeric antigen receptor. The effector function of HER2-specific T cells against autologous GBM cells, including CD133-positive stem cells, was evaluated in vitro and in an orthotopic murine xenograft model. Stimulation of HER2-specific T cells with HER2-positive autologous GBM cells resulted in T-cell proliferation and secretion of IFN-gamma and interleukin-2 in a HER2-dependent manner. Patients' HER2-specific T cells killed CD133-positive and CD133-negative cells derived from primary HER2-positive GBMs, whereas HER2-negative tumor cells were not killed. Injection of HER2-specific T cells induced sustained regression of autologous GBM xenografts established in the brain of severe combined immunodeficient mice. Gene transfer allows the reliable generation of HER2-specific T cells from GBM patients, which have potent antitumor activity against autologous HER2-positive tumors including their putative stem cells. Hence, the adoptive transfer of HER2-redirected T cells may be a promising immunotherapeutic approach for GBM.

The post-surgical era of GBM: How molecular biology has impacted on our clinical management. A review.

PubMed

Monticelli, M; Zeppa, P; Zenga, F; Altieri, R; Mammi, M; Bertero, L; Castellano, I; Cassoni, P; Melcarne, A; La Rocca, G; Sabatino, G; Ducati, A; Garbossa, D

2018-07-01

Glioblastoma (GBM) is the most common glioma in adults, with incidence increasing by 3% per year. According to the World Health Organization Classification of Central Nervous System Tumors, GBM is considered a grade IV tumor due to its malignant behavior. The aim of this review is to summarize the main biological aspects of GBM. In particular, we focused our attention on those alterations which have been proven to have an impact on patients' outcome, mainly in terms of overall survival (OS), or on the tumor response to therapies. We have also analyzed the cellular biology and the interactions between GBM and the surrounding environment. Copyright © 2018 Elsevier B.V. All rights reserved.

Glioblastoma: new therapeutic strategies to address cellular and genomic complexity

PubMed Central

Cai, Xue; Sughrue, Michael E.

2018-01-01

Glioblastoma (GBM) is the most invasive and devastating primary brain tumor with a median overall survival rate about 18 months with aggressive multimodality therapy. Its unique characteristics of heterogeneity, invasion, clonal populations maintaining stem cell-like cells and recurrence, have limited responses to a variety of therapeutic approaches, and have made GBM the most difficult brain cancer to treat. A great effort and progress has been made to reveal promising molecular mechanisms to target therapeutically. Especially with the emerging of new technologies, the mechanisms underlying the pathology of GBM are becoming more clear. The purpose of this review is to summarize the current knowledge of molecular mechanisms of GBM and highlight the novel strategies and concepts for the treatment of GBM. PMID:29507709

Osthole Suppresses the Migratory Ability of Human Glioblastoma Multiforme Cells via Inhibition of Focal Adhesion Kinase-Mediated Matrix Metalloproteinase-13 Expression

PubMed Central

Tsai, Cheng-Fang; Yeh, Wei-Lan; Chen, Jia-Hong; Lin, Chingju; Huang, Shiang-Suo; Lu, Dah-Yuu

2014-01-01

Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK) is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP)-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells. PMID:24599080

The Safety of Available Immunotherapy for the Treatment of Glioblastoma

PubMed Central

Farber, S. Harrison; Elsamadicy, Aladine A.; Atik, Fatih; Suryadevara, Carter M.; Chongsathidkiet, Pakawat; Fecci, Peter E.; Sampson, John H.

2017-01-01

Introduction Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Current standard of care involves maximal surgical resection combined with adjuvant chemoradiation. Growing support exists for a role of immunotherapy in treating these tumors with the goal of targeted cytotoxicity. Here we review data on the safety for current immunotherapies being tested in GBM. Areas covered Safety data from published clinical trials, including ongoing clinical trials were reviewed. Immunotherapeutic classes currently under investigation in GBM include various vaccination strategies, adoptive T cell immunotherapy, immune checkpoint blockade, monoclonal antibodies, and cytokine therapies. Trials include children, adolescents, and adults with either primary or recurrent GBM. Expert commentary Based on the reviewed clinical trials, the current immunotherapies targeting GBM are safe and well-tolerated with minimal toxicities which should be noted. However, the gains in patient survival have been modest. A safe and well-tolerated combinatory immunotherapeutic approach may be essential for optimal efficacy towards GBM. PMID:27989218

Multiple bone metastases from glioblastoma multiforme without local brain relapse: a case report and review of the literature.

PubMed

Takanen, Silvia; Bangrazi, Caterina; Caiazzo, Rossella; Raffetto, Nicola; Tombolini, Vincenzo

2013-01-01

Extracranial metastases from glioblastoma multiforme (GBM) are a very rare event, even if an increasing incidence has been documented. We report the case of a young woman with primary GBM who developed bone metastases without local brain relapse. Because of persistent headache and visual disturbances, in March 2011 the patient underwent magnetic resonance imaging (MRI) evidencing a temporoparietal mass, which was surgically resected. Histology revealed GBM. She was given concomitant chemoradiotherapy according to the Stupp regimen. After a 4-week break, the patient received 6 cycles of adjuvant temozolomide according to the standard 5-day schedule every 28 days. In December 2011 she complained of progressive low back pain, and MRI showed multiple bone metastases from primary GBM, confirmed by histology. Cases of metastatic GBM in concurrence with a primary brain tumor or local relapse are more common in the literature; only a few cases have been reported where extracranial metastases from GBM occurred without any relapse in the brain. Here we report our experience.

Survey of the effect of doxorubicin and flavonoid extract of white Morus alba leaf on apoptosis induction in a-172 GBM cell line.

PubMed

Dabili, Sheyda; Fallah, Soudabeh; Aein, Mojdeh; Vatannejad, Akram; Panahi, Ghodratollah; Fadaei, Reza; Moradi, Nariman; Shojaii, Asie

2018-02-20

In this study, the effect of doxorubicin, flavonoid extract of white Morus alba leaf (MFE) and a combination of doxorubicin and flavonoid extract on Bax and Bcl2 levels and caspase 3 activity of cancer A-172 GBM cell line was investigated. Bax/Bcl2 levels of treated A-172 GBM cell line with flavonoid extract of white mulberry leaf were estimated by ELISA methods. Caspase 3 activity of treated A-172 GBM cells was determined by calorimetric assay. The flow cytometry assessment was used to estimate the apoptosis percent of treated A-172 GBM cells. Treatment of A-172 GBM cells with MFE, doxorubicin and a combination of MFE and doxorubicin caused a significant decrease in Bcl2 level and an increase in Bax level. The apoptosis percent of treated cells were also elevated significantly. Present results suggest that concomitant use of herbal medicine and chemotherapy may be an effective alternative method for the treatment of cancers.

Nanoparticle-mediated knockdown of DNA repair sensitizes cells to radiotherapy and extends survival in a genetic mouse model of glioblastoma.

PubMed

Kievit, Forrest M; Wang, Kui; Ozawa, Tatsuya; Tarudji, Aria W; Silber, John R; Holland, Eric C; Ellenbogen, Richard G; Zhang, Miqin

2017-10-01

Glioblastoma (GBM) remains incurable, and recurrent tumors rarely respond to standard-of-care radiation and chemo-therapies. Therefore, strategies that enhance the effects of these therapies should provide significant benefits to GBM patients. We have developed a nanoparticle delivery vehicle that can stably bind and protect nucleic acids for specific delivery into brain tumor cells. These nanoparticles can deliver therapeutic siRNAs to sensitize GBM cells to radiotherapy and improve GBM treatment via systemic administration. We show that nanoparticle-mediated knockdown of the DNA repair protein apurinic endonuclease 1 (Ape1) sensitizes GBM cells to radiotherapy and extend survival in a genetic mouse model of GBM. Specific knockdown of Ape1 activity by 30% in brain tumor tissue doubled the extended survival achieved with radiotherapy alone. Ape1 is a promising target for increasing the effectiveness of radiotherapy, and nanoparticle-mediated delivery of siRNA is a promising strategy for tumor specific knockdown of Ape1. Copyright © 2017. Published by Elsevier Inc.

A quantitative study of shape descriptors from glioblastoma multiforme phenotypes for predicting survival outcome

PubMed Central

Desrosiers, Christian; Hassan, Lama; Tanougast, Camel

2016-01-01

Objective: Predicting the survival outcome of patients with glioblastoma multiforme (GBM) is of key importance to clinicians for selecting the optimal course of treatment. The goal of this study was to evaluate the usefulness of geometric shape features, extracted from MR images, as a potential non-invasive way to characterize GBM tumours and predict the overall survival times of patients with GBM. Methods: The data of 40 patients with GBM were obtained from the Cancer Genome Atlas and Cancer Imaging Archive. The T1 weighted post-contrast and fluid-attenuated inversion-recovery volumes of patients were co-registered and segmented into delineate regions corresponding to three GBM phenotypes: necrosis, active tumour and oedema/invasion. A set of two-dimensional shape features were then extracted slicewise from each phenotype region and combined over slices to describe the three-dimensional shape of these phenotypes. Thereafter, a Kruskal–Wallis test was employed to identify shape features with significantly different distributions across phenotypes. Moreover, a Kaplan–Meier analysis was performed to find features strongly associated with GBM survival. Finally, a multivariate analysis based on the random forest model was used for predicting the survival group of patients with GBM. Results: Our analysis using the Kruskal–Wallis test showed that all but one shape feature had statistically significant differences across phenotypes, with p-value < 0.05, following Holm–Bonferroni correction, justifying the analysis of GBM tumour shapes on a per-phenotype basis. Furthermore, the survival analysis based on the Kaplan–Meier estimator identified three features derived from necrotic regions (i.e. Eccentricity, Extent and Solidity) that were significantly correlated with overall survival (corrected p-value < 0.05; hazard ratios between 1.68 and 1.87). In the multivariate analysis, features from necrotic regions gave the highest accuracy in predicting the survival group of patients, with a mean area under the receiver-operating characteristic curve (AUC) of 63.85%. Combining the features of all three phenotypes increased the mean AUC to 66.99%, suggesting that shape features from different phenotypes can be used in a synergic manner to predict GBM survival. Conclusion: Results show that shape features, in particular those extracted from necrotic regions, can be used effectively to characterize GBM tumours and predict the overall survival of patients with GBM. Advances in knowledge: Simple volumetric features have been largely used to characterize the different phenotypes of a GBM tumour (i.e. active tumour, oedema and necrosis). This study extends previous work by considering a wide range of shape features, extracted in different phenotypes, for the prediction of survival in patients with GBM. PMID:27781499

Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma: clinical article.

PubMed

Sloan, Andrew E; Ahluwalia, Manmeet S; Valerio-Pascua, Jose; Manjila, Sunil; Torchia, Mark G; Jones, Stephen E; Sunshine, Jeffrey L; Phillips, Michael; Griswold, Mark A; Clampitt, Mark; Brewer, Cathy; Jochum, Jennifer; McGraw, Mary V; Diorio, Dawn; Ditz, Gail; Barnett, Gene H

2013-06-01

Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose-escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM). Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation. Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals-Case Medical Center). Their average age was 55 years (range 34-69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70-90). The mean tumor volume was 6.8 ± 5 cm(3) (range 2.6-19 cm(3)), the percentage of tumor treated was 78% ± 12% (range 57%-90%), and the conformality index was 1.21 ± 0.33 (range 1.00-2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62-767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose. NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. CLINICAL TRIAL REGISTRATION NO.: NCT00747253 ( ClinicalTrials.gov ).

New metastable form of glibenclamide prepared by redispersion from ternary solid dispersions containing polyvinylpyrrolidone-K30 and sodium lauryl sulfate.

PubMed

Thongnopkoon, Thanu; Puttipipatkhachorn, Satit

2016-01-01

Modification of polymorphic forms of poorly water-soluble drugs is one way to achieve the desirable properties. In this study, glibenclamide (GBM) particles with different polymorphic forms, including a new metastable form, were obtained from redispersion of ternary solid dispersion systems. The ternary solid dispersion systems, consisting of GBM, polyvinylpyrrolidone-K30 (PVP-K30) and sodium lauryl sulfate (SLS), were prepared by solvent evaporation method and subsequently redispersed in deionized water. The precipitated drug particles were then collected at a given time period. The drug particles with different polymorphic forms could be achieved depending on the polymer/surfactant ratio. Amorphous drug nanoparticles could be obtained by using a high polymer/surfactant ratio, whereas two different crystalline forms were obtained from the systems containing low polymer/surfactant ratios. Interestingly, a new metastable form IV of GBM with improved dissolution behavior could be obtained from the system of GBM:PVP-K30:SLS with the weight ratio of 2:2:4. This new polymorphic form IV of GBM was confirmed by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffractometry (PXRD) and solid state 13 C nuclear magnetic resonance (NMR) spectroscopy. The molecular arrangement of the new polymorphic form IV of GBM was proposed. The GBM particles with polymorphic form IV also showed an improved dissolution behavior. In addition, it was found that the formation of the new polymorphic form IV of GBM by this process was reproducible.

Disulfiram, a drug widely used to control alcoholism, suppresses self-renewal of glioblastoma and overrides resistance to temozolomide

PubMed Central

Triscott, Joanna; Lee, Cathy; Hu, Kaiji; Fotovati, Abbas; Berns, Rachel; Pambid, Mary; Luk, Margaret; Kast, Richard E.; Kong, Esther; Toyota, Eric; Yip, Stephen; Toyota, Brian; Dunn, Sandra E.

2012-01-01

Glioblastomas (GBM) are associated with high rates of relapse. These brain tumors are often resistant to chemotherapies like temozolomide (TMZ) and there are very few treatment options available to patients. We recently reported that polo-like kinase-1 (PLK1) is associated with the proliferative subtype of GBM; which has the worst prognosis. In this study, we addressed the potential of repurposing disulfiram (DSF), a drug widely used to control alcoholism for the past six decades. DSF has good safety profiles and penetrates the blood-brain barrier. Here we report that DSF inhibited the growth of TMZ resistant GBM cells, (IC90=100 nM), but did not affect normal human astrocytes. At similar DSF concentrations, self-renewal was blocked by ~100% using neurosphere growth assays. Likewise the drug completely inhibited the self-renewal of the BT74 and GBM4 primary cell lines. Additionally, DSF suppressed growth and self-renewal of primary cells from two GBM tumors. These cells were resistant to TMZ, had unmethylated MGMT, and expressed high levels of PLK1. Consistent with its role in suppressing GBM growth, DSF inhibited the expression of PLK1 in GBM cells. Likewise, PLK1 inhibition with siRNA, or small molecules (BI-2536 or BI-6727) blocked growth of TMZ resistant cells. Our studies suggest that DSF has the potential to be repurposed for treatment of refractory GBM. PMID:23047041

ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA.

PubMed

Talamillo, A; Grande, L; Ruiz-Ontañon, P; Velasquez, C; Mollinedo, P; Torices, S; Sanchez-Gomez, P; Aznar, A; Esparis-Ogando, A; Lopez-Lopez, C; Lafita, C; Berciano, M T; Montero, J A; Vazquez-Barquero, A; Segura, V; Villagra, N T; Pandiella, A; Lafarga, M; Leon, J; Martinez-Climent, J A; Sanz-Moreno, V; Fernandez-Luna, J L

2017-03-23

Long-term survival remains low for most patients with glioblastoma (GBM), which reveals the need for markers of disease outcome and novel therapeutic targets. We describe that ODZ1 (also known as TENM1), a type II transmembrane protein involved in fetal brain development, plays a crucial role in the invasion of GBM cells. Differentiation of glioblastoma stem-like cells drives the nuclear translocation of an intracellular fragment of ODZ1 through proteolytic cleavage by signal peptide peptidase-like 2a. The intracellular fragment of ODZ1 promotes cytoskeletal remodelling of GBM cells and invasion of the surrounding environment both in vitro and in vivo. Absence of ODZ1 by gene deletion or downregulation of ODZ1 by small interfering RNAs drastically reduces the invasive capacity of GBM cells. This activity is mediated by an ODZ1-triggered transcriptional pathway, through the E-box binding Myc protein, that promotes the expression and activation of Ras homolog family member A (RhoA) and subsequent activation of Rho-associated, coiled-coil containing protein kinase (ROCK). Overexpression of ODZ1 in GBM cells reduced survival of xenografted mice. Consistently, analysis of 122 GBM tumour samples revealed that the number of ODZ1-positive cells inversely correlated with overall and progression-free survival. Our findings establish a novel marker of invading GBM cells and consequently a potential marker of disease progression and a therapeutic target in GBM.

An intrinsic DFF40/CAD endonuclease deficiency impairs oligonucleosomal DNA hydrolysis during caspase-dependent cell death: a common trait in human glioblastoma cells

PubMed Central

Sánchez-Osuna, María; Martínez-Escardó, Laura; Granados-Colomina, Carla; Martínez-Soler, Fina; Pascual-Guiral, Sònia; Iglesias-Guimarais, Victoria; Velasco, Roser; Plans, Gerard; Vidal, Noemi; Tortosa, Avelina; Barcia, Carlos; Bruna, Jordi; Yuste, Victor J.

2016-01-01

Background Glioblastoma (GBM) or grade IV astrocytoma is one of the most devastating human cancers. The loss of DFF40/CAD, the key endonuclease that triggers oligonucleosomal DNA fragmentation during apoptosis, has been linked to genomic instability and cell survival after radiation. Despite the near inevitability of GBM tumor recurrence after treatment, the relationship between DFF40/CAD and GBM remains unexplored. Methods We studied the apoptotic behavior of human GBM-derived cells after apoptotic insult. We analyzed caspase activation and the protein levels and subcellular localization of DFF40/CAD apoptotic endonuclease. DFF40/CAD was also evaluated in histological sections from astrocytic tumors and nontumoral human brain. Results We showed that GBM cells undergo incomplete apoptosis without generating oligonucleosomal DNA degradation despite the correct activation of executioner caspases. The major defect of GBM cells relied on the improper accumulation of DFF40/CAD at the nucleoplasmic subcellular compartment. Supporting this finding, DFF40/CAD overexpression allowed GBM cells to display oligonucleosomal DNA degradation after apoptotic challenge. Moreover, the analysis of histological slices from astrocytic tumors showed that DFF40/CAD immunoreactivity in tumoral GFAP-positive cells was markedly reduced when compared with nontumoral samples. Conclusions Our data highlight the low expression levels of DFF40/CAD and the absence of DNA laddering as common molecular traits in GBM. These findings could be of major importance for understanding the malignant behavior of remaining tumor cells after radiochemotherapy. PMID:26755073

GRB 170817A as a jet counterpart to gravitational wave trigger GW 170817

NASA Astrophysics Data System (ADS)

Lamb, Gavin P.; Kobayashi, Shiho

2018-05-01

Fermi/GBM (Gamma-ray Burst Monitor) and INTEGRAL (the International Gamma-ray Astrophysics Laboratory) reported the detection of the γ-ray counterpart, GRB 170817A, to the LIGO (Light Interferometer Gravitational-wave Observatory)/Virgo gravitational wave detected binary neutron star merger, GW 170817. GRB 170817A is likely to have an internal jet or another origin such as cocoon emission, shock-breakout, or a flare from a viscous disc. In this paper we assume that the γ-ray emission is caused by energy dissipation within a relativistic jet and we model the afterglow synchrotron emission from a reverse- and forward-shock in the outflow. We show the afterglow for a low-luminosity γ-ray burst (GRB) jet with a high Lorentz-factor (Γ); a low-Γ and low-kinetic energy jet; a low-Γ, high kinetic energy jet; structured jets viewed at an inclination within the jet-half-opening angle; and an off-axis `typical' GRB jet. All jet models will produce observable afterglows on various timescales. The late-time afterglow from 10-110 days can be fit by a Gaussian structured jet viewed at a moderate inclination, however the GRB is not directly reproduced by this model. These jet afterglow models can be used for future GW detected NS merger counterparts with a jet afterglow origin.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamaoka, Kazutaka; Yoshida, Atsumasa; Kotani, Taro

The CALET mission is a Japanese-led effort involving candidate experiments on the International Space Station, planned for launch in 2013. The CALET main detector is a pair conversion telescope which is dedicated to observing high energy electrons and gamma-rays in the GeV-TeV range. CALET can observe gamma-ray bursts over an unprecedented 9 decade energy range from {approx}keV to {approx}TeV with a combination of a gamma-ray burst monitor (GBM) with low energy coverage. GBM is now designed as multiple scintillators made of BGO and LaBr{sub 3}(Ce) scintillators. The prototype LaBr{sub 3}(Ce) crystal with 3 inch diameter and 0.5 inch thickness displaysmore » a very good performance: 2.9{+-}0.1% FWHM energy resolution at 662 keV and 4 keV lower energy threshold. Furthermore, degradations in performance by the anticipated proton irradiation in the orbit are not significant. Results on proton-induced background are also presented.« less

A simple quantitative diagnostic alternative for MGMT DNA-methylation testing on RCL2 fixed paraffin embedded tumors using restriction coupled qPCR.

PubMed

Pulverer, Walter; Hofner, Manuela; Preusser, Matthias; Dirnberger, Elisabeth; Hainfellner, Johannes A; Weinhaeusel, Andreas

2014-01-01

MGMT promoter methylation is associated with favorable prognosis and chemosensitivity in glioblastoma multiforme (GBM), especially in elderly patients. We aimed to develop a simple methylation-sensitive restriction enzyme (MSRE)-based quantitative PCR (qPCR) assay, allowing the quantification of MGMT promoter methylation. DNA was extracted from non-neoplastic brain (n = 24) and GBM samples (n = 20) upon 3 different sample conservation conditions (-80 °C, formalin-fixed and paraffin-embedded (FFPE); RCL2-fixed). We evaluated the suitability of each fixation method with respect to the MSRE-coupled qPCR methylation analyses. Methylation data were validated by MALDITOF. qPCR was used for evaluation of alternative tissue conservation procedures. DNA from FFPE tissue failed reliable testing; DNA from both RCL2-fixed and fresh frozen tissues performed equally well and was further used for validation of the quantitative MGMT methylation assay (limit of detection (LOD): 19.58 pg), using individual's undigested sample DNA for calibration. MGMT methylation analysis in non-neoplastic brain identified a background methylation of 0.10 ± 11% which we used for defining a cut-off of 0.32% for patient stratification. Of GBM patients 9 were MGMT methylationpositive (range: 0.56 - 91.95%), and 11 tested negative. MALDI-TOF measurements resulted in a concordant classification of 94% of GBM samples in comparison to qPCR. The presented methodology allows quantitative MGMT promoter methylation analyses. An amount of 200 ng DNA is sufficient for triplicate analyses including control reactions and individual calibration curves, thus excluding any DNA qualityderived bias. The combination of RCL2-fixation and quantitative methylation analyses improves pathological routine examination when histological and molecular analyses on limited amounts of tumor samples are necessary for patient stratification.

In vivo bioluminescence imaging validation of a human biopsy-derived orthotopic mouse model of glioblastoma multiforme.

PubMed

Jarzabek, Monika A; Huszthy, Peter C; Skaftnesmo, Kai O; McCormack, Emmet; Dicker, Patrick; Prehn, Jochen H M; Bjerkvig, Rolf; Byrne, Annette T

2013-05-01

Glioblastoma multiforme (GBM), the most aggressive brain malignancy, is characterized by extensive cellular proliferation, angiogenesis, and single-cell infiltration into the brain. We have previously shown that a xenograft model based on serial xenotransplantation of human biopsy spheroids in immunodeficient rodents maintains the genotype and phenotype of the original patient tumor. The present work further extends this model for optical assessment of tumor engraftment and growth using bioluminescence imaging (BLI). A method for successful lentiviral transduction of the firefly luciferase gene into multicellular spheroids was developed and implemented to generate optically active patient tumor cells. Luciferase-expressing spheroids were injected into the brains of immunodeficient mice. BLI photon counts and tumor volumes from magnetic resonance imaging (MRI) were correlated. Luciferase-expressing tumors recapitulated the histopathologic hallmarks of human GBMs and showed proliferation rates and microvessel density counts similar to those of wild-type xenografts. Moreover, we detected widespread invasion of luciferase-positive tumor cells in the mouse brains. Herein we describe a novel optically active model of GBM that closely mimics human pathology with respect to invasion, angiogenesis, and proliferation indices. The model may thus be routinely used for the assessment of novel anti-GBM therapeutic approaches implementing well-established and cost-effective optical imaging strategies.

A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion.

PubMed

Shelton, Laura M; Mukherjee, Purna; Huysentruyt, Leanne C; Urits, Ivan; Rosenberg, Joshua A; Seyfried, Thomas N

2010-09-01

Glioblastoma multiforme (GBM) is a rapidly progressive disease of morbidity and mortality and is the most common form of primary brain cancer in adults. Lack of appropriate in vivo models has been a major roadblock to developing effective therapies for GBM. A new highly invasive in vivo GBM model is described that was derived from a spontaneous brain tumor (VM-M3) in the VM mouse strain. Highly invasive tumor cells could be identified histologically on the hemisphere contralateral to the hemisphere implanted with tumor cells or tissue. Tumor cells were highly expressive for the chemokine receptor CXCR4 and the proliferation marker Ki-67 and could be identified invading through the pia mater, the vascular system, the ventricular system, around neurons, and over white matter tracts including the corpus callosum. In addition, the brain tumor cells were labeled with the firefly luciferase gene, allowing for non-invasive detection and quantitation through bioluminescent imaging. The VM-M3 tumor has a short incubation time with mortality occurring in 100% of the animals within approximately 15 days. The VM-M3 brain tumor model therefore can be used in a pre-clinical setting for the rapid evaluation of novel anti-invasive therapies.

Imaging and Selective Elimination of Glioblastoma Stem Cells with Theranostic Near-Infrared-Labeled CD133-Specific Antibodies.

PubMed

Jing, Hua; Weidensteiner, Claudia; Reichardt, Wilfried; Gaedicke, Simone; Zhu, Xuekai; Grosu, Anca-Ligia; Kobayashi, Hisataka; Niedermann, Gabriele

2016-01-01

Near-infrared photoimmunotherapy (NIR-PIT), which employs monoclonal antibody (mAb)-phototoxic phthalocyanine dye IR700 conjugates, permits the specific, image-guided and spatiotemporally controlled elimination of tumor cells. Here, we report the highly efficient NIR-PIT of human tumor xenografts initiated from patient-derived cancer stem cells (CSCs). Using glioblastoma stem cells (GBM-SCs) expressing the prototypic CSC marker AC133/CD133, we also demonstrate here for the first time that NIR-PIT is highly effective against brain tumors. The intravenously injected theranostic AC133 mAb conjugate enabled the non-invasive detection of orthotopic gliomas by NIR fluorescence imaging, and reached AC133+ GBM-SCs at the invasive tumor front. AC133-targeted NIR-PIT induced the rapid cell death of AC133+ GBM-SCs and thereby strong shrinkage of both subcutaneous and invasively growing brain tumors. A single round of NIR-PIT extended the overall survival of mice with established orthotopic gliomas by more than a factor of two, even though the harmless NIR light was applied through the intact skull. Humanised versions of this theranostic agent may facilitate intraoperative imaging and histopathological evaluation of tumor borders and enable the highly specific and efficient eradication of CSCs.

Orthotopic Patient-Derived Glioblastoma Xenografts in Mice.

PubMed

Xu, Zhongye; Kader, Michael; Sen, Rajeev; Placantonakis, Dimitris G

2018-01-01

Patient-derived xenografts (PDX) provide in vivo glioblastoma (GBM) models that recapitulate actual tumors. Orthotopic tumor xenografts within the mouse brain are obtained by injection of GBM stem-like cells derived from fresh surgical specimens. These xenografts reproduce GBM's histologic complexity and hallmark biological behaviors, such as brain invasion, angiogenesis, and resistance to therapy. This method has become essential for analyzing mechanisms of tumorigenesis and testing the therapeutic effect of candidate agents in the preclinical setting. Here, we describe a protocol for establishing orthotopic tumor xenografts in the mouse brain with human GBM cells.

Tumor-associated mesenchymal stem-like cells provide extracellular signaling cue for invasiveness of glioblastoma cells

PubMed Central

Yoo, Ki-Chun; Lee, Ji-Hyun; Kim, In-Gyu; Kim, Min-Jung; Chang, Jong Hee; Kang, Seok-Gu; Lee, Su-Jae

2017-01-01

Hyaluronic acid (HA) is abundant in tumor microenvironment and closely associated with invasiveness of glioblastoma (GBM) cells. However, the cellular mechanism underlying HA-rich microenvironment in GBM remains unexplored. Here, we show that tumor-associated mesenchymal stem-like cells (tMSLCs) contribute to abundance of hyaluronic acid (HA) in tumor microenvironment through HA synthase-2 (HAS2) induction, and thereby enhances invasiveness of GBM cells. In an autocrine manner, C5a secreted by tMSLCs activated ERK MAPK for HAS2 induction in tMSLCs. Importantly, HA acted as a signaling ligand of its cognate receptor RHAMM for intracellular signaling activation underlying invasiveness of GBM cells. Taken together, our study suggests that tMSLCs contribute to HA-rich proinvasive ECM microenvironment in GBM. PMID:27903965

Suppression of Peroxiredoxin 4 in Glioblastoma Cells Increases Apoptosis and Reduces Tumor Growth

PubMed Central

Kim, Tae Hyong; Song, Jieun; Alcantara Llaguno, Sheila R.; Murnan, Eric; Liyanarachchi, Sandya; Palanichamy, Kamalakannan; Yi, Ji-Yeun; Viapiano, Mariano Sebastian; Nakano, Ichiro; Yoon, Sung Ok; Wu, Hong; Parada, Luis F.; Kwon, Chang-Hyuk

2012-01-01

Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future. PMID:22916164

Microvascular fractal dimension predicts prognosis and response to chemotherapy in glioblastoma: an automatic image analysis study.

PubMed

Chen, Cong; He, Zhi-Cheng; Shi, Yu; Zhou, Wenchao; Zhang, Xia; Xiao, Hua-Liang; Wu, Hai-Bo; Yao, Xiao-Hong; Luo, Wan-Chun; Cui, You-Hong; Bao, Shideng; Kung, Hsiang-Fu; Bian, Xiu-Wu; Ping, Yi-Fang

2018-05-15

The microvascular profile has been included in the WHO glioma grading criteria. Nevertheless, microvessels in gliomas of the same WHO grade, e.g., WHO IV glioblastoma (GBM), exhibit heterogeneous and polymorphic morphology, whose possible clinical significance remains to be determined. In this study, we employed a fractal geometry-derived parameter, microvascular fractal dimension (mvFD), to quantify microvessel complexity and developed a home-made macro in Image J software to automatically determine mvFD from the microvessel-stained immunohistochemical images of GBM. We found that mvFD effectively quantified the morphological complexity of GBM microvasculature. Furthermore, high mvFD favored the survival of GBM patients as an independent prognostic indicator and predicted a better response to chemotherapy of GBM patients. When investigating the underlying relations between mvFD and tumor growth by deploying Ki67/mvFD as an index for microvasculature-normalized tumor proliferation, we discovered an inverse correlation between mvFD and Ki67/mvFD. Furthermore, mvFD inversely correlated with the expressions of a glycolytic marker, LDHA, which indicated poor prognosis of GBM patients. Conclusively, we developed an automatic approach for mvFD measurement, and demonstrated that mvFD could predict the prognosis and response to chemotherapy of GBM patients.

Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy.

PubMed

Kriz, Wilhelm; Löwen, Jana; Federico, Giuseppina; van den Born, Jacob; Gröne, Elisabeth; Gröne, Hermann Josef

2017-06-01

Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918 biopsies with DN revealed strong evidence that these mechanisms are connected to each other, wherein excess GBM components fail to undergo degradation and are deposited in the mesangium. These data do not exclude that mesangial cells also synthesize components that contribute to the accumulation of matrix in the mesangium. Light, electron microscopic, immunofluorescence, and in situ hybridization studies clearly show that the thickening of the GBM is due not only to overproduction of components of the mature GBM (α3 and α5 chains of collagen IV and agrin) by podocytes but also to resumed increased synthesis of the α1 chain of collagen IV and of perlecan by endothelial cells usually seen during embryonic development. We hypothesize that these abnormal production mechanisms are caused by different processes: overproduction of mature GBM-components by the diabetic milieu and regression of endothelial cells to an embryonic production mode by decreased availability of mediators from podocytes. Copyright © 2017 the American Physiological Society.

Metformin inhibits TGF-β1-induced epithelial-to-mesenchymal transition-like process and stem-like properties in GBM via AKT/mTOR/ZEB1 pathway.

PubMed

Song, Yang; Chen, Yong; Li, Yunqian; Lyu, Xiaoyan; Cui, Jiayue; Cheng, Ye; Zhao, Liyan; Zhao, Gang

2018-01-23

Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. In spite of advances in diagnosis and therapy, the prognosis is still relatively poor. The invasive property of GBM is the major cause of death in patients. Epithelial-to-mesenchymal transition-like process (EMT-like process) is considered to play an important role in the invasive property. Metformin has been reported as a regulator of EMT-like process. In this study, we confirmed that metformin inhibited TGF-β1-induced EMT-like process and EMT-associated migration and invasion in LN18 and U87 GBM cells. Our results also showed that metformin significantly suppressed self-renewal capacity of glioblastoma stem cells (GSCs), and expression of stem cell markers Bmi1, Sox2 and Musashi1, indicating that metformin can inhibit cancer stem-like properties of GBM cells. We further clarified that metformin specifically inhibited TGF-β1 activated AKT, the downstream molecular mTOR and the leading transcription factor ZEB1. Taken together, our data demonstrate that metformin inhibits TGF-β1-induced EMT-like process and cancer stem-like properties in GBM cells via AKT/mTOR/ZEB1 pathway and provide evidence of metformin for further clinical investigation targeted GBM.

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.

PubMed

Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing; Xie, Xiao Qiang; Yu, Shang Bin; Chen, Xiao Qian

2017-06-17

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. Copyright © 2017. Published by Elsevier Inc.

Interaction of bovine gallbladder mucin and calcium-binding protein: effects on calcium phosphate precipitation.

PubMed

Afdhal, N H; Ostrow, J D; Koehler, R; Niu, N; Groen, A K; Veis, A; Nunes, D P; Offner, G D

1995-11-01

Gallstones consist of calcium salts and cholesterol crystals, arrayed on a matrix of gallbladder mucin (GBM), and regulatory proteins like calcium-binding protein (CBP). To determine if interactions between CBP and GBM follow a biomineralization scheme, their mutual binding and effects on CaHPO4 precipitation were studied. Binding of CBP to GBM was assessed by inhibition of the fluorescence of the complex of GBM with bis-1,8-anilinonaphthalene sulfonic acid (bis-ANS). The effects of the proteins on precipitation of CaHPO4 were assessed by nephelometry and gravimetry. Precipitates were analyzed for calcium, phosphate, and protein. CBP and bis-ANS competitively displaced each other from 30 binding sites on mucin, with a 1:1 stoichiometry and similar affinity. The rate of precipitation of CaHPO4 was retarded by mucin and CBP. Precipitate mass was unaffected by GBM alone but decreased with the addition of CBP. Complexing CBP with GBM abolished or moderated this latter effect, altered precipitate morphology, and changed the stoichiometric ratios of Ca to PO4 in the precipitates from 1:1 to 3:2. Mucin and CBP were incorporated into the precipitates. These studies suggest that the formation of calcium-containing gallstones is a biomineralization process regulated by both GBM and CBP.

Prediction of survival with multi-scale radiomic analysis in glioblastoma patients.

PubMed

Chaddad, Ahmad; Sabri, Siham; Niazi, Tamim; Abdulkarim, Bassam

2018-06-19

We propose a multiscale texture features based on Laplacian-of Gaussian (LoG) filter to predict progression free (PFS) and overall survival (OS) in patients newly diagnosed with glioblastoma (GBM). Experiments use the extracted features derived from 40 patients of GBM with T1-weighted imaging (T1-WI) and Fluid-attenuated inversion recovery (FLAIR) images that were segmented manually into areas of active tumor, necrosis, and edema. Multiscale texture features were extracted locally from each of these areas of interest using a LoG filter and the relation between features to OS and PFS was investigated using univariate (i.e., Spearman's rank correlation coefficient, log-rank test and Kaplan-Meier estimator) and multivariate analyses (i.e., Random Forest classifier). Three and seven features were statistically correlated with PFS and OS, respectively, with absolute correlation values between 0.32 and 0.36 and p < 0.05. Three features derived from active tumor regions only were associated with OS (p < 0.05) with hazard ratios (HR) of 2.9, 3, and 3.24, respectively. Combined features showed an AUC value of 85.37 and 85.54% for predicting the PFS and OS of GBM patients, respectively, using the random forest (RF) classifier. We presented a multiscale texture features to characterize the GBM regions and predict he PFS and OS. The efficiency achievable suggests that this technique can be developed into a GBM MR analysis system suitable for clinical use after a thorough validation involving more patients. Graphical abstract Scheme of the proposed model for characterizing the heterogeneity of GBM regions and predicting the overall survival and progression free survival of GBM patients. (1) Acquisition of pretreatment MRI images; (2) Affine registration of T1-WI image with its corresponding FLAIR images, and GBM subtype (phenotypes) labelling; (3) Extraction of nine texture features from the three texture scales fine, medium, and coarse derived from each of GBM regions; (4) Comparing heterogeneity between GBM regions by ANOVA test; Survival analysis using Univariate (Spearman rank correlation between features and survival (i.e., PFS and OS) based on each of the GBM regions, Kaplan-Meier estimator and log-rank test to predict the PFS and OS of patient groups that grouped based on median of feature), and multivariate (random forest model) for predicting the PFS and OS of patients groups that grouped based on median of PFS and OS.

Secondary Glioblastoma: Molecular and Clinical Factors That Affect Outcome After Malignant Progression of a Lower Grade Tumor.

PubMed

Gessler, Florian; Zappi, Johannes; Konczalla, Juergen; Bernstock, Joshua D; Forster, Marie-Therese; Wagner, Marlies; Mittelbronn, Michel; Seifert, Volker; Senft, Christian

2017-06-01

There is limited information on prognostic factors and outcomes in patients with secondary glioblastoma (sGBM). Herein we report on the outcomes of patients with sGBM and identify clinically relevant prognostic factors. We retrospectively analyzed our institutional database for patients with histologic evidence of World Health Organization (WHO) grade II-III gliomas that went on to develop WHO grade IV sGBM. The assessment of the isocitrate dehydrogenase-1 (IDH1) R132H mutation was performed by immunohistochemical staining. Forty-five patients with sGBM were included within our analysis (median age, 41 years). Mutated IDH1 (R132H) protein was present within the gliomas of 24 patients and was absent in 17. Immunohistochemistry assessment could not be performed for 4 patients. The median time between first diagnosis of glioma and sGBM was 158.9 weeks. Median overall survival (OS) after a diagnosis of sGBM was 63.6 weeks. When assessing patient-specific (i.e., therapy-independent) factors, mutated IDH1 (R132H) protein (P = 0.01; hazard ratio (HR), 0.54; confidence interval (CI) 0.33-0.87), WHO grade II tumor as precursor lesion (P = 0.05; HR, 0.49; CI 0.25-0.97), and a frontal tumor location (P = 0.04; HR, 0.48; CI 0.23-0.99) were found to be associated with better OS by multivariate analysis. Our data further indicate that complete tumor removal is associated with better patient survival in sGBM patients within certain risk groups (time period to development of sGBM, >104 weeks; initial WHO grade II tumor, IDH1 mutation, and time period to development of sGBM, >104 weeks; initial WHO grade II or III tumor, IDH1 wild type, frontal lobe localization). Our retrospective analysis suggested that the presence of an IDH1 (R132H) mutation, frontal tumor location, and WHO grade of the initial tumor are associated with OS after progression to sGBM. In addition, some patients with sGBM may benefit from complete tumor resection depending on these patient-specific parameters. This is a finding that will ultimately need prospective validation. Copyright © 2017 Elsevier Inc. All rights reserved.

DETECTION OF VERY LOW-FREQUENCY, QUASI-PERIODIC OSCILLATIONS IN THE 2015 OUTBURST OF V404 CYGNI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huppenkothen, D.; Younes, G.; Kouveliotou, C.

2017-01-01

In 2015 June, the black hole X-ray binary (BHXRB) V404 Cygni went into outburst for the first time since 1989. Here, we present a comprehensive search for quasi-periodic oscillations (QPOs) of V404 Cygni during its recent outburst, utilizing data from six instruments on board five different X-ray missions: Swift /XRT, Fermi /GBM, Chandra /ACIS, INTEGRAL ’s IBIS/ISGRI and JEM-X, and NuSTAR . We report the detection of a QPO at 18 mHz simultaneously with both Fermi /GBM and Swift /XRT, another example of a rare but slowly growing new class of mHz-QPOs in BHXRBs linked to sources with a highmore » orbital inclination. Additionally, we find a duo of QPOs in a Chandra /ACIS observation at 73 mHz and 1.03 Hz, as well as a QPO at 136 mHz in a single Swift /XRT observation that can be interpreted as standard Type-C QPOs. Aside from the detected QPOs, there is significant structure in the broadband power, with a strong feature observable in the Chandra observations between 0.1 and 1 Hz. We discuss our results in the context of current models for QPO formation.« less

Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome.

PubMed

Favero, F; McGranahan, N; Salm, M; Birkbak, N J; Sanborn, J Z; Benz, S C; Becq, J; Peden, J F; Kingsbury, Z; Grocok, R J; Humphray, S; Bentley, D; Spencer-Dene, B; Gutteridge, A; Brada, M; Roger, S; Dietrich, P-Y; Forshew, T; Gerlinger, M; Rowan, A; Stamp, G; Eklund, A C; Szallasi, Z; Swanton, C

2015-05-01

Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Implantation of GL261 neurospheres into C57/BL6 mice: a more reliable syngeneic graft model for research on glioma-initiating cells.

PubMed

Yi, Liang; Zhou, Chun; Wang, Bing; Chen, Tunan; Xu, Minhui; Xu, Lunshan; Feng, Hua

2013-08-01

Recent studies have demonstrated that inflammatory cells and inflammatory mediators are indispensable components of the tumor-initiating cell (TIC) niche and regulate the malignant behavior of TICs. However, conventional animal models for glioma-initiating cell (GIC) studies are based on the implantation of GICs from human glioblastoma (GBM) into immunodeficient mice without the regulation of immune system. Whether animal models can mimic the cellular microenvironment of malignancy and evaluate the biological features of GICs accurately is unclear. Here, we detected the biological features of neurosphere-like tumor cells derived from the murine GBM cell line GL261 (GL261-NS) and from primary human GBM (PGBM-NS) in vitro, injected GL261-NS into syngeneic C57/BL6 mouse brain and injected PGBM-NS into NOD/SCID mouse brain, respectively. The tumorigenic characteristics of the two different orthotopic transplantation models were analyzed and the histological discrepancy between grafts and human primary GBM was compared. We found that GICs enriched in GL261-NS, GL261-NS and PGBM-NS exhibited increased GIC potential and enhanced chemoresistance in vitro. GL261-NS was significantly more aggressive compared to GL261 adhesive cells (GL261-AC) in vivo and the enhanced aggression was more significant in syngeneic mice compared to immunodeficient mice. The discrepancy of tumorigenicity between GL261-NS and GL261-AC in C57/BL6 mice was also larger compared to that between PGBM-NS and PGBM-AC in immunodeficient mice. Syngrafts derived from GL261-NS in C57/BL6 mice corresponded to the human GBM histologically better, compared with xenografts derived from PGBM-NS in NOD/SCID mice, which lack inflammatory cells and inflammatory mediators. We conclude that the inflammatory niche is involved in the tumorigenicity of GICs and implantation of GL261-NS into C57/BL6 mice is a more reliable syngeneic graft model for in vivo study on GICs relative to the immunodeficiency model.

Oncolytic vesicular stomatitis virus induces apoptosis in U87 glioblastoma cells by a type II death receptor mechanism and induces cell death and tumor clearance in vivo.

PubMed

Cary, Zachary D; Willingham, Mark C; Lyles, Douglas S

2011-06-01

Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM), an aggressive brain tumor. Matrix (M) protein mutants of VSV have shown greater selectivity for killing GBM cells versus normal brain cells than VSV with wild-type M protein. The goal of this research was to determine the contribution of death receptor and mitochondrial pathways to apoptosis induced by an M protein mutant (M51R) VSV in U87 human GBM tumor cells. Compared to controls, U87 cells expressing a dominant negative form of Fas (dnFas) or overexpressing Bcl-X(L) had reduced caspase-3 activation following infection with M51R VSV, indicating that both the death receptor pathway and mitochondrial pathways are important for M51R VSV-induced apoptosis. Death receptor signaling has been classified as type I or type II, depending on whether signaling is independent (type I) or dependent on the mitochondrial pathway (type II). Bcl-X(L) overexpression inhibited caspase activation in response to a Fas-inducing antibody, similar to the inhibition in response to M51R VSV infection, indicating that U87 cells behave as type II cells. Inhibition of apoptosis in vitro delayed, but did not prevent, virus-induced cell death. Murine xenografts of U87 cells that overexpress Bcl-X(L) regressed with a time course similar to that of control cells following treatment with M51R VSV, and tumors were not detectable at 21 days postinoculation. Immunohistochemical analysis demonstrated similar levels of viral antigen expression but reduced activation of caspase-3 following virus treatment of Bcl-X(L)-overexpressing tumors compared to controls. Further, the pathological changes in tumors following treatment with virus were quite different in the presence versus the absence of Bcl-X(L) overexpression. These results demonstrate that M51R VSV efficiently induces oncolysis in GBM tumor cells despite deregulation of apoptotic pathways, underscoring its potential use as a treatment for GBM.

Radar and Atmospheric Sounding observations around 23 TGFs

NASA Astrophysics Data System (ADS)

Chronis, T.; Briggs, M. S.; Priftis, G.

2014-12-01

This study employs 23 Terrestrial Gamma-ray Flashes (TGF) detected with NASA's Fermi Gamma-ray Burst Monitor (GBM) and collocated with the World Wide Lightning Location Network and the Earth Networks Total Lightning Network with 9 WSR-88D (NEXRAD) located in Brownsville and Corpus Christy (Texas), Lake Charles (Louisiana), Key West, Miami, Tampa and Eglin Air Force Base (Florida), San Juan (Puerto Rico) and Andersen Air Force Base (Guam). The NEXRAD Enhanced Echo Tops (EET) and Vertical Integrated Liquid Density (VILD) are traditional proxies to storm height and severity. To retrieve the storm characteristics we construct probability histograms of respective EET and VILD values around each TGF.Here we show that although high-topped storms are consistently present in the vicinity of TGFs, the VILD values indicate storms of disparate convective strengths. In particular, the majority of our TGF sample is encompassed by storms of high EET (>10-11 km) values and in their majority overall VILD < ~2.0 gr m-3.These EET and VILD values are common in summertime oceanic/coastal low-latitude thunderstorms where the main convective core is limited in the first few kilometres and the updrafts are weak and narrow. Qualitative observations from the temporal evolution of the volumetric radar reflectivity shows that in a few cases the TGF emission signals the dissipation stage of the main convective core, although this suggestion is tentative and requires more sophisticated and currently ongoing storm tracking techniques. The atmospheric soundings (where available in spatial and temporal proximity with the respective TGF) indicate that TGF producing storms can exhibit a significant variation in their respective thermodynamic environment and type (e.g. regular to high CAPE, pulse vs. high shear etc). The authors acknowledge the valuable contributions of the GBM Team, Bob Holtzworth (WWLLN) and Stan Heckman (ENTLN).

X-Ray and Optical Observations of A 0535+26

NASA Technical Reports Server (NTRS)

Camero-Arranz, A.; Finger, M. H.; Wilson-Hodge, C. A.; Jenke, P.; Steele, I.; Coe, M. J.; Gutierrez-Soto, J.; Kretschmar, P.; Caballero, I.; Yan, J.;

MARCKS Regulates Growth, Radiation Sensitivity and is a Novel Prognostic Factor for Glioma

PubMed Central

Jarboe, John S.; Anderson, Joshua C.; Duarte, Christine W.; Mehta, Tapan; Nowsheen, Somaira; Hicks, Patricia H.; Whitley, Alexander C.; Rohrbach, Timothy D.; McCubrey, Raymond O.; Chiu, Sherard; Burleson, Tamara M.; Bonner, James A.; Gillespie, G. Yancey; Yang, Eddy S.; Willey, Christopher D.

2013-01-01

Purpose This study assessed whether Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) can regulate glioblastoma (GBM) growth, radiation sensitivity and clinical outcome. Experimental Design MARCKS protein levels were analyzed in five GBM explant cell lines and eight patient-derived xenograft tumors by immunoblot, and these levels were correlated to proliferation rates and intracranial growth rates, respectively. Manipulation of MARCKS protein levels was assessed by lentiviral-mediated shRNA knockdown in the U251 cell line and MARCKS over-expression in the U87 cell line. The effect of manipulation of MARCKS on proliferation, radiation sensitivity and senescence was assessed. MARCKS gene expression was correlated with survival outcomes in the Repository of Molecular Brain Neoplasia Data (REMBRANDT) Database and The Cancer Genome Atlas (TCGA). Results MARCKS protein expression was inversely correlated with GBM proliferation and intracranial xenograft growth rates. Genetic silencing of MARCKS promoted GBM proliferation and radiation resistance, while MARCKS overexpression greatly reduced GBM growth potential and induced senescence. We found MARCKS gene expression to be directly correlated with survival in both the REMBRANDT and TCGA databases. Specifically, patients with high MARCKS expressing tumors of the Proneural molecular subtype had significantly increased survival rates. This effect was most pronounced in tumors with unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoters, a traditionally poor prognostic factor. Conclusions MARCKS levels impact GBM growth and radiation sensitivity. High MARCKS expressing GBM tumors are associated with improved survival, particularly with unmethylated MGMT promoters. These findings suggest the use of MARCKS as a novel target and biomarker for prognosis in the Proneural subtype of GBM. PMID:22619307

The Na, K-ATPase β-Subunit Isoforms Expression in Glioblastoma Multiforme: Moonlighting Roles

PubMed Central

Rotoli, Deborah; Cejas, Mariana-Mayela; Maeso, María-del-Carmen; Pérez-Rodríguez, Natalia-Dolores; Morales, Manuel; Ávila, Julio

2017-01-01

Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Recent studies point out that gliomas exploit ion channels and transporters, including Na, K-ATPase, to sustain their singular growth and invasion as they invade the brain parenchyma. Moreover, the different isoforms of the β-subunit of Na, K-ATPase have been implicated in regulating cellular dynamics, particularly during cancer progression. The aim of this study was to determine the Na, K-ATPase β subunit isoform subcellular expression patterns in all cell types responsible for microenvironment heterogeneity of GBM using immunohistochemical analysis. All three isoforms, β1, β2/AMOG (Adhesion Molecule On Glia) and β3, were found to be expressed in GBM samples. Generally, β1 isoform was not expressed by astrocytes, in both primary and secondary GBM, although other cell types (endothelial cells, pericytes, telocytes, macrophages) did express this isoform. β2/AMOG and β3 positive expression was observed in the cytoplasm, membrane and nuclear envelope of astrocytes and GFAP (Glial Fibrillary Acidic Protein) negative cells. Interestingly, differences in isoforms expression have been observed between primary and secondary GBM: in secondary GBM, β2 isoform expression in astrocytes was lower than that observed in primary GBM, while the expression of the β3 subunit was more intense. These changes in β subunit isoforms expression in GBM could be related to a different ionic handling, to a different relationship between astrocyte and neuron (β2/AMOG) and to changes in the moonlighting roles of Na, K-ATPase β subunits as adaptor proteins and transcription factors. PMID:29117147

Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells

PubMed Central

Liu, P; Brown, S; Goktug, T; Channathodiyil, P; Kannappan, V; Hugnot, J-P; Guichet, P-O; Bian, X; Armesilla, A L; Darling, J L; Wang, W

2012-01-01

Background: Glioblastoma multiforme (GBM) cells are resistant to anticancer drugs. Cancer stem cells (CSCs) are a key mediator of chemoresistance. We have reported that disulfiram (DS), an aldehyde dehydrogenase (ALDH) inhibitor, targets breast CSC-like cells. In this study, the effect of DS and combination of DS and gemcitabine (dFdC) on GBM cells and GBM stem-like cells was investigated. Methods: 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)-isobologram, western blot, luciferase reporter gene assay, electrophoretic mobility-shift assay and ALDH analysis were used in this study. Results: Disulfiram is cytotoxic in GBM cell lines in a copper (Cu)-dependent manner. Disulfiram/copper enhances the cytotoxicity of dFdC. Combination index-isobologram analysis indicates a synergistic effect between DS/Cu and dFdC. Disulfiram/copper induces reactive oxygen species (ROS), activates JNK and p38 pathways and inhibits nuclear factor-kappa B activity in GBM cell lines. Disulfiram/copper may trigger intrinsic apoptotic pathway via modulation of the Bcl2 family. Disulfiram/copper abolishes stem-like cell population in GBM cell lines. Conclusion: Our findings indicate that the cytotoxicity of DS/Cu and the enhancing effect of DS/Cu on the cytotoxicity of dFdC in GBM stem-like cells may be caused by induction of ROS and inhibition of both ALDH and the NFkB pathway. Both DS and dFdC can traverse the blood–brain barrier. Further study may lead them into GBM chemotherapy. PMID:23033007

Ficus carica latex prevents invasion through induction of let-7d expression in GBM cell lines.

PubMed

Tezcan, Gulcin; Tunca, Berrin; Bekar, Ahmet; Yalcin, Murat; Sahin, Saliha; Budak, Ferah; Cecener, Gulsah; Egeli, Unal; Demir, Cevdet; Guvenc, Gokcen; Yilmaz, Gozde; Erkan, Leman Gizem; Malyer, Hulusi; Taskapilioglu, Mevlut Ozgur; Evrensel, Turkkan; Bilir, Ayhan

2015-03-01

Glioblastoma multiforme (GBM) is one of the deadliest human malignancies. A cure for GBM remains elusive, and the overall survival time is less than 1 year. Thus, the development of more efficient therapeutic approaches for the treatment of these patients is required. Induction of tumor cell death by certain phytochemicals derived from medicinal herbs and dietary plants has become a new frontier for cancer therapy research. Although the cancer suppressive effect of Ficus carica (fig) latex (FCL) has been determined in a few cancer types, the effect of this latex on GBM tumors has not been investigated. Therefore, in the current study, the anti-proliferative activity of FCL and the effect of the FCL-temozolomide (TMZ) combination were tested in the T98G, U-138 MG, and U-87 MG GBM cell lines using the WST-1 assay. The mechanism of cell death was analyzed using Annexin-V/FITC and TUNEL assays, and the effect of FCL on invasion was tested using the chick chorioallantoic membrane assay. To determine the effect of FCL on GBM progression, the expression levels of 40 GBM associated miRNAs were analyzed in T98G cells using RT-qPCR. According to the obtained data, FCL causes cell death in GBM cells with different responses to TMZ, and this effect is synergistically increased in combination with TMZ. In addition, the current study is the first to demonstrate the effect of FCL on modulation of let-7d expression, which may be an important underlying mechanism of the anti-invasive effect of this extract.

Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma.

PubMed

Pangeni, Rajendra P; Zhang, Zhou; Alvarez, Angel A; Wan, Xuechao; Sastry, Namratha; Lu, Songjian; Shi, Taiping; Huang, Tianzhi; Lei, Charles X; James, C David; Kessler, John A; Brennan, Cameron W; Nakano, Ichiro; Lu, Xinghua; Hu, Bo; Zhang, Wei; Cheng, Shi-Yuan

2018-06-21

Glioma stem cells (GSCs), a subpopulation of tumor cells, contribute to tumor heterogeneity and therapy resistance. Gene expression profiling classified glioblastoma (GBM) and GSCs into four transcriptomically-defined subtypes. Here, we determined the DNA methylation signatures in transcriptomically pre-classified GSC and GBM bulk tumors subtypes. We hypothesized that these DNA methylation signatures correlate with gene expression and are uniquely associated either with only GSCs or only GBM bulk tumors. Additional methylation signatures may be commonly associated with both GSCs and GBM bulk tumors, i.e., common to non-stem-like and stem-like tumor cell populations and correlating with the clinical prognosis of glioma patients. We analyzed Illumina 450K methylation array and expression data from a panel of 23 patient-derived GSCs. We referenced these results with The Cancer Genome Atlas (TCGA) GBM datasets to generate methylomic and transcriptomic signatures for GSCs and GBM bulk tumors of each transcriptomically pre-defined tumor subtype. Survival analyses were carried out for these signature genes using publicly available datasets, including from TCGA. We report that DNA methylation signatures in proneural and mesenchymal tumor subtypes are either unique to GSCs, unique to GBM bulk tumors, or common to both. Further, dysregulated DNA methylation correlates with gene expression and clinical prognoses. Additionally, many previously identified transcriptionally-regulated markers are also dysregulated due to DNA methylation. The subtype-specific DNA methylation signatures described in this study could be useful for refining GBM sub-classification, improving prognostic accuracy, and making therapeutic decisions.

A novel NFIA-NFκB feed-forward loop contributes to glioblastoma cell survival

PubMed Central

Lee, JunSung; Hoxha, Edlira

2017-01-01

Abstract Background. The nuclear factor I-A (NFIA) transcription factor promotes glioma growth and inhibits apoptosis in glioblastoma (GBM) cells. Here we report that the NFIA pro-survival effect in GBM is mediated in part via a novel NFIA–nuclear factor-kappaB (NFκB) p65 feed-forward loop. Methods. We examined effects of gain- and loss-of-function manipulations of NFIA and NFκB p65 on each other’s transcription, cell growth, apoptosis and sensitivity to chemotherapy in patient-derived GBM cells and established GBM cell lines. Results. NFIA enhanced apoptosis evasion by activating NFκB p65 and its downstream anti-apoptotic factors tumor necrosis factor receptor-associated factor 1 (TRAF1) and cellular inhibitor of apoptosis proteins (cIAPs). Induction of NFκB by NFIA was required to protect cells from apoptosis, and inhibition of NFκB effectively reversed the NFIA anti-apoptotic effect. Conversely, NFIA knockdown decreased expression of NFκB and anti-apoptotic genes TRAF1 and cIAPs, and increased baseline apoptosis. NFIA positively regulated NFκB transcription and NFκB protein level. Interestingly, NFκB also activated the NFIA promoter and increased NFIA level, and knockdown of NFIA was sufficient to attenuate the NFκB pro-survival effect, suggesting a reciprocal regulation between NFIA and NFκB in governing GBM cell survival. Supporting this, NFIA and NFκB expression levels were highly correlated in human GBM and patient-derived GBM cells. Conclusions. These data define a previously unknown NFIA-NFκB feed-forward regulation that may contribute to GBM cell survival. PMID:27994064

Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma

PubMed Central

Larson, Erik W; Peterson, Halloran E; Lamoreaux, Wayne T; MacKay, Alexander R; Fairbanks, Robert K; Call, Jason A; Carlson, Jonathan D; Ling, Benjamin C; Demakas, John J; Cooke, Barton S; Lee, Christopher M

2014-01-01

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with a survival prognosis of 14-16 mo for the highest functioning patients. Despite aggressive, multimodal upfront therapies, the majority of GBMs will recur in approximately six months. Salvage therapy options for recurrent GBM (rGBM) are an area of intense research. This study compares recent survival and quality of life outcomes following Gamma Knife radiosurgery (GKRS) salvage therapy. Following a PubMed search for studies using GKRS as salvage therapy for malignant gliomas, nine articles from 2005 to July 2013 were identified which evaluated rGBM treatment. In this review, we compare Overall survival following diagnosis, Overall survival following salvage treatment, Progression-free survival, Time to recurrence, Local tumor control, and adverse radiation effects. This report discusses results for rGBM patient populations alone, not for mixed populations with other tumor histology grades. All nine studies reported median overall survival rates (from diagnosis, range: 16.7-33.2 mo; from salvage, range: 9-17.9 mo). Three studies identified median progression-free survival (range: 4.6-14.9 mo). Two showed median time to recurrence of GBM. Two discussed local tumor control. Six studies reported adverse radiation effects (range: 0%-46% of patients). The greatest survival advantages were seen in patients who received GKRS salvage along with other treatments, like resection or bevacizumab, suggesting that appropriately tailored multimodal therapy should be considered with each rGBM patient. However, there needs to be a randomized clinical trial to test GKRS for rGBM before the possibility of selection bias can be dismissed. PMID:24829861

Prognostic Relevance of Histomolecular Classification of Diffuse Adult High-Grade Gliomas with Necrosis.

PubMed

Figarella-Branger, Dominique; Mokhtari, Karima; Colin, Carole; Uro-Coste, Emmanuelle; Jouvet, Anne; Dehais, Caroline; Carpentier, Catherine; Villa, Chiara; Maurage, Claude-Alain; Eimer, Sandrine; Polivka, Marc; Vignaud, Jean-Michel; Laquerriere, Annie; Sevestre, Henri; Lechapt-Zalcman, Emmanuelle; Quintin-Roué, Isabelle; Aubriot-Lorton, Marie-Hélène; Diebold, Marie-Danièle; Viennet, Gabriel; Adam, Clovis; Loussouarn, Delphine; Michalak, Sophie; Rigau, Valérie; Heitzmann, Anne; Vandenbos, Fanny; Forest, Fabien; Chiforeanu, Danchristian; Tortel, Marie-Claire; Labrousse, François; Chenard, Marie-Pierre; Nguyen, Anh Tuan; Varlet, Pascale; Kemeny, Jean Louis; Levillain, Pierre-Marie; Cazals-Hatem, Dominique; Richard, Pomone; Delattre, Jean-Yves

2015-07-01

Diffuse adult high-grade gliomas (HGGs) with necrosis encompass anaplastic oligodendrogliomas (AOs) with necrosis (grade III), glioblastomas (GBM, grade IV) and glioblastomas with an oligodendroglial component (GBMO, grade IV). Here, we aimed to search for prognostic relevance of histological classification and molecular alterations of these tumors. About 210 patients were included (63 AO, 56 GBM and 91 GBMO). GBMO group was split into "anaplastic oligoastrocytoma (AOA) with necrosis grade IV/GBMO," restricted to tumors showing intermingled astrocytic and oligodendroglial component, and "GBM/GBMO" based on tumors presenting oligodendroglial foci and features of GBM. Genomic arrays, IDH1 R132H expression analyses and IDH direct sequencing were performed. 1p/19q co-deletion characterized AO, whereas no IDH1 R132H expression and intact 1p/19q characterized both GBM and GBM/GBMO. AOA with necrosis/GBMO mainly demonstrated IDH1 R132H expression and intact 1p/19q. Other IDH1 or IDH2 mutations were extremely rare. Both histological and molecular classifications were predictive of progression free survival (PFS) and overall survival (OS) (P < 10(-4) ). Diffuse adult HGGs with necrosis can be split into three histomolecular groups of prognostic relevance: 1p/19q co-deleted AO, IDH1 R132H-GBM and 1p/19q intact IDH1 R132H+ gliomas that might be classified as IDH1 R132H+ GBM. Because of histomolecular heterogeneity, we suggest to remove the name GBMO. © 2014 International Society of Neuropathology.

Glutathione S-transferase Mu 2-transduced mesenchymal stem cells ameliorated anti-glomerular basement membrane antibody-induced glomerulonephritis by inhibiting oxidation and inflammation

PubMed Central

2014-01-01

Introduction Oxidative stress is implicated in tissue inflammation, and plays an important role in the pathogenesis of immune-mediated nephritis. Using the anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) mouse model, we found that increased expression of glutathione S-transferase Mu 2 (GSTM2) was related to reduced renal damage caused by anti-GBM antibodies. Furthermore, mesenchymal stem cell (MSC)-based therapy has shed light on the treatment of immune-mediated kidney diseases. The aim of this study was to investigate if MSCs could be utilized as vehicles to deliver the GSTM2 gene product into the kidney and to evaluate its potential therapeutic effect on anti-GBM-GN. Methods The human GSTM2 gene (hGSTM2) was transduced into mouse bone marrow-derived MSCs via a lentivirus vector to create a stable cell line (hGSTM2-MSC). The cultured hGSTM2-MSCs were treated with 0.5mM H2O2, and apoptotic cells were measured by terminal dUTP nick-end labeling (TUNEL) assay. The 129/svj mice, which were challenged with anti-GBM antibodies, were injected with 106 hGSTM2-MSCs via the tail vein. Expression of hGSTM2 and inflammatory cytokines in the kidney was assayed by quantitative PCR and western blotting. Renal function of mice was evaluated by monitoring proteinuria and levels of blood urea nitrogen (BUN), and renal pathological changes were analyzed by histochemistry. Immunohistochemical analysis was performed to measure inflammatory cell infiltration and renal cell apoptosis. Results MSCs transduced with hGSTM2 exhibited similar growth and differentiation properties to MSCs. hGSTM2-MSCs persistently expressed hGSTM2 and resisted H2O2-induced apoptosis. Upon injection into 129/svj mice, hGSTM2-MSCs migrated to the kidney and expressed hGSTM2. The anti-GBM-GN mice treated with hGSTM2-MSCs exhibited reduced proteinuria and BUN (58% and 59% reduction, respectively) and ameliorated renal pathological damage, compared with control mice. Mice injected with hGSTM2-MSCs showed alleviated renal inflammatory cell infiltration and reduced expression of chemokine (C-C motif) ligand 2 (CCL2), interleukin (IL)-1β and IL-6 (53%, 46% and 52% reduction, respectively), compared with controls. Moreover, hGSTM2-MSCs increased expression of renal superoxide dismutase and catalase, which may associate with detoxifying reactive oxygen species to prevent oxidative renal damage. Conclusions Our data suggest that the enhanced protective effect of GSTM2-transduced MSCs against anti-GBM-GN might be associated with inhibition of oxidative stress-induced renal cell apoptosis and inflammation, through over-expression of hGSTM2 in mouse kidneys. PMID:24480247

Glutathione S-transferase Mu 2-transduced mesenchymal stem cells ameliorated anti-glomerular basement membrane antibody-induced glomerulonephritis by inhibiting oxidation and inflammation.

PubMed

Li, Yajuan; Yan, Mei; Yang, Jichen; Raman, Indu; Du, Yong; Min, Soyoun; Fang, Xiangdong; Mohan, Chandra; Li, Quan-Zhen

2014-01-30

Oxidative stress is implicated in tissue inflammation, and plays an important role in the pathogenesis of immune-mediated nephritis. Using the anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) mouse model, we found that increased expression of glutathione S-transferase Mu 2 (GSTM2) was related to reduced renal damage caused by anti-GBM antibodies. Furthermore, mesenchymal stem cell (MSC)-based therapy has shed light on the treatment of immune-mediated kidney diseases. The aim of this study was to investigate if MSCs could be utilized as vehicles to deliver the GSTM2 gene product into the kidney and to evaluate its potential therapeutic effect on anti-GBM-GN. The human GSTM2 gene (hGSTM2) was transduced into mouse bone marrow-derived MSCs via a lentivirus vector to create a stable cell line (hGSTM2-MSC). The cultured hGSTM2-MSCs were treated with 0.5 mM H2O2, and apoptotic cells were measured by terminal dUTP nick-end labeling (TUNEL) assay. The 129/svj mice, which were challenged with anti-GBM antibodies, were injected with 10⁶ hGSTM2-MSCs via the tail vein. Expression of hGSTM2 and inflammatory cytokines in the kidney was assayed by quantitative PCR and western blotting. Renal function of mice was evaluated by monitoring proteinuria and levels of blood urea nitrogen (BUN), and renal pathological changes were analyzed by histochemistry. Immunohistochemical analysis was performed to measure inflammatory cell infiltration and renal cell apoptosis. MSCs transduced with hGSTM2 exhibited similar growth and differentiation properties to MSCs. hGSTM2-MSCs persistently expressed hGSTM2 and resisted H2O2-induced apoptosis. Upon injection into 129/svj mice, hGSTM2-MSCs migrated to the kidney and expressed hGSTM2. The anti-GBM-GN mice treated with hGSTM2-MSCs exhibited reduced proteinuria and BUN (58% and 59% reduction, respectively) and ameliorated renal pathological damage, compared with control mice. Mice injected with hGSTM2-MSCs showed alleviated renal inflammatory cell infiltration and reduced expression of chemokine (C-C motif) ligand 2 (CCL2), interleukin (IL)-1β and IL-6 (53%, 46% and 52% reduction, respectively), compared with controls. Moreover, hGSTM2-MSCs increased expression of renal superoxide dismutase and catalase, which may associate with detoxifying reactive oxygen species to prevent oxidative renal damage. Our data suggest that the enhanced protective effect of GSTM2-transduced MSCs against anti-GBM-GN might be associated with inhibition of oxidative stress-induced renal cell apoptosis and inflammation, through over-expression of hGSTM2 in mouse kidneys.

Brain tumor detection and segmentation in a CRF (conditional random fields) framework with pixel-pairwise affinity and superpixel-level features.

PubMed

Wu, Wei; Chen, Albert Y C; Zhao, Liang; Corso, Jason J

2014-03-01

Detection and segmentation of a brain tumor such as glioblastoma multiforme (GBM) in magnetic resonance (MR) images are often challenging due to its intrinsically heterogeneous signal characteristics. A robust segmentation method for brain tumor MRI scans was developed and tested. Simple thresholds and statistical methods are unable to adequately segment the various elements of the GBM, such as local contrast enhancement, necrosis, and edema. Most voxel-based methods cannot achieve satisfactory results in larger data sets, and the methods based on generative or discriminative models have intrinsic limitations during application, such as small sample set learning and transfer. A new method was developed to overcome these challenges. Multimodal MR images are segmented into superpixels using algorithms to alleviate the sampling issue and to improve the sample representativeness. Next, features were extracted from the superpixels using multi-level Gabor wavelet filters. Based on the features, a support vector machine (SVM) model and an affinity metric model for tumors were trained to overcome the limitations of previous generative models. Based on the output of the SVM and spatial affinity models, conditional random fields theory was applied to segment the tumor in a maximum a posteriori fashion given the smoothness prior defined by our affinity model. Finally, labeling noise was removed using "structural knowledge" such as the symmetrical and continuous characteristics of the tumor in spatial domain. The system was evaluated with 20 GBM cases and the BraTS challenge data set. Dice coefficients were computed, and the results were highly consistent with those reported by Zikic et al. (MICCAI 2012, Lecture notes in computer science. vol 7512, pp 369-376, 2012). A brain tumor segmentation method using model-aware affinity demonstrates comparable performance with other state-of-the art algorithms.

Adiponectin as novel regulator of cell proliferation in human glioblastoma.

PubMed

Porcile, Carola; Di Zazzo, Erika; Monaco, Maria Ludovica; D'Angelo, Giorgia; Passarella, Daniela; Russo, Claudio; Di Costanzo, Alfonso; Pattarozzi, Alessandra; Gatti, Monica; Bajetto, Adriana; Zona, Gianluigi; Barbieri, Federica; Oriani, Giovannangelo; Moncharmont, Bruno; Florio, Tullio; Daniele, Aurora

2014-10-01

Adiponectin (Acrp30) is an adipocyte-secreted hormone with pleiotropic metabolic effects, whose reduced levels were related to development and progression of several malignancies. We looked at the presence of Acrp30 receptors in human glioblastomas (GBM), hypothesizing a role for Acrp30 also in this untreatable cancer. Here we demonstrate that human GBM express Acrp30 receptors (AdipoR1 and AdipoR2), which are often co-expressed in GBM samples (70% of the analyzed tumors). To investigate the effects of Acrp30 on GBM growth, we used human GBM cell lines U87-MG and U251, expressing both AdipoR1 and AdipoR2 receptors. In these cells, Acrp30 treatment inhibits DNA synthesis and cell proliferation rate, inducing arrest in G1 phase of the cell cycle. These effects were correlated to a sustained activation of ERK1/2 and Akt kinases, upon Acrp30 treatment. Our results suggest that Acrp30 may represent a novel endogenous negative regulator of GBM cell proliferation, to be evaluated for the possible development of novel pharmacological approaches. © 2014 Wiley Periodicals, Inc.

The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model.

PubMed

Garcia, Celina; Dubois, Luiz Gustavo; Xavier, Anna Lenice; Geraldo, Luiz Henrique; da Fonseca, Anna Carolina Carvalho; Correia, Ana Helena; Meirelles, Fernanda; Ventura, Grasiella; Romão, Luciana; Canedo, Nathalie Henriques Silva; de Souza, Jorge Marcondes; de Menezes, João Ricardo Lacerda; Moura-Neto, Vivaldo; Tovar-Moll, Fernanda; Lima, Flavia Regina Souza

2014-12-08

Glioblastoma (GBM) is the most common primary brain tumor and the most aggressive glial tumor. This tumor is highly heterogeneous, angiogenic, and insensitive to radio- and chemotherapy. Here we have investigated the progression of GBM produced by the injection of human GBM cells into the brain parenchyma of immunocompetent mice. Xenotransplanted animals were submitted to magnetic resonance imaging (MRI) and histopathological analyses. Our data show that two weeks after injection, the produced tumor presents histopathological characteristics recommended by World Health Organization for the diagnosis of GBM in humans. The tumor was able to produce reactive gliosis in the adjacent parenchyma, angiogenesis, an intense recruitment of macrophage and microglial cells, and presence of necrosis regions. Besides, MRI showed that tumor mass had enhanced contrast, suggesting a blood-brain barrier disruption. This study demonstrated that the xenografted tumor in mouse brain parenchyma develops in a very similar manner to those found in patients affected by GBM and can be used to better understand the biology of GBM as well as testing potential therapies.

Altered Expression of Polycomb Group Genes in Glioblastoma Multiforme

PubMed Central

Li, Gang; Warden, Charles; Zou, Zhaoxia; Neman, Josh; Krueger, Joseph S.; Jain, Alisha; Jandial, Rahul; Chen, Mike

2013-01-01

The Polycomb group (PcG) proteins play a critical role in histone mediated epigenetics which has been implicated in the malignant evolution of glioblastoma multiforme (GBM). By systematically interrogating The Cancer Genome Atlas (TCGA), we discovered widespread aberrant expression of the PcG members in GBM samples compared to normal brain. The most striking differences were upregulation of EZH2, PHF19, CBX8 and PHC2 and downregulation of CBX7, CBX6, EZH1 and RYBP. Interestingly, changes in EZH2, PHF19, CBX7, CBX6 and EZH1 occurred progressively as astrocytoma grade increased. We validated the aberrant expression of CBX6, CBX7, CBX8 and EZH2 in GBM cell lines by Western blotting and qRT-PCR, and further the aberrant expression of CBX6 in GBM tissue samples by immunohistochemical staining. To determine if there was functional significance to the diminished CBX6 levels in GBM, CBX6 was overexpressed in GBM cells resulting in decreased proliferative capacity. In conclusion, aberrant expression of PcG proteins in GBMs may play a role in the development or maintenance of the malignancy. PMID:24260522

Altered expression of polycomb group genes in glioblastoma multiforme.

PubMed

Li, Gang; Warden, Charles; Zou, Zhaoxia; Neman, Josh; Krueger, Joseph S; Jain, Alisha; Jandial, Rahul; Chen, Mike

2013-01-01

The Polycomb group (PcG) proteins play a critical role in histone mediated epigenetics which has been implicated in the malignant evolution of glioblastoma multiforme (GBM). By systematically interrogating The Cancer Genome Atlas (TCGA), we discovered widespread aberrant expression of the PcG members in GBM samples compared to normal brain. The most striking differences were upregulation of EZH2, PHF19, CBX8 and PHC2 and downregulation of CBX7, CBX6, EZH1 and RYBP. Interestingly, changes in EZH2, PHF19, CBX7, CBX6 and EZH1 occurred progressively as astrocytoma grade increased. We validated the aberrant expression of CBX6, CBX7, CBX8 and EZH2 in GBM cell lines by Western blotting and qRT-PCR, and further the aberrant expression of CBX6 in GBM tissue samples by immunohistochemical staining. To determine if there was functional significance to the diminished CBX6 levels in GBM, CBX6 was overexpressed in GBM cells resulting in decreased proliferative capacity. In conclusion, aberrant expression of PcG proteins in GBMs may play a role in the development or maintenance of the malignancy.

The Combined Influence of Hydrogel Stiffness and Matrix-Bound Hyaluronic Acid Content on Glioblastoma Invasion.

PubMed

Chen, Jee-Wei Emily; Pedron, Sara; Harley, Brendan A C

2017-08-01

Glioblastoma (GBM) is the most common and lethal form of brain cancer. Its high mortality is associated with its aggressive invasion throughout the brain. The heterogeneity of stiffness and hyaluronic acid (HA) content within the brain makes it difficult to study invasion in vivo. A dextran-bead assay is employed to quantify GBM invasion within HA-functionalized gelatin hydrogels. Using a library of stiffness-matched hydrogels with variable levels of matrix-bound HA, it is reported that U251 GBM invasion is enhanced in softer hydrogels but reduced in the presence of matrix-bound HA. Inhibiting HA-CD44 interactions reduces invasion, even in hydrogels lacking matrix-bound HA. Analysis of HA biosynthesis suggests that GBM cells compensate for a lack of matrix-bound HA by producing soluble HA to stimulate invasion. Together, a robust method is showed to quantify GBM invasion over long culture times to reveal the coordinated effect of matrix stiffness, immobilized HA, and compensatory HA production on GBM invasion. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel delivery methods bypassing the blood-brain and blood-tumor barriers.

PubMed

Hendricks, Benjamin K; Cohen-Gadol, Aaron A; Miller, James C

2015-03-01

Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood-cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeutic interventions. Although ongoing research has yielded some potential options for future GBM therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications.

HSP27 knockdown produces synergistic induction of apoptosis by HSP90 and kinase inhibitors in glioblastoma multiforme.

PubMed

Belkacemi, Louiza; Hebb, Matthew O

2014-09-01

The heat-shock proteins HSP27 and HSP90 perpetuate the malignant nature of glioblastoma multiforme (GBM) and offer promise as targets for novel cancer therapeutics. The present study sought to define synergistic antitumor benefits of concurrent HSP27-knockdown and the HSP90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) or, comparatively, the non-selective kinase inhibitor, staurosporine, in GBM cells. Dose-response relations were determined for 17-AAG and staurosporine in three GBM cell lines. HSP27-targeted siRNA was administered alone or in combination with subtherapeutic concentrations of each drug and cells were evaluated for viability, proliferation and apoptosis. Adjuvant HSP27 knockdown with 17-AAG or staurosporine produced marked and synergistic decrease in GBM cell viability and proliferation, with robust elevation of apoptotic fractions and caspase-3 activation. HSP27 knockdown confers potent chemosensitization of GBM cells. These novel data support the development of HSP-targeting strategies and, specifically, anti-HSP27 agents for the treatment of GBM. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Swelling-induced chloride current in glioblastoma proliferation, migration, and invasion.

PubMed

Wong, Raymond; Chen, Wenliang; Zhong, Xiao; Rutka, James T; Feng, Zhong-Ping; Sun, Hong-Shuo

2018-01-01

Glioblastoma (GBM) remains as the most common and aggressive brain tumor. The survival of GBM has been linked to the aberrant activation of swelling-induced chloride current I Cl,swell . In this study, we investigated the effects of I Cl,swell on cell viability, proliferation, and migration in the human GBM cell lines, U251 and U87, using a combination of patch clamp electrophysiology, MTT, colony formation, wound healing assays and Western immunoblotting. First, we showed that the specific inhibitor of I Cl,swell , DCPIB, potently reduced the I Cl,swell in U87 cells. Next, in both U87 and U251 cells, we found that DCPIB reduced GBM viability, proliferation, colony formation, migration, and invasion. In addition, our Western immunoblot assay showed that DCPIB-treated U251 cells had a reduction in JAK2, STAT3, and Akt phosphorylation, thus, suggesting that DCPIB potentially suppresses GBM functions through inhibition of the JAK2/STAT3 and PI3K/Akt signaling pathways. Therefore, the I Cl,swell may be a potential drug target for GBM. © 2017 Wiley Periodicals, Inc.

Single Cell Mathematical Model Successfully Replicates Key Features of GBM: Go-Or-Grow Is Not Necessary.

PubMed

Scribner, Elizabeth; Fathallah-Shaykh, Hassan M

2017-01-01

Glioblastoma (GBM) is a malignant brain tumor that continues to be associated with neurological morbidity and poor survival times. Brain invasion is a fundamental property of malignant glioma cells. The Go-or-Grow (GoG) phenotype proposes that cancer cell motility and proliferation are mutually exclusive. Here, we construct and apply a single glioma cell mathematical model that includes motility and angiogenesis and lacks the GoG phenotype. Simulations replicate key features of GBM including its multilayer structure (i.e.edema, enhancement, and necrosis), its progression patterns associated with bevacizumab treatment, and replicate the survival times of GBM treated or untreated with bevacizumab. These results suggest that the GoG phenotype is not a necessary property for the formation of the multilayer structure, recurrence patterns, and the poor survival times of patients diagnosed with GBM.

Clonal Evolution of Glioblastoma under Therapy

PubMed Central

Wang, Jiguang; Cazzato, Emanuela; Ladewig, Erik; Frattini, Veronique; Rosenbloom, Daniel I. S.; Zairis, Sakellarios; Abate, Francesco; Liu, Zhaoqi; Elliott, Oliver; Shin, Yong-Jae; Lee, Jin-Ku; Lee, In-Hee; Park, Woong-Yang; Eoli, Marica; Blumberg, Andrew J.; Lasorella, Anna; Nam, Do-Hyun; Finocchiaro, Gaetano; Iavarone, Antonio; Rabadan, Raul

2017-01-01

Glioblastoma (GBM) constitutes the most common and aggressive primary brain tumor. To better understand how GBM evolves we analyzed longitudinal genomic and transcriptomic data of 114 patients. The analysis reveals a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern together with estimates of evolutionary rates suggest that the relapse associated clone typically preexisted years before diagnosis. 15% of tumors present hypermutations at relapse in highly expressed genes with a clear mutational signature. We find that 11% of recurrent tumors harbor mutations in LTBP4, a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to TGF-β activity suppression and decreased proliferation. In IDH1-wild-type recurrent GBM, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM. PMID:27270107

Evolutionary Consequences of DNA Methylation in a Basal Metazoan

PubMed Central

Dixon, Groves B.; Bay, Line K.; Matz, Mikhail V.

2016-01-01

Gene body methylation (gbM) is an ancestral and widespread feature in Eukarya, yet its adaptive value and evolutionary implications remain unresolved. The occurrence of gbM within protein-coding sequences is particularly puzzling, because methylation causes cytosine hypermutability and hence is likely to produce deleterious amino acid substitutions. We investigate this enigma using an evolutionarily basal group of Metazoa, the stony corals (order Scleractinia, class Anthozoa, phylum Cnidaria). We show that patterns of coral gbM are similar to other invertebrate species, predicting wide and active transcription and slower sequence evolution. We also find a strong correlation between gbM and codon bias, resulting from systematic replacement of CpG bearing codons. We conclude that gbM has strong effects on codon evolution and speculate that this may influence establishment of optimal codons. PMID:27189563

Loss of MYC and E-box3 binding contributes to defective MYC-mediated transcriptional suppression of human MC-let-7a-1~let-7d in glioblastoma

PubMed Central

Wang, Zifeng; Lin, Sheng; Zhang, Ji; Xu, Zhenhua; Xiang, Yu; Yao, Hong; Ge, Lei; Xie, Dan; Kung, Hsiang-fu; Lu, Gang; Poon, Wai Sang; Liu, Quentin; Lin, Marie Chia-mi

2016-01-01

Previously, we reported that MYC oncoprotein down-regulates the transcription of human MC-let-7a-1~let-7d microRNA cluster in hepatocarcinoma (HCC). Surprisingly, in silico analysis indicated that let-7 miRNA expression levels are not reduced in glioblastoma (GBM). Here we investigated the molecular basis of this differential expression. Using human GBM U87 and U251 cells, we first demonstrated that forced over-expression of MYC indeed could not down-regulate the expression of human MC-let-7a-1~let-7d microRNA cluster in GBM. Furthermore, analysis of MC-let-7a-1~let-7d promoter in GBM indicated that MYC failed to inhibit the promoter activity. Pearson's correlation and Linear Regression analysis using the expression data from GSE55092 (HCC) and GSE4290 (GBM) demonstrated a converse relationship of MC-let-7a-1~let-7d and MYC only in HCC but not in GBM. To understand the underlying mechanisms, we examined whether MYC could bind to the non-canonical E-box 3 located in the promoter of MC-let-7a-1~let-7d. Results from both chromatin immune-precipitation (ChIP) and super-shift assays clearly demonstrated the loss of MYC and E-box 3 binding in GBM, suggesting for the first time that a defective MYC and E-box3 binding in GBM is responsible for the differential MYC mediated transcriptional inhibition of MC-let-7a-1~let-7d and potentially other tumor suppressors. MYC and let-7 are key oncoprotein and tumor suppressor, respectively. Understanding the molecular mechanisms of their regulations will provide new insight and have important implications in the therapeutics of GBM as well as other cancers. PMID:27409345

Impact of mesenchymal stem cells' secretome on glioblastoma pathophysiology.

PubMed

Vieira de Castro, Joana; Gomes, Eduardo D; Granja, Sara; Anjo, Sandra I; Baltazar, Fátima; Manadas, Bruno; Salgado, António J; Costa, Bruno M

2017-10-02

Glioblastoma (GBM) is a highly aggressive primary brain cancer, for which curative therapies are not available. An emerging therapeutic approach suggested to have potential to target malignant gliomas has been based on the use of multipotent mesenchymal stem cells (MSCs), either unmodified or engineered to deliver anticancer therapeutic agents, as these cells present an intrinsic capacity to migrate towards malignant tumors. Nevertheless, it is still controversial whether this innate tropism of MSCs towards the tumor area is associated with cancer promotion or suppression. Considering that one of the major mechanisms by which MSCs interact with and modulate tumor cells is via secreted factors, we studied how the secretome of MSCs modulates critical hallmark features of GBM cells. The effect of conditioned media (CM) from human umbilical cord perivascular cells (HUCPVCs, a MSC population present in the Wharton's jelly of the umbilical cord) on GBM cell viability, migration, proliferation and sensitivity to temozolomide treatment of U251 and SNB-19 GBM cells was evaluated. The in vivo chicken chorioallantoic membrane (CAM) assay was used to evaluate the effect of HUCPVCs CM on tumor growth and angiogenesis. The secretome of HUCPVCs was characterized by proteomic analyses. We found that both tested GBM cell lines exposed to HUCPVCs CM presented significantly higher cellular viability, proliferation and migration. In contrast, resistance of GBM cells to temozolomide chemotherapy was not significantly affected by HUCPVCs CM. In the in vivo CAM assay, CM from HUCPVCs promoted U251 and SNB-19 tumor cells growth. Proteomic analysis to characterize the secretome of HUCPVCs identified several proteins involved in promotion of cell survival, proliferation and migration, revealing novel putative molecular mediators for the effects observed in GBM cells exposed to HUCPVCs CM. These findings provide novel insights to better understand the interplay between GBM cells and MSCs, raising awareness to potential safety issues regarding the use of MSCs as stem-cell based therapies for GBM.

Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation

PubMed Central

Akimoto, Keiko; Kimura, Kenichi; Nagano, Masumi; Takano, Shingo; To'a Salazar, Georgina; Yamashita, Toshiharu

2013-01-01

Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties. However, the effect of different MSC properties on their application in anticancer therapies has not been thoroughly investigated. In this study, to characterize the anticancer therapeutic application of MSCs from different sources, we established two different kinds of human MSCs: umbilical cord blood-derived MSCs (UCB-MSCs) and adipose-tissue-derived MSCs (AT-MSCs). We used these MSCs in a coculture assay with primary glioblastoma multiforme (GBM) cells to analyze how MSCs from different sources can inhibit GBM growth. We found that UCB-MSCs inhibited GBM growth and caused apoptosis, but AT-MSCs promoted GBM growth. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling assay clearly demonstrated that UCB-MSCs promoted apoptosis of GBM via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL was expressed more highly by UCB-MSCs than by AT-MSCs. Higher mRNA expression levels of angiogenic factors (vascular endothelial growth factor, angiopoietin 1, platelet-derived growth factor, and insulin-like growth factor) and stromal-derived factor-1 (SDF-1/CXCL12) were observed in AT-MSCs, and highly vascularized tumors were developed when AT-MSCs and GBM were cotransplanted. Importantly, CXCL12 inhibited TRAIL activation of the apoptotic pathway in GBM, suggesting that AT-MSCs may support GBM development in vivo by at least two distinct mechanisms—promoting angiogenesis and inhibiting apoptosis. The opposite effects of AT-MSCs and UCB-MSCs on GBM clearly demonstrate that differences must be considered when choosing a stem cell source for safety in clinical application. PMID:23231075

Upregulation of miR-181a suppresses the formation of glioblastoma stem cells by targeting the Notch2 oncogene and correlates with good prognosis in patients with glioblastoma multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Shi-Xiong; Zhao, Zhong-Yan; Weng, Guo-Hu

Glioblastoma stem-like cells (GSCs) are responsible for the initiation and progression of glioblastoma multiforme (GBM), and microRNAs (miRNAs) play an important role in this disease. However, the mechanisms underlying the role of miRNAs in the stemness of GSCs have not been completely elucidated. We previously showed that miR-181a is downregulated in GBM and may predict prognosis in patients with this disease. Here, we demonstrate that the upregulation of miR-181a suppressed GSC formation and inhibited GBM tumorigenesis by targeting the Notch2 oncogene. We found that miR-181a was downregulated in GSCs derived from human glioblastoma U87MG and U373MG cells. The high expressionmore » of miR-181a inhibited the levels of stemness-related markers CD133 and BMI1, attenuated sphere proliferation, promoted cell apoptosis, and reduced the tumorigenicity of GSCs. MiR-181a decreased the expression of Notch2 by targeting the 3’-untranslated region of its mRNA. Notch2 overexpression inhibited the effects of miR-181a downregulation on GSCs, and was negatively correlated with miR-181a expression. Moreover, high Notch2 expression together with low miR-181a expression was correlated with a shorter median overall survival for GBM patients. Together, these data show that miR-181a may play an essential role in GSC formation and GBM progression by targeting Notch2, suggesting that Notch2 and miR-181a have potential prognostic value as tumor biomarkers in GBM patients. - Highlights: • MiR-181a suppressed GSC formation and GBM tumorigenesis by targeting Notch2. • Notch2 and miR-181a expression were correlated with OS for GBM patients. • Notch2 and miR-181a have potential prognostic value in GBM patients.« less

Integrating the glioblastoma microenvironment into engineered experimental models

PubMed Central

Xiao, Weikun; Sohrabi, Alireza; Seidlits, Stephanie K

2017-01-01

Glioblastoma (GBM) is the most lethal cancer originating in the brain. Its high mortality rate has been attributed to therapeutic resistance and rapid, diffuse invasion – both of which are strongly influenced by the unique microenvironment. Thus, there is a need to develop new models that mimic individual microenvironmental features and are able to provide clinically relevant data. Current understanding of the effects of the microenvironment on GBM progression, established experimental models of GBM and recent developments using bioengineered microenvironments as ex vivo experimental platforms that mimic the biochemical and physical properties of GBM tumors are discussed. PMID:28883992

Multifuntional Nanotherapeutics for the Combinatorial Drug and Gene Therapy in the Treatment of Glioblastoma Multiforme

NASA Astrophysics Data System (ADS)

Hourigan, Breanne

Glioblastoma multiforme (GBM), a grade IV glioma, is the most common primary brain tumor, affecting about 3 out of 100,000 persons per year in the United States. GBM accounts for about 80% of primary malignant brain tumors, and is also the most aggressive of malignant brain tumors. With exhaustive treatment, survival only averages between 12 and 15 months, with a 2-year survival rate less than 25%. New therapeutic strategies are necessary to improve the outcomes of this disease. Chemotherapy with temozolomide (TMZ), a DNA alkylating agent, is used as a first-line of treatment for GBM. However, GBM tumors develop resistance to TMZ over time due to increased expression of O6-methylguanine-DNA methyltransferase (MGMT), a gene responsible for DNA repair. We previously developed cationic, amphiphilic copolymer poly(lactide-co-glycolide)-g-polyethylenimine (PgP) and demonstrated its utility for nucleic acid delivery. Here, we examine the ability of PgP polyplexes to overcome TMZ resistance and improve therapeutic efficacy through combination drug and gene therapy for GBM treatment. In this study, we evaluated the ability of PgP to deliver siRNA targeting to MGMT (siMGMT), a gene responsible for drug resistance in GBM. Our results demonstrated that PgP effectively forms stable complex with siRNA and protects siRNAs from heparin competition assay, serum- and ribonuclease-mediated degradation, confirming the potential of the polyplex for in vivo delivery. Results from MTT assays showed that PgP/siRNA polyplexes exhibited minimal cytotoxicity compared to untreated cells when incubated with T98G human GBM cells. We also demonstrated that PgP/siMGMT polyplexes mediate knockdown of MGMT protein as well as a significant ˜56% and ˜68% knockdown of MGMT mRNA in T98G GBM cells compared to cells treated with PgP complexed with non-targeting siRNA (siNT) at a 60:1 and 80:1 nitrogen:phosphate (N:P) ratio, respectively. Further, co-incubation of PgP/siMGMT polyplexes with TMZ enhanced therapeutic efficacy in T98G GBM cells compared to treatment with the polyplex or TMZ alone. After generation of athymic mouse GBM model, PgP/siMGMT polyplexes were locally injected into the tumor. Relative to untreated injury only, PgP/siMGMT polyplexes significantly reduced MGMT mRNA and protein expression at 3 days post-injection. These studies demonstrate that PgP is an efficient non-viral delivery carrier for therapeutic siMGMT to the tumor cells and may be a promising platform for the combinatorial siRNA/drug therapy for GBM treatment. In the future, we will study the therapeutic efficacy of combination of PgP/siMGMT and TMZ in athymic mouse GBM model.

CREKA peptide-conjugated dendrimer nanoparticles for glioblastoma multiforme delivery.

PubMed

Zhao, Jingjing; Zhang, Bo; Shen, Shun; Chen, Jun; Zhang, Qizhi; Jiang, Xinguo; Pang, Zhiqing

2015-07-15

Glioblastoma multiforme (GBM) is the most aggressive central nervous system (CNS) tumor because of its fast development, poor prognosis, difficult control and terrible mortality. Poor penetration and retention in the glioblastoma parenchyma were crucial challenges in GBM nanomedicine therapy. Nanoparticle diameter can significantly influence the delivery efficiency in tumor tissue. Decreasing nanoparticle size can improve the nanoparticle penetration in tumor tissue but decrease the nanoparticle retention effect. Therefore, small nanoparticles with high retention effect in tumor are urgently needed for effective GBM drug delivery. In present study, a small nanoparticle drug delivery system was developed by conjugating fibrin-binding peptide CREKA to Polyamidoamine (PAMAM) dendrimer, where PEGylated PAMAM is used as drug carrier due to its small size and good penetration in tumor and CREKA is used to target the abundant fibrin in GBM for enhanced retention in tumor. In vitro binding ability tests demonstrated that CREKA can significantly enhanced nanoparticle binding with fibrin. In vivo fluorescence imaging of GBM bearing nude mice, ex vivo brain imaging and frozen slices fluorescence imaging further revealed that the CREKA-modified PAMAM achieved higher accumulation and deeper penetration in GBM tissue than unmodified one. These results indicated that the CREKA-modified PAMAM could penetrate the GBM tissue deeply and enhance the retention effect, which was a promising strategy for brain tumor therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Glioblastoma cells labeled by robust Raman tags for enhancing imaging contrast.

PubMed

Huang, Li-Ching; Chang, Yung-Ching; Wu, Yi-Syuan; Sun, Wei-Lun; Liu, Chan-Chuan; Sze, Chun-I; Chen, Shiuan-Yeh

2018-05-01

Complete removal of a glioblastoma multiforme (GBM), a highly malignant brain tumor, is challenging due to its infiltrative characteristics. Therefore, utilizing imaging agents such as fluorophores to increase the contrast between GBM and normal cells can help neurosurgeons to locate residual cancer cells during image guided surgery. In this work, Raman tag based labeling and imaging for GBM cells in vitro is described and evaluated. The cell membrane of a GBM adsorbs a substantial amount of functionalized Raman tags through overexpression of the epidermal growth factor receptor (EGFR) and "broadcasts" stronger pre-defined Raman signals than normal cells. The average ratio between Raman signals from a GBM cell and autofluorescence from a normal cell can be up to 15. In addition, the intensity of these images is stable under laser illuminations without suffering from the severe photo-bleaching that usually occurs in fluorescent imaging. Our results show that labeling and imaging GBM cells via robust Raman tags is a viable alternative method to distinguish them from normal cells. This Raman tag based method can be used solely or integrated into an existing fluorescence system to improve the identification of infiltrative glial tumor cells around the boundary, which will further reduce GBM recurrence. In addition, it can also be applied/extended to other types of cancer to improve the effectiveness of image guided surgery.

Glioblastoma cells labeled by robust Raman tags for enhancing imaging contrast

PubMed Central

Huang, Li-Ching; Chang, Yung-Ching; Wu, Yi-Syuan; Sun, Wei-Lun; Liu, Chan-Chuan; Sze, Chun-I; Chen, Shiuan-Yeh

2018-01-01

Complete removal of a glioblastoma multiforme (GBM), a highly malignant brain tumor, is challenging due to its infiltrative characteristics. Therefore, utilizing imaging agents such as fluorophores to increase the contrast between GBM and normal cells can help neurosurgeons to locate residual cancer cells during image guided surgery. In this work, Raman tag based labeling and imaging for GBM cells in vitro is described and evaluated. The cell membrane of a GBM adsorbs a substantial amount of functionalized Raman tags through overexpression of the epidermal growth factor receptor (EGFR) and “broadcasts” stronger pre-defined Raman signals than normal cells. The average ratio between Raman signals from a GBM cell and autofluorescence from a normal cell can be up to 15. In addition, the intensity of these images is stable under laser illuminations without suffering from the severe photo-bleaching that usually occurs in fluorescent imaging. Our results show that labeling and imaging GBM cells via robust Raman tags is a viable alternative method to distinguish them from normal cells. This Raman tag based method can be used solely or integrated into an existing fluorescence system to improve the identification of infiltrative glial tumor cells around the boundary, which will further reduce GBM recurrence. In addition, it can also be applied/extended to other types of cancer to improve the effectiveness of image guided surgery. PMID:29760976

Validation of an imageable surgical resection animal model of Glioblastoma (GBM).

PubMed

Sweeney, Kieron J; Jarzabek, Monika A; Dicker, Patrick; O'Brien, Donncha F; Callanan, John J; Byrne, Annette T; Prehn, Jochen H M

2014-08-15

Glioblastoma (GBM) is the most common and malignant primary brain tumour having a median survival of just 12-18 months following standard therapy protocols. Local recurrence, post-resection and adjuvant therapy occurs in most cases. U87MG-luc2-bearing GBM xenografts underwent 4.5mm craniectomy and tumour resection using microsurgical techniques. The cranial defect was repaired using a novel modified cranial window technique consisting of a circular microscope coverslip held in place with glue. Immediate post-operative bioluminescence imaging (BLI) revealed a gross total resection rate of 75%. At censor point 4 weeks post-resection, Kaplan-Meier survival analysis revealed 100% survival in the surgical group compared to 0% in the non-surgical cohort (p=0.01). No neurological defects or infections in the surgical group were observed. GBM recurrence was reliably imaged using facile non-invasive optical bioluminescence (BLI) imaging with recurrence observed at week 4. For the first time, we have used a novel cranial defect repair method to extend and improve intracranial surgical resection methods for application in translational GBM rodent disease models. Combining BLI and the cranial window technique described herein facilitates non-invasive serial imaging follow-up. Within the current context we have developed a robust methodology for establishing a clinically relevant imageable GBM surgical resection model that appropriately mimics GBM recurrence post resection in patients. Copyright © 2014 Elsevier B.V. All rights reserved.

Role for Macrophage Metalloelastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome

PubMed Central

Rao, Velidi H.; Meehan, Daniel T.; Delimont, Duane; Nakajima, Motowo; Wada, Takashi; Ann Gratton, Michael; Cosgrove, Dominic

2006-01-01

Alport syndrome is a glomerular basement membrane (GBM) disease caused by mutations in type IV collagen genes. A unique irregular thickening and thinning of the GBM characterizes the progressive glomerular pathology. The metabolic imbalances responsible for these GBM irregularities are not known. Here we show that macrophage metalloelastase (MMP-12) expression is >40-fold induced in glomeruli from Alport mice and is markedly induced in glomeruli of both humans and dogs with Alport syndrome. Treatment of Alport mice with MMI270 (CGS27023A), a broad spectrum MMP inhibitor that blocks MMP-12 activity, results in largely restored GBM ultrastructure and function. Treatment with BAY-129566, a broad spectrum MMP inhibitor that does not inhibit MMP-12, had no effect. We show that inhibition of CC chemokine receptor 2 (CCR2) receptor signaling with propagermanium blocks induction of MMP-12 mRNA and prevents GBM damage. CCR2 receptor is expressed in glomerular podocytes of Alport mice, suggesting MCP-1 activation of CCR2 on podocytes may underlie induction of MMP-12. These data indicate that the irregular GBM that characterizes Alport syndrome may be mediated, in part, by focal degradation of the GBM due to MMP dysregulation, in particular, MMP-12. Thus, MMP-12/CCR2 inhibitors may provide a novel and effective therapeutic strategy for Alport glomerular disease. PMID:16816359

Anti-GBM disease after nephrectomy for xanthogranulomatous pyelonephritis in a patient expressing HLA DR15 major histocompatibility antigens: a case report.

PubMed

O'Hagan, Emma; Mallett, Tamara; Convery, Mairead; McKeever, Karl

2015-01-01

Antiglomerular basement membrane (anti-GBM) antibody disease is uncommon in the pediatric population. There are no cases in the literature describing the development of anti-GBM disease following XGP or nephrectomy. We report the case of a 7-year-old boy with no past history of urological illness, treated with antimicrobials and nephrectomy for diffuse, unilateral xanthogranulomatous pyelonephritis (XGP). Renal function and ultrasound scan of the contralateral kidney postoperatively were normal. Three months later, the child represented in acute renal failure with rapidly progressive glomerulonephritis requiring hemodialysis. Renal biopsy showed severe crescentic glomerulonephritis with 95% of glomeruli demonstrating circumferential cellular crescents. Strong linear IgG staining of the glomerular basement membranes was present, in keeping with anti-GBM disease. Circulating anti-GBM antibodies were positive. Treatment with plasma exchange, methylprednisolone, and cyclophosphamide led to normalization of anti-GBM antibody titers. Frequency of hemodialysis was reduced as renal function improved, and he is currently independent of dialysis with estimated glomerular filtration rate 20.7 mls/min/1.73 m 2 . Case studies in the adult literature have reported the development of a rapidly progressive anti-GBM antibody-induced glomerulonephritis following renal surgery where patients expressed HLA DR2/HLA DR15 major histocompatibility (MHC) antigens. Of note, our patient also expresses the HLA DR15 MHC antigen.

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity.

PubMed

Oizel, Kristell; Chauvin, Cynthia; Oliver, Lisa; Gratas, Catherine; Geraldo, Fanny; Jarry, Ulrich; Scotet, Emmanuel; Rabe, Marion; Alves-Guerra, Marie-Clotilde; Teusan, Raluca; Gautier, Fabien; Loussouarn, Delphine; Compan, Vincent; Martinou, Jean-Claude; Vallette, François M; Pecqueur, Claire

2017-10-15

Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM. Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry. Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLN High and GLN Low , mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN High cultures are CD133 neg and display a mesenchymal signature in contrast to CD133 pos GLN Low GBM cells. Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. Clin Cancer Res; 23(20); 6292-304. ©2017 AACR . ©2017 American Association for Cancer Research.

EVA1A inhibits GBM cell proliferation by inducing autophagy and apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Xue; Kan, Shifeng; Liu, Zhen

Eva-1 homolog A (EVA1A) is a novel lysosome and endoplasmic reticulum-associated protein involved in autophagy and apoptosis. In this study, we constructed a recombinant adenovirus 5-EVA1A vector (Ad5-EVA1A) to overexpress EVA1A in glioblastoma (GBM) cell lines and evaluated its anti-tumor activities in vitro and in vivo. We found that overexpression of EVA1A in three GBM cell lines (U251, U87 and SHG44) resulted in a suppression of tumor cell growth via activation of autophagy and induction of cell apoptosis in a dose- and time-dependent manner. EVA1A-mediated autophagy was associated with inactivation of the mTOR/RPS6KB1 signaling pathway. Furthermore in vivo, overexpression ofmore » EVA1A successfully inhibited tumor growth in NOD/SCID mice. Our data suggest that EVA1A-induced autophagy and apoptosis play a role in suppressing the development of GBM and their up-regulation may be an effective method for treating this form of cancer. - Highlights: • Overexpression of EVA1A suppresses GBM cell growth. • EVA1A induces autophagy through the mTOR/RPS6KB1 pathway. • EVA1A induces GBM cell apoptosis. • EVA1A inhibits the development of GBM in vivo.« less

Cyclophilin B Supports Myc and Mutant p53 Dependent Survival of Glioblastoma Multiforme Cells

PubMed Central

Choi, Jae Won; Schroeder, Mark A.; Sarkaria, Jann N.; Bram, Richard J.

2014-01-01

Glioblastoma multiforme (GBM) is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in GBM cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human GBM cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of GBM cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-MAPK pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1 and JAK/STAT3 signaling. Elevated reactive oxygen species, ER expansion and abnormal unfolded protein responses in CypB-depleted GBM cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of GBM tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for GBM therapy. PMID:24272483

Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors.

PubMed

Roy, Laurent-Olivier; Poirier, Marie-Belle; Fortin, David

2018-04-08

Glioblastoma (GBM) represents the most common and aggressive malignant primary brain tumors in adults. Response to standard treatment is transitory and the survival of clinical trial cohorts are little more than 14 months. GBM are characterized by excessive proliferation, invasiveness, and radio-/chemoresistance features; which are strongly upregulated by transforming growth factor-beta (TGF-β). We hypothesized that TGF-β gene expression could correlate with overall survival (OS) and serve as a prognostic biomarker. TGF-β₁ and -β₂ expression were analyzed by qPCR in 159 GBM tumor specimens. Kaplan-Meier and multivariate analyses were used to correlate expression with OS and progression-free survival (PFS). In GBM, TGF-β₁ and -β₂ levels were 33- and 11-fold higher respectively than in non-tumoral samples. Kaplan-Meier and multivariate analyses revealed that high to moderate expressions of TGF-β₁ significantly conferred a strikingly poorer OS and PFS in newly diagnosed patients. Interestingly, at relapse, neither isoforms had meaningful impact on clinical evolution. We demonstrate that TGF-β₁ is the dominant isoform in newly diagnosed GBM rather than the previously acknowledged TGF-β₂. We believe our study is the first to unveil a significant relationship between TGF-β₁ expression and OS or PFS in newly diagnosed GBM. TGF-β₁ could serve as a prognostic biomarker or target affecting treatment planning and patient follow-up.

MASTER-OAFA: Fermi GRB faded optical counterpart detection

NASA Astrophysics Data System (ADS)

Pogrosheva, T.; Lipunov, V.; Podesta, R.; Levato, H.; Buckley, D.; Gorbovskoy, E.; Tiurina, N.; Balanutsa, P.; Kuznetsov, A.; Gress, O.; Kornilov, V.; Vladimirov, V.; Chazov, V.; Gorbunov, I.; Krylov, A.; Shumkov, V.; Kuvshinov, D.

2017-02-01

During Fermi GBM 508295323 trigger ( GRB_TIME: 2017-02-09 01:08:38.08 UT https://gcn.gsfc.nasa.gov/other/508295323.fermi ) inspection MASTER-OAFA auto-detection system ( Lipunov et al., "MASTER Global Robotic Net", Advances in Astronomy, 2010, 30L ) discovered new OT source (Podesta et al. GCN #20650) at (RA, Dec) = 07h 23m 07.30s -52d 14m 46.6s on 2017-02-09 02:07:07.478UT with unfiltered m_OT=17.4 (mlimit=18.1m).

Circulating gamma delta T cells are activated and depleted during progression of high-grade gliomas: Implications for gamma delta T cell therapy of GBM

USDA-ARS?s Scientific Manuscript database

Glioblastoma multiforme (GBM) remains frustratingly impervious to any existing therapy. We have previously shown that GBM is sensitive to recognition and lysis by ex vivo activated gamma delta T cells, a minor subset of lymphocytes that innately recognize autologous stress-associated target antigens...

Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas.

PubMed

Abou-El-Ardat, Khalil; Seifert, Michael; Becker, Kerstin; Eisenreich, Sophie; Lehmann, Matthias; Hackmann, Karl; Rump, Andreas; Meijer, Gerrit; Carvalho, Beatriz; Temme, Achim; Schackert, Gabriele; Schröck, Evelin; Krex, Dietmar; Klink, Barbara

2017-04-01

The evolution of primary glioblastoma (GBM) is poorly understood. Multifocal GBM (ie, multiple synchronous lesions in one patient) could elucidate GBM development. We present the first comprehensive study of 12 GBM foci from 6 patients using array-CGH, spectral karyotyping, gene expression arrays, and next-generation sequencing. Multifocal GBMs genetically resemble primary GBMs. Comparing foci from the same patient proved their monoclonal origin. All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs and might account for their highly malignant and invasive phenotype. Surprisingly, the types of mutations in these genes/pathways were different in tumor foci from the same patients. For example, we found distinct mutations/aberrations in PTEN, TP53, EGFR, and CDKN2A/B, which therefore must have occurred independently and late during tumor development. We also identified chromothripsis as a late event and in tumors with wild-type TP53. Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations. Multifocal GBMs develop through parallel genetic evolution. The high frequency of alterations in 3 main pathways suggests that these are essential steps in GBM evolution; however, their late occurrence indicates that they are not founder events but rather subclonal drivers. This might account for the marked genetic heterogeneity seen in primary GBM and therefore has important implications for GBM therapy. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.

PubMed

McAdoo, Stephen P; Tanna, Anisha; Hrušková, Zdenka; Holm, Lisa; Weiner, Maria; Arulkumaran, Nishkantha; Kang, Amy; Satrapová, Veronika; Levy, Jeremy; Ohlsson, Sophie; Tesar, Vladimir; Segelmark, Mårten; Pusey, Charles D

2017-09-01

Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such 'double-positive' cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Differential role of EGF and BFGF in human GBM-TIC proliferation: relationship to EGFR-tyrosine kinase inhibitor sensibility.

PubMed

Bajetto, A; Porcile, C; Pattarozzi, A; Scotti, L; Aceto, A; Daga, A; Barbieri, F; Florio, T

2013-01-01

Glioblastoma multiforme (GBM) is among the most devastating human tumors being rapidly fatal despite aggressive surgery, radiation and chemotherapies. It is characterized by extensive dissemination of tumor cells within the brain that hinders complete surgical resection. GBM tumor initiating-cells (TICs) are a rare subpopulation of cells responsible for tumor development, growth, invasiveness and recurrence after chemotherapy. TICs from human GBM can be selected in vitro using the same conditions permissive for the growth of normal neural cells, of which share some features including marker expression, self-renewal capacity, long-term proliferation, and ability to differentiate into neuronal and glial cells. EGFR overexpression and its constitutive activation is one of the most important signaling alteration identified in GBM, and its pharmacological targeting represents an attractive therapeutic goal. We previously demonstrated that human GBM TICs have different sensitivity to the EGFR kinase inhibitors erlotinib and gefitinib, depending on the differential modulation of downstream signaling cascades. In this work we investigated the mechanisms of resistance to erlotinib in two human GBM TIC cultures, analyzing EGF and bFGF individual contribution to proliferation, clonogenicity, and migration. We demonstrated the presence of a small cell subpopulation whose proliferation is supported by EGF and a larger one mainly dependent on bFGF. Thus, insensitivity to EGFR kinase inhibitors as far as TIC proliferation results from a predominant FGFR activation that hides the inhibitory effects induced on EGFR signaling. Conversely, EGF and bFGF induced cell migration with similar efficacy. In addition, unlike neural stem/progenitors cells, the removal of chondroitin sulphate proteoglycans from cell surface was unable to discern EGF- and bFGF-dependent subpopulations in GBM TICs.

Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors.

PubMed

Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar

2014-02-01

F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.

Encapsulation of temozolomide in a tumor-targeting nanocomplex enhances anti-cancer efficacy and reduces toxicity in a mouse model of glioblastoma.

PubMed

Kim, Sang-Soo; Rait, Antonina; Kim, Eric; DeMarco, James; Pirollo, Kathleen F; Chang, Esther H

2015-12-01

Although temozolomide (TMZ) is the current first-line chemotherapy for glioblastoma multiforme (GBM), most patients either do not respond or ultimately fail TMZ treatment. Both intrinsic tumor resistance and limited access of TMZ to brain tumors as a result of the blood-brain barrier (BBB) contribute to poor response and ultimately to poor prognosis for GBM patients. We have developed a "dual-targeting" nanomedicine that both actively crosses the BBB and actively targets cancer cells once in the brain parenchyma. This nanomedicine (termed scL-TMZ) is sized ~40 nm and comprised of a cationic liposome (DOTAP:DOPE) encapsulating TMZ. The surface of liposome is decorated with anti-transferrin receptor single-chain antibody fragments to facilitate the crossing of the BBB by the scL-TMZ in addition to targeting GBM in the brain. This novel formulation was found to be markedly more effective than standard TMZ in both TMZ-resistant and TMZ-sensitive GBM. Encapsulation of TMZ also markedly enhanced its efficacy in killing a variety of non-GBM tumor cells. The scL-TMZ nanocomplex was shown to target cancer stem cells, which have been linked to both drug resistance and recurrence in GBM. Most significantly, systemically administered scL-TMZ significantly prolonged survival in mice bearing intracranial GBM tumors. The improved efficacy of scL-TMZ compared to standard TMZ was accompanied by reduced toxicity, so we conclude that the scL-TMZ nanomedicine holds great promise as a more effective therapy for GBM and other tumor types. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A multi-targeted natural flavonoid myricetin impedes abnormal glioblastoma cell motility and invasiveness via suppressing lamellipodia and focal adhesions formation.

PubMed

Zhao, Hua-Fu; Wang, Gang; Wu, Chang-Peng; Zhou, Xiu-Ming; Wang, Jing; Chen, Zhong-Ping; To, Shing-Shun Tony; Li, Wei-Ping

2018-06-10

Glioblastoma multiforme (GBM) is the most aggressive and malignant primary brain tumor characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma, which contribute to tumor recurrence and poor prognosis. Myricetin is a natural flavonoid with potent anti-oxidant, anti-inflammatory and anti-cancer activities, which may serve as a potential and harmless agent for GBM treatment. To investigate the anti-glioblastoma effects of myricetin, GBM cells were treated with myricetin alone or in combination with temozolomide. Its effects on GBM cell motility and cytoskeletal structures including lamellipodia, focal adhesions and membrane ruffles were also evaluated. We showed that myricetin alone inhibited glioblastoma U-87 MG cell proliferation, migration and invasion, whereas combination of myricetin and temozolomide did not exhibit any synergistic effect. The inhibitory effect on GBM cell proliferation is independent of PTEN status. Moreover, myricetin showed less cytotoxicity to normal astrocytes than GBM cells. Formation of lamellipodia, focal adhesions, membrane ruffles and vasculogenic mimicry were blocked by myricetin though suppressing ROCK2, paxillin and cortactin phosphorylation. In addition, myricetin could bind to a series of kinases and scaffold proteins including PI3K catalytic isoforms (p110α, p110β and p110δ), PDK1, JNK, c-Jun, ROCK2, paxillin, vinculin and VE-cadherin, leading to inactivation of PI3K/Akt and JNK signaling. In conclusion, myricetin is a multi-targeted drug that has potent anti-migratory and anti-invasive effects on GBM cells via suppressing formation of lamellipodia and focal adhesions, suggesting that it may serve as an alternative option for GBM treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Correlation of Higher Levels of Soluble TNF-R1 with a Shorter Survival, Independent of Age, in Recurrent Glioblastoma

PubMed Central

Ahluwalia, Manmeet S.; Bou-Anak, Stephanie; Burgett, Monica E.; Sarmey, Nehaw; Khosla, Divya; Dahiya, Saurabh; Weil, Robert J.; Bae, Eunnyung; Huang, Ping; McGraw, Mary; Grove, Lisa M.; Olman, Mitchell A.; Prayson, Richard A.; Suh, John H.; Gillespie, G. Yancey; Barnholtz-Sloan, Jill; Nowacki, Amy S.; Barnett, Gene H.; Gladson, Candece L.

2016-01-01

The circulating levels of soluble tumor necrosis factor receptor-1 (sTNF-R1) and sTNF-R2 are altered in numerous diseases, including several types of cancer. Correlations with the risk of progression in some cancers, as well as systemic manifestations of the disease and therapeutic side-effects, have been described. However, there is very little information on the levels of these soluble receptors in glioblastoma (GBM). Here, we report on an exploratory retrospective study of the levels of sTNF-Rs in the vascular circulation of patients with GBM. Banked samples were obtained from 112 GBM patients (66 untreated, newly-diagnosed patients and 46 with recurrent disease) from two institutions. The levels of sTNF-R1 in the plasma were significantly lower in patients with newly-diagnosed or recurrent GBM than apparently healthy individuals and correlated with the intensity of expression of TNF-R1 on the tumor-associated endothelial cells (ECs) in the corresponding biopsies. Elevated levels of sTNF-R1 in patients with recurrent, but not newly-diagnosed GBM, were significantly associated with a shorter survival, independent of age (p=0.02) or steroid medication. In contrast, the levels of circulating sTNF-R2 were significantly higher in recurrent GBM than healthy individuals and there was no significant correlation with expression of TNF-R2 on the tumor-associated ECs or survival time. The results indicate that larger, prospective studies are warranted to determine the predictive value of the levels of sTNF-R1 in patients with recurrent GBM and the factors that regulate the levels of sTNF-Rs in the circulation in GBM patients. PMID:27858267

Adult, embryonic and fetal hemoglobin are expressed in human glioblastoma cells.

PubMed

Emara, Marwan; Turner, A Robert; Allalunis-Turner, Joan

2014-02-01

Hemoglobin is a hemoprotein, produced mainly in erythrocytes circulating in the blood. However, non-erythroid hemoglobins have been previously reported in other cell types including human and rodent neurons of embryonic and adult brain, but not astrocytes and oligodendrocytes. Human glioblastoma multiforme (GBM) is the most aggressive tumor among gliomas. However, despite extensive basic and clinical research studies on GBM cells, little is known about glial defence mechanisms that allow these cells to survive and resist various types of treatment. We have shown previously that the newest members of vertebrate globin family, neuroglobin (Ngb) and cytoglobin (Cygb), are expressed in human GBM cells. In this study, we sought to determine whether hemoglobin is also expressed in GBM cells. Conventional RT-PCR, DNA sequencing, western blot analysis, mass spectrometry and fluorescence microscopy were used to investigate globin expression in GBM cell lines (M006x, M059J, M059K, M010b, U87R and U87T) that have unique characteristics in terms of tumor invasion and response to radiotherapy and hypoxia. The data showed that α, β, γ, δ, ζ and ε globins are expressed in all tested GBM cell lines. To our knowledge, we are the first to report expression of fetal, embryonic and adult hemoglobin in GBM cells under normal physiological conditions that may suggest an undefined function of those expressed hemoglobins. Together with our previous reports on globins (Ngb and Cygb) expression in GBM cells, the expression of different hemoglobins may constitute a part of series of active defence mechanisms supporting these cells to resist various types of treatments including chemotherapy and radiotherapy.

An intrinsic DFF40/CAD endonuclease deficiency impairs oligonucleosomal DNA hydrolysis during caspase-dependent cell death: a common trait in human glioblastoma cells.

PubMed

Sánchez-Osuna, María; Martínez-Escardó, Laura; Granados-Colomina, Carla; Martínez-Soler, Fina; Pascual-Guiral, Sònia; Iglesias-Guimarais, Victoria; Velasco, Roser; Plans, Gerard; Vidal, Noemi; Tortosa, Avelina; Barcia, Carlos; Bruna, Jordi; Yuste, Victor J

2016-07-01

Glioblastoma (GBM) or grade IV astrocytoma is one of the most devastating human cancers. The loss of DFF40/CAD, the key endonuclease that triggers oligonucleosomal DNA fragmentation during apoptosis, has been linked to genomic instability and cell survival after radiation. Despite the near inevitability of GBM tumor recurrence after treatment, the relationship between DFF40/CAD and GBM remains unexplored. We studied the apoptotic behavior of human GBM-derived cells after apoptotic insult. We analyzed caspase activation and the protein levels and subcellular localization of DFF40/CAD apoptotic endonuclease. DFF40/CAD was also evaluated in histological sections from astrocytic tumors and nontumoral human brain. We showed that GBM cells undergo incomplete apoptosis without generating oligonucleosomal DNA degradation despite the correct activation of executioner caspases. The major defect of GBM cells relied on the improper accumulation of DFF40/CAD at the nucleoplasmic subcellular compartment. Supporting this finding, DFF40/CAD overexpression allowed GBM cells to display oligonucleosomal DNA degradation after apoptotic challenge. Moreover, the analysis of histological slices from astrocytic tumors showed that DFF40/CAD immunoreactivity in tumoral GFAP-positive cells was markedly reduced when compared with nontumoral samples. Our data highlight the low expression levels of DFF40/CAD and the absence of DNA laddering as common molecular traits in GBM. These findings could be of major importance for understanding the malignant behavior of remaining tumor cells after radiochemotherapy. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Correlates and subgroups of injecting drug use in UK gay and bisexual men: Findings from the 2014 Gay Men's Sex Survey.

PubMed

Melendez-Torres, G J; Bourne, Adam; Hickson, Ford; Reid, David; Weatherburn, Peter

2018-04-16

Evidence to understand which gay and bisexual men (GBM) inject drugs remains scant, especially in the UK. We describe correlates of last-year injecting in UK GBM, and characterise subgroups of GBM who inject drugs by types of drugs used. Using data from the 2014 Gay Men's Sex Survey, an opportunistic internet-based survey conducted of GBM living in the UK, we examined via logistic regression correlates with any injecting of six drugs (amphetamine/speed, crystal methamphetamine, heroin, mephedrone, GHB/GBL, and ketamine) in the last year. We estimated latent class models to understand underlying subgroups of injecting drug use among GBM reporting injecting drug use in the last year. Injecting was most common in GBM who were of middle age, who were HIV seropositive, and who lived in London, and was significantly associated with sexual risk with multiple partners in the last year, whether steady or non-steady. Most GBM who engaged in injecting either injected crystal methamphetamine, mephedrone or both (class 1, chemsex, 88.6% of injectors), whereas a smaller group had a focus on opiates (class 2, opiate, 7.9%). A small but identifiable subgroup (class 3, eclectic, 3.5%) engaged in injecting across the range of drugs examined. This is the first epidemiological analysis to describe subgroups of injecting, and to describe correlates of injecting drug use, in UK GBM. Implications for design of harm reduction services include a need to focus on injecting drug use beyond opiates, currently the focus of most harm reduction services. Copyright © 2018 Elsevier B.V. All rights reserved.

PD-L1 expression and prognostic impact in glioblastoma

PubMed Central

Nduom, Edjah K.; Wei, Jun; Yaghi, Nasser K.; Huang, Neal; Kong, Ling-Yuan; Gabrusiewicz, Konrad; Ling, Xiaoyang; Zhou, Shouhao; Ivan, Cristina; Chen, Jie Qing; Burks, Jared K.; Fuller, Greg N.; Calin, George A.; Conrad, Charles A.; Creasy, Caitlin; Ritthipichai, Krit; Radvanyi, Laszlo; Heimberger, Amy B.

2016-01-01

Background Therapeutic targeting of the immune checkpoints cytotoxic T-lymphocyte-associated molecule-4 (CTLA-4) and PD-1/PD-L1 has demonstrated tumor regression in clinical trials, and phase 2 trials are ongoing in glioblastoma (GBM). Previous reports have suggested that responses are more frequent in patients with tumors that express PD-L1; however, this has been disputed. At issue is the validation of PD-L1 biomarker assays and prognostic impact. Methods Using immunohistochemical analysis, we measured the incidence of PD-L1 expression in 94 patients with GBM. We categorized our results according to the total number of PD-L1-expressing cells within the GBMs and then validated this finding in ex vivo GBM flow cytometry with further analysis of the T cell populations. We then evaluated the association between PD-L1 expression and median survival time using the protein expression datasets and mRNA from The Cancer Genome Atlas. Results The median percentage of PD-L1-expressing cells in GBM by cell surface staining is 2.77% (range: 0%–86.6%; n = 92), which is similar to the percentage found by ex vivo flow cytometry. The majority of GBM patients (61%) had tumors with at least 1% or more PD-L1-positive cells, and 38% had at least 5% or greater PD-L1 expression. PD-L1 is commonly expressed on the GBM-infiltrating T cells. Expression of both PD-L1 and PD-1 are negative prognosticators for GBM outcome. Conclusions The incidence of PD-L1 expression in GBM patients is frequent but is confined to a minority subpopulation, similar to other malignancies that have been profiled for PD-L1 expression. Higher expression of PD-L1 is correlated with worse outcome. PMID:26323609

A novel 3D human glioblastoma cell culture system for modeling drug and radiation responses

PubMed Central

Stevenson, Katrina; Gilmour, Lesley; Hamilton, Graham; Chalmers, Anthony J

2017-01-01

Abstract Background. Glioblastoma (GBM) is the most common primary brain tumor, with dismal prognosis. The failure of drug–radiation combinations with promising preclinical data to translate into effective clinical treatments may relate to the use of simplified 2-dimensional in vitro GBM cultures. Methods. We developed a customized 3D GBM culture system based on a polystyrene scaffold (Alvetex) that recapitulates key histological features of GBM and compared it with conventional 2D cultures with respect to their response to radiation and to molecular targeted agents for which clinical data are available. Results. In 3 patient-derived GBM lines, no difference in radiation sensitivity was observed between 2D and 3D cultures, as measured by clonogenic survival. Three different molecular targeted agents, for which robust clinical data are available were evaluated in 2D and 3D conditions: (i) temozolomide, which improves overall survival and is standard of care for GBM, exhibited statistically significant effects on clonogenic survival in both patient-derived cell lines when evaluated in the 3D model compared with only one cell line in 2D cells; (ii) bevacizumab, which has been shown to increase progression-free survival when added to standard chemoradiation in phase III clinical trials, exhibited marked radiosensitizing activity in our 3D model but had no effect on 2D cells; and (iii) erlotinib, which had no efficacy in clinical trials, displayed no activity in our 3D GBM model, but radiosensitized 2D cells. Conclusions. Our 3D model reliably predicted clinical efficacy, strongly supporting its clinical relevance and potential value in preclinical evaluation of drug–radiation combinations for GBM. PMID:27576873

IDH1 mutation is associated with lower expression of VEGF but not microvessel formation in glioblastoma multiforme

PubMed Central

Polívka, Jiří; Pešta, Martin; Pitule, Pavel; Hes, Ondřej; Holubec, Luboš; Polívka, Jiří; Kubíková, Tereza; Tonar, Zbyněk

2018-01-01

Introduction Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor characterized by pathological vascularization. Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) were observed in GBM. We aimed to assess the intra-tumor hypoxia, angiogenesis and microvessel formation in GBM and to find their associations with IDH1 mutation status and patients prognosis. Methods 52 patients with a diagnosis of GBM were included into the study. IDH1 R132H mutation was assessed by RT-PCR from FFPE tumor samples obtained during surgery. The expression of markers of hypoxia (HIF2α), angiogenesis (VEGF), tumor microvascularity (CD31, CD34, vWF, CD105), and proliferation (Ki-67) were assessed immunohistochemically (IHC). IDH1 mutation and IHC markers were correlated with the patient survival. Results 20 from 52 GBM tumor samples comprised IDH1 R132H mutation (38.5%). The majority of mutated tumors were classified as secondary glioblastomas (89.9%). Patients with IDH1 mutated tumors experienced better progression-free survival (P = 0.037) as well as overall survival (P = 0.035) compared with wild type tumors. The significantly lower expression of VEGF was observed in GBM with IDH1 mutation than in wild type tumors (P = 0.01). No such association was found for microvascular markers. The increased expression of newly-formed microvessels (ratio CD105/CD31) in tumor samples was associated with worse patient’s progression-free survival (P = 0.026). Summary No increase in HIF/VEGF-mediated angiogenesis was observed in IDH1-mutated GBM compared with IDH1 wild type tumors. The histological assessment of the portion of newly-formed microvessels in tumor tissue can be used for the prediction of GBM patient’s prognosis. PMID:29662659

Discontinuation of Hemodialysis in a Patient with Anti-GBM Disease by the Treatment with Corticosteroids and Plasmapheresis despite Several Predictors for Dialysis-Dependence.

PubMed

Fujigaki, Yoshihide; Morimoto, Chikayuki; Iino, Risa; Taniguchi, Kei; Kawamorita, Yosuke; Asakawa, Shinichiro; Toyoki, Daigo; Miyano, Shinako; Fujii, Wataru; Ota, Tatsuru; Shibata, Shigeru; Uchida, Shunya

2017-01-01

A 26-year-old man highly suspected of having antiglomerular basement membrane (GBM) disease was treated with corticosteroid pulse therapy 9 days after initial infection-like symptoms with high procalcitonin value. The patient required hemodialysis the next day of the treatment due to oliguria. In addition to corticosteroid therapy, plasmapheresis was introduced and the patient could discontinue hemodialysis 43 days after the treatment. Kidney biopsy after initiation of hemodialysis confirmed anti-GBM disease with 86.3% crescent formation. Physician should keep in mind that active anti-GBM disease shows even high procalcitonin value in the absence of infection. To pursue recovery of renal function, the challenge of the immediate and persistent treatment with high-dose corticosteroids plus plasmapheresis for highly suspected anti-GBM disease is vitally important despite the presence of reported predictors for dialysis-dependence including oliguria and requiring hemodialysis at presentation.

Cell of Origin and Cancer Stem Cells in Tumor Suppressor Mouse Models of Glioblastoma.

PubMed

Alcantara Llaguno, Sheila R; Xie, Xuanhua; Parada, Luis F

2016-01-01

The cellular origins and the mechanisms of progression, maintenance of tumorigenicity, and therapeutic resistance are central questions in the glioblastoma multiforme (GBM) field. Using tumor suppressor mouse models, our group recently reported two independent populations of adult GBM-initiating central nervous system progenitors. We found different functional and molecular subtypes depending on the tumor-initiating cell lineage, indicating that the cell of origin is a driver of GBM subtype diversity. Using an in vivo model, we also showed that GBM cancer stem cells (CSCs) or glioma stem cells (GSCs) contribute to resistance to chemotherapeutic agents and that genetic ablation of GSCs leads to a delay in tumor progression. These studies are consistent with the cell of origin and CSCs as critical regulators of the pathogenesis of GBM. © 2016 Alcantara Llaguno et al; Published by Cold Spring Harbor Laboratory Press.

An Observer's View of Magnetars

NASA Technical Reports Server (NTRS)

Kouveliotou, Chryssa

2014-01-01

Magnetar bursts were first recorded in 1979, although mistaken as a subclass of softer Gamma Ray Bursts at the time. Thirty five years later, we have 23 confirmed magnetar sources and 5 more that are awaiting acceptance to this exclusive group. I will give a brief overview of the field today and report on the results of the last 10 years of magnetars, and in particular the successful synergy between Swift and Fermi/Gamma Ray burst Monitor (GBM) in identifying new sources.

Brain Tumor Diagnostics and Therapeutics with Superparamagnetic Ferrite Nanoparticles.

PubMed

Hyder, Fahmeed; Manjura Hoque, S

2017-01-01

Ferrite nanoparticles (F-NPs) can transform both cancer diagnostics and therapeutics. Superparamagnetic F-NPs exhibit high magnetic moment and susceptibility such that in presence of a static magnetic field transverse relaxation rate of water protons for MRI contrast is augmented to locate F-NPs (i.e., diagnostics) and exposed to an alternating magnetic field local temperature is increased to induce tissue necrosis (i.e., thermotherapy). F-NPs are modified by chemical synthesis of mixed spinel ferrites as well as their size, shape, and coating. Purposely designed drug-containing nanoparticles (D-NPs) can slowly deliver drugs (i.e., chemotherapy). Convection-enhanced delivery (CED) of D-NPs with MRI guidance improves glioblastoma multiforme (GBM) treatment. MRI monitors the location of chemotherapy when D-NPs and F-NPs are coadministered with CED. However superparamagnetic field gradients produced by F-NPs complicate MRI readouts (spatial distortions) and MRS (extensive line broadening). Since extracellular pH (pH e ) is a cancer hallmark, pH e imaging is needed to screen cancer treatments. Biosensor imaging of redundant deviation in shifts (BIRDS) extrapolates pH e from paramagnetically shifted signals and the pH e accuracy remains unaffected by F-NPs. Hence effect of both chemotherapy and thermotherapy can be monitored (by BIRDS), whereas location of F-NPs is revealed (by MRI). Smarter tethering of nanoparticles and agents will impact GBM theranostics.

Sexual Agreement Classifications for Gay and Bisexual Men and Implications for Harm Reduction HIV Prevention

ERIC Educational Resources Information Center

Wilkerson, J. Michael; Smolenski, Derek J.; Morgan, Richard; Rosser, B. R. Simon

2012-01-01

HIV prevention educators frequently encourage gay and bisexual men (GBM) to negotiate condom use prior to sexual engagement. Identifying groups of GBM based on their presexual agreements can aid efforts to tailor interventions. Using cross-sectional data from 1,188 GBM who reported having sex with a nonprimary sex partner in the 90 days prior to…

MiR-9 Promotes Apoptosis Via Suppressing SMC1A Expression in GBM Cell Lines.

PubMed

Zu, Yong; Zhu, Zhichuan; Lin, Min; Xu, Dafeng; Liang, Yongjun; Wang, Yueqian; Qiao, Zhengdong; Cao, Ting; Yang, Dan; Gao, Lili; Jin, Pengpeng; Zhang, Peng; Fu, Jianjun; Zheng, Jing

2017-01-01

Glioblastomas multiforme (GBM) is the most malignant brain cancer, which presented vast genomic variation with complicated pathologic mechanism. MicroRNA is a delicate post-transcriptional tuner of gene expression in the organisms by targeting and regulating protein coding genes. MiR-9 was reported as a significant biomarker for GBM patient prognosis and a key factor in regulation of GBM cancer stem cells. To explore the effect of miR-9 on GBM cell growth, we over expressed miR-9 in U87 and U251 cells. The cell viability decreased and apoptosis increased after miR-9 overexpression in these cells. To identify the target of miR-9, we scanned miR-9 binding site in the 3'UTRs region of expression SMC1A (structural maintenance of chromosomes 1A) genes and designed a fluorescent reporter assay to measure miR-9 binding to this region. Our results revealed that miR-9 binds to the 3'sUTR region of SMC1A and down-regulated SMC1A expression. Our results indicated that miR-9 was a potential therapeutic target for GBM through triggering apoptosis of cancer cells.

Adhesion- and stress-related adaptation of glioma radiochemoresistance is circumvented by β1 integrin/JNK co-targeting.

PubMed

Vehlow, Anne; Klapproth, Erik; Storch, Katja; Dickreuter, Ellen; Seifert, Michael; Dietrich, Antje; Bütof, Rebecca; Temme, Achim; Cordes, Nils

2017-07-25

Resistance of cancer stem-like and cancer tumor bulk cells to radiochemotherapy and destructive infiltration of the brain fundamentally influence the treatment efficiency to cure of patients suffering from Glioblastoma (GBM). The interplay of adhesion and stress-related signaling and activation of bypass cascades that counteract therapeutic approaches remain to be identified in GBM cells. We here show that combined inhibition of the adhesion receptor β1 integrin and the stress-mediator c-Jun N-terminal kinase (JNK) induces radiosensitization and blocks invasion in stem-like and patient-derived GBM cultures as well as in GBM cell lines. In vivo, this treatment approach not only significantly delays tumor growth but also increases median survival of orthotopic, radiochemotherapy-treated GBM mice. Both, in vitro and in vivo, effects seen with β1 integrin/JNK co-inhibition are superior to the monotherapy. Mechanistically, the in vitro radiosensitization provoked by β1 integrin/JNK targeting is caused by defective DNA repair associated with chromatin changes, enhanced ATM phosphorylation and prolonged G2/M cell cycle arrest. Our findings identify a β1 integrin/JNK co-dependent bypass signaling for GBM therapy resistance, which might be therapeutically exploitable.

Encapsulated Stem Cells Loaded With Hyaluronidase-expressing Oncolytic Virus for Brain Tumor Therapy

PubMed Central

Martinez-Quintanilla, Jordi; He, Derek; Wakimoto, Hiroaki; Alemany, Ramon; Shah, Khalid

2015-01-01

Despite the proven safety of oncolytic viruses (OV) in clinical trials for glioblastoma (GBM), their efficacy has been hindered by suboptimal spreading within the tumor. We show that hyaluronan or hyaluronic acid (HA), an important component of extracellular matrix (ECM), is highly expressed in a majority of tumor xenografts established from patient-derived GBM lines that present both invasive and nodular phenotypes. Intratumoral injection of a conditionally replicating adenovirus expressing soluble hyaluronidase (ICOVIR17) into nodular GBM, mediated HA degradation and enhanced viral spread, resulting in a significant antitumor effect and mice survival. In an effort to translate OV-based therapeutics into clinical settings, we encapsulated human adipose-derived mesenchymal stem cells (MSC) loaded with ICOVIR17 in biocompatible synthetic extracellular matrix (sECM) and tested their efficacy in a clinically relevant mouse model of GBM resection. Compared with direct injection of ICOVIR17, sECM-MSC loaded with ICOVIR17 resulted in a significant decrease in tumor regrowth and increased mice survival. This is the first report of its kind revealing the expression of HA in GBM and the role of OV-mediated HA targeting in clinically relevant mouse model of GBM resection and thus has clinical implications. PMID:25352242

Engineering toxin-resistant therapeutic stem cells to treat brain tumors

PubMed Central

Stuckey, Daniel W.; Hingtgen, Shawn D.; Karakas, Nihal; Rich, Benjamin E.; Shah, Khalid

2014-01-01

Pseudomonas exotoxin (PE) potently blocks protein synthesis by catalyzing the inactivation of elongation factor-2 (EF-2), and PE-cytotoxins have been used as anti-tumor agents. However, their effective clinical translation in solid tumors has been confounded by off-target delivery, systemic toxicity and short chemotherapeutic half-life. To overcome these limitations we have created toxin-resistant stem cells by modifying endogenous EF-2, and engineered them to secrete PE-cytotoxins targeting IL13Rα2 and EGFR expressed by many glioblastomas (GBM). Molecular analysis correlated efficacy of PE-targeted cytotoxins with levels of cognate receptor expression, and optical imaging was applied to simultaneously track the kinetics of protein synthesis inhibition and GBM cell viability in vivo. Stem cell-based delivery of IL13-PE in a clinically-relevant GBM resection model led to increased long-term survival of mice compared to IL13-PE protein infusion. Moreover, multiple patient-derived GBM lines responded to treatment, underscoring its clinical relevance. In sum, integrating stem cell-based engineering, multimodal imaging and delivery of PE-cytotoxins in a clinically-relevant GBM model represents a novel strategy and a potential advancement in GBM therapy. PMID:25346520

The NSL chromatin-modifying complex subunit KANSL2 regulates cancer stem-like properties in glioblastoma that contribute to tumorigenesis

PubMed Central

Ferreyra-Solari, Nazarena; Belforte, Fiorella S.; Canedo, Lucía; Videla-Richardson, Guillermo A.; Espinosa, Joaquín M.; Rossi, Mario; Serna, Eva; Riudavets, Miguel A.; Martinetto, Horacio; Sevlever, Gustavo; Perez-Castro, Carolina

2016-01-01

KANSL2 is an integral subunit of the Non-Specific Lethal (NSL) chromatin-modifying complex which contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. PMID:27406830

Recent advances and future of immunotherapy for glioblastoma.

PubMed

Kamran, Neha; Calinescu, Alexandra; Candolfi, Marianela; Chandran, Mayuri; Mineharu, Yohei; Asad, Antonela S; Koschmann, Carl; Nunez, Felipe J; Lowenstein, Pedro R; Castro, Maria G

2016-10-01

Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM. Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies. Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.

DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation.

PubMed

Sun, Peng; Xia, Shuli; Lal, Bachchu; Eberhart, Charles G; Quinones-Hinojosa, Alfredo; Maciaczyk, Jarek; Matsui, William; Dimeco, Francesco; Piccirillo, Sara M; Vescovi, Angelo L; Laterra, John

2009-07-01

Neurospheres derived from glioblastoma (GBM) and other solid malignancies contain neoplastic stem-like cells that efficiently propagate tumor growth and resist cytotoxic therapeutics. The primary objective of this study was to use histone-modifying agents to elucidate mechanisms by which the phenotype and tumor-promoting capacity of GBM-derived neoplastic stem-like cells are regulated. Using established GBM-derived neurosphere lines and low passage primary GBM-derived neurospheres, we show that histone deacetylase (HDAC) inhibitors inhibit growth, induce differentiation, and induce apoptosis of neoplastic neurosphere cells. A specific gene product induced by HDAC inhibition, Delta/Notch-like epidermal growth factor-related receptor (DNER), inhibited the growth of GBM-derived neurospheres, induced their differentiation in vivo and in vitro, and inhibited their engraftment and growth as tumor xenografts. The differentiating and tumor suppressive effects of DNER, a noncanonical Notch ligand, contrast with the previously established tumor-promoting effects of canonical Notch signaling in brain cancer stem-like cells. Our findings are the first to implicate noncanonical Notch signaling in the regulation of neoplastic stem-like cells and suggest novel neoplastic stem cell targeting treatment strategies for GBM and potentially other solid malignancies.

ErbB2/HER2-Specific NK Cells for Targeted Therapy of Glioblastoma.

PubMed

Zhang, Congcong; Burger, Michael C; Jennewein, Lukas; Genßler, Sabrina; Schönfeld, Kurt; Zeiner, Pia; Hattingen, Elke; Harter, Patrick N; Mittelbronn, Michel; Tonn, Torsten; Steinbach, Joachim P; Wels, Winfried S

2016-05-01

Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults and currently incurable. To specifically target natural killer (NK) cell activity to GBM, we employed NK-92/5.28.z cells that are continuously expanding human NK cells expressing an ErbB2-specific chimeric antigen receptor (CAR). ErbB2 expression in 56 primary tumors, four primary cell cultures, and seven established cell lines was assessed by immunohistochemistry and flow cytometry. Cell killing activity of NK-92/5.28.z cells was analyzed in in vitro cytotoxicity assays. In vivo antitumor activity was evaluated in NOD-SCID IL2Rγ(null) (NSG) mice carrying orthotopic human GBM xenografts (6 to 11 mice per group) and C57BL/6 mice carrying subcutaneous and orthotopic ErbB2-expressing murine GBM tumors (5 to 8 mice per group). Statistical tests were two-sided. We found elevated ErbB2 protein expression in 41% of primary GBM samples and in the majority of GBM cell lines investigated. In in vitro assays, NK-92/5.28.z in contrast to untargeted NK-92 cells lysed all ErbB2-positive established and primary GBM cells analyzed. Potent in vivo antitumor activity of NK-92/5.28.z was observed in orthotopic GBM xenograft models in NSG mice, leading to a marked extension of symptom-free survival upon repeated stereotactic injection of CAR NK cells into the tumor area (median survival of 200.5 days upon treatment with NK-92/5.28.z vs 73 days upon treatment with parental NK-92 cells, P < .001). In immunocompetent mice, local therapy with NK-92/5.28.z cells resulted in cures of transplanted syngeneic GBM in four of five mice carrying subcutaneous tumors and five of eight mice carrying intracranial tumors, induction of endogenous antitumor immunity, and long-term protection against tumor rechallenge at distant sites. Our data demonstrate the potential of ErbB2-specific NK-92/5.28.z cells for adoptive immunotherapy of glioblastoma, justifying evaluation of this approach for the treatment of ErbB2-positive GBM in clinical studies. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Activation of Aurora A kinase through the FGF1/FGFR signaling axis sustains the stem cell characteristics of glioblastoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsu, Yi-Chao; Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan; Kao, Chien-Yu

Fibroblast growth factor 1 (FGF1) binds and activates FGF receptors, thereby regulating cell proliferation and neurogenesis. Human FGF1 gene 1B promoter (−540 to +31)-driven SV40 T antigen has been shown to result in tumorigenesis in the brains of transgenic mice. FGF1B promoter (−540 to +31)-driven green fluorescent protein (F1BGFP) has also been used in isolating neural stem cells (NSCs) with self-renewal and multipotency from developing and adult mouse brains. In this study, we provide six lines of evidence to demonstrate that FGF1/FGFR signaling is implicated in the expression of Aurora A (AurA) and the activation of its kinase domain (Thr288more » phosphorylation) in the maintenance of glioblastoma (GBM) cells and NSCs. First, treatment of FGF1 increases AurA expression in human GBM cell lines. Second, using fluorescence-activated cell sorting, we observed that F1BGFP reporter facilitates the isolation of F1BGFP(+) GBM cells with higher expression levels of FGFR and AurA. Third, both FGFR inhibitor (SU5402) and AurA inhibitor (VX680) could down-regulate F1BGFP-dependent AurA activity. Fourth, inhibition of AurA activity by two different AurA inhibitors (VX680 and valproic acid) not only reduced neurosphere formation but also induced neuronal differentiation of F1BGFP(+) GBM cells. Fifth, flow cytometric analyses demonstrated that F1BGFP(+) GBM cells possessed different NSC cell surface markers. Finally, inhibition of AurA by VX680 reduced the neurosphere formation of different types of NSCs. Our results show that activation of AurA kinase through FGF1/FGFR signaling axis sustains the stem cell characteristics of GBM cells. Implications: This study identified a novel mechanism for the malignancy of GBM, which could be a potential therapeutic target for GBM. - Highlights: • We report that FGF1 treatment can stimulate AurA kinase expression in human GBM cells. • FGF1/FGFR signaling is involved in the activation of AurA kinase. • FGF1 sustains the self-renewal of human GBM cells and embryonic stem cells via AurA activation.« less

Targeted Vascular Drug Delivery in Cerebral Cancer.

PubMed

Humle, Nanna; Johnsen, Kasper Bendix; Arendt, Gitte Abildgaard; Nielsen, Rikke Paludan; Moos, Torben; Thomsen, Louiza Bohn

2016-01-01

This review presents the present-day literature on the anatomy and physiological mechanisms of the blood-brain barrier and the problematic of cerebral drug delivery in relation to malignant brain tumors. First step in treatment of malignant brain tumors is resection, but there is a high risk of single remnant infiltrative tumor cells in the outer zone of the brain tumor. These infiltrative single-cells will be supplied by capillaries with an intact BBB as opposed to the partly leaky BBB found in the tumor tissue before resection. Even though BBB penetrance of a chemotherapeutic agent is considered irrelevant though the limited success rate for chemotherapeutic treatability of GBM tumors indicate otherwise. Therefore drug delivery strategies to cerebral cancer after resection should be tailored to being able to both penetrate the intact BBB and target the cancer cells. In this review the intact bloodbrain barrier and cerebral cancer with main focus on glioblastoma multiforme (GBM) is introduced. The GBM induced formation of a blood-tumor barrier and the consequences hereof is described and discussed with emphasis on the impact these changes of the BBB has on drug delivery to GBM. The most commonly used drug carriers for drug delivery to GBM is described and the current drug delivery strategies for glioblastoma multiforme including possible routes through the BBB and epitopes, which can be targeted on the GBM cells is outlined. Overall, this review aims to address targeted drug delivery in GBM treatment when taking the differing permeability of the BBB into consideration.

Sprouty2 enhances the tumorigenic potential of glioblastoma cells.

PubMed

Park, Jong-Whi; Wollmann, Guido; Urbiola, Carles; Fogli, Barbara; Florio, Tullio; Geley, Stephan; Klimaschewski, Lars

2018-02-23

Sprouty2 (SPRY2), a feedback regulator of receptor tyrosine kinase (RTK) signaling, has been shown to be associated with drug resistance and cell proliferation in glioblastoma (GBM), but the underlying mechanisms are still poorly defined. SPRY2 expression and survival patterns of patients with gliomas were analyzed using publicly available databases. Effects of RNA interference targeting SPRY2 on cellular proliferation in established GBM or patient-derived GBM stemlike cells were examined. Loss- or gain-of-function of SPRY2 to regulate the tumorigenic capacity was assessed in both intracranial and subcutaneous xenografts. SPRY2 was found to be upregulated in GBM, which correlated with reduced survival in GBM patients. SPRY2 knockdown significantly impaired proliferation of GBM cells but not of normal astrocytes. Silencing of SPRY2 increased epidermal growth factor-induced extracellular signal-regulated kinase (ERK) and Akt activation causing premature onset of DNA replication, increased DNA damage, and impaired proliferation, suggesting that SPRY2 suppresses DNA replication stress. Abrogating SPRY2 function strongly inhibited intracranial tumor growth and led to significantly prolonged survival of U87 xenograft-bearing mice. In contrast, SPRY2 overexpression promoted tumor propagation of low-tumorigenic U251 cells. The present study highlights an antitumoral effect of SPRY2 inhibition that is based on excessive activation of ERK signaling and DNA damage response, resulting in reduced cell proliferation and increased cytotoxicity, proposing SPRY2 as a promising pharmacological target in GBM patients.

Variant allele frequency enrichment analysis in vitro reveals sonic hedgehog pathway to impede sustained temozolomide response in GBM.

PubMed

Biswas, Nidhan K; Chandra, Vikas; Sarkar-Roy, Neeta; Das, Tapojyoti; Bhattacharya, Rabindra N; Tripathy, Laxmi N; Basu, Sunandan K; Kumar, Shantanu; Das, Subrata; Chatterjee, Ankita; Mukherjee, Ankur; Basu, Pryiadarshi; Maitra, Arindam; Chattopadhyay, Ansuman; Basu, Analabha; Dhara, Surajit

2015-01-21

Neoplastic cells of Glioblastoma multiforme (GBM) may or may not show sustained response to temozolomide (TMZ) chemotherapy. We hypothesize that TMZ chemotherapy response in GBM is predetermined in its neoplastic clones via a specific set of mutations that alter relevant pathways. We describe exome-wide enrichment of variant allele frequencies (VAFs) in neurospheres displaying contrasting phenotypes of sustained versus reversible TMZ-responses in vitro. Enrichment of VAFs was found on genes ST5, RP6KA1 and PRKDC in cells showing sustained TMZ-effect whereas on genes FREM2, AASDH and STK36, in cells showing reversible TMZ-effect. Ingenuity pathway analysis (IPA) revealed that these genes alter cell-cycle, G2/M-checkpoint-regulation and NHEJ pathways in sustained TMZ-effect cells whereas the lysine-II&V/phenylalanine degradation and sonic hedgehog (Hh) pathways in reversible TMZ-effect cells. Next, we validated the likely involvement of the Hh-pathway in TMZ-response on additional GBM neurospheres as well as on GBM patients, by extracting RNA-sequencing-based gene expression data from the TCGA-GBM database. Finally, we demonstrated TMZ-sensitization of a TMZ non-responder neurosphere in vitro by treating them with the FDA-approved pharmacological Hh-pathway inhibitor vismodegib. Altogether, our results indicate that the Hh-pathway impedes sustained TMZ-response in GBM and could be a potential therapeutic target to enhance TMZ-response in this malignancy.

Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM.

PubMed

Dai, Dong-Wei; Lu, Qiong; Wang, Lai-Xing; Zhao, Wen-Yuan; Cao, Yi-Qun; Li, Ya-Nan; Han, Guo-Sheng; Liu, Jian-Min; Yue, Zhi-Jian

2013-10-14

MiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive. The association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation. Here we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells. Taken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM.

Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.

PubMed

Nigim, Fares; Cavanaugh, Jill; Patel, Anoop P; Curry, William T; Esaki, Shin-ichi; Kasper, Ekkehard M; Chi, Andrew S; Louis, David N; Martuza, Robert L; Rabkin, Samuel D; Wakimoto, Hiroaki

2015-07-01

Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

Integrative radiogenomic analysis for multicentric radiophenotype in glioblastoma

PubMed Central

Kong, Doo-Sik; Kim, Jinkuk; Lee, In-Hee; Kim, Sung Tae; Seol, Ho Jun; Lee, Jung-Il; Park, Woong-Yang; Ryu, Gyuha; Wang, Zichen; Ma'ayan, Avi; Nam, Do-Hyun

2016-01-01

We postulated that multicentric glioblastoma (GBM) represents more invasiveness form than solitary GBM and has their own genomic characteristics. From May 2004 to June 2010 we retrospectively identified 51 treatment-naïve GBM patients with available clinical information from the Samsung Medical Center data registry. Multicentricity of the tumor was defined as the presence of multiple foci on the T1 contrast enhancement of MR images or having high signal for multiple lesions without contiguity of each other on the FLAIR image. Kaplan-Meier survival analysis demonstrated that multicentric GBM had worse prognosis than solitary GBM (median, 16.03 vs. 20.57 months, p < 0.05). Copy number variation (CNV) analysis revealed there was an increase in 11 regions, and a decrease in 17 regions, in the multicentric GBM. Gene expression profiling identified 738 genes to be increased and 623 genes to be decreased in the multicentric radiophenotype (p < 0.001). Integration of the CNV and expression datasets identified twelve representative genes: CPM, LANCL2, LAMP1, GAS6, DCUN1D2, CDK4, AGAP2, TSPAN33, PDLIM1, CLDN12, and GTPBP10 having high correlation across CNV, gene expression and patient outcome. Network and enrichment analyses showed that the multicentric tumor had elevated fibrotic signaling pathways compared with a more proliferative and mitogenic signal in the solitary tumors. Noninvasive radiological imaging together with integrative radiogenomic analysis can provide an important tool in helping to advance personalized therapy for the more clinically aggressive subset of GBM. PMID:26863628

The Emergence of a Lanthanide-rich Kilonova Following the Merger of Two Neutron Stars

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanvir, N. R.; Levan, A. J.; González-Fernández, C.

Here, we report the discovery and monitoring of the near-infrared counterpart (AT2017gfo) of a binary neutron-star merger event detected as a gravitational wave source by Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)/Virgo (GW170817) and as a short gamma-ray burst by Fermi Gamma-ray Burst Monitor (GBM) and Integral SPI-ACS (GRB 170817A). The evolution of the transient light is consistent with predictions for the behavior of a "kilonova/macronova" powered by the radioactive decay of massive neutron-rich nuclides created via r-process nucleosynthesis in the neutron-star ejecta. In particular, evidence for this scenario is found from broad features seen in Hubble Space Telescope infrared spectroscopy, similar to those predicted for lanthanide-dominated ejecta, and the much slower evolution in the near-infraredmore » $${K}_{{\\rm{s}}}$$-band compared to the optical. This indicates that the late-time light is dominated by high-opacity lanthanide-rich ejecta, suggesting nucleosynthesis to the third r-process peak (atomic masses $$A\\approx 195$$). This discovery thus confirms that neutron-star mergers produce kilo-/macronovae and that they are at least a major—if not the dominant—site of rapid neutron capture nucleosynthesis in the universe.« less

The Emergence of a Lanthanide-rich Kilonova Following the Merger of Two Neutron Stars

DOE PAGES

Tanvir, N. R.; Levan, A. J.; González-Fernández, C.; ...

2017-10-16

Here, we report the discovery and monitoring of the near-infrared counterpart (AT2017gfo) of a binary neutron-star merger event detected as a gravitational wave source by Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)/Virgo (GW170817) and as a short gamma-ray burst by Fermi Gamma-ray Burst Monitor (GBM) and Integral SPI-ACS (GRB 170817A). The evolution of the transient light is consistent with predictions for the behavior of a "kilonova/macronova" powered by the radioactive decay of massive neutron-rich nuclides created via r-process nucleosynthesis in the neutron-star ejecta. In particular, evidence for this scenario is found from broad features seen in Hubble Space Telescope infrared spectroscopy, similar to those predicted for lanthanide-dominated ejecta, and the much slower evolution in the near-infraredmore » $${K}_{{\\rm{s}}}$$-band compared to the optical. This indicates that the late-time light is dominated by high-opacity lanthanide-rich ejecta, suggesting nucleosynthesis to the third r-process peak (atomic masses $$A\\approx 195$$). This discovery thus confirms that neutron-star mergers produce kilo-/macronovae and that they are at least a major—if not the dominant—site of rapid neutron capture nucleosynthesis in the universe.« less

Photodynamic diagnosis and related optical techniques for the management of malignant glioma

NASA Astrophysics Data System (ADS)

Sroka, R.; Stepp, H.; Beyer, W.; Markwardt, N.; Rühm, A.

2017-04-01

Malignant gliomas are a devastating brain tumor disease with very poor prognosis. Stereotactic biopsy sampling is routinely used in larger neurosurgical centers to confirm the diagnosis of a suspected brain tumor. This procedure is associated with risk of blood vessel rupture as well as false-negative results. Recent investigations suggest a potential of light-based techniques to improve both therapy and diagnosis of GBM. Optical guidance can be utilized to improve the biopsy sampling procedure in terms of safety, reliability, and efficacy. Recording of optical signals (transmission, remission, fluorescence) can be potentially integrated into a biopsy needle for providing optical detection of tumor tissue and blood vessel recognition during the biopsy sampling. Optical signals can also be used for monitoring purposes during photodynamic therapy. Here, fluorescence signals recorded before the treatment indicate the presence and accumulation level of photosensitizer, while photobleaching of the photosensitizer fluorescence during the treatment can be used as a measure of the effectiveness of the therapy. Finally, transmitted light can reveal problematic tissue-optical conditions as well as changes of the optical properties of the treated tissue, which may be relevant with regard to treatment prognosis and strategy. Different optical concepts for interstitial PDT monitoring and optical tissue property assessment are presented.

Segmentation of peritumoral oedema offers a valuable radiological feature of cerebral metastasis

PubMed Central

Zhou, Chengcheng; Yang, Zixiao; Yao, Zhengwei; Yin, Bo; Pan, Jiawei; Yu, Yang; Zhu, Wei; Mao, Ying

2016-01-01

Objective: Peritumoral oedema (PTO) is commonly observed on MRI in malignant brain tumours including brain metastasis (bMET) and glioblastoma multiforme (GBM). This study aimed to differentiate bMET from GBM by comparing the volume ratio of PTO to tumour lesion (Rvol). Methods: 56 patients with solitary bMET or GBM were enrolled, and MRI was analyzed by a semi-automatic methodology based on MATLAB (Mathworks, Natick, MA). The PTO volume (Voedema) was segmented for quantification using T2 fluid-attenuated inversion-recovery images, while the tumour volume was quantified with enhanced T1 images. The quantitative volume of the tumour, PTO and the ratio of PTO to tumour were interpreted using SPSS® (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) by considering different locations and pathologies. Results: The tumour volumes of supratentorial GBM, supratentorial bMET (supra-bMET) and infratentorial bMET were 32.22 ± 21.9, 18.45 ± 17.28 and 11.40 ± 5.63 ml, respectively. The corresponding Voedema were 44.08 ± 25.84, 73.20 ± 40.35 and 23.74 ± 7.78 ml, respectively. The Voedema difference between supratentorial and infratentorial lesions is significant (p-value = 0.002). Supra-bMET has a smaller tumour volume (p-value = 0.032), but a larger PTO (p-value = 0.007). The ratio of Voedema to the tumour volume in bMET is statistically higher than that in GBM (p-value = 0.015). The cut-off ratio for identifying bMET from GBM is 3.9, with a specificity and sensitivity of 90.0% and 68.8%, respectively. Conclusion: Segmentation is an efficient method to quantify irregular PTO. bMET possesses more extensive oedema with smaller tumour volume than does GBM. The Rvol is a valuable index to distinguish bMET from GBM. Advances in knowledge: This study presents a new method for the quantitation of PTO to differentiate bMET from GBM. PMID:27119727

Segmentation of peritumoral oedema offers a valuable radiological feature of cerebral metastasis.

PubMed

Zhou, Chengcheng; Yang, Zixiao; Yao, Zhengwei; Yin, Bo; Pan, Jiawei; Yu, Yang; Zhu, Wei; Hua, Wei; Mao, Ying

2016-07-01

Peritumoral oedema (PTO) is commonly observed on MRI in malignant brain tumours including brain metastasis (bMET) and glioblastoma multiforme (GBM). This study aimed to differentiate bMET from GBM by comparing the volume ratio of PTO to tumour lesion (Rvol). 56 patients with solitary bMET or GBM were enrolled, and MRI was analyzed by a semi-automatic methodology based on MATLAB (Mathworks, Natick, MA). The PTO volume (Voedema) was segmented for quantification using T2 fluid-attenuated inversion-recovery images, while the tumour volume was quantified with enhanced T1 images. The quantitative volume of the tumour, PTO and the ratio of PTO to tumour were interpreted using SPSS(®) (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) by considering different locations and pathologies. The tumour volumes of supratentorial GBM, supratentorial bMET (supra-bMET) and infratentorial bMET were 32.22 ± 21.9, 18.45 ± 17.28 and 11.40 ± 5.63 ml, respectively. The corresponding Voedema were 44.08 ± 25.84, 73.20 ± 40.35 and 23.74 ± 7.78 ml, respectively. The Voedema difference between supratentorial and infratentorial lesions is significant (p-value = 0.002). Supra-bMET has a smaller tumour volume (p-value = 0.032), but a larger PTO (p-value = 0.007). The ratio of Voedema to the tumour volume in bMET is statistically higher than that in GBM (p-value = 0.015). The cut-off ratio for identifying bMET from GBM is 3.9, with a specificity and sensitivity of 90.0% and 68.8%, respectively. Segmentation is an efficient method to quantify irregular PTO. bMET possesses more extensive oedema with smaller tumour volume than does GBM. The Rvol is a valuable index to distinguish bMET from GBM. This study presents a new method for the quantitation of PTO to differentiate bMET from GBM.

GBM skin metastasis: a case report and review of the literature

PubMed Central

Lewis, Gary D; Rivera, Andreana L; Tremont-Lukats, Ivo W; Ballester-Fuentes, Leomar Y; Zhang, Yi Jonathan; Teh, Bin S

2017-01-01

Glioblastoma (GBM) is the most common type of malignant tumor found in the brain, and acts very aggressively by quickly and diffusely infiltrating the surrounding brain parenchyma. Despite its aggressive nature, GBM is rarely found to spread extracranially and develop distant metastases. The most common sites of these rare metastases are the lungs, pleura and cervical lymph nodes. There are also a few case reports of skin metastasis. We present the clinical, imaging and pathologic features of a case of a GBM with metastasis to the soft tissue scar and skin near the original craniotomy site. In addition, we discuss the details of this case in the context of the previously reported literature. PMID:28718312

Fermi Gamma-Ray Space Telescope

NASA Technical Reports Server (NTRS)

McEnery, Julie E.; Michelson, Peter F.; Paclesas, William S.; Ritz, Steven

2012-01-01

The Fermi Gamma-ray Space Telescope, launched in June 2008, is an observatory designed to survey the high-energy gamma-ray sky. The primary instrument, the Large Area Telescope (LAT), provides observations from 20 MeV to greater than 300 GeV. A second instrument, the Gamma-ray Burst Monitor (GBM), provides observations of transients from less than 10 keV to 40 MeV. We describe the design and performance of the instruments and their subsystems, the spacecraft and the ground system.

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

PubMed Central

Koch, Katharina; Hartmann, Rudolf; Schröter, Friederike; Suwala, Abigail Kora; Maciaczyk, Donata; Krüger, Andrea Caroline; Willbold, Dieter; Kahlert, Ulf Dietrich; Maciaczyk, Jaroslaw

2016-01-01

Glioblastoma (GBM) is the most malignant brain tumor with very limited therapeutic options. Standard multimodal treatments, including surgical resection and combined radio-chemotherapy do not target the most aggressive subtype of glioma cells, brain tumor stem cells (BTSCs). BTSCs are thought to be responsible for tumor initiation, progression, and relapse. Furthermore, they have been associated with the expression of mesenchymal features as a result of epithelial-mesenchymal transition (EMT) thereby inducing tumor dissemination and chemo resistance. Using high resolution proton nuclear magnetic resonance spectroscopy (1H NMR) on GBM cell cultures we provide evidence that the expression of well-known EMT activators of the ZEB, TWIST and SNAI families and EMT target genes N-cadherin and VIMENTIN is associated with aberrant choline metabolism. The cholinic phenotype is characterized by high intracellular levels of phosphocholine and total choline derivatives and was associated with malignancy in various cancers. Both genetic and pharmacological inhibition of the cardinal choline metabolism regulator choline kinase alpha (CHKα) significantly reduces the cell viability, invasiveness, clonogenicity, and expression of EMT associated genes in GBM cells. Moreover, in some cell lines synergetic cytotoxic effects were observed when combining the standard of care chemotherapeutic temozolomide with the CHKα inhibitor V-11-0711. Taken together, specific inhibition of the enzymatic activity of CHKα is a powerful strategy to suppress EMT which opens the possibility to target chemo-resistant BTSCs through impairing their mesenchymal transdifferentiation. Moreover, the newly identified EMT-oncometabolic network may be helpful to monitor the invasive properties of glioblastomas and the success of anti-EMT therapy. PMID:27705917

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?

PubMed

Prinzing, Brooke L; Gottschalk, Stephen M; Krenciute, Giedre

2018-05-01

The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics. Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function. Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients.

MiR-26a enhances the radiosensitivity of glioblastoma multiforme cells through targeting of ataxia–telangiectasia mutated

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Pin; Lan, Jin; Ge, Jianwei

Glioblastoma multiforme (GBM) is notoriously resistant to radiation, and consequently, new radiosensitizers are urgently needed. MicroRNAs are a class of endogenous gene modulators with emerging roles in DNA repair. We found that overexpression of miR-26a can enhance radiosensitivity and reduce the DNA repair ability of U87 cells. However, knockdown miR-26a in U87 cells could act the converse manner. Mechanistically, this effect is mediated by direct targeting of miR-26a to the 3′UTR of ATM, which leads to reduced ATM levels and consequent inhibition of the homologous recombination repair pathway. These results suggest that miR-26a may act as a new radiosensitizer ofmore » GBM. - Highlights: ●miR-26a directly target ATM in GBM cells. ●miR-26a enhances the radiosensitivity of GBM cells. ●miR-26a could reduce the DNA repair capacity of GBM cells.« less

Patient-specific orthotopic glioblastoma xenograft models recapitulate the histopathology and biology of human glioblastomas in situ.

PubMed

Joo, Kyeung Min; Kim, Jinkuk; Jin, Juyoun; Kim, Misuk; Seol, Ho Jun; Muradov, Johongir; Yang, Heekyoung; Choi, Yoon-La; Park, Woong-Yang; Kong, Doo-Sik; Lee, Jung-Il; Ko, Young-Hyeh; Woo, Hyun Goo; Lee, Jeongwu; Kim, Sunghoon; Nam, Do-Hyun

2013-01-31

Frequent discrepancies between preclinical and clinical results of anticancer agents demand a reliable translational platform that can precisely recapitulate the biology of human cancers. Another critical unmet need is the ability to predict therapeutic responses for individual patients. Toward this goal, we have established a library of orthotopic glioblastoma (GBM) xenograft models using surgical samples of GBM patients. These patient-specific GBM xenograft tumors recapitulate histopathological properties and maintain genomic characteristics of parental GBMs in situ. Furthermore, in vivo irradiation, chemotherapy, and targeted therapy of these xenograft tumors mimic the treatment response of parental GBMs. We also found that establishment of orthotopic xenograft models portends poor prognosis of GBM patients and identified the gene signatures and pathways signatures associated with the clinical aggressiveness of GBMs. Together, the patient-specific orthotopic GBM xenograft library represent the preclinically and clinically valuable "patient tumor's phenocopy" that represents molecular and functional heterogeneity of GBMs. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

IGFBP2 promotes glioma tumor stem cell expansion and survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsieh, David, E-mail: dhs.zfs@gmail.com; Hsieh, Antony; Stea, Baldassarre

2010-06-25

IGFBP2 is overexpressed in the most common brain tumor, glioblastoma (GBM), and its expression is inversely correlated to GBM patient survival. Previous reports have demonstrated a role for IGFBP2 in glioma cell invasion and astrocytoma development. However, the function of IGFBP2 in the restricted, self-renewing, and tumorigenic GBM cell population comprised of tumor-initiating stem cells has yet to be determined. Herein we demonstrate that IGFBP2 is overexpressed within the stem cell compartment of GBMs and is integral for the clonal expansion and proliferative properties of glioma stem cells (GSCs). In addition, IGFBP2 inhibition reduced Akt-dependent GSC genotoxic and drug resistance.more » These results suggest that IGFBP2 is a selective malignant factor that may contribute significantly to GBM pathogenesis by enriching for GSCs and mediating their survival. Given the current dearth of selective molecular targets against GSCs, we anticipate our results to be of high therapeutic relevance in combating the rapid and lethal course of GBM.« less