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

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

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

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

Abatement of thermal noise due to internal damping in 2D oscillators with rapidly rotating test masses.

Mechanical oscillators can be sensitive to very small forces. Low frequency effects are up-converted to higher frequency by rotating the oscillator. We show that for 2-dimensional oscillators rotating at frequency much higher than the signal the thermal noise force due to internal losses and competing with it is abated as the square root of the rotation frequency. We also show that rotation at frequency much higher than the natural one is possible if the oscillator has 2 degrees of freedom, and describe how this property applies also to torsion balances. In addition, in the 2D oscillator the signal is up-converted above resonance without being attenuated as in the 1D case, thus relaxing requirements on the read out. This work indicates that proof masses weakly coupled in 2D and rapidly rotating can play a major role in very small force physics experiments

Luminance-polarity distribution across the symmetry axis affects the electrophysiological response to symmetry

Electrophysiological studies of symmetry have found a difference wave termed the Sustained Posterior Negativity (SPN) related to the presence of symmetry. Yet the extent to which the SPN is modulated by luminance-polarity and colour content is unknown. Here we examine how luminance-polarity distribution across the symmetry axis, grouping by luminance polarity, and the number of colours in the stimuli, modulate the SPN. Stimuli were dot patterns arranged either symmetrically or quasi-randomly. There were several arrangements: ’segregated’-symmetric dots were of one polarity and random dots of the other; ‘unsegregated’-symmetric dots were of both polarities in equal proportions; ‘anti-symmetric’-dots were of opposite polarity across the symmetry axis; ‘polarity-grouped anti-symmetric’-as anti-symmetric but with half the pattern of one polarity and the other opposite; multi-colour symmetric patterns made of either two, three and four colours. We found that the SPN is: reduced by the amount of position-symmetry, sensitive to luminance-polarity mismatch across the symmetry axis and not modulated by the number of colours in the stimuli. Our results show that the sustained nature of the SPN coincides with the late onset of a topographic microstate sensitive to symmetry. These findings emphasise the importance of not only position symmetry, but also luminance polarity matching across the symmetry axis

Constraints on the steady and pulsed very high energy gamma-ray emission from observations of PSR B1951+32/CTB 80 with the MAGIC Telescope

We report on very high energy gamma-observations with the MAGIC Telescope of the pulsar PSR B1951+32 and its associated nebula, CTB 80. Our data constrain the cutoff energy of the pulsar to be less than 32 GeV, assuming the pulsed gamma-ray emission to be exponentially cut off. The upper limit on the flux of pulsed gamma-ray emission above 75 GeV is 4.3*10^-11 photons cm^-2 sec^-1, and the upper limit on the flux of steady emission above 140 GeV is 1.5*10^-11 photons cm^-2 sec^-1. We discuss our results in the framework of recent model predictions and other studies.Comment: 7 pages, 7 figures, replaced with published versio

First bounds on the very high energy gamma-ray emission from Arp 220

Using the Major Atmospheric Gamma Imaging Cherenkov Telescope (MAGIC), we have observed the nearest ultra-luminous infrared galaxy Arp 220 for about 15 hours. No significant signal was detected within the dedicated amount of observation time. The first upper limits to the very high energy $\gamma$-ray flux of Arp 220 are herein reported and compared with theoretical expectations.Comment: Accepted for publication in Ap

MAGIC upper limits on the very high energy emission from GRBs

The fast repositioning system of the MAGIC Telescope has allowed during its first data cycle, between 2005 and the beginning of year 2006, observing nine different GRBs as possible sources of very high energy gammas. These observations were triggered by alerts from Swift, HETE-II, and Integral; they started as fast as possible after the alerts and lasted for several minutes, with an energy threshold varying between 80 and 200 GeV, depending upon the zenith angle of the burst. No evidence for gamma signals was found, and upper limits for the flux were derived for all events, using the standard analysis chain of MAGIC. For the bursts with measured redshift, the upper limits are compatible with a power law extrapolation, when the intrinsic fluxes are evaluated taking into account the attenuation due to the scattering in the Metagalactic Radiation Field (MRF).Comment: 25 pages, 9 figures, final version accepted by ApJ. Changet title to "MAGIC upped limits on the VERY high energy emission from GRBs", re-organized chapter with description of observation, removed non necessaries figures, added plot of effective area depending on zenith angle, added an appendix explaining the upper limit calculation, added some reference

Systematic search for VHE gamma-ray emission from X-ray bright high-frequency BL Lac objects

All but three (M87, BL Lac and 3C 279) extragalactic sources detected so far at very high energy (VHE) gamma-rays belong to the class of high-frequency peaked BL Lac (HBL) objects. This suggested to us a systematic scan of candidate sources with the MAGIC telescope, based on the compilation of X-ray blazars by Donato et al. (2001). The observations took place from December 2004 to March 2006 and cover sources on the northern sky visible under small zenith distances zd < 30 degrees at culmination. The sensitivity of the search was planned for detecting X-ray bright F(1 keV) > 2 uJy) sources emitting at least the same energy flux at 200 GeV as at 1 keV. In order to avoid strong gamma-ray attenuation close to the energy threshold, the redshift of the sources was constrained to values z<0.3. Of the fourteen sources observed, 1ES 1218+304 and 1ES 2344+514 have been detected in addition to the known bright TeV blazars Mrk 421 and Mrk 501. A marginal excess of 3.5 sigma from the position of 1ES 1011+496 was observed and has been confirmed as a source of VHE gamma-rays by a second MAGIC observation triggered by a high optical state (Albert et al. 2007). For the remaining sources, we present here the 99% confidence level upper limits on the integral flux above ~200 GeV. We characterize the sample of HBLs (including all HBLs detected at VHE so far) by looking for correlations between their multi-frequency spectral indices determined from simultaneous optical, archival X-ray, and radio luminosities, finding that the VHE emitting HBLs do not seem to constitute a unique subclass. The absorption corrected gamma-ray luminosities at 200 GeV of the HBLs are generally not higher than their X-ray luminosities at 1 keV.Comment: 15 pages, 7 figures, 5 tables, submitted to ApJ (revised version