Background: CB-839 is a first-in-class highly selective inhibitor of glutaminase (GLS), a key enzyme in the utilization of glutamine by many cancer types. CB-839 has broad monotherapy activity in ...preclinical models, including RCC, where GLS is highly expressed. CB-839 combines synergistically with everolimus in vitro and in vivo in pre-clinical models to inhibit both glutamine and glucose metabolism and tumor cell growth. CX-839-001 is an ongoing Phase 1 study of CB-839 as monotherapy and in combination with approved agents in multiple indications. It was previously reported that CB-839 robustly inhibits GLS in blood and tumors and is well tolerated as monotherapy and in combination with everolimus. We report here updated results of the combination of CB-839 and everolimus (CBE) in pts with previously treated advanced/metastatic (adv/met) clear cell (cc) and papillary (pap) RCC. Material and Methods: Key eligibility criteria included adv/met RCC with cc or pap histology, ≤ 4 prior lines of therapy (if cc histology at least 1 prior VEGF targeting therapy), ECOG 0-1, and RECIST measurable disease. Prior treatment with mTOR inhibitor and checkpoint inhibitor were allowed. Pts received escalating doses of CB-839 (400-800 mg PO BID) in combination with fixed-dose everolimus at 10 mg PO QD. Disease assessment per RECIST 1.1 was performed every 8 weeks. Upon demonstration of safety and tolerability expansion cohorts of CBE in cc and pap RCC were opened. Results: To date, 10 pts have received CBE on the dose escalation cohort: 7 pts at 400 mg BID and 3 pts at 600 mg BID with dose escalation ongoing. Histologic subtypes were cc (6 pts), pap (2 pts) and other (2 pts, chromophobe and hereditary FH mutant). The median number of prior therapies was 2 and 9 pts had received prior TKI, 2 pts mTOR inhibitor, and 3 pts checkpoint inhibitor (CPi) therapy. IMDC risk status was intermediate for all 10 pts. The CBE combination was well tolerated, with 1 DLT (G3 rash) occurring at the 400 mg BID dose level. There were no G4/5 AEs and G3 AEs were generally consistent with late stage cancer and/or everolimus toxicity with none occurring in >1 pt. In the 8 pts with cc/pap RCC, best tumor response was PR in 1 pt (12.5%) and SD in 7 pts (88%) resulting in a DCR (CR + PR + SD) of 100%. 7 of 8 cc/pap RCC pts remain on study treatment at a median of 6.5 months. In the 2 pts with non-cc/non-pap RCC best tumor response was PD. Conclusions: The CBE combination has been well tolerated and demonstrates clinical activity in patients with 2nd line and later adv/met RCC, including pts with prior exposure to mTORi and CPi. In cc and pap RCC the DCR has been 100% with median time on study 6.5+ months and 7 of 8 pts remaining on study treatment at data cutoff. Updated safety and efficacy data for the CBE dose escalation and expansion cohorts will be presented.
Observations of the shell-type supernova remnant SN1006 have been carried out with the HESS system of Cherenkov telescopes during 2003 (18.2 h with two operating telescopes) and 2004 (6.3 h with all ...four telescopes). No evidence for TeV γ-ray emission from any compact or extended region associated with the remnant is seen and resulting upper limits at the 99.9% confidence level are up to a factor 10 lower than previously-published fluxes from CANGAROO. For SN1006 at its current epoch of evolution we define limits for a number of important global parameters. Upper limits on the γ-ray luminosity (for E = 0.26 to 10 TeV, distance d = 2 kpc) of $L_\gamma < 1.7$ $\times$ 1033 erg s-1, and the total energy in corresponding accelerated protons, $W_{\rm p}<1.6$ $\times$ 1050 erg are estimated (for proton energies $E_{\rm p} \sim 1.5$ to 60 TeV and assuming the lowest value $n=0.05$ cm-3 of the ambient target density discussed in literature). Extending this estimate to cover the range of proton energies observed in the cosmic ray spectrum up to the knee (we take here $E_{\rm p} \sim$ 1 GeV to 3 PeV, assuming a differential particle index -2) gives $W_{\rm p}<6.3$ $\times$ 1050 erg. A lower limit on the post-shock magnetic field of $B>25~\mu$G results when considering the synchrotron/inverse-Compton framework for the observed X-ray flux and γ-ray upper limits.
Observations of the Crab nebula with HESS Aharonian, F.; Akhperjanian, A. G.; Bazer-Bachi, A. R. ...
Astronomy and astrophysics (Berlin),
10/2006, Letnik:
457, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Context.The Crab nebula was observed with the HESS stereoscopic Cherenkov-telescope array between October 2003 and January 2005 for a total of 22.9 h (after data quality selection). This period of ...time partly overlapped with the commissioning phase of the experiment; observations were made with three operational telescopes in late 2003 and with the complete 4 telescope array in January–February 2004 and October 2004–January 2005. Aims.Observations of the Crab nebula are discussed and used as an example to detail the flux and spectral analysis procedures of HESS. The results are used to evaluate the systematic uncertainties in HESS flux measurements. Methods.The Crab nebula data are analysed using standard HESS analysis procedures, which are described in detail. The flux and spectrum of γ-rays from the source are calculated on run-by-run and monthly time-scales, and a correction is applied for long-term variations in the detector sensitivity. Comparisons of the measured flux and spectrum over the observation period, along with the results from a number of different analysis procedures are used to estimate systematic uncertainties in the measurements. Results.The data, taken at a range of zenith angles between $45^{\circ}$ and $65^{\circ}$, show a clear signal with over 7500 excess events. The energy spectrum is found to follow a power law with an exponential cutoff, with photon index $\Gamma = 2.39$ ± $0.03_{{\rm {stat}}}$ and cutoff energy $E_{\rm c} = (14.3 \pm 2.1_{{\rm {stat}}})~{\rm TeV}$ between 440 GeV and 40 TeV. The observed integral flux above 1 TeV is $(2.26 \pm 0.08_{{\rm {stat}}}) \times 10^{-11}~{{\rm cm}^{-2}~{\rm s}^{-1}}$. The estimated systematic error on the flux measurement is estimated to be 20%, while the estimated systematic error on the spectral slope is 0.1.
The measurement of an excess in the cosmic-ray electron spectrum between 300 and 800 GeV by the ATIC experiment has – together with the PAMELA detection of a rise in the positron fraction up to ...≈100 GeV – motivated many interpretations in terms of dark matter scenarios; alternative explanations assume a nearby electron source like a pulsar or supernova remnant. Here we present a measurement of the cosmic-ray electron spectrum with H.E.S.S. starting at 340 GeV. While the overall electron flux measured by H.E.S.S. is consistent with the ATIC data within statistical and systematic errors, the H.E.S.S. data exclude a pronounced peak in the electron spectrum as suggested for interpretation by ATIC. The H.E.S.S. data follow a power-law spectrum with spectral index of 3.0±0.1(stat.)± 0.3(syst.), which steepens at about 1 TeV.
Context.The detection of gamma rays in the very-high-energy (VHE) energy range (100 GeV–100 TeV) provides a direct view of the parent population of ultra-relativistic particles found in astrophysical ...sources. For this reason, VHE gamma rays are useful for understanding the underlying astrophysical processes in non-thermal sources. Aims.We investigate unidentified VHE gamma-ray sources that have been discovered with HESS in the most sensitive blind survey of the Galactic plane at VHE energies conducted so far. Methods.The HESS array of imaging atmospheric Cherenkov telescopes (IACTs) has a high sensitivity compared with previous instruments (~$0.01\:\mathrm{Crab}$ in 25 h observation time for a $5\sigma$ point-source detection), and with its large field of view, is well suited for scan-based observations. The on-going HESS survey of the inner Galaxy has revealed a large number of new VHE sources, and for each we attempt to associate the VHE emission with multi-wavelength data in the radio through X-ray wavebands. Results. For each of the eight unidentified VHE sources considered here, we present the energy spectra and sky maps of the sources and their environment. The VHE morphology is compared with available multi-wavelength data (mainly radio and X-rays). No plausible counterparts are found.
We report the discovery of very-high-energy (VHE) g-ray emission of the binary system PSR B 1259-63/SS 2883 of a radio pulsar orbiting a massive, luminous Be star in a highly eccentric orbit. The ...observations around the 2004 periastron passage of the pulsar were performed with the four 13 m Cherenkov telescopes of the HESS experiment, recently installed in Namibia and in full operation since December 2003. Between February and June 2004, a g-ray signal from the binary system was detected with a total significance above 13s. The flux was found to vary significantly on timescales of days which makes PSR B 1259-63 the first variable galactic source of VHE g-rays observed so far. Strong emission signals were observed in pre- and post-periastron phases with a flux minimum around periastron, followed by a gradual flux decrease in the months after. The measured time-averaged energy spectrum above a mean threshold energy of 380 GeV can be fitted by a simple power law F0(E/1 TeV)G with a photon index G = 2.7 c 0.2stat c 0.2sys and flux normalisation F0 = (1.3 c 0.1stat c 0.3sys) x 10-12 TeV-1 cm-2 s-1. This detection of VHE g-rays provides unambiguous evidence for particle acceleration to multi-TeV energies in the binary system. In combination with coeval observations of the X-ray synchrotron emission by the RXTE and INTEGRAL instruments, and assuming the VHE g-ray emission to be produced by the inverse Compton mechanism, the magnetic field strength can be directly estimated to be of the order of 1 G.
The diffuse extragalactic background light consists of the sum of the starlight emitted by galaxies through the history of the Universe, and it could also have an important contribution from the ...‘first stars’, which may have formed before galaxy formation began. Direct measurements are difficult and not yet conclusive, owing to the large uncertainties caused by the bright foreground emission associated with zodiacal light. An alternative approach is to study the absorption features imprinted on the γ-ray spectra of distant extragalactic objects by interactions of those photons with the background light photons. Here we report the discovery of γ-ray emission from the blazars H 2356 - 309 and 1ES 1101 - 232, at redshifts z = 0.165 and z = 0.186, respectively. Their unexpectedly hard spectra provide an upper limit on the background light at optical/near-infrared wavelengths that appears to be very close to the lower limit given by the integrated light of resolved galaxies. The background flux at these wavelengths accordingly seems to be strongly dominated by the direct starlight from galaxies, thus excluding a large contribution from other sources—in particular from the first stars formed. This result also indicates that intergalactic space is more transparent to γ-rays than previously thought.
Aims. Recent theoretical predictions of the lowest very high energy (VHE) luminosity of SN 1006 are only a factor 5 below the previously published HESS upper limit, thus motivating further in-depth ...observations of this source. Methods. Deep observations at VHE energies (above 100 GeV) were carried out with the high energy stereoscopic system (HESS) of Cherenkov Telescopes from 2003 to 2008. More than 100 h of data have been collected and subjected to an improved analysis procedure. Results. Observations resulted in the detection of VHE γ-rays from SN 1006. The measured γ-ray spectrum is compatible with a power-law, the flux is of the order of 1% of that detected from the Crab Nebula, and is thus consistent with the previously established HESS upper limit. The source exhibits a bipolar morphology, which is strongly correlated with non-thermal X-rays. Conclusions. Because the thickness of the VHE-shell is compatible with emission from a thin rim, particle acceleration in shock waves is likely to be the origin of the γ-ray signal. The measured flux level can be accounted for by inverse Compton emission, but a mixed scenario that includes leptonic and hadronic components and takes into account the ambient matter density inferred from observations also leads to a satisfactory description of the multi-wavelength spectrum.
Aims. Observations of shell-type supernova remnants (SNRs) in the GeV to multi-TeV γ-ray band, coupled with those at millimetre radio wavelengths, are motivated by the search for cosmic-ray ...accelerators in our Galaxy. The old-age mixed-morphology SNR W 28 (distance ~2 kpc) is a prime target due to its interaction with molecular clouds along its northeastern boundary and other clouds situated nearby. Methods. We observed the W 28 field (for ~40 h) at very high energy (VHE) γ-ray energies ($E > 0.1$ TeV) with the HESS. Cherenkov telescopes. A reanalysis of EGRET $E > 100$ MeV data was also undertaken. Results from the NANTEN 4 m telescope Galactic plane survey and other CO observations were used to study molecular clouds. Results. We have discovered VHE γ-ray emission (HESS J1801-233) coincident with the northeastern boundary of W 28 and a complex of sources (HESS J1800-240A, B and C) ~0.5° south of W 28 in the Galactic disc. The EGRET source (GRO J1801-2320) is centred on HESS J1801-233 but may also be related to HESS J1800-240 given the large EGRET point spread function. The VHE differential photon spectra are well fit by pure power laws with indices Γ ~2.3 to 2.7. The spectral indices of HESS J1800-240A, B, and C are consistent within statistical errors. All VHE sources are ~10′ in intrinsic radius except for HESS J1800-240C, which appears pointlike. The NANTEN 12CO($J = 1{-}0$) data reveal molecular clouds positionally associating with the VHE emission, spanning a ~15 km s-1 range in local standard of rest velocity. Conclusions. The VHE/molecular cloud association could indicate a hadronic origin for HESS J1801-233 and HESS J1800-240, and several cloud components in projection may contribute to the VHE emission. The clouds have components covering a broad velocity range encompassing the distance estimates for W 28 (~2 kpc) and extending up to ~4 kpc. Assuming hadronic origin and distances of 2 and 4 kpc for cloud components, the required cosmic-ray density enhancement factors (with respect to the solar value) are in the range ~10 to ~30. If situated at 2 kpc distance, such cosmic-ray densities may be supplied by SNRs like W 28. Additionally and/or alternatively, particle acceleration may come from several catalogued SNRs and SNR candidates, the energetic ultra compact HII region W 28A2, and the HII regions M 8 and M 20, along with their associated open clusters. Further sub-mm observations would be recommended to probe in detail the dynamics of the molecular clouds at velocites > 10 km s-1 and their possible connection to W 28.
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