163 research outputs found
Comparison of spheroids formed by rat glioma stem cells and neural stem cells reveals differences in glucose metabolism and promising therapeutic applications
Cancer stem cells (CSCs) are thought to be partially responsible for cancer resistance to current therapies and tumor recurrence. Dichloroacetate (DCA), a compound capable of shifting metabolism from glycolysis to glucose oxidation, via an inhibition of pyruvate dehydrogenase kinase was used. We show that DCA is able to shift the pyruvate metabolism in rat glioma CSCs but has no effect in rat neural stem cells. DCA forces CSCs into oxidative phosphorylation but does not trigger the production of reactive oxygen species and consecutive anti-cancer apoptosis. However, DCA, associated with etoposide or irradiation, induced a Bax-dependent apoptosis in CSCs in vitro and decreased their proliferation in vivo. The former phenomenon is related to DCA-induced Foxo3 and p53 expression, resulting in the overexpression of BH3-only proteins (Bad, Noxa, and Puma), which in turn facilitates Bax-dependent apoptosis. Our results demonstrate that a small drug available for clinical studies potentiates the induction of apoptosis in glioma CSCs
Search for new resonant states in 10C and 11C and their impact on the cosmological lithium problem
The observed primordial 7Li abundance in metal-poor halo stars is found to be
lower than its Big-Bang nucleosynthesis (BBN) calculated value by a factor of
approximately three. Some recent works suggested the possibility that this
discrepancy originates from missing resonant reactions which would destroy the
7Be, parent of 7Li. The most promising candidate resonances which were found
include a possibly missed 1- or 2- narrow state around 15 MeV in the compound
nucleus 10C formed by 7Be+3He and a state close to 7.8 MeV in the compound
nucleus 11C formed by 7Be+4He. In this work, we studied the high excitation
energy region of 10C and the low excitation energy region in 11C via the
reactions 10B(3He,t)10C and 11B(3He,t)11C, respectively, at the incident energy
of 35 MeV. Our results for 10C do not support 7Be+3He as a possible solution
for the 7Li problem. Concerning 11C results, the data show no new resonances in
the excitation energy region of interest and this excludes 7Be+4He reaction
channel as an explanation for the 7Li deficit.Comment: Accepted for publication in Phys. Rev. C (Rapid Communication
Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform.
Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients' molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency
EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand
Background: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.Methods: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.Results: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.Conclusions: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.</p
Search for resonant states in 10C and 11C and their impact on the primordial 7Li abundance
The cosmological 7Li problem arises from the significant discrepancy of about a factor 3 between the predicted primordial 7Li abundance and the observed one. The main process for the production of 7Li during Big-Bang nucleosynthesis is the decay of 7Be. Many key nuclear reactions involved in the production and destruction of 7Be were investigated in attempt to explain the 7Li deficit but none of them led to successful conclusions. However, some authors suggested recently the possibility that the destruction of 7Be by 3He and 4He may reconcile the predictions and observations if missing resonant states in the compound nuclei 10C and 11C exist. Hence, a search of these missing resonant states in 10C and 11C was investigated at the Orsay Tandem-Alto facility through 10B(3He,t)10C and 11B(3He,t)11C charge-exchange reactions respectively. After a short overview of the cosmological 7Li problem from a nuclear physics point of view, a description of the Orsay experiment will be given as well as the obtained results and their impact on the 7Li problem
Study of the 26Al(n,p)26Mg and 26Al(n,α)23Na reactions using the 27Al(p,p')27Al inelastic scattering reaction
26Al was the first cosmic radioactivity ever detected in the galaxy as well as one of the first extinct radioactivity observed in refractory phases of meteorites. Its nucleosynthesis in massive stars is still uncertain mainly due to the lack of nuclear information concerning the 26Al(n,p)26Mg and 26 Al(n,α)23Na reactions. We report on a single and coincidence measurement of the 27Al(p,p')27Al(p)26Mg and 27Al(p,p')27Al(α)23Na reactions performed at the Orsay TANDEM facility aiming at the spectroscopy study of 27Al above the neutron threshold. Fourteen states are observed for the first time within 350 keV above the 26Al+n threshold
Neutron-proton pairing in the N=Z radioactive fp-shell nuclei 56Ni and 52Fe probed by pair transfer
The isovector and isoscalar components of neutron-proton pairing are
investigated in the N=Z unstable nuclei of the \textit{fp}-shell through the
two-nucleon transfer reaction (p,He) in inverse kinematics. The combination
of particle and gamma-ray detection with radioactive beams of Ni and
Fe, produced by fragmentation at the GANIL/LISE facility, made it
possible to carry out this study for the first time in a closed and an
open-shell nucleus in the \textit{fp}-shell. The transfer cross-sections for
ground-state to ground-state (J=0,T=1) and to the first (J=1,T=0) state
were extracted for both cases together with the transfer cross-section ratios
(0,T=1) /(1,T=0). They are compared with second-order
distorted-wave born approximation (DWBA) calculations. The enhancement of the
ground-state to ground-state pair transfer cross-section close to mid-shell, in
Fe, points towards a superfluid phase in the isovector channel. For the
"deuteron-like" transfer, very low cross-sections to the first (J=1,T=0)
state were observed both for \Ni\phe\, and \Fe\phe\, and are related to a
strong hindrance of this channel due to spin-orbit effect. No evidence for an
isoscalar deuteron-like condensate is observed.Comment: 7 pages, 4 figure
Defining EGFR amplification status for clinical trial inclusion
Background. Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma
patients require selection for EGFR-amplified tumors. However, there is currently no gold standard in determining
the amplification status of EGFR or variant III (EGFRvIII) expression. Here, we aimed to determine which technique
and which cutoffs are suitable to determine EGFR amplification status.
Methods. We compared fluorescence in-situ hybridization (FISH) and real-time quantitative (RT-q)PCR data from
patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation
sequencing (NGS) platform (both DNA and RNA).
Results. By using data from >1000 samples, we show that at least 50% of EGFR amplified nuclei should be present
to define EGFR gene amplification by FISH. Gene amplification (as determined by FISH) correlates with EGFR
expression levels (as determined by RT-qPCR) with receiver operating characteristics analysis showing an area
under the curve of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate
marker for EGFR amplification. Our NGS data show that EGFR copy numbers can strongly vary between tumors,
with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define
EGFR-amplification by NGS; below this level, FISH detects very few (if any) EGFR amplified nuclei and none of the
samples express EGFRvIII.
Conclusion. Our data from central laboratories and diagnostic sequencing facilities, using material from patients
eligible for clinical trial inclusion, help define the optimal cutoff for various techniques to determine EGFR amplification for diagnostic purposes
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