The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence ...that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter.
We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype.
TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation.
In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.
Background: MET amplification has been detected in ∼20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to ...tyrosine kinase inhibitor (TKI) therapy. Patients and methods: We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents. Results: HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line. Conclusions: MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.
Inland waters are increasingly recognized as critical sites of methane emissions to the atmosphere, but the biogeochemical reactions driving such fluxes are less well understood. The Prairie Pothole ...Region (PPR) of North America is one of the largest wetland complexes in the world, containing millions of small, shallow wetlands. The sediment pore waters of PPR wetlands contain some of the highest concentrations of dissolved organic carbon (DOC) and sulfur species ever recorded in terrestrial aquatic environments. Using a suite of geochemical and microbiological analyses, we measured the impact of sedimentary carbon and sulfur transformations in these wetlands on methane fluxes to the atmosphere. This research represents the first study of coupled geochemistry and microbiology within the PPR and demonstrates how the conversion of abundant labile DOC pools into methane results in some of the highest fluxes of this greenhouse gas to the atmosphere ever reported. Abundant DOC and sulfate additionally supported some of the highest sulfate reduction rates ever measured in terrestrial aquatic environments, which we infer to account for a large fraction of carbon mineralization in this system. Methane accumulations in zones of active sulfate reduction may be due to either the transport of free methane gas from deeper locations or the co‐occurrence of methanogenesis and sulfate reduction. If both respiratory processes are concurrent, any competitive inhibition of methanogenesis by sulfate‐reducing bacteria may be lessened by the presence of large labile DOC pools that yield noncompetitive substrates such as methanol. Our results reveal some of the underlying mechanisms that make PPR wetlands biogeochemical hotspots, which ultimately leads to their critical, but poorly recognized role in regional greenhouse gas emissions.
Wetland sediments recovered from the Prairie Pothole Region of North America host microbial communities catalyzing some of the highest sulfate reduction rates ever measured. Concurrently, these same sediments drive some of the highest methane fluxes to atmosphere ever measured. Together, these data indicate that the PPR may play an oversized role in carbon cycling and greenhouse gas fluxes to the atmosphere.
•Despite high efficacy, resistance to target therapies in NSCLC always occurs.•When occurrence is limited to few sites, local therapies can be beneficial.•Stereotactic Body Radiation Therapy is an ...ideal candidate thanks to high efficacy and safety•Literature data suggest that local therapies while continuing the same TKI prolong PFS.•Consolidation of persisting disease after few months of TKI can change the natural history of the disease.
Oncogene-driven non small cell lung cancer (NSCLC) is a distinct entity in thoracic oncology. The availability of effective target therapies, like EGFR inhibitors or ALK inhibitors, have revolutionized the prognosis of these patients. However, despite an initial response in the majority of patients, drug resistance ultimately occurs. In some cases, this resistance develops in few clonal cells (oligoprogression), so that a local ablation of these resistant deposits could allow to maintain the same systemic therapy and possibly to prolong patients’ survival. For these purposes, stereotactic body radiation therapy (SBRT) is an ideal local ablative treatment, because it is effective, non invasive and with limited side effects.
In this review, we aim to analyze available clinical data to verify whether SBRT can allow these patients to continue with existing target therapy longer, delay the switch to other systemic therapies and improve their outcome modifying the natural history of the disease.
Background: Standardized conditions to distinguish subpopulations of colorectal cancer (CRC) patients more and less sensitive to cetuximab therapy remain undefined. Materials and methods: We ...retrospectively analyzed epidermal growth factor receptor (EGFR) copy number by fluorescence in situ hybridization (FISH) in paraffin-embedded tumor blocks from 85 chemorefractory CRC patients treated with cetuximab. Results were analyzed according to different score systems previously reported in colorectal and lung cancers. The primary end point of the study was identification of the EGFR FISH score that best associates with response rate (RR). Results: Using receiver operating characteristic (ROC) analysis, the cut-off that best discriminated responders versus nonresponders to cetuximab was a mean of 2.92 EGFR gene copies per cell. This model showed sensitivity of 58.6% 95% confidence interval (CI) = 47.1–70.1) and specificity of 93.3% (95% CI = 80.6–100). EGFR FISH-positive patients (N = 43, 50.6%) had significantly higher RR (P = 0.0001) and significantly longer time to disease progression (P = 0.02) than EGFR FISH negative (N = 42, 49.4%). Other scoring systems resulted less accurate in discriminating patients with the highest likelihood of response to cetuximab therapy. Conclusions: CRC patients with high EGFR gene copy number have an increased likelihood to respond to cetuximab therapy. Prospective clinical trials with a careful standardization of assay conditions and pattern interpretation are urgently needed.
The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive (EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not ...been previously investigated. In the present study, we analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH+ patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. PI3KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role in primary resistance. The potential prognostic implication of IGF1R expression merits further evaluation.
Abstract Aims The aim of this observational study was the evaluation of toxicity, local control and overall survival in non-small cell lung cancer (NSCLC) oligometastatic patients who had undergone ...stereotactic ablative body radiotherapy (SABR) for lung metastatic lesions. Materials and methods SABR was carried out in oligometastatic patients with controlled primary tumour (adequate pulmonary function). We adopted the following dose prescriptions according to the site and the maximum diameter of the lung lesions: 60 Gy in three fractions for peripheral lesions with diameter ≤2 cm, 48 Gy in four fractions for peripheral lesions between 2 and 5 cm and 60 Gy in eight fractions for central lesions. A radiological response was defined according to RECIST criteria. Toxicity was recorded according to the Common Toxicity Criteria version 4.0. Results Between October 2010 and December 2014, 60 NSCLC patients with 90 lung lesions in total were treated at our institution. A radiological response was obtained in most patients. No pulmonary toxicity grade 4, chest pain or rib fracture occurred. The median follow-up from diagnosis was 28 months (range 5.4–104.5 months). The local control at 2 years was 88.9%. Overall survival at 1 and 2 years was 94.5 and 74.6%, respectively. Conclusion SABR is well tolerated with a good radiological response and toxicity profile. Discussion within a multidisciplinary team is crucial to identify the oligometastatic patients who would probably benefit from ablative local therapy.
Abstract An innovative ECR ion trap facility, called PANDORA (Plasma for Astrophysics, Nuclear Decay Observation and Radiation for Archaeometry), was designed for fundamental plasma processes and ...nuclear physics investigations. The overall structure consists of three subsystems: a) a large (70 cm in length, 28 cm in inner diameter) ECR plasma trap with a fully superconducting B-minimum magnetic system (B max = 3.0 T) and an innovative design to host detectors and diagnostic tools; b) an advanced non-invasive plasma multidiagnostics system to locally characterize the plasma thermodynamic properties; c) an array of 14 HPGe detectors. The PANDORA facility is conceived to measure, for the first time, in-plasma β -decaying isotope rates under stellar-like conditions. The experimental approach consists in a direct correlation of plasma parameters and nuclear activity by disentangling - by means of the multidiagnostic system that will work in synergy with the γ-ray array - the photons emitted by the plasma (from microwave to hard X-ray) and γ-rays emitted after the isotope β -decay. In addition to nuclear physics research, fundamental plasma physics studies can be conducted in this unconventional ion source equipped with tens of detection and diagnostic devices (RF polarimeter, optical emission spectroscopy (OES), X-ray imaging, space and time-resolved spectroscopy, RF probes, scope), with relevant implications for R&D of ion sources for accelerator physics and technology. Several studies have already been performed in downsized nowadays operating ECRIS. Stable and turbulent plasma regimes have been described quantitatively, studying the change of plasma morphology, confinement, and dynamics of losses using space resolved X-ray spectroscopy.
Abstract The two-close frequency heating (TCFH) is a new implementation of the well-known two frequency heating. In TCFH, the two frequencies differ around 200-300 MHz each other in order to ...establish two contiguous ECR resonance zones. TCFH has been proved to be a powerful technique to suppress plasma instabilities in Electron Cyclotron Resonance Ion Sources (ECRIS), as well as to improve their performances. Its beneficial effect, compared to the application of a single frequency, is always deduced from the extracted charge states distributions and from the detection of the plasma self-emission in the X-ray and microwave ranges. This paper presents the first approach to a numerical description of the two-close frequency effect, based on the relevant plasma parameters of the ECRIS setup operating at ATOMKI-Debrecen. Simulations have been performed by our PIC-Full Wave code, joining electron kinetics and FEM solution of Maxwell equations in a cold plasma model. Results on plasma electron density and energy distribution will be shown, together with a direct comparison with the already published data on X ray emission.
The experimental findings reported in our original paper de Sangro et al. (Eur. Phys. J. C 75:137,
2015
) have been criticized in Shabad (Eur. Phys. J. C 76:508,
2016
). We believe that the arguments ...brought in Shabad (Eur. Phys. J. C 76:508,
2016
) are not correct and we show evidence for this.
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