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Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT–PCR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a ‘hot spot’ of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype ( P <0.01), and they were frequently associated with CDKN2A gene inactivation ( P =0.03). In conclusion, a subgroup of MPM presents TERT promoter mutations, which lead to TERT mRNA upregulation. This is the first recurrent gain-of-function oncogenic mutations identified in MPM.

We report the measurement of the two-neutrino double-beta ( 2 ν β β ) decay of 100 Mo to the ground state of 100 Ru using lithium molybdate ( Li 2 100 MoO 4 ) scintillating bolometers. The detectors were developed for the CUPID-Mo program and operated at the EDELWEISS-III low background facility in the Modane underground laboratory (France). From a total exposure of 42.235 kg × day, the half-life of 100 Mo is determined to be T 1 / 2 2 ν = [ 7 . 12 - 0.14 + 0.18 ( stat . ) ± 0.10 ( syst . ) ] × 10 18  years. This is the most accurate determination of the 2 ν β β half-life of 100 Mo to date.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK), which is transiently expressed during development of the central and peripheral nervous system. ALK has been recently identified as a major neuroblastoma predisposition gene and activating mutations have also been identified in a subset of sporadic neuroblastoma tumors. Two hot spots of ALK mutations have been observed at positions F1174 and R1275. Here, we studied stably transfected cell lines expressing wild-type or F1174L- or R1275Q-mutated ALK in parallel with a neuroblastoma cell line (CLB-GE) in which the allele mutated at position F1174 is amplified. We observed that the mutated ALK variants were essentially intracellular and were largely retained in the reticulum/Golgi compartments. This localization was corroborated by a defect of N -linked glycosylation. Although the mutated receptors exhibited a constitutive activation, the minor pool of receptor addressed to the plasma membrane was much more tyrosine phosphorylated than the intracellular pool. The use of antagonist monoclonal antibodies suggested that the constitutive activity of the mutated receptors did not require the dimerization of the receptor, whereas adequate dimerization triggered by agonist monoclonal antibodies increased this activity. Finally, kinase inactivation of the mutated receptors restored maturation and cell-surface localization. Our results show that constitutive activation of ALK results in its impaired maturation and intracellular retention. Furthermore, they provide a rationale for the potential use of kinase inhibitors and antibodies in ALK-dependent tumors.

The excellent energy resolution and low threshold of cryogenic detectors have brought them to the forefront of the search for low-mass Weakly Interacting Massive Particles. The next generation of large cryogenic detectors for dark matter search promises further improvements in sensitivity, yet it is difficult and in some cases impossible to test and fully characterize these detectors in an unshielded environment. Therefore, the Queen's SuperCDMS team is installing a well shielded Cryogenic Underground detector TEst facility (CUTE) at SNOLAB to support detector testing and characterization for SuperCDMS and future cryogenic rare event search experiments. Significant effort is put into achieving a very low background environment which may open the door for early science results with the first set of SuperCDMS detectors during the time the main experimental apparatus is being installed. We discuss some of the challenges and solutions implemented in the design of this facility as well as the status and schedule for the start of operations underground at SNOLAB.

The EDELWEISS collaboration aims for direct detection of light dark matter using germanium cryogenic detectors with low threshold phonon sensor technologies and efficient charge readout designs. We describe here the development of Ge bolometers equipped with high impedance thermistors based on a Nb x Si 1−x TES alloy. High aspect ratio spiral designs allow the TES impedance to match with JFET or HEMT front-end amplifiers. We detail the behavior of the superconducting transition properties of these sensors and the detector optimization in terms of sensitivity to a-thermal phonons. We report preliminary results of a 200 g Ge detector that was calibrated using 71 Ge activation by neutrons at the LSM underground laboratory.

The Cryogenic Underground Test (CUTE) facility will be located 2 km underground in the SNOLAB laboratory, near Sudbury (Ontario, Canada). It is primarily designed to test the performances of cryogenic detectors of the Super-Cryogenic Dark Matter Search (SuperCDMS) experiment which will be installed next to CUTE. As a facility, it will also be accessible to scientists developing innovative cryogenic detectors for rare events search like dark matter or double-beta decay. The low temperature required to operate the cryogenic detectors is reached via an advanced dry dilution refrigerator from CryoConcept (France). The ‘Ultra Quiet Technique’ (UQT ® ) reduces the vibration transmission by using a proprietary gas-coupled thermal link between the two-stage pulse tube and the cryostat. In order to install the cryostat into a shielding water tank, we have developed a suspension system which decouples the cryostat from the environment with a low stiffness support, making a mechanical low-pass filter with a roll-off below 2 Hz for the vertical attenuation. We report the design choices made for the mechanical architecture to limit the vibration transmission and the material selection to achieve a low radioactive background rate in the detector. The expected background rate is less than 5 counts/day per kg of Ge detector in the 0–1 keV energy range.

An optimization of the CERN SPL beam line has been performed guided by the sensitivities to the Θ13 mixing angle and to the δCP Dirac CP violating phase. A UNO-like 440 ktons water Čerenkov detector located at 130 km from the target in a new foreseen Fréjus laboratory has been used as a generic detector. Concerning the δCP independent Θ13 sensitivity, a gain of about 20% may be reached using a 3.5 GeV proton beam with a 40 m long, 2 m radius decay tunnel compared to the up to now considered 2.2 GeV beam energy and 20 m long, 1 m radius decay tunnel. This may motivate new machine developments to upgrade the nominal SPL proton beam energy.

CUPID-Mo is a bolometric experiment to search for neutrinoless double-beta decay ( 0 ν β β ) of 100 Mo . In this article, we detail the CUPID-Mo detector concept, assembly and installation in the Modane underground laboratory, providing results from the first datasets. The CUPID-Mo detector consists of an array of 20 100 Mo -enriched 0.2 kg Li 2 MoO 4 crystals operated as scintillating bolometers at ∼ 20 mK . The Li 2 MoO 4 crystals are complemented by 20 thin Ge optical bolometers to reject α events by the simultaneous detection of heat and scintillation light. We observe a good detector uniformity and an excellent energy resolution of 5.3 keV (6.5 keV) FWHM at 2615 keV, in calibration (physics) data. Light collection ensures the rejection of α particles at a level much higher than 99.9% – with equally high acceptance for γ / β events – in the region of interest for 100 Mo 0 ν β β . We present limits on the crystals’ radiopurity: ≤ 3 μ Bq/kg of 226 Ra and ≤ 2 μ Bq/kg of 232 Th . We discuss the science reach of CUPID-Mo, which can set the most stringent half-life limit on the 100 Mo 0 ν β β decay in half-a-year’s livetime. The achieved results show that CUPID-Mo is a successful demonstrator of the technology developed by the LUMINEU project and subsequently selected for the CUPID experiment, a proposed follow-up of CUORE, the currently running first tonne-scale bolometric 0 ν β β experiment.

Pleural mesothelioma is a rare cancer with an often-challenging diagnosis because of its potential to be a great mimicker of many other tumors. Among them, primary lung and breast cancers are the 2 main causes of pleural metastasis. The development and application of targeted therapeutic agents have made it even more important to achieve an accurate diagnosis. In this setting, international guidelines have recommended the use of 2 positive and 2 negative immunohistochemical biomarkers. To define the most highly specific and sensitive minimum set of antibodies for routine practice to use for the separation of epithelioid malignant mesothelioma from lung and breast metastasis and to determine the most relevant expression cutoff. To provide information at different levels of expression of 16 mesothelial and epithelial biomarkers, we performed a systematic review of articles published between 1979 and 2017, and we compared those data to results from the Mesothelioma Telepathology Network (MESOPATH) of the standardized panel used in routine practice database since 1998. Our results indicate that the following panel of markers-calretinin (poly)/thyroid transcription factor 1 (TTF-1; clone 8G7G3/1) and calretinin (poly)/estrogen receptor-α (ER-α; clone EP1)-should be recommended; ultimately, based on the MESOPATH database, we highlight their relevance which are the most sensitive and specific panel useful to the differential diagnosis at 10% cutoff. Highlighted by their relevance in the large cohort reported, we recommend 2 useful panels to the differential diagnosis at 10% cutoff.