The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTpWT-IDHWT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTpWT-IDHWT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1.

The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O 6 -methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n = 52), grade (n = 128) and ALT activation (n = 46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.

Proportional scintillation in liquid xenon has a promising application in the field of direct dark matter detection, potentially allowing for simpler, more sensitive detectors. However, knowledge of the basic properties of the phenomenon as well as guidelines for its practical use are currently limited. We report here on measurements of proportional scintillation light emitted in liquid xenon around thin wires. The maximum proportional scintillation gain of 287 +97 −75 photons per drift electron was obtained using 10 µm diameter gold plated tungsten wire. The thresholds for electron multiplication and proportional scintillation are measured as 725 +48 −139 and 412 +10 −133 kV/cm, respectively. The threshold for proportional scintillation is in good agreement with a previously published result, while the electron multiplication threshold represents a novel measurement. A complete set of parameters for the practical use of the electron multiplication and proportional scintillation processes in liquid xenon was also obtained for the first time.

MeV-GeV dark matter (DM) is theoretically well motivated but remarkably unexplored. This proposal presents the MeV-GeV DM discovery potential for a ∼1 m 3 segmented CsI(Tl) scintillator detector placed downstream of the Hall A beam-dump at Jefferson Lab, receiving up to 10 22 electrons-on-target (EOT) in 285 days. This experiment (Beam-Dump eXperiment or BDX) would be sensitive to elastic DM-electron and to inelastic DM scattering at the level of 10 counts per year, reaching the limit of the neutrino irreducible background. The distinct signature of a DM interaction will be an electromagnetic shower of few hundreds of MeV, together with a reduced activity in the surrounding active veto counters. A detailed description of the DM particle χ production in the dump and subsequent interaction in the detector has been performed by means of Monte Carlo simulations. Different approaches have been used to evaluate the expected backgrounds: the cosmogenic background has been extrapolated from the results obtained with a prototype detector running at INFN-LNS (Italy), while the beam-related background has been evaluated by GEANT4 Monte Carlo simulations. The proposed experiment will be sensitive to large regions of DM parameter space, exceeding the discovery potential of existing and planned experiments in the MeV-GeV DM mass range by up to two orders of magnitude. 4We propose a beam-dump experiment to search for light (MeV-GeV) Dark Matter (DM). DM in this mass range is motivated by both experimental and theoretical considerations. On the theory side, simple extensions to the Standard Model (SM) can accommodate DM-SM interactions that yield the observed DM cosmological abundance. On the experimental side, such models also generically feature particles that explain the currently discrepant value of the muon's anomalous magnetic moment and resolve anomalies in astrophysical observations, while simultaneously evading cosmological and direct-production constraints.This experiment could be performed by placing a detector downstream of one of the JLab experimental Halls to detect DM particles that could be produced by the electron beam in the dump, pass through surrounding shielding material, and deposit visible energy inside the detector by scattering off various target particles or -if unstable -by decaying inside the detector volume. A new underground facility placed ∼ 20m downstream of the beam dump of the experimental Hall-A will host the detector, serving as a general-purpose facility for any future beam-dump experiments. The run would be completely parasitic without affecting the normal operations and the physics program of the Hall. The most striking signal that this experiment would look for consists of events with ∼ GeV electromagnetic energy deposition. With the detector and the experimental set-up we are proposing, this signal will be easily detected over a negligible background. This striking signature can arise in two classes of models: in those where DM scatters elastically off atomic electrons in the detector, an...

A new evaluation of previously published data suggested to us that the accumulation of mutations might slow, rather than increase, as individuals age. To explain this unexpected finding, we hypothesized that normal stem cell division rates might decrease as we age. To test this hypothesis, we evaluated cell division rates in the epithelium of human colonic, duodenal, esophageal, and posterior ethmoid sinonasal tissues. In all 4 tissues, there was a significant decrease in cell division rates with age. In contrast, cell division rates did not decrease in the colon of aged mice, and only small decreases were observed in their small intestine or esophagus. These results have important implications for understanding the relationship between normal stem cells, aging, and cancer. Moreover, they provide a plausible explanation for the enigmatic age-dependent deceleration in cancer incidence in very old humans but not in mice.

TERT promoter mutations were more frequent in SFT with higher risk of metastasis, but TERT promoter mutation status was not a reliable predictor of clinical outcome by itself. However, mutations in the TERT promoter may be useful in further stratifying patients with intermediate risk tumours.

Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.

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