Quality of life (QoL) is a relevant end point and a topic of growing interest by both scientific community and regulatory authorities. Our aim was to review QoL prevalence as an end point in cancer ...phase III trials published in major journals and to evaluate QoL reporting deficiencies in terms of under-reporting and delay of publication. All issues published between 2012 and 2016 by 11 major journals were hand-searched for primary publications of phase III trials in adult patients with solid tumors. Information about end points was derived from paper and study protocol, when available. Secondary QoL publications were searched in PubMed. In total, 446 publications were eligible. In 210 (47.1%), QoL was not included among end points. QoL was not an end point in 40.1% of trials in the advanced/metastatic setting, 39.7% of profit trials and 53.6% of non-profit trials. Out of 231 primary publications of trials with QoL as secondary or exploratory end point, QoL results were available in 143 (61.9%). QoL results were absent in 37.6% of publications in the advanced/metastatic setting, in 37.1% of profit trials and 39.3% of non-profit trials. Proportion of trials not including QoL as end point or with missing QoL results was relevant in all tumor types and for all treatment types. Overall, 70 secondary QoL publications were found: for trials without QoL results in the primary publication, probability of secondary publication was 12.5%, 30.9% and 40.3% at 1, 2 and 3 years, respectively. Proportion of trials not reporting QoL results was similar in trials with positive results (36.5%) and with negative results (39.4%), but the probability of secondary publication was higher in positive trials. QoL is not included among end points in a relevant proportion of recently published phase III trials in solid tumors. In addition, QoL results are subject to significant under-reporting and delay in publication.
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.
In complex tectonics regions, seismological, geophysical, and geodynamic modeling require accurate definition of the Moho geometry. Various active and passive seismic experiments performed in the ...central Mediterranean region revealed local information on the Moho depth, in some cases used to produce interpolated maps. In this paper, we present a new and original map of the 3‐D Moho geometry obtained by integrating selected high‐quality controlled source seismic and teleseismic receiver function data. The very small cell size makes the retrieved model suitable for detailed regional studies, crustal corrections in teleseismic tomography, advanced 3‐D ray tracing in regional earthquake location, and local earthquake tomography. Our results show the geometry of three different Moho interfaces: the European, Adriatic‐Ionian, and Tyrrhenian. The three distinct Moho are fashioned following the Alpine and Apennines subduction, collision, and back‐arc spreading and show medium‐ to high‐frequency topographic undulations reflecting the complexity of the geodynamic evolution.
Key Points
Extension and update of the Moho map of Italy and surrounding region
Data consistency (only seismological data) and quality check
Reference data set and constraint for future geodynamic and geophysical modeling
Aldehyde dehydrogenases (ALDHs) are multifunctional enzymes that oxidize diverse endogenous and exogenous aldehydes. We conducted a meta-analysis based on The Cancer Genome Atlas and Gene Expression ...Omnibus data and detected genetic alterations in ALDH1A1, ALDH1A3, or ALDH3A1, 86% of which were gene amplification or mRNA upregulation, in 31% of nonsmall cell lung cancers (NSCLCs). The expression of these isoenzymes impacted chemoresistance and shortened survival times in patients. We hypothesized that these enzymes provide an oxidative advantage for the persistence of NSCLC. To test this hypothesis, we used genetic and pharmacological approaches with DIMATE, an irreversible inhibitor of ALDH1/3. DIMATE showed cytotoxicity in 73% of NSCLC cell lines tested and demonstrated antitumor activity in orthotopic xenografts via hydroxynonenal-protein adduct accumulation, GSTO1-mediated depletion of glutathione and increased H
O
. Consistent with this result, ALDH1/3 disruption synergized with ROS-inducing agents or glutathione synthesis inhibitors to trigger cell death. In lung cancer xenografts with high to moderate cisplatin resistance, combination treatment with DIMATE promoted strong synergistic responses with tumor regression. These results indicate that NSCLCs with increased expression of ALDH1A1, ALDH1A3, or ALDH3A1 may be targeted by strategies involving inhibitors of these isoenzymes as monotherapy or in combination with chemotherapy to overcome patient-specific drug resistance.
NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide ...mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.
We studied the anatomy of the fault system where the 2009 L'Aquila earthquake (MW 6.1) nucleated by means of ~64 k high‐precision earthquake locations spanning 1 year. Data were analyzed by combining ...an automatic picking procedure for P and S waves, together with cross‐correlation and double‐difference location methods reaching a completeness magnitude for the catalogue equal to 0.7 including 425 clusters of similar earthquakes. The fault system is composed by two major faults: the high‐angle L'Aquila fault and the listric Campotosto fault, both located in the first 10 km of the upper crust. We detect an extraordinary degree of detail in the anatomy of the single fault segments resembling the degree of complexity observed by field geologists on fault outcrops. We observe multiple antithetic and synthetic fault segments tens of meters long in both the hanging wall and footwall along with bends and cross fault intersections along the main fault and fault splays. The width of the L'Aquila fault zone varies along strike from 0.3 km where the fault exhibits the simplest geometry and experienced peaks in the slip distribution, up to 1.5 km at the fault tips with an increase in the geometrical complexity. These characteristics, similar to damage zone properties of natural faults, underline the key role of aftershocks in fault growth and co‐seismic rupture propagation processes. Additionally, we interpret the persistent nucleation of similar events at the seismicity cutoff depth as the presence of a rheological (i.e., creeping) discontinuity explaining how normal faults detach at depth.
Key Points
The fault architecture resembles features observed at outcrop scale
Normal faults terminate at depth along a basal creeping decòllment
Aftershocks image the damage zone width which is comparable to geological ones
The accumulation of large boulders related to waves generated by either tsunamis or extreme storm events have been observed in different areas of the Mediterranean Sea. Along the eastern low-lying ...rocky coasts of Malta, five sites with large boulder deposits have been investigated, measured and mapped. These boulders have been detached and moved from the nearshore and the lowest parts of the coast by sea wave action. In the Sicily–Malta channel, heavy storms are common and originate from the NE and NW winds. Conversely, few tsunamis have been recorded in historical documents to have reached the Maltese archipelago. We present a multi-disciplinary study, which aims to define the characteristics of these boulder accumulations, in order to assess the coastal geo-hazard implications triggered by the sheer ability of extreme waves to detach and move large rocky blocks inland. The wave heights required to transport 77 coastal boulders were calculated using various hydrodynamic equations. Particular attention was given to the quantification of the input parameters required in the workings of these equations, such as size, density and distance from the coast. In addition, accelerator mass spectrometry (AMS) 14C ages were determined from selected samples of marine organisms encrusted on some of the coastal boulders. The combination of the results obtained both by the hydrodynamic equations, which provided values comparable with those observed and measured during the storms, and radiocarbon dating suggests that the majority of the boulders have been detached and moved by intense storm waves. These boulders testify to the existence of a real hazard for the coasts of Malta, i.e. that of very high storm waves, which, during exceptional storms, are able to detach large blocks of volumes exceeding 10 m3 from the coastal edge and the nearshore bottom, and also to transport them inland. Nevertheless, the occurrence of one or more tsunami events cannot be ruled out, since radiocarbon dating of some marine organisms did reveal ages which may be related to historically known tsunamis in the Mediterranean region, such as the ones in AD 963, 1329, 1693 and 1743.
Axial-flux permanent magnet (PM) synchronous machines are suitable for direct drive applications. Axial-flux PM synchronous machines with fractional windings provide high power density, low torque ...ripple, and sinusoidal phase voltages, but suffer from high rotor losses due to stator field harmonics and slotting. This paper formulates an electromagnetic model based on the polar coordinate representation of the air-gap magnetic field. No-load and load tests are carried out on a soft-magnetic-composite stator axial-flux machine to validate the model. Rotor losses represent the largest loss figure in this machine. Most rotor losses are due to slotting harmonics.
The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might ...reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.
We present the first limits on inelastic electron-scattering dark matter and dark photon absorption using a prototype SuperCDMS detector having a charge resolution of 0.1 electron-hole pairs (CDMS ...HVeV, a 0.93 g CDMS high-voltage device). These electron-recoil limits significantly improve experimental constraints on dark matter particles with masses as low as 1 MeV/c^{2}. We demonstrate a sensitivity to dark photons competitive with other leading approaches but using substantially less exposure (0.49 g d). These results demonstrate the scientific potential of phonon-mediated semiconductor detectors that are sensitive to single electronic excitations.
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