We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
ALK-rearranged stage IIIB/IV NSCLC patients were analyzed ...with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients PFS 3.9months (95% CI: 2.4–5.6) versus 10.3months (95% CI: 8.6–12.0), P<0.001; OS 15.0months (95% CI: 5.0–24.9) versus 50.0months (95% CI: 22.9–77.1), P=0.002. This difference was confirmed in all treatment-related subgroups including chemotherapy only PFS first-line chemotherapy 2.6months (95% CI: 1.3–4.1) versus 6.2months (95% CI: 1.8–10.5), P=0.021; OS 2.0months (95% CI: 0.0–4.6) versus 9.0months (95% CI: 6.1–11.9), P=0.035, crizotinib plus chemotherapy PFS crizotinib 5.0months (95% CI: 2.9–7.2) versus 14.0months (95% CI: 8.0–20.1), P<0.001; OS 17.0months (95% CI: 6.7–27.3) versus not reached, P=0.049 and crizotinib followed by next-generation ALK-inhibitor PFS next-generation inhibitor 5.4months (95% CI: 0.1–10.7) versus 9.9months (95% CI: 6.4–13.5), P=0.039; OS 7.0months versus 50.0months (95% CI: not reached), P=0.001).
In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Riggs ER, Church DM, Hanson K, Horner VL, Kaminsky EB, Kuhn RM, Wain KE, Williams ES, Aradhya S, Kearney HM, Ledbetter DH, South ST, Thorland EC, Martin CL. Towards an evidence‐based process for the ...clinical interpretation of copy number variation.
The evidence‐based review (EBR) process has been widely used to develop standards for medical decision‐making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large‐scale case‐control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We build an accurate data base of 5200 HCN and HNC rotation-vibration energy levels, determined from existing laboratory data. 20 000 energy levels in the Harris et al. linelist are assigned ...approximate quantum numbers. These assignments, lab-determined energy levels and Harris et al. energy levels are incorporated in to a new energy level list. A new linelist is presented, in which frequencies are computed using the lab-determined energy levels where available, and the ab initio energy levels otherwise. The new linelist is then used to compute new model atmospheres and synthetic spectra for the carbon star WZ Cas. This results in better fit to the spectrum of WZ Cas in which the absorption feature at 3.56 μm is reproduced to a higher degree of accuracy than has previously been possible. We improve the reproduction of HCN absorption features by reducing the abundance of Si to Si/H=−0.5 dex, however, the strengths of the Δv= 2 CS band heads are overpredicted.
Aims. The aim of the project is to define metallicity/gravity/temperature scales for different spectral types of metal-poor M dwarfs. Methods. We obtained intermediate-resolution ultraviolet (R ∼ ...3300), optical (R ∼ 5400), and near-infrared (R ∼ 3900) spectra of 43 M subdwarfs (sdM), extreme subdwarfs (esdM), and ultra-subdwarfs (usdM) with the X-shooter spectrograph on the European Southern Observatory Very Large Telescope. We compared our atlas of spectra to the latest BT-Settl synthetic spectral energy distribution over a wide range of metallicities, gravities, and effective temperatures to infer the physical properties for the whole M dwarf sequence (M0–M9.5) at sub-solar metallicities and constrain the latest atmospheric models. Results. The BT-Settl models accurately reproduce the observed spectra across the 450–2500 nm wavelength range except for a few regions. We find that the best fits are obtained for gravities of log (g) = 5.0–5.5 for the three metal classes. We infer metallicities of Fe/H = −0.5, −1.5, and −2.0 ± 0.5 dex and effective temperatures of 3700–2600 K, 3800–2900 K, and 3700–2900 K for subdwarfs, extreme subdwarfs, and ultra-subdwarfs, respectively. Metal-poor M dwarfs tend to be warmer by about 200 ± 100 K and exhibit higher gravity than their solar-metallicity counterparts. We derive abundances of several elements (Fe, Na, K, Ca, Ti) for our sample but cannot describe their atmospheres with a single metallicity parameter. Our metallicity scale expands the current scales available for mildly metal-poor planet-host low-mass stars. Our compendium of moderate-resolution spectra covering the 0.45–2.5 micron range represents an important resource for large-scale surveys and space missions to come.
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FMFMET, NUK, UL, UM, UPUK
We report on a search for electronic recoil event rate modulation signatures in the XENON100 data accumulated over a period of 4 yr, from January 2010 to January 2014. A profile likelihood method, ...which incorporates the stability of the XENON100 detector and the known electronic recoil background model, is used to quantify the significance of periodicity in the time distribution of events. There is a weak modulation signature at a period of 431_{-14}^{+16} day in the low energy region of (2.0-5.8) keV in the single scatter event sample, with a global significance of 1.9σ; however, no other more significant modulation is observed. The significance of an annual modulation signature drops from 2.8σ, from a previous analysis of a subset of this data, to 1.8σ with all data combined. Single scatter events in the low energy region are thus used to exclude the DAMA/LIBRA annual modulation as being due to dark matter electron interactions via axial vector coupling at 5.7σ.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
ABSTRACT
We present an analysis of the red giant component of the recurrent nova V3890 Sgr, using data obtained before and after its 2019 eruption. Its effective temperature is Teff = 3050 ± 200 K ...for log g = 0.7, although there are modest changes in Teff. There is an overabundance of both carbon (0.20 ± 0.05 dex) and sodium (1.0 ± 0.3 dex) relative to their solar values, possibly the result of ejecta from the 1990 nova eruption being entrained into the red giant photosphere. We find 12C/13C =25 ± 2, a value similar to that found in red giants in other recurrent novae. The interpretation of the quiescent spectrum in the 5–38$\, \mu$m region requires the presence of photospheric SiO absorption and cool (∼400 K) dust in the red giant environment. The spectrum in the region of the Na i D lines is complex, and includes at least six interstellar components, together with likely evidence for interaction between ejecta from the 2019 eruption and material accumulated in the plane of the binary. Three recurrent novae with giant secondaries have been shown to have environments with different dust content, but photospheres with similar 12C/13C ratios. The SiO fundamental bands most likely have a photospheric origin in the all three stars.
Context. We report the results from the determination of stellar masses, carbon, and oxygen abundances in the atmospheres of 107 stars from the Calan-Hertfordshire Extrasolar Planet Search (CHEPS) ...programme. Our stars are drawn from a population with a significantly super-solar metallicity. At least 10 of these stars are known to host orbiting planets. Aims. In this work, we set out to understand the behaviour of carbon and oxygen abundance in stars with different spectral classes, metallicities, and V sin i within the metal-rich stellar population. Methods. Masses of these stars were determined using data from Gaia DR2. Oxygen and carbon abundances were determined by fitting the absorption lines. We determined oxygen abundances with fits to the 6300.304 Å O I line, and we used 3 lines of the C I atom and 12 lines of the C2 molecule for the determination of carbon abundances. Results. We determine masses and abundances of 107 CHEPS stars. There is no evidence that the C/O ratio depends on V sin i or the mass of the star within our constrained range of masses, i.e. 0.82 < M*∕M⊙ < 1.5 and metallicities − 0.27 < Fe∕H < +0.39. We also confirm that metal-rich dwarf stars with planets are more carbon rich in comparison with non-planet host stars with a statistical significance of 96%. Conclusions. We find tentative evidence that there is a slight offset to lower abundance and a greater dispersion in oxygen abundances relative to carbon. We interpret this as potentially arising because the production of oxygen is more effective at more metal-poor epochs. We also find evidence that for lower mass stars the angular momentum loss in stars with planets as measured by V sin i is steeper than stars without planets. In general, we find that the fast rotators (V sin i > 5 km s−1) are massive stars.
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ABSTRACT
We present an analysis of archival Spitzer InfraRed Spectrograph (IRS) observations of the recurrent nova RS Ophiuchi obtained on several occasions, beginning about 7 months after the ...outburst in 2006. These data show atomic emission lines, absorption bands due to photospheric SiO, and the well-known silicate dust features at 9.7 and $18\, \mu$m. The dust emission, arising in the wind of the secondary star, is fitted by dusty models for mass-loss rates in the range 1.0–1.7 × 10−7 M⊙ yr−1. The silicate features are similar in profile to those seen in circumstellar environments of isolated late-type stars and some dusty symbiotic binaries, although the longer wavelength feature peaks at $17\, \mu$m, instead of the usual $18\, \mu$m, indicating peculiar grain properties. The dust features are variable, appearing stronger in 2006–2007 during outburst than in 2008–2009 when the system was in the quiescent state. This variability is attributed to changes in the ultraviolet output and the reformation of the accretion disc, although a decline in the mass-loss rate of the red giant secondary star could also play a role. Further observations, in the aftermath of the 2021 eruption, could provide a definitive conclusion.
Laboratory experiments searching for galactic dark matter particles scattering off nuclei have so far not been able to establish a discovery. We use data from the XENON100 experiment to search for ...dark matter interacting with electrons. With no evidence for a signal above the low background of our experiment, we exclude a variety of representative dark matter models that would induce electronic recoils. For axial-vector couplings to electrons, we exclude cross sections above 6 × 10–35 cm2 for particle masses of mx = 2 GeV/c2. Independent of the dark matter halo, we exclude leptophilic models as an explanation for the long-standing DAMA/LIBRA signal, such as couplings to electrons through axial-vector interactions at a 4.4σ. confidence level, mirror dark matter at 3.6σ, and luminous dark matter at 4.6σ.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Trauma-related symptoms and post-traumatic stress disorder (PTSD) are common during pregnancy and have adverse effects on pregnancy and birth outcomes, post-partum maternal mental health, and child ...development. The arousal symptoms associated with PTSD, including heightened or dysregulated physiology, may contribute to these adverse outcomes. Low-income minoritized women may be at highest risk given more lifetime exposure to trauma and limited access to mental health care. While evidence-based psychotherapies for PTSD exist, none are targeted to non-treatment seeking individuals nor specifically integrated with prenatal care. Thus, we developed and tested the efficacy of a short-term (four sessions) brief (30–45 min) psychotherapeutic intervention designed to address PTSD symptoms in pregnant women receiving prenatal care at two urban medical centers. Participants were 32 pregnant women with an average gestational age of 18.5 weeks at the time of enrollment. The sample was overwhelmingly non-Caucasian, single, and reported very low income. Participants completed measures of trauma-related symptoms (Post-traumatic Stress Disorder Checklist, PCL), and depression (Edinburgh post-natal Depression Scale, EPDS) at baseline, twice during treatment, post-treatment, and at 10–14 weeks post-partum. The intervention was successful at significantly decreasing symptoms of PTSD (PCL score = −20.27, 95% CI: −25.62, −14.92,
P
< 0.001, W = −7.43) and depression (EPDS score = −4.81, 95% CI: −7.55, −2.06,
P
= 0.001, W = −3.23) by the final session. These benefits were sustained at post-treatment and post-partum follow ups. Future research should further explore the effectiveness of this treatment in a randomized controlled trial.
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