Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations ...observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRASG12C inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRASG12C-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRASG12C-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRASG12C inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC.
•Better understanding of RAS signaling has led to the development of promising directly blocking compounds in KRAS-mutant tumors.•New drug candidates take advantage of the increased knowledge of the KRAS mutation complex and relevant protein structures.•Increasing evidence continues to demonstrate the genomic heterogeneity in KRAS-mutated NSCLC.•Current efforts include understanding and overcoming resistance after treatment with KRASG12C inhibitors.
Abstract
We performed simulations of a large number of so-called very faint X-ray transient sources from surveys obtained using the X-ray telescope aboard the Neil Gehrels Swift Observatory on two ...Galactic globular clusters, and the Galactic Centre. We calculated the ratio between the duty cycle (DC) we input in our simulations and the one we measure after the simulations. We found that fluctuations in outburst duration and recurrence times affect our estimation of the DC more than non-detected outbursts. This biases our measures to overestimate the simulated DC of sources. Moreover, we determined that compact surveys are necessary to detect outbursts with short duration because they could fall in gaps between observations, if such gaps are longer than their duration. On the other hand, long surveys are necessary to detect sources with low DC because the smallest DC a survey can observe is given by the ratio between the shortest outburst duration and the total length of the survey. If one has a limited amount of observing time, these two effects are competing, and a compromise is required which is set by the goals of the proposed survey. We have also performed simulations with several artificial survey strategies in order to evaluate the optimal observing campaign aimed at detecting transients as well as at having the most accurate estimates of the DC. As expected, the best campaign would be a regular and dense monitoring that extends for a very long period. The closest real example of such a data set is the monitoring of the Galactic Centre.
Highlights ► BDNF plays a critical role in the development and maintenance of the CNS. ► BDNF expression and activity are regulated by estrogen. ► Glucocorticoid may influence the activity of BDNF. ► ...Abnormalities in fetal hormone exposure may program atypical BDNF expression.
Bioepoxy based monomers were formulated with a cure inhibitor and a cleavable amine to obtain a recyclable epoxy system suitable for resin infusion at room temperature. Hybrid flax/carbon fiber layup ...were used. Tensile, flexural and dynamo-mechanical properties for the composites were studied. The cured laminates were chemically recycled obtaining from the epoxy matrix a thermoplastic. The recycled was processed by fused deposition modelling (FDM) and injection molding after mixing with short kenaf fibers.
Repeated bone mineral density (BMD) testing to screen for osteoporosis requires resources. For patient counseling and optimal resource use, it is important for clinicians to know whether repeated BMD ...measurement (compared with baseline BMD measurement alone) improves the ability to discriminate between postmenopausal women who will and will not experience a fracture.
To assess whether a second BMD measurement approximately 3 years after the initial assessment is associated with improved ability to estimate fracture risk beyond the baseline BMD measurement alone.
The Women's Health Initiative is a prospective observational study. Participants in the present cohort study included 7419 women with a mean (SD) follow-up of 12.1 (3.4) years between 1993 and 2010 at 3 US clinical centers. Data analysis was conducted between May 2019 and December 2019.
Incident major osteoporotic fracture (ie, hip, clinical spine, forearm, or shoulder fracture), hip fracture, baseline BMD, and absolute change in BMD were assessed. The area under the receiver operating characteristic curve (AU-ROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD were calculated to assess incident fracture risk discrimination during follow-up.
Of 7419 participants, the mean (SD) age at baseline was 66.1 (7.2) years, the mean (SD) body mass index was 28.7 (6.0), and 1720 (23%) were nonwhite individuals. During the study follow-up (mean SD 9.0 3.5 years after the second BMD measurement), 139 women (1.9%) experienced hip fractures, and 732 women (9.9%) experienced major osteoporotic fracture. In discriminating between women who experience hip fractures and those who do not, AU-ROC values were 0.71 (95% CI, 0.67-0.75) for baseline total hip BMD, 0.61 (95% CI, 0.56-0.65) for change in total hip BMD, and 0.73 (95% CI, 0.69-0.77) for the combination of baseline total hip BMD and change in total hip BMD. Femoral neck and lumbar spine BMD values had similar discrimination for hip fracture. For discrimination of major osteoporotic fracture, AU-ROC values were 0.61 (95% CI, 0.59-0.63) for baseline total hip BMD, 0.53 (95% CI, 0.51-0.55) for change in total hip BMD, and 0.61 (95% CI, 0.59-0.63) for the combination of baseline total hip BMD and change in total hip BMD. Femoral neck and lumbar spine BMD values had similar ability to discriminate between women who experienced major osteoporotic fracture and those who did not. Associations between change in bone density and fracture risk did not differ by subgroup, including diabetes, age, race/ethnicity, body mass index, or baseline BMD T score.
The findings of this study suggest that a second BMD assessment approximately 3 years after the initial measurement was not associated with improved discrimination between women who did and did not experience subsequent hip fracture or major osteoporotic fracture beyond the baseline BMD value alone and should not routinely be performed.
A technique to measure the momentum vector of the ions produced in a nuclear reaction and analyzed by a magnetic spectrometer is presented. It consists of a powerful procedure for the reconstruction ...of the ions trajectory based on the use of a focal plane detector, accurate three-dimensional models of the magnetic fields and efficient algorithms to solve the highly non-linear transport equations. The technique is quite general and reliable even with large acceptance optical devices. Experimental results obtained with the MAGNEX spectrometer show a remarkable resolution of about 0.2° in the horizontal direction, 0.7° in the vertical one and 1/1800 in the momentum modulus. A high degree of accuracy is also found in the reconstruction of both the direction and the modulus of the momentum vector, with the latter strongly depending on the order of reconstruction.
Abstract Exposure to glucocorticoids (GCs) in early development can lead to long-term changes in brain function and behavior, although little is known about the underlying neural mechanisms. ...Perinatal exposure to GCs alters adult anxiety and neuroendocrine responses to stress. Therefore, we investigated the effects of either late gestational or neonatal exposure to the GC receptor agonist dexamethasone (DEX), on apoptosis within the amygdala, a region critical for emotional regulation. DEX was administered to timed-pregnant rat dams from gestational day 18 until parturition, or postnatal day 4–6. Offspring were sacrificed the day following the last DEX treatment, and tissue was processed for immunohistochemical detection of cleaved caspase-3, a marker for apoptotic cells. Prenatal DEX treatment significantly increased the number of cleaved caspase-3–positive cells in the amygdala of both sexes, largely due to increases within the medial and basomedial subregions. Postnatal DEX treatment also increased cleaved caspase-3 immunoreactivity within the amygdala, although effects reached significance only in the central nucleus of females. Overall, DEX induction of cleaved caspase-3 in the amygdala was greater following prenatal compared with postnatal treatment, yet in both instances, elevations in cleaved caspase-3 correlated with an increase in pro-apoptotic Bax mRNA expression. Dual-label immunohistochemistry of cleaved caspase-3 and the neuronal marker NeuN confirmed that virtually all cleaved caspase-3–positive cells in the amygdala were neurons, and a subset of these cells (primarily following postnatal treatment) expressed a GABAergic calcium-binding protein phenotype (calbindin or calretinin). Together these results indicate that early developmental GC exposure induces neuronal apoptosis within the amygdala in an age-, sex-, and region-dependent manner.
Abstract
We present the full panchromatic afterglow light-curve data of GW170817, including new radio data as well as archival optical and X-ray data, between 0.5 and 940 days post-merger. By ...compiling all archival data and reprocessing a subset of it, we have evaluated the impact of differences in data processing or flux determination methods used by different groups and attempted to mitigate these differences to provide a more uniform data set. Simple power-law fits to the uniform afterglow light curve indicate a
t
0.86±0.04
rise, a
t
−1.92±0.12
decline, and a peak occurring at 155 ± 4 days. The afterglow is optically thin throughout its evolution, consistent with a single spectral index (−0.584 ± 0.002) across all epochs. This gives a precise and updated estimate of the electron power-law index,
p
= 2.168 ± 0.004. By studying the diffuse X-ray emission from the host galaxy, we place a conservative upper limit on the hot ionized interstellar medium density, <0.01 cm
−3
, consistent with previous afterglow studies. Using the late-time afterglow data we rule out any long-lived neutron star remnant having a magnetic field strength between 10
10.4
and 10
16
G. Our fits to the afterglow data using an analytical model that includes Very Long Baseline Interferometry proper motion from Mooley et al., and a structured jet model that ignores the proper motion, indicates that the proper-motion measurement needs to be considered when seeking an accurate estimate of the viewing angle.
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