The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although ...microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer.
Most large (over a kilometre in diameter) near-Earth asteroids are now known, but recognition that airbursts (or fireballs resulting from nuclear-weapon-sized detonations of meteoroids in the ...atmosphere) have the potential to do greater damage than previously thought has shifted an increasing portion of the residual impact risk (the risk of impact from an unknown object) to smaller objects. Above the threshold size of impactor at which the atmosphere absorbs sufficient energy to prevent a ground impact, most of the damage is thought to be caused by the airburst shock wave, but owing to lack of observations this is uncertain. Here we report an analysis of the damage from the airburst of an asteroid about 19 metres (17 to 20 metres) in diameter southeast of Chelyabinsk, Russia, on 15 February 2013, estimated to have an energy equivalent of approximately 500 (±100) kilotons of trinitrotoluene (TNT, where 1 kiloton of TNT = 4.185×10(12) joules). We show that a widely referenced technique of estimating airburst damage does not reproduce the observations, and that the mathematical relations based on the effects of nuclear weapons--almost always used with this technique--overestimate blast damage. This suggests that earlier damage estimates near the threshold impactor size are too high. We performed a global survey of airbursts of a kiloton or more (including Chelyabinsk), and find that the number of impactors with diameters of tens of metres may be an order of magnitude higher than estimates based on other techniques. This suggests a non-equilibrium (if the population were in a long-term collisional steady state the size-frequency distribution would either follow a single power law or there must be a size-dependent bias in other surveys) in the near-Earth asteroid population for objects 10 to 50 metres in diameter, and shifts more of the residual impact risk to these sizes.
ABSTRACT
16 yr of meteor radar data from the Canadian Meteor Orbit Radar (CMOR) were used to investigate the link between observed meteor rates and both solar and geomagnetic activity. Meteor rates ...were corrected for transmitter power and receiver noise, and seasonal effects were removed. A strong negative correlation is seen between solar activity, as measured with the 10.7 cm flux, and observed meteor rates. This lends support to the idea that heating in the atmosphere at times of elevated solar activity changes the scale height and therefore the length and maximum brightness of meteors; a larger scale height near solar maximum leads to longer, fainter meteors and therefore lower rates. A weaker negative correlation was observed with geomagnetic activity as measured with the K index; this correlation was still present when solar activity effects were removed. Meteor activity at solar maximum is as much as 30 per cent lower than at solar minimum, strictly due to observing biases; geomagnetic activity usually affects meteor rates by less than 10 per cent.
To evaluate the clinical usefulness of a quantitative deep learning-derived vascular severity score for retinopathy of prematurity (ROP) by assessing its correlation with clinical ROP diagnosis and ...by measuring clinician agreement in applying a novel scale.
Analysis of existing database of posterior pole fundus images and corresponding ophthalmoscopic examinations using 2 methods of assigning a quantitative scale to vascular severity.
Images were from clinical examinations of patients in the Imaging and Informatics in ROP Consortium. Four ophthalmologists and 1 study coordinator evaluated vascular severity on a scale from 1 to 9.
A quantitative vascular severity score (1-9) was applied to each image using a deep learning algorithm. A database of 499 images was developed for assessment of interobserver agreement.
Distribution of deep learning-derived vascular severity scores with the clinical assessment of zone (I, II, or III), stage (0, 1, 2, or 3), and extent (<3 clock hours, 3-6 clock hours, and >6 clock hours) of stage 3 evaluated using multivariate linear regression and weighted κ values and Pearson correlation coefficients for interobserver agreement on a 1-to-9 vascular severity scale.
For deep learning analysis, a total of 6344 clinical examinations were analyzed. A higher deep learning-derived vascular severity score was associated with more posterior disease, higher disease stage, and higher extent of stage 3 disease (P < 0.001 for all). For a given ROP stage, the vascular severity score was higher in zone I than zones II or III (P < 0.001). Multivariate regression found zone, stage, and extent all were associated independently with the severity score (P < 0.001 for all). For interobserver agreement, the mean ± standard deviation weighted κ value was 0.67 ± 0.06, and the Pearson correlation coefficient ± standard deviation was 0.88 ± 0.04 on the use of a 1-to-9 vascular severity scale.
A vascular severity scale for ROP seems feasible for clinical adoption; corresponds with zone, stage, extent of stage 3, and plus disease; and facilitates the use of objective technology such as deep learning to improve the consistency of ROP diagnosis.
There is increasing recognition that platelets have a functional role in the pathophysiology of sepsis, though this role has not been precisely defined. Whether sepsis alters the human platelet ...transcriptome and translational landscape has never been established. We used parallel techniques of RNA sequencing and ribosome footprint profiling to interrogate the platelet transcriptome and translatome in septic patients and healthy donors. We identified 1806 significantly differentially expressed (false discovery rate <0.05) transcripts in platelets from septic patients. Platelet translational events during sepsis were also upregulated. To explore the relevance of a murine model of sepsis, cecal ligation and puncture (CLP), we compared sepsis-induced changes in platelet gene expression between septic patients and mice subjected to CLP. Platelet transcriptional (ρ = 0.42, P = 3.2 × 10−285) and translational (ρ = 0.65, P = 1.09 × 10−56) changes were significantly correlated between septic patients and mice. We focused on ITGA2B, tracking and validating the expression, regulation, and functional impact of changes in ITGA2B during sepsis. Increased ITGA2B was identified in bone marrow megakaryocytes within 24 hours of sepsis onset. Subsequent increases in ITGA2B were seen in circulating platelets, suggesting dynamic trafficking of the messenger RNA. Transcriptional changes in ITGA2B were accompanied by de novo protein synthesis of αIIb and integrin αIIbβ3 activation. Increased αIIb was associated with mortality in humans and mice. These findings provide previously unrecognized evidence that human and murine sepsis similarly alters the platelet transcriptional and translational landscape. Moreover, ITGA2B is upregulated and functional in sepsis due to trafficking from megakaryocytes and de novo synthesis in platelets and is associated with increased mortality.
•Sepsis triggers transcriptional and translational alterations in platelets.•Sepsis-induced upregulation of ITGA2B predicts mortality.
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ABSTRACT
We measure the activity, orbital characteristics, and mass index of the strongest daytime Taurid meteor showers (ζ-Perseids and β-Taurids) as observed by the Canadian Meteor Orbit Radar ...during 2002–2020. This survey recorded ∼2 × 104 stream orbits and more than 4 × 104 single-station events with speed measurements, for meteoroids with masses ${\sim }1 \times 10^{-7}{\, \mathrm{kg}}$ and sizes ${\sim }5 \times 10^{-4}\, \mathrm{m}$. ζ-Perseid activity occurred during the interval 56○ ≤ λ⊙ ≤ 92○ and peaked at λ⊙ = 77.0○, while the β-Taurids were active during the overlapping period 85○ ≤ λ⊙ ≤ 103○ and peaked at λ⊙ = 95.0○. The corrected out-of-atmosphere velocities at these activity peaks were 26.4 and 26.3 km s−1, respectively. The showers display a broad period of activity with an asymmetric profile, with a gradual increase at the beginning and a sharper decrease after the peak. The mass indices of the ζ-Perseids and β-Taurids during their periods of activity were found to be 1.81 ± 0.05 and 1.87 ± 0.05, with the ζ-Perseids reaching a minimum of 1.71 ± 0.05 around the peak of activity.
Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on ...analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.
Context.
Several authors predicted an outburst of the Draconid meteor shower in 2018, but with an uncertain level of activity.
Aims.
Optical meteor observations were used to derive the population and ...mass indices, flux, and radiant positions of Draconid meteors.
Methods.
We performed 90 min of multi-station observations after the predicted peak of activity using highly sensitive Electron Multiplying Charge Coupled Device cameras. The data calibration is discussed in detail. A novel maximum likelihood estimation method was developed to compute the population and mass index with robust error estimation. We applied the method to observed Draconids and used the values to derive the flux. Meteor trajectories were computed and compared to predicted radiant positions from meteoroid ejection models.
Results.
We find a mass index of 1.74 ± 0.18 in the 30 min bin after the predicted peak, and 2.32 ± 0.27 in the subsequent 60 min. The location and the dispersion of the radiant are a good match to modeled values, but there is an offset of 0.4° in solar longitude.
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