We report the results of a series of three-dimensional (3D) simulations of the deflagration phase of the gravitationally confined detonation mechanism for Type Ia supernovae. In this mechanism, ...ignition occurs at one or several off-center points, resulting in a burning bubble of hot ash that rises rapidly, breaks through the surface of the star, and collides at a point opposite the breakout on the stellar surface. We find that detonation conditions are robustly reached in our 3D simulations for a range of initial conditions and resolutions. Detonation conditions are achieved as the result of an inwardly directed jet that is produced by the compression of unburnt surface material when the surface flow collides with itself. A high-velocity outwardly directed jet is also produced. The initial conditions explored in this paper lead to conditions at detonation that can be expected to produce large amounts of super(56)Ni and small amounts of intermediate-mass elements. These particular simulations are therefore relevant only to high-luminosity Type Ia supernovae. Recent observations of Type Ia supernovae imply a compositional structure that is qualitatively consistent with that expected from these simulations.
This work describes the NASA Atmospheric CO2 Observations from Space (ACOS) XCO2 retrieval algorithm, and its performance on highly realistic, simulated observations. These tests, restricted to ...observations over land, are used to evaluate retrieval errors in the face of realistic clouds and aerosols, polarized non-Lambertian surfaces, imperfect meteorology, and uncorrelated instrument noise. We find that post-retrieval filters are essential to eliminate the poorest retrievals, which arise primarily due to imperfect cloud screening. The remaining retrievals have RMS errors of approximately 1 ppm. Modeled instrument noise, based on the Greenhouse Gases Observing SATellite (GOSAT) in-flight performance, accounts for less than half the total error in these retrievals. A small fraction of unfiltered clouds, particularly thin cirrus, lead to a small positive bias of ~0.3 ppm. Overall, systematic errors due to imperfect characterization of clouds and aerosols dominate the error budget, while errors due to other simplifying assumptions, in particular those related to the prior meteorological fields, appear small.
We describe a method of evaluating systematic errors in measurements of total column dry-air mole fractions of CO2 (XCO2 ) from space, and we illustrate the method by applying it to the v2.8 ...Atmospheric CO2 Observations from Space retrievals of the Greenhouse Gases Observing Satellite (ACOS-GOSAT) measurements over land. The approach exploits the lack of large gradients in XCO2 south of 25° S to identify large-scale offsets and other biases in the ACOS-GOSAT data with several retrieval parameters and errors in instrument calibration. We demonstrate the effectiveness of the method by comparing the ACOS-GOSAT data in the Northern Hemisphere with ground truth provided by the Total Carbon Column Observing Network (TCCON). We use the observed correlation between free-tropospheric potential temperature and XCO2 in the Northern Hemisphere to define a dynamically informed coincidence criterion between the ground-based TCCON measurements and the ACOS-GOSAT measurements. We illustrate that this approach provides larger sample sizes, hence giving a more robust comparison than one that simply uses time, latitude and longitude criteria. Our results show that the agreement with the TCCON data improves after accounting for the systematic errors, but that extrapolation to conditions found outside the region south of 25° S may be problematic (e.g., high airmasses, large surface pressure biases, M-gain, measurements made over ocean). A preliminary evaluation of the improved v2.9 ACOS-GOSAT data is also discussed.
Following neoadjuvant chemotherapy (NAC), the optimal strategies for postmastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) after breast-conserving surgery (BCS) are controversial. ...In this analysis, we evaluate the impact of these radiotherapy (RT) approaches for women with clinically node-positive breast cancer treated with NAC in the National Cancer Database (NCDB).
Women with cT1–3 cN1 M0 breast cancer treated with NAC were divided into four cohorts by surgery Mastectomy (Mast) versus BCS and post-chemotherapy pathologic nodal status (ypN0 versus ypN+). Overall survival (OS) was estimated using the Kaplan–Meier method and RT approaches were analyzed using the log-rank test, multivariate Cox models, and propensity score-matched analyses.
From 2003 to 2011, 15 315 cases were identified including 3040 Mast-ypN0, 7243 Mast-ypN+, 2070 BCS-ypN0, and 2962 BCS-ypN+ patients. On univariate analysis, PMRT was associated with improved OS for both Mast-ypN0 (P = 0.019) and Mast-ypN+ (P < 0.001) patients. On multivariate analyses adjusted for factors including age, comorbidity score, cT stage, in-breast pathologic complete response, axillary surgery, ypN stage, estrogen receptor status and hormone therapy, PMRT remained independently associated with improved OS among Mast-ypN0 hazard ratio (HR) = 0.729, 95% confidence interval (CI) 0.566–0.939, P = 0.015 and Mast-ypN+ patients (HR = 0.772, 95% CI 0.689–0.866, P < 0.001). No differences in OS were observed with the addition of RNI to breast RT for BCS-ypN0 or BCS-ypN+ patients. Propensity score-matched analyses demonstrated identical patterns of significance. On subset analysis, OS was improved with PMRT in each pathologic nodal subgroup (ypN0, ypN1, and ypN2-3) (all P < 0.05).
In the largest reported analysis of RT for cN1 patients treated with NAC, PMRT was associated with improved OS for all pathologic nodal subgroups. No OS differences were observed with the addition of RNI to breast RT.
To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials ...to identify points on the treatment pathway where outcomes differ from BRAF wild-types.
2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status.
231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months.
BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression.
Little is known about treatment expectations of patients with spinal metastases undergoing radiotherapy and/or surgery. Assuming that patients with spinal metastases share characteristics with ...patients who had spinal surgery for non-cancer related conditions and with advanced cancer patients, we performed a systematic review to summarize the literature on patient expectations regarding treatment outcomes of spinal surgery and advanced cancer care.
A comprehensive search was performed in MEDLINE, EMBASE and PsycINFO for studies between 2000 and sep-2019. Studies including adult patients (> 18 years), undergoing spinal surgery or receiving advanced cancer care, investigating patients' pre-treatment expectations regarding treatment outcomes were included. Two independent reviewers screened titles, abstracts and full-texts, extracted data and assessed methodological quality.
The search identified 7343 articles, of which 92 were selected for full-text review. For this review, 31 articles were included. Patients undergoing spinal surgery had overly optimistic expectations regarding pain and symptom relief, they underestimated the probability of functional disability, and overestimated the probability of (complete) recovery and return to work. Studies highlighted that patients feel not adequately prepared for surgery in terms of post-treatment expectations. Similarly, advanced cancer patients receiving palliative treatment often had overly optimistic expectations regarding their survival probability and cure rates.
Patients tend to have overly optimistic expectations regarding pain and symptom relief, recovery and prognosis following spinal surgery or advanced cancer care. Pretreatment consultation about the expected pain and symptom relief, recovery and prognosis may improve understanding of prognosis, and promote and manage expectations, which, in turn, may lead to better perceived outcomes.
PROSPERO registration number: CRD42020145151 .
Increasing evidence indicates that epigenetic changes regulate cell genesis. Here, we ask about neural precursors, focusing on CREB binding protein (CBP), a histone acetyltransferase that, when ...haploinsufficient, causes Rubinstein-Taybi syndrome (RTS), a genetic disorder with cognitive dysfunction. We show that neonatal cbp+/− mice are behaviorally impaired, displaying perturbed vocalization behavior. cbp haploinsufficiency or genetic knockdown with siRNAs inhibited differentiation of embryonic cortical precursors into all three neural lineages, coincident with decreased CBP binding and histone acetylation at promoters of neuronal and glial genes. Inhibition of histone deacetylation rescued these deficits. Moreover, CBP phosphorylation by atypical protein kinase C ζ was necessary for histone acetylation at neural gene promoters and appropriate differentiation. These data support a model in which environmental cues regulate CBP activity and histone acetylation to control neural precursor competency to differentiate, and indicate that cbp haploinsufficiency disrupts this mechanism, thereby likely causing cognitive dysfunction in RTS.
► CBP+/− mice show early cognitive dysfunction, like Rubinstein-Taybi syndrome (RTS) ► CBP promotes neurogenesis by enhancing histone acetylation at neural promoters ► Atypical PKC phosphorylates CBP to regulate histone acetylation
Identification of a biomarker that can inform on extracellular serotonin (5-HT) levels in the brains of living humans would enable greater understanding of the way brain circuits are modulated by ...serotonergic neurotransmission. Substantial evidence from studies in animals and humans indicates an inverse relationship between central 5-HT tonus and 5-HT type 4 receptor (5-HT4R) density, suggesting that 5-HT4R receptor density may be a biomarker marker for 5-HT tonus. Here, we investigated whether a 3-week administration of a selective serotonin reuptake inhibitor, expected to increase brain 5-HT levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified at baseline and at follow-up with (11)CSB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent with a model, wherein the 5-HT4R density adjusts to changes in the extracellular 5-HT tonus. Our data demonstrate for the first time in humans that the imaging of central 5-HT4R binding may be used as an in vivo biomarker of the central 5-HT tonus.
We have shown previously that lumpectomy with radiation therapy was more effective than lumpectomy alone for the treatment of ductal carcinoma in situ (DCIS). We did a double-blind randomised ...controlled trial to find out whether lumpectomy, radiation therapy, and tamoxifen was of more benefit than lumpectomy and radiation therapy alone for DCIS.
1804 women with DCIS, including those whose resected sample margins were involved with tumour, were randomly assigned lumpectomy, radiation therapy (50 Gy), and placebo (n=902), or lumpectomy, radiation therapy, and tamoxifen (20 mg daily for 5 years, n=902). Median follow-up was 74 months (range 57–93). We compared annual event rates and cumulative probability of invasive or non-invasive ipsilateral and contralateral tumours over 5 years.
Women in the tamoxifen group had fewer breast-cancer events at 5 years than did those on placebo (8·2 vs 13·4%, p=0·0009). The cumulative incidence of all invasive breast-cancer events in the tamoxifen group was 4·1% at 5 years: 2·1% in the ipsilateral breast, 1·8% in the contralateral breast, and 0·2% at regional or distant sites. The risk of ipsilateral-breast cancer was lower in the tamoxifen group even when sample margins contained tumour and when DCIS was associated with comedonecrosis.
The combination of lumpectomy, radiation therapy, and tamoxifen was effective in the prevention of invasive cancer.
Motivated by the challenge of capturing complex hierarchical chemical detail in natural material from a wide range of applications, the Maia detector array and integrated realtime processor have been ...developed to acquire X-ray fluorescence images using X-ray Fluorescence Microscopy (XFM). Maia has been deployed initially at the XFM beamline at the Australian Synchrotron and more recently, demonstrating improvements in energy resolution, at the P06 beamline at Petra III in Germany. Maia captures fine detail in element images beyond 100 M pixels. It combines a large solid-angle annular energy-dispersive 384 detector array, stage encoder and flux counter inputs and dedicated FPGA-based real-time event processor with embedded spectral deconvolution. This enables high definition imaging and enhanced trace element sensitivity to capture complex trace element textures and place them in a detailed spatial context. Maia hardware and software methods provide per pixel correction for dwell, beam flux variation, dead-time and pileup, as well as off-line parallel processing for enhanced throughput. Methods have been developed for real-time display of deconvoluted SXRF element images, depth mapping of rare particles and the acquisition of 3D datasets for fluorescence tomography and XANES imaging using a spectral deconvolution method that tracks beam energy variation.
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