Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for ...predicting pCR and risk of metastatic recurrence.
Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years.
At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).
Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.
•Lack of ctDNA clearance early during NAC portends poor response.•Detectable ctDNA during NAC is associated with poor outcomes.•Failure to clear ctDNA after NAC is associated with inferior distant disease-free recurrence survival.•Clearance of ctDNA is associated with improved survival even in patients who did not achieve pCR.
Zinc is an essential micronutrient for all living organisms. When facing a shortage in zinc supply, plants adapt by enhancing the zinc uptake capacity. The molecular regulators controlling this ...adaptation are not known. We present the identification of two closely related members of the Arabidopsis thaliana basic-region leucine-zipper (bZIP) transcription factor gene family, bZIP19 and bZIP23, that regulate the adaptation to low zinc supply. They were identified, in a yeast-one-hybrid screening, to associate to promoter regions of the zinc deficiency-induced ZIP4 gene of the Zrt- and Irt-related protein (ZIP) family of metal transporters. Although mutation of only one of the bZIP genes hardly affects plants, we show that the bzip19 bzip23 double mutant is hypersensitive to zinc deficiency. Unlike the wild type, the bzip19 bzip23 mutant is unable to induce the expression of a small set of genes that constitutes the primary response to zinc deficiency, comprising additional ZIP metal transporter genes. This set of target genes is characterized by the presence of one or more copies of a 10-bp imperfect palindrome in their promoter region, to which both bZIP proteins can bind. The bZIP19 and bZIP23 transcription factors, their target genes, and the characteristic cis zinc deficiency response elements they can bind to are conserved in higher plants. These findings are a significant step forward to unravel the molecular mechanism of zinc homeostasis in plants, allowing the improvement of zinc bio-fortification to alleviate human nutrition problems and phytoremediation strategies to clean contaminated soils.
Superconductivity and charge density waves (CDWs) are competitive, yet coexisting, orders in cuprate superconductors. To understand their microscopic interdependence, a probe capable of discerning ...their interaction on its natural length and time scale is necessary. We use ultrafast resonant soft x-ray scattering to track the transient evolution of CDW correlations in YBa
Cu
O
after the quench of superconductivity by an infrared laser pulse. We observe a nonthermal response of the CDW order characterized by a near doubling of the correlation length within ≈1 picosecond of the superconducting quench. Our results are consistent with a model in which the interaction between superconductivity and CDWs manifests inhomogeneously through disruption of spatial coherence, with superconductivity playing the dominant role in stabilizing CDW topological defects, such as discommensurations.
The cost effective synthesis and patterning of carbon nanomaterials is a challenge in electronic and energy storage devices. Here we report a one-step, scalable approach for producing and patterning ...porous graphene films with three-dimensional networks from commercial polymer films using a CO
infrared laser. The sp
-carbon atoms are photothermally converted to sp
-carbon atoms by pulsed laser irradiation. The resulting laser-induced graphene (LIG) exhibits high electrical conductivity. The LIG can be readily patterned to interdigitated electrodes for in-plane microsupercapacitors with specific capacitances of >4 mF cm
and power densities of ~9 mW cm
. Theoretical calculations partially suggest that enhanced capacitance may result from LIG's unusual ultra-polycrystalline lattice of pentagon-heptagon structures. Combined with the advantage of one-step processing of LIG in air from commercial polymer sheets, which would allow the employment of a roll-to-roll manufacturing process, this technique provides a rapid route to polymer-written electronic and energy storage devices.
Objective To characterize the absolute risks for older patients of readmission to hospital and death in the year after hospitalization for heart failure, acute myocardial infarction, or ...pneumonia.Design Retrospective cohort study.Setting 4767 hospitals caring for Medicare fee for service beneficiaries in the United States, 2008-10.Participants More than 3 million Medicare fee for service beneficiaries, aged 65 years or more, surviving hospitalization for heart failure, acute myocardial infarction, or pneumonia.Main outcome measures Daily absolute risks of first readmission to hospital and death for one year after discharge. To illustrate risk trajectories, we identified the time required for risks of readmission to hospital and death to decline 50% from maximum values after discharge; the time required for risks to approach plateau periods of minimal day to day change, defined as 95% reductions in daily changes in risk from maximum daily declines after discharge; and the extent to which risks are higher among patients recently discharged from hospital compared with the general elderly population.Results Within one year of hospital discharge, readmission to hospital and death, respectively, occurred following 67.4% and 35.8% of hospitalizations for heart failure, 49.9% and 25.1% for acute myocardial infarction, and 55.6% and 31.1% for pneumonia. Risk of first readmission had declined 50% by day 38 after hospitalization for heart failure, day 13 after hospitalization for acute myocardial infarction, and day 25 after hospitalization for pneumonia; risk of death declined 50% by day 11, 6, and 10, respectively. Daily change in risk of first readmission to hospital declined 95% by day 45, 38, and 45; daily change in risk of death declined 95% by day 21, 19, and 21. After hospitalization for heart failure, acute myocardial infarction, or pneumonia, the magnitude of the relative risk for hospital admission over the first 90 days was 8, 6, and 6 times greater than that of the general older population; the relative risk of death was 11, 8, and 10 times greater.Conclusions Risk declines slowly for older patients after hospitalization for heart failure, acute myocardial infarction, or pneumonia and is increased for months. Specific risk trajectories vary by discharge diagnosis and outcome. Patients should remain vigilant for deterioration in health for an extended time after discharge. Health providers can use knowledge of absolute risks and their changes over time to better align interventions designed to reduce adverse outcomes after discharge with the highest risk periods for patients.
In this paper, we demonstrate that by simple laser induction, commercial polyimide films can be readily transformed into porous graphene for the fabrication of flexible, solid-state supercapacitors. ...Two different solid-state electrolyte supercapacitors are described, namely vertically stacked graphene supercapacitors and in-plane graphene microsupercapacitors, each with enhanced electrochemical performance, cyclability, and flexibility. Devices with a solid-state polymeric electrolyte exhibit areal capacitance of >9 mF/cm2 at a current density of 0.02 mA/cm2, more than twice that of conventional aqueous electrolytes. Moreover, laser induction on both sides of polyimide sheets enables the fabrication of vertically stacked supercapacitors to multiply its electrochemical performance while preserving device flexibility.
We describe the Geophysical Fluid Dynamics Laboratory's CM4.0 physical climate model, with emphasis on those aspects that may be of particular importance to users of this model and its simulations. ...The model is built with the AM4.0/LM4.0 atmosphere/land model and OM4.0 ocean model. Topics include the rationale for key choices made in the model formulation, the stability as well as drift of the preindustrial control simulation, and comparison of key aspects of the historical simulations with observations from recent decades. Notable achievements include the relatively small biases in seasonal spatial patterns of top‐of‐atmosphere fluxes, surface temperature, and precipitation; reduced double Intertropical Convergence Zone bias; dramatically improved representation of ocean boundary currents; a high‐quality simulation of climatological Arctic sea ice extent and its recent decline; and excellent simulation of the El Niño‐Southern Oscillation spectrum and structure. Areas of concern include inadequate deep convection in the Nordic Seas; an inaccurate Antarctic sea ice simulation; precipitation and wind composites still affected by the equatorial cold tongue bias; muted variability in the Atlantic Meridional Overturning Circulation; strong 100 year quasiperiodicity in Southern Ocean ventilation; and a lack of historical warming before 1990 and too rapid warming thereafter due to high climate sensitivity and strong aerosol forcing, in contrast to the observational record. Overall, CM4.0 scores very well in its fidelity against observations compared to the Coupled Model Intercomparison Project Phase 5 generation in terms of both mean state and modes of variability and should prove a valuable new addition for analysis across a broad array of applications.
Plain Language Summary
The Geophysical Fluid Dynamics Laboratory (GFDL) of the National Oceanic and Atmospheric Administration participates along with a number of model centers around the world in constructing state‐of‐the‐art climate models for use in studies for climate change and prediction. GFDL's latest multipurpose atmosphere‐ocean coupled climate model, CM4.0, is described here. It consists of GFDL's latest atmosphere and land models at about 100 km horizontal resolution and ocean and sea ice models at roughly 25 km horizontal resolution. A handful of standard experiments have been conducted with CM4.0 for participation in the Coupled Model Intercomparison Project Phase 6, an archive of climate model results utilized by the Intergovernmental Panel on Climate Change and the climate research community more generally. The model results have been extensively evaluated against observations. This paper makes the case that CM4.0 ranks high among state‐of‐the‐art coupled climate models by many measures of bias in the simulated climatology and in its ability to capture modes of climate variability such as the El Niño‐Southern Oscillation and Madden‐Julian Oscillation. The paper also discusses some potential weaknesses, including unrealistically large internal variability in the Southern Ocean and insufficient warming before 1990 in the simulation of the twentieth century.
Key Points
A team at GFDL has developed a new model of the physical climate system referred to as CM4.0
Strengths of model include ENSO simulation and small biases in TOA fluxes, precipitation, Arctic sea ice extent, and sea surface temperature
Problematic aspects include large variability in Southern Ocean and historical simulation with little warming prior to 1990
To evaluate the visual function before and after cataract surgery in children with congenital posterior lens opacities as well as the factors associated with a good visual outcome.
Perspective ...case-series study.
Pediatric patients with posterior lens opacities who underwent cataract surgery were recruited in this study. The cataract type, location, area of opacities, and strabismus were examined perioperatively. Moreover, visual acuity, modulation transfer function (MTF), ocular aberrations, and stereopsis were measured before and after cataract surgery.
Sixty-nine eyes of 63 patients were studied. The mean age of patients at surgery was 6.5 ± 2.9 years. Visual function including corrected distance visual acuity (CDVA), MTF cutoff frequency, and ocular aberrations were significantly affected in eyes with posterior lens opacities. Postoperatively, CDVA was significantly improved from 0.81 ± 0.53 logMAR to 0.40 ± 0.40 logarithm of the minimum angle of resolution (logMAR) (P < .001). Thirty-nine patients (56.5%) achieved a final VA of 20/40 or better. Moreover, MTF cutoff values were significantly improved, and total ocular aberrations were decreased after cataract removal (both P < .001). The stereopsis was also improved postoperatively (P < .001). The multivariate analysis of the risk factors for postoperative CDVA showed that worse preoperative CDVA, larger size of lens opacities, and mean keratometry were the risk factors (all P < .05).
Visual function can be significantly decreased in children with posterior lens opacities, and surgery was effective in improving visual function. Patients with a CDVA of 0.52 logMAR or better, a size of lens opacity <6.5 mm2 and smaller mean keratometry had a greater CDVA postoperatively.
A measurement of electron antineutrino oscillation by the Daya Bay Reactor Neutrino Experiment is described in detail. Six 2.9-GWth nuclear power reactors of the Daya Bay and Ling Ao nuclear power ...facilities served as intense sources of ν¯e’s. Comparison of the ν¯e rate and energy spectrum measured by antineutrino detectors far from the nuclear reactors (∼1500–1950 m) relative to detectors near the reactors (∼350–600 m) allowed a precise measurement of ν¯e disappearance. More than 2.5 million ν¯e inverse beta-decay interactions were observed, based on the combination of 217 days of operation of six antineutrino detectors (December, 2011–July, 2012) with a subsequent 1013 days using the complete configuration of eight detectors (October, 2012–July, 2015). The ν¯e rate observed at the far detectors relative to the near detectors showed a significant deficit, R=0.949±0.002(stat)±0.002(syst). The energy dependence of ν¯e disappearance showed the distinct variation predicted by neutrino oscillation. Analysis using an approximation for the three-flavor oscillation probability yielded the flavor-mixing angle sin22θ13=0.0841±0.0027(stat)±0.0019(syst) and the effective neutrino mass-squared difference of |Δmee2|=(2.50±0.06(stat)±0.06(syst))×10−3 eV2. Analysis using the exact three-flavor probability found Δm322=(2.45±0.06(stat)±0.06(syst))×10−3 eV2 assuming the normal neutrino mass hierarchy and Δm322=(−2.56±0.06(stat)±0.06(syst))×10−3 eV2 for the inverted hierarchy.
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