Summary Background Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain ...survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. Methods We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov , numbers NCT02048020 and NCT01716195. Findings Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54–67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26–37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77–97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 39%) and neutropenia (five 11%), and during chemoradiotherapy were dysphagia (four 9%) and mucositis (four 9%). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. Interpretation Chemoradiotherapy with radiation doses reduced by 15–20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. Funding University of California.
The genetic programs that maintain leukemia stem cell (LSC) self-renewal and oncogenic potential have been well defined; however, the comprehensive epigenetic landscape that sustains LSC cellular ...identity and functionality is less well established. We report that LSCs in MLL-associated leukemia reside in an epigenetic state of relative genome-wide high-level H3K4me3 and low-level H3K79me2. LSC differentiation is associated with reversal of these broad epigenetic profiles, with concomitant downregulation of crucial MLL target genes and the LSC maintenance transcriptional program that is driven by the loss of H3K4me3, but not H3K79me2. The H3K4-specific demethylase KDM5B negatively regulates leukemogenesis in murine and human MLL-rearranged AML cells, demonstrating a crucial role for the H3K4 global methylome in determining LSC fate.
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•MLL LSCs are maintained in a hyper-H3K4me3 and hypo-H3K79me2 epigenomic state•LSC differentiation is associated with global inversion of the histone methylome•H3K4me3 serves a crucial mechanistic role in LSC maintenance•Histone demethylase KDM5B negatively regulates LSC potential
Wong et al. show that leukemia stem cells (LSCs) in MLL-rearranged leukemia are in a relative genome-wide high-H3K4me3 and low-H3K79me2 state. Differentiation of LSCs reverses this pattern, but the reduced expression of key MLL target genes is driven mainly by the loss of H3K4me3, which is regulated by KDM5B.
The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater ...insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography–MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.
Prokaryotic life has dominated most of the evolutionary history of our planet, evolving to occupy virtually all available environmental niches. Extremophiles, especially those thriving under multiple ...extremes, represent a key area of research for multiple disciplines, spanning from the study of adaptations to harsh conditions, to the biogeochemical cycling of elements. Extremophile research also has implications for origin of life studies and the search for life on other planetary and celestial bodies. In this article, we will review the current state of knowledge for the biospace in which life operates on Earth and will discuss it in a planetary context, highlighting knowledge gaps and areas of opportunity.
Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide ...mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.
We quantify the amount of nitrogen oxides (NOx) produced through lightning and photochemical processes in the Hadean atmosphere to be available in the Hadean ocean for the emergence of life. ...Atmospherically generated nitrate (NO
) and nitrite (NO
) are the most attractive high-potential electron acceptors for pulling and enabling crucial redox reactions of autotrophic metabolic pathways at submarine alkaline hydrothermal vents. The Hadean atmosphere, dominated by CO
and N
, will produce nitric oxide (NO) when shocked by lightning. Photochemical reactions involving NO and H
O vapor will then produce acids such as HNO, HNO
, HNO
, and HO
NO
that rain into the ocean. There, they dissociate into or react to form nitrate and nitrite. We present new calculations based on a novel combination of early-Earth global climate model and photochemical modeling, and we predict the flux of NOx to the Hadean ocean. In our 0.1-, 1-, and 10-bar pCO
models, we calculate the NOx delivery to be 2.4 × 10
, 6.5 × 10
, and 1.9 × 10
molecules cm
s
. After only tens of thousands to tens of millions of years, these NOx fluxes are expected to produce sufficient (micromolar) ocean concentrations of high-potential electron acceptors for the emergence of life. Key Words: Nitrogen oxides-Nitrate-Nitrite-Photochemistry-Lightning-Emergence of life. Astrobiology 17, 975-983.
Halide perovskite materials have promising performance characteristics for low-cost optoelectronic applications. Photovoltaic devices fabricated from perovskite absorbers have reached power ...conversion efficiencies above 25 per cent in single-junction devices and 28 per cent in tandem devices
. This strong performance (albeit below the practical limits of about 30 per cent and 35 per cent, respectively
) is surprising in thin films processed from solution at low-temperature, a method that generally produces abundant crystalline defects
. Although point defects often induce only shallow electronic states in the perovskite bandgap that do not affect performance
, perovskite devices still have many states deep within the bandgap that trap charge carriers and cause them to recombine non-radiatively. These deep trap states thus induce local variations in photoluminescence and limit the device performance
. The origin and distribution of these trap states are unknown, but they have been associated with light-induced halide segregation in mixed-halide perovskite compositions
and with local strain
, both of which make devices less stable
. Here we use photoemission electron microscopy to image the trap distribution in state-of-the-art halide perovskite films. Instead of a relatively uniform distribution within regions of poor photoluminescence efficiency, we observe discrete, nanoscale trap clusters. By correlating microscopy measurements with scanning electron analytical techniques, we find that these trap clusters appear at the interfaces between crystallographically and compositionally distinct entities. Finally, by generating time-resolved photoemission sequences of the photo-excited carrier trapping process
, we reveal a hole-trapping character with the kinetics limited by diffusion of holes to the local trap clusters. Our approach shows that managing structure and composition on the nanoscale will be essential for optimal performance of halide perovskite devices.
Resolving momentum degrees of freedom of excitons, which are electron-hole pairs bound by the Coulomb attraction in a photoexcited semiconductor, has remained an elusive goal for decades. In ...atomically thin semiconductors, such a capability could probe the momentum-forbidden dark excitons, which critically affect proposed opto-electronic technologies but are not directly accessible using optical techniques. Here, we probed the momentum state of excitons in a tungsten diselenide monolayer by photoemitting their constituent electrons and resolving them in time, momentum, and energy. We obtained a direct visual of the momentum-forbidden dark excitons and studied their properties, including their near degeneracy with bright excitons and their formation pathways in the energy-momentum landscape. These dark excitons dominated the excited-state distribution, a surprising finding that highlights their importance in atomically thin semiconductors.
The gravitational-wave astronomical revolution began in 2015 with LIGO's observation of the coalescence of two stellar-mass black holes. Over the coming decades, ground-based detectors like laser ...interferometer gravitational-wave observatory (LIGO), Virgo and KAGRA will extend their reach, discovering thousands of stellar-mass binaries. In the 2030s, the space-based laser interferometer space antenna (LISA) will enable gravitational-wave observations of the massive black holes in galactic centres. Between ground-based observatories and LISA lies the unexplored dHz gravitational-wave frequency band. Here, we show the potential of a decihertz observatory (DO) which could cover this band, and complement discoveries made by other gravitational-wave observatories. The dHz range is uniquely suited to observation of intermediate-mass (∼102-104M⊙) black holes, which may form the missing link between stellar-mass and massive black holes, offering an opportunity to measure their properties. DOs will be able to detect stellar-mass binaries days to years before they merge and are observed by ground-based detectors, providing early warning of nearby binary neutron star mergers, and enabling measurements of the eccentricity of binary black holes, providing revealing insights into their formation. Observing dHz gravitational-waves also opens the possibility of testing fundamental physics in a new laboratory, permitting unique tests of general relativity (GR) and the standard model of particle physics. Overall, a DO would answer outstanding questions about how black holes form and evolve across cosmic time, open new avenues for multimessenger astronomy, and advance our understanding of gravitation, particle physics and cosmology.
Lead halide perovskites are promising semiconductors for light-emitting applications because they exhibit bright, bandgap-tunable luminescence with high colour purity
. Photoluminescence quantum ...yields close to unity have been achieved for perovskite nanocrystals across a broad range of emission colours, and light-emitting diodes with external quantum efficiencies exceeding 20 per cent-approaching those of commercial organic light-emitting diodes-have been demonstrated in both the infrared and the green emission channels
. However, owing to the formation of lower-bandgap iodide-rich domains, efficient and colour-stable red electroluminescence from mixed-halide perovskites has not yet been realized
. Here we report the treatment of mixed-halide perovskite nanocrystals with multidentate ligands to suppress halide segregation under electroluminescent operation. We demonstrate colour-stable, red emission centred at 620 nanometres, with an electroluminescence external quantum efficiency of 20.3 per cent. We show that a key function of the ligand treatment is to 'clean' the nanocrystal surface through the removal of lead atoms. Density functional theory calculations reveal that the binding between the ligands and the nanocrystal surface suppresses the formation of iodine Frenkel defects, which in turn inhibits halide segregation. Our work exemplifies how the functionality of metal halide perovskites is extremely sensitive to the nature of the (nano)crystalline surface and presents a route through which to control the formation and migration of surface defects. This is critical to achieve bandgap stability for light emission and could also have a broader impact on other optoelectronic applications-such as photovoltaics-for which bandgap stability is required.
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