ABSTRACT
In 2019 November, MAXI detected an X-ray outburst from the known Be X-ray binary system RX J0209.6−7427 located in the outer wing of the Small Magellanic Cloud. We followed the outburst of ...the system with NICER, which led to the discovery of X-ray pulsations with a period of 9.3 s. We analysed simultaneous X-ray data obtained with NuSTAR and NICER, allowing us to characterize the spectrum and provide an accurate estimate of its bolometric luminosity. During the outburst, the maximum broad-band X-ray luminosity of the system reached (1–2) × 1039 erg s−1, thus exceeding by about one order of magnitude the Eddington limit for a typical 1.4 M⊙ mass neutron star (NS). Monitoring observations with Fermi/GBM and NICER allowed us to study the spin evolution of the NS and compare it with standard accretion torque models. We found that the NS magnetic field should be of the order of 3 × 1012 G. We conclude that RX J0209.6−7427 exhibited one of the brightest outbursts observed from a Be X-ray binary pulsar in the Magellanic Clouds, reaching similar luminosity level to the 2016 outburst of SMC X-3. Despite the super-Eddington luminosity of RX J0209.6−7427, the NS appears to have only a moderate magnetic field strength.
From 2007 to 2013, the globally averaged mole fraction of methane in the atmosphere increased by 5.7 ± 1.2 ppb yr−1. Simultaneously, δ13CCH4 (a measure of the 13C/12C isotope ratio in methane) has ...shifted to significantly more negative values since 2007. Growth was extreme in 2014, at 12.5 ± 0.4 ppb, with a further shift to more negative values being observed at most latitudes. The isotopic evidence presented here suggests that the methane rise was dominated by significant increases in biogenic methane emissions, particularly in the tropics, for example, from expansion of tropical wetlands in years with strongly positive rainfall anomalies or emissions from increased agricultural sources such as ruminants and rice paddies. Changes in the removal rate of methane by the OH radical have not been seen in other tracers of atmospheric chemistry and do not appear to explain short‐term variations in methane. Fossil fuel emissions may also have grown, but the sustained shift to more 13C‐depleted values and its significant interannual variability, and the tropical and Southern Hemisphere loci of post‐2007 growth, both indicate that fossil fuel emissions have not been the dominant factor driving the increase. A major cause of increased tropical wetland and tropical agricultural methane emissions, the likely major contributors to growth, may be their responses to meteorological change.
Plain Language Summary
Atmospheric methane, which is a powerful greenhouse gas, is increasing rapidly. In the 20th century, methane growth was primarily driven by emissions from fossil fuel sources, such as the natural gas industry and coal mining. Then, in the early years of the 21st century, came a period of stability in methane. However, since 2007, growth has resumed, with especially strong growth in 2014. Evidence from carbon isotopes implies that the primary cause of the new growth is an increase in biogenic emissions, probably from wetlands and also agricultural sources, such as rice fields and cattle. The evidence presented in this research study, from a wide range of measurement sites both in the northern and southern hemispheres, suggests increased tropical emissions, for example from tropical wetlands, may be a principal cause of the global rise in methane. Contributions to the growth may also come from agricultural sources and perhaps some fossil fuel emissions also.
Key Points
Atmospheric methane is growing rapidly
Isotopic evidence implies that the growth is driven by biogenic sources
Growth is dominated by tropical sources
The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune ...polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes.
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•Heterozygous mutations in AIRE cause organ-specific autoimmune disease•Mono-allelic mutations with dominant effects cluster within the PHD1 domain of AIRE•These mutations suppress wild-type AIRE in a dominant-negative manner•Relatively high frequencies of these mutations are found in the population
This paper by Husebye and colleagues directly links heterozygous mutations in the autoimmune regulator (AIRE) gene to organ-specific autoimmunity, including APS-1. The authors show that these mutations cluster within the first PHD domain of AIRE and exert a dominant-negative effect on wild-type AIRE in vitro.
Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not ...been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response residual cancer burden (RCB)-0/1 to single-agent cisplatin or paclitaxel.
This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I–III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response.
One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39–23.68) or paclitaxel OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19–4.95). There was no evidence of an interaction between HRD and pathologic response to chemotherapy.
In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.
•This trial prospectively evaluated the predictive capacity of the HRD biomarker for pathologic response in early TNBC.•Pathologic responses to preoperative cisplatin or taxane monotherapy in germline BRCA1/2 wild-type TNBC were similar.•HRD score was not predictive of pathologic response to either cisplatin or paclitaxel chemotherapy.•HRD testing cannot be recommended as a tool to select chemotherapy agents in the management of early-stage TNBC.
The Nadir and Occultation for MArs Discovery (NOMAD) instrument on board ExoMars Trace Gas Orbiter measured a large increase in water vapor at altitudes in the range of 40–100 km during the 2018 ...global dust storm on Mars. Using a three-dimensional general circulation model, we examine the mechanism responsible for the enhancement of water vapor in the upper atmosphere. Experiments with different prescribed vertical profiles of dust show that when more dust is present higher in the atmosphere, the temperature increases, and the amount of water ascending over the tropics is not limited by saturation until reaching heights of 70–100 km. The warmer temperatures allow more water to ascend to the mesosphere. Photochemical simulations show a strong increase in high-altitude atomic hydrogen following the high-altitude water vapor increase by a few days.
HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from ...anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy.
Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab with endocrine therapy for estrogen receptor (ER)+ tumors in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n=56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast).
Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P=0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P=0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P=0.0031).
Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.
Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 ...antibody–drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.
•Targeting HER2-low expression with novel antibody-drug conjugates has reshaped the treatment of metastatic breast cancer.•This advancement raised relevant questions pertaining to the definition, diagnosis and management of HER2-low breast cancer.•We gathered 32 international experts to build consensus regarding key controversial topics pertaining HER2-low breast cancer.•A modified Delphi voting methodology was deployed, leading to 20 consensus statements, each with at least 90% consensus among experts.•Ongoing studies may lead to further refinement in our understanding of HER2-low breast cancer.
The hydroxyl radical (OH) removes most atmospheric pollutants from air. The loss frequency of OH radicals due to the combined effect of all gas-phase OH reactive species is a measureable quantity ...termed total OH reactivity. Here we present total OH reactivity observations in pristine Amazon rainforest air, as a function of season, time-of-day and height (0-80 m). Total OH reactivity is low during wet (10 s(-1)) and high during dry season (62 s(-1)). Comparison to individually measured trace gases reveals strong variation in unaccounted for OH reactivity, from 5 to 15% missing in wet-season afternoons to mostly unknown (average 79%) during dry season. During dry-season afternoons isoprene, considered the dominant reagent with OH in rainforests, only accounts for ∼20% of the total OH reactivity. Vertical profiles of OH reactivity are shaped by biogenic emissions, photochemistry and turbulent mixing. The rainforest floor was identified as a significant but poorly characterized source of OH reactivity.
The purpose of this study was to evaluate the affinity of docetaxel for 14 transporter proteins and assess the functional significance of 17 variants in five genes involved in drug elimination. Among ...the transfected models investigated, OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel. None of the observed genotypes (SLCO1B3, ABCB1, and ABCC2) was related with docetaxel clearance in 92 white patients (P > 0.17). However, the simultaneous presence of the CYP3A4*1B and CYP3A5*1A alleles was associated with a 64% increase in docetaxel clearance (P = 0.0015), independent of both sex and CYP3A activity (as determined using the erythromycin breath test). This haplotype was also associated with increased midazolam clearance in another population (P = 0.0198). An analysis of the CYP3A locus among CEPH‐HapMap samples revealed that CYP3A4*1B is present exclusively among a subset of CYP3A5 expressors. Therefore, future studies should first stratify the population on the basis of CYP3A5 genotype and then compare CYP3A activity between individuals with and without the CYP3A4*1B allele.
Clinical Pharmacology & Therapeutics (2009); 85, 2, 155–163 doi:10.1038/clpt.2008.95
The Amazonian rainforest is a large tropical ecosystem, which is one of the last pristine continental terrains. This ecosystem is ideally located for the study of diel and seasonal behaviour of ...biogenic volatile organic compounds (BVOCs) in the absence of local human interference. In this study, we report the first atmospheric BVOC measurements at the Amazonian Tall Tower Observatory (ATTO) site, located in central Amazonia. A quadrupole proton-transfer-reaction mass spectrometer (PTR-MS), with seven ambient air inlets, positioned from near ground to about 80 m (0.05, 0.5, 4, 24, 38, 53 and 79 m above the forest floor), was deployed for BVOC monitoring. We report diel and seasonal (February–March 2013 as wet season and September 2013 as dry season) ambient mixing ratios for isoprene, monoterpenes, isoprene oxidation products, acetaldehyde, acetone, methyl ethyl ketone (MEK), methanol and acetonitrile. Clear diel and seasonal patterns were observed for all compounds. In general, lower mixing ratios were observed during night, while maximum mixing ratios were observed during the wet season (February–March 2013), with the peak in solar irradiation at 12:00 LT (local time) and during the dry season (September 2013) with the peak in temperature at 16:00 LT. Isoprene and monoterpene mixing ratios were the highest within the canopy with a median of 7.6 and 1 ppb, respectively (interquartile range (IQR) of 6.1 and 0.38 ppb) during the dry season (at 24 m, from 12:00 to 15:00 LT). The increased contribution of oxygenated volatile organic compounds (OVOCs) above the canopy indicated a transition from dominating forest emissions during the wet season (when mixing ratios were higher than within the canopy), to a blend of biogenic emission, photochemical production and advection during the dry season when mixing ratios were higher above the canopy. Our observations suggest strong seasonal interactions between environmental (insolation, temperature) and biological (phenology) drivers of leaf BVOC emissions and atmospheric chemistry. Considerable differences in the magnitude of BVOC mixing ratios, as compared to other reports of Amazonian BVOC, demonstrate the need for long-term observations at different sites and more standardized measurement procedures, in order to better characterize the natural exchange of BVOCs between the Amazonian rainforest and the atmosphere.
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