Purpose
Tumor-infiltrating lymphocytes (TILs) are associated with pathological complete response (pCR) and survival after neoadjuvant chemotherapy (NAC) in patients with early breast cancer. We ...investigated the prognostic and predictive role of TILs, macrophages, and HLA class 1 expression after NAC with or without the potentially immune modulating compound zoledronic acid (ZA).
Methods
Baseline tumor biopsies from 196 patients in the NEOZOTAC trial were analyzed for CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), CD68 (macrophages), and HLA class I (HCA2/HC10) expression by immunohistochemistry and subsequently related to pCR and disease-free survival (DFS).
Results
A strong intratumoral CD8+ infiltration or expression of HLA class 1 by cancer cells was associated with a higher pCR rate (
p
< 0.05). Clinical benefit of high CD8+ T-cell infiltration was found when cancer cells expressed HLA class 1 (pCR: 21.8% vs. 6.7%,
p
= 0.04) but not when HLA class 1 expression was lost or downregulated (pCR: 5.9% vs. 0%,
p
= 0.38). Interaction analyses revealed survival benefit between HLA class 1 expression and strong CD8+ T-cell infiltration, whereas in the absence or downregulation of HLA class 1 expression, high levels of CD8+ T-cells were associated with survival disadvantage (p for interaction 0.01; hazard ratio 0.41, 95% CI 0.15–1.10,
p
= 0.08 and hazard ratio 7.67, 95% CI 0.88–66.4,
p
= 0.07, respectively). Baseline immune markers were not related to ZA treatment.
Conclusions
Strong baseline tumor infiltration with CD8+ T-cells in the presence of tumoral HLA class 1 expression in patients with HER2-negative breast cancer is related to a higher pCR rate and a better DFS after NAC.
By the end of 2018, 42 years after the landing of the two Viking seismometers on Mars, InSight will deploy onto Mars’ surface the SEIS (
S
eismic
E
xperiment for
I
nternal
S
tructure) instrument; a ...six-axes seismometer equipped with both a long-period three-axes Very Broad Band (VBB) instrument and a three-axes short-period (SP) instrument. These six sensors will cover a broad range of the seismic bandwidth, from 0.01 Hz to 50 Hz, with possible extension to longer periods. Data will be transmitted in the form of three continuous VBB components at 2 sample per second (sps), an estimation of the short period energy content from the SP at 1 sps and a continuous compound VBB/SP vertical axis at 10 sps. The continuous streams will be augmented by requested event data with sample rates from 20 to 100 sps. SEIS will improve upon the existing resolution of Viking’s Mars seismic monitoring by a factor of
∼
2500
at 1 Hz and
∼
200
000
at 0.1 Hz. An additional major improvement is that, contrary to Viking, the seismometers will be deployed via a robotic arm directly onto Mars’ surface and will be protected against temperature and wind by highly efficient thermal and wind shielding. Based on existing knowledge of Mars, it is reasonable to infer a moment magnitude detection threshold of
M
w
∼
3
at
40
∘
epicentral distance and a potential to detect several tens of quakes and about five impacts per year. In this paper, we first describe the science goals of the experiment and the rationale used to define its requirements. We then provide a detailed description of the hardware, from the sensors to the deployment system and associated performance, including transfer functions of the seismic sensors and temperature sensors. We conclude by describing the experiment ground segment, including data processing services, outreach and education networks and provide a description of the format to be used for future data distribution.
When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the ...mother has hypothyroidism during pregnancy is not known.
In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance.
The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism.
Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.
Global Carbon Budget 2015 Le Quéré, C; Moriarty, R; Andrew, R. M ...
Earth system science data,
12/2015, Letnik:
7, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere is important to better understand the global carbon ...cycle, support the development of climate policies, and project future climate change. Here we describe data sets and a methodology to quantify all major components of the global carbon budget, including their uncertainties, based on the combination of a range of data, algorithms, statistics, and model estimates and their interpretation by a broad scientific community. We discuss changes compared to previous estimates as well as consistency within and among components, alongside methodology and data limitations. CO2 emissions from fossil fuels and industry (EFF) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on combined evidence from land-cover-change data, fire activity associated with deforestation, and models. The global atmospheric CO2 concentration is measured directly and its rate of growth (GATM) is computed from the annual changes in concentration. The mean ocean CO2 sink (SOCEAN) is based on observations from the 1990s, while the annual anomalies and trends are estimated with ocean models. The variability in SOCEAN is evaluated with data products based on surveys of ocean CO2 measurements. The global residual terrestrial CO2 sink (SLAND) is estimated by the difference of the other terms of the global carbon budget and compared to results of independent dynamic global vegetation models forced by observed climate, CO2, and land-cover change (some including nitrogen–carbon interactions). We compare the mean land and ocean fluxes and their variability to estimates from three atmospheric inverse methods for three broad latitude bands. All uncertainties are reported as ±1σ, reflecting the current capacity to characterise the annual estimates of each component of the global carbon budget. For the last decade available (2005–2014), EFF was 9.0 ± 0.5 GtC yr−1, ELUC was 0.9 ± 0.5 GtC yr−1, GATM was 4.4 ± 0.1 GtC yr−1, SOCEAN was 2.6 ± 0.5 GtC yr−1, and SLAND was 3.0 ± 0.8 GtC yr−1. For the year 2014 alone, EFF grew to 9.8 ± 0.5 GtC yr−1, 0.6 % above 2013, continuing the growth trend in these emissions, albeit at a slower rate compared to the average growth of 2.2 % yr−1 that took place during 2005–2014. Also, for 2014, ELUC was 1.1 ± 0.5 GtC yr−1, GATM was 3.9 ± 0.2 GtC yr−1, SOCEAN was 2.9 ± 0.5 GtC yr−1, and SLAND was 4.1 ± 0.9 GtC yr−1. GATM was lower in 2014 compared to the past decade (2005–2014), reflecting a larger SLAND for that year. The global atmospheric CO2 concentration reached 397.15 ± 0.10 ppm averaged over 2014. For 2015, preliminary data indicate that the growth in EFF will be near or slightly below zero, with a projection of −0.6 range of −1.6 to +0.5 %, based on national emissions projections for China and the USA, and projections of gross domestic product corrected for recent changes in the carbon intensity of the global economy for the rest of the world. From this projection of EFF and assumed constant ELUC for 2015, cumulative emissions of CO2 will reach about 555 ± 55 GtC (2035 ± 205 GtCO2) for 1870–2015, about 75 % from EFF and 25 % from ELUC. This living data update documents changes in the methods and data sets used in this new carbon budget compared with previous publications of this data set (Le Quéré et al., 2015, 2014, 2013). All observations presented here can be downloaded from the Carbon Dioxide Information Analysis Center (doi:10.3334/CDIAC/GCP_2015).
The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and ...complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries.
We present an analysis of Parker Solar Probe (PSP) IS IS observations of ∼30-300 keV n−1 ions on 2018 November 11 when PSP was about 0.25 au from the Sun. Five hours before the onset of a solar ...energetic particle (SEP) event, a coronal mass ejection (CME) was observed by STEREO-A/COR2, which crossed PSP about a day later. No shock was observed locally at PSP, but the CME may have driven a weak shock earlier. The SEP event was dispersive, with higher energy ions arriving before the lower energy ones. Timing suggests the particles originated at the CME when it was at ∼7.4R . SEP intensities increased gradually from their onset over a few hours, reaching a peak, and then decreased gradually before the CME arrived at PSP. The event was weak, having a very soft energy spectrum (−4 to −5 spectral index). The earliest arriving particles were anisotropic, moving outward from the Sun, but later, the distribution was observed to be more isotropic. We present numerical solutions of the Parker transport equation for the transport of 30-300 keV n−1 ions assuming a source comoving with the CME. Our model agrees well with the observations. The SEP event is consistent with ion acceleration at a weak shock driven briefly by the CME close to the Sun, which later dissipated before arriving at PSP, followed by the transport of ions in the interplanetary magnetic field.
Context.
Aims.
We systematically search for magnetic flux rope structures in the solar wind to within the closest distance to the Sun of ~0.13 AU, using data from the third and fourth orbits of the ...Parker Solar Probe.
Methods.
We extended our previous magnetic helicity-based technique of identifying magnetic flux rope structures. The method was improved upon to incorporate the azimuthal flow, which becomes larger as the spacecraft approaches the Sun.
Results.
A total of 21 and 34 magnetic flux ropes are identified during the third (21-day period) and fourth (17-day period) orbits of the Parker Solar Probe, respectively. We provide a statistical analysis of the identified structures, including their relation to the streamer belt and heliospheric current sheet crossing.
THE PERDIGÃO Fernando, H. J. S.; Mann, J.; Palma, J. M. L. M. ...
Bulletin of the American Meteorological Society,
05/2019, Letnik:
100, Številka:
5
Journal Article
Recenzirano
Odprti dostop
A grand challenge from the wind energy industry is to provide reliable forecasts on mountain winds several hours in advance at microscale (∼100 m) resolution. This requires better microscale ...wind-energy physics included in forecasting tools, for which field observations are imperative. While mesoscale (∼1 km) measurements abound, microscale processes are not monitored in practice nor do plentiful measurements exist at this scale. After a decade of preparation, a group of European and U.S. collaborators conducted a field campaign during 1 May–15 June 2017 in Vale Cobrão in central Portugal to delve into microscale processes in complex terrain. This valley is nestled within a parallel double ridge near the town of Perdigão with dominant wind climatology normal to the ridges, offering a nominally simple yet natural setting for fundamental studies. The dense instrument ensemble deployed covered a ∼4 km × 4 km swath horizontally and ∼10 km vertically, with measurement resolutions of tens of meters and seconds. Meteorological data were collected continuously, capturing multiscale flow interactions from synoptic to microscales, diurnal variability, thermal circulation, turbine wake and acoustics, waves, and turbulence. Particularly noteworthy are the extensiveness of the instrument array, space–time scales covered, use of leading-edge multiple-lidar technology alongside conventional tower and remote sensors, fruitful cross-Atlantic partnership, and adaptive management of the campaign. Preliminary data analysis uncovered interesting new phenomena. All data are being archived for public use.
Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one ...has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients.
Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified.
One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N=52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N=6) or neurological disorders (N=5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N=67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3–4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.
In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.
The fundamental building blocks of the proton-quarks and gluons-have been known for decades. However, we still have an incomplete theoretical and experimental understanding of how these particles and ...their dynamics give rise to the quantum bound state of the proton and its physical properties, such as its spin
. The two up quarks and the single down quark that comprise the proton in the simplest picture account only for a few per cent of the proton mass, the bulk of which is in the form of quark kinetic and potential energy and gluon energy from the strong force
. An essential feature of this force, as described by quantum chromodynamics, is its ability to create matter-antimatter quark pairs inside the proton that exist only for a very short time. Their fleeting existence makes the antimatter quarks within protons difficult to study, but their existence is discernible in reactions in which a matter-antimatter quark pair annihilates. In this picture of quark-antiquark creation by the strong force, the probability distributions as a function of momentum for the presence of up and down antimatter quarks should be nearly identical, given that their masses are very similar and small compared to the mass of the proton
. Here we provide evidence from muon pair production measurements that these distributions are considerably different, with more abundant down antimatter quarks than up antimatter quarks over a wide range of momenta. These results are expected to revive interest in several proposed mechanisms for the origin of this antimatter asymmetry in the proton that had been disfavoured by previous results
, and point to future measurements that can distinguish between these mechanisms.
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