Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor ...prognosis. Currently, there is no generally accepted strategy for identifying these patients.
We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis.
Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21-0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TIL(high)=96%, HPV-positive/TIL(low)=59%). Survival of HPV-positive/TIL(low) patients did not differ from HPV-negative patients (HR, 1.01; P=0.98). We developed a prognostic model for HPV-positive tumours using a 'training' cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0·87). This model was validated on patients from the other centres (detection rate 67%; false-positive rate 5.6%; AUROC=0·82).
Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.
SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing ...effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.
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•mRNA vaccines induce robust type 1 CD4+ and CD8+ T cells in the spleen and lung•Vaccine-induced T cells readily exit the vasculature and enter the lung parenchyma•mRNA vaccines elicit strong long-lived plasma cell and memory B cell responses•mRNA vaccines induce antibodies with potent anti-SARS-CoV-2 neutralization activity
SARS-CoV-2 mRNA-based vaccines are among the most promising vaccine candidates against COVID-19. Laczkó et al. evaluate two nucleoside-modified mRNA vaccine candidates in mice and demonstrate that they induce potent T and B cell immune responses and high levels of neutralizing antibodies after administration of a single vaccine dose.
Optical image-guided cancer surgery is a promising technique to adequately determine tumor margins by tumor-specific targeting, potentially resulting in complete resection of tumor tissue with ...improved survival. However, identification of the photons coming from the fluorescent contrast agent is complicated by autofluorescence, optical tissue properties, and accurate fluorescent targeting agents and imaging systems. All these factors have an important influence on the image that is presented to the surgeon. Considering the clinical consequences at stake, it is a prerequisite to answer the questions that are essential for the surgeon. What is optical image-guided surgery and how can it improve patient care? What should the oncologic surgeon know about the fundamental principles of optical imaging to understand which conclusions can be drawn from the images? And how do the limitations influence clinical decision making? This article discusses these questions and provides a clear overview of the basic principles and practical applications. Although there are limitations to the intrinsic capacity of the technique, when practical and technical surgical possibilities are considered, optical imaging can be a very powerful intraoperative tool in guiding the future oncologic surgeon toward radical resection and optimal clinical results.
Billions of hectares of natural ecosystems have been degraded through human actions. The global community has agreed on targets to halt and reverse these declines, and the restoration sector faces ...the important but arduous task of implementing programmes to meet these objectives. Existing and emerging genomics tools offer the potential to improve the odds of achieving these targets. These tools include population genomics that can improve seed sourcing, meta-omics that can improve assessment and monitoring of restoration outcomes, and genome editing that can generate novel genotypes for restoring challenging environments. We identify barriers to adopting these tools in a restoration context and emphasize that regulatory and ethical frameworks are required to guide their use.
Near-field acoustic holography (NAH) is an effective tool for visualizing acoustic sources from pressure measurements made in the near-field of sources using a microphone array. The method involving ...the Fourier transform and some processing in the frequency-wavenumber domain is suitable for the study of stationary acoustic sources, providing an image of the spatial acoustic field for one frequency. When the behavior of acoustic sources fluctuates in time, NAH may not be used. Unlike time domain holography or transient method, the method proposed in the paper needs no transformation in the frequency domain or any assumption about local stationary properties. It is based on a time formulation of forward sound prediction or backward sound radiation in the time-wavenumber domain. The propagation is described by an analytic impulse response used to define a digital filter. The implementation of one filter in forward propagation and its inverse to recover the acoustic field on the source plane implies by simulations that real-time NAH is viable. Since a numerical filter is used rather than a Fourier transform of the time-signal, the emission on a point of the source may be rebuilt continuously and used for other post-processing applications.
The final fate of massive stars, and the nature of the compact remnants they leave behind (black holes and neutron stars), are open questions in astrophysics. Many massive stars are stripped of their ...outer hydrogen envelopes as they evolve. Such Wolf-Rayet stars
emit strong and rapidly expanding winds with speeds greater than 1,000 kilometres per second. A fraction of this population is also helium-depleted, with spectra dominated by highly ionized emission lines of carbon and oxygen (types WC/WO). Evidence indicates that the most commonly observed supernova explosions that lack hydrogen and helium (types Ib/Ic) cannot result from massive WC/WO stars
, leading some to suggest that most such stars collapse directly into black holes without a visible supernova explosion
. Here we report observations of SN 2019hgp, beginning about a day after the explosion. Its short rise time and rapid decline place it among an emerging population of rapidly evolving transients
. Spectroscopy reveals a rich set of emission lines indicating that the explosion occurred within a nebula composed of carbon, oxygen and neon. Narrow absorption features show that this material is expanding at high velocities (greater than 1,500 kilometres per second), requiring a compact progenitor. Our observations are consistent with an explosion of a massive WC/WO star, and suggest that massive Wolf-Rayet stars may be the progenitors of some rapidly evolving transients.
Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and ...presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.
Microorganisms are ubiquitous and highly diverse in the atmosphere. Despite the potential impacts of airborne bacteria found in the lower atmosphere over the Southern Ocean (SO) on the ecology of ...Antarctica and on marine cloud phase, no previous region-wide assessment of bioaerosols over the SO has been reported. We conducted bacterial profiling of boundary layer shipboard aerosol samples obtained during an Austral summer research voyage, spanning 42.8 to 66.5°S. Contrary to findings over global subtropical regions and the Northern Hemisphere, where transport of microorganisms from continents often controls airborne communities, the great majority of the bacteria detected in our samples were marine, based on taxonomy, back trajectories, and source tracking analysis. Further, the beta diversity of airborne bacterial communities varied with latitude and temperature, but not with other meteorological variables. Limited meridional airborne transport restricts southward community dispersal, isolating Antarctica and inhibiting microorganism and nutrient deposition from lower latitudes to these same regions. A consequence and implication for this region’s marine boundary layer and the clouds that overtop it is that it is truly pristine, free from continental and anthropogenic influences, with the ocean as the dominant source controlling low-level concentrations of cloud condensation nuclei and ice nucleating particles.
Enzymes have been exploited by humans for thousands of years in brewing and baking, but it is only recently that biocatalysis has become a mainstream technology for synthesis. Today, enzymes are used ...extensively in the manufacturing of pharmaceuticals, food, fine chemicals, flavors, fragrances and other products. Enzyme immobilization technology has also developed in parallel as a means of increasing enzyme performance and reducing process costs. The aim of this review is to present and discuss some of the more recent promising technical developments in enzyme immobilization, including the supports used, methods of fabrication, and their application in synthesis. The review highlights new support technologies such as the use of well-established polysaccharides in novel ways, the use of magnetic particles, DNA, renewable materials and hybrid organic–inorganic supports. The review also addresses how immobilization is being integrated into developing biocatalytic technology, for example in flow biocatalysis, the use of 3D printing and multi-enzymatic cascade reactions.
A number of new measurement methods for ice nucleating particles (INPs) have been introduced in recent years, and it is important to address how these methods compare. Laboratory comparisons of ...instruments sampling major INP types are common, but few comparisons have occurred for ambient aerosol measurements exploring the utility, consistency and complementarity of different methods to cover the large dynamic range of INP concentrations that exists in the atmosphere. In this study, we assess the comparability of four offline immersion freezing measurement methods (Colorado State University ice spectrometer, IS; North Carolina State University cold stage, CS; National Institute for Polar Research Cryogenic Refrigerator Applied to Freezing Test, CRAFT; University of British Columbia micro-orifice uniform deposit impactor–droplet freezing technique, MOUDI-DFT) and an online method (continuous flow diffusion chamber, CFDC) used in a manner deemed to promote/maximize immersion freezing, for the detection of INPs in ambient aerosols at different locations and in different sampling scenarios. We also investigated the comparability of different aerosol collection methods used with offline immersion freezing instruments. Excellent agreement between all methods could be obtained for several cases of co-sampling with perfect temporal overlap. Even for sampling periods that were not fully equivalent, the deviations between atmospheric INP number concentrations measured with different methods were mostly less than 1 order of magnitude. In some cases, however, the deviations were larger and not explicable without sampling and measurement artifacts. Overall, the immersion freezing methods seem to effectively capture INPs that activate as single particles in the modestly supercooled temperature regime (> −20 °C), although more comparisons are needed in this temperature regime that is difficult to access with online methods. Relative to the CFDC method, three immersion freezing methods that disperse particles into a bulk liquid (IS, CS, CRAFT) exhibit a positive bias in measured INP number concentrations below −20 °C, increasing with decreasing temperature. This bias was present but much less pronounced for a method that condenses separate water droplets onto limited numbers of particles prior to cooling and freezing (MOUDI-DFT). Potential reasons for the observed differences are discussed, and further investigations proposed to elucidate the role of all factors involved.
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