Summary Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment ...can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.
Stars with initial masses such that 10 ≤ Minitial ≤ 100, where is the solar mass, fuse progressively heavier elements in their centres, until the core is inert iron. The core then gravitationally ...collapses to a neutron star or a black hole, leading to an explosion-an iron-core-collapse supernova. By contrast, extremely massive stars with Minitial ≥ 140 (if such exist) develop oxygen cores with masses, Mcore, that exceed 50, where high temperatures are reached at relatively low densities. Conversion of energetic, pressure-supporting photons into electron-positron pairs occurs before oxygen ignition and leads to a violent contraction which triggers a nuclear explosion that unbinds the star in a pair-instability supernova. Transitional objects with 100 < Minitial < 140 may end up as iron-core-collapse supernovae following violent mass ejections, perhaps as a result of brief episodes of pair instability, and may already have been identified. Here we report observations of supernova SN 2007bi, a luminous, slowly evolving object located within a dwarf galaxy. We estimate the exploding core mass to be Mcore 100, in which case theory unambiguously predicts a pair-instability supernova. We show that >3 of radioactive 56Ni was synthesized during the explosion and that our observations are well fitted by models of pair-instability supernovae. This indicates that nearby dwarf galaxies probably host extremely massive stars, above the apparent Galactic stellar mass limit, which perhaps result from processes similar to those that created the first stars in the Universe.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Animals respond to changes in power requirements during locomotion by modulating the intensity of recruitment of their propulsive musculature, but many questions concerning how muscle recruitment ...varies with speed across modes of locomotion remain unanswered. We measured normalized average burst EMG (aEMG) for pectoralis major and biceps brachii at different flight speeds in two relatively distantly related bat species: the aerial insectivore
, and the primarily fruit-eating
These ecologically distinct species employ different flight behaviors but possess similar wing aspect ratio, wing loading and body mass. Because propulsive requirements usually correlate with body size, and aEMG likely reflects force, we hypothesized that these species would deploy similar speed-dependent aEMG modulation. Instead, we found that aEMG was speed independent in
and modulated in a U-shaped or linearly increasing relationship with speed in
This interspecific difference may be related to differences in muscle fiber type composition and/or overall patterns of recruitment of the large ensemble of muscles that participate in actuating the highly articulated bat wing. We also found interspecific differences in the speed dependence of 3D wing kinematics:
modulates wing flexion during upstroke significantly more than
Overall, we observed two different strategies to increase flight speed:
tends to modulate aEMG, and
tends to modulate wing kinematics. These strategies may reflect different requirements for avoiding negative lift and overcoming drag during slow and fast flight, respectively, a subject we suggest merits further study.
Tendon springs influence locomotor movements in many terrestrial animals, but their roles in locomotion through fluids as well as in small-bodied mammals are less clear. We measured muscle, tendon ...and joint mechanics in an elbow extensor of a small fruit bat during ascending flight. At the end of downstroke, the tendon was stretched by elbow flexion as the wing was folded. At the end of upstroke, elastic energy was recovered via tendon recoil and extended the elbow, contributing to unfurling the wing for downstroke. Compared with a hypothetical ‘string-like’ system lacking series elastic compliance, the tendon spring conferred a 22.5% decrease in muscle fascicle strain magnitude. Our findings demonstrate tendon elastic action in a small flying mammal and expand our understanding of the occurrence and action of series elastic actuator mechanisms in fluid-based locomotion.
Abstract
BACKGROUND
Glioblastoma is the most common malignant primary brain tumour in adults and is usually incurable. Post-operative magnetic resonance imaging (MRI) is used to assess extent of ...resection, and subsequent follow-up MRI is used to monitor response to treatment and to detect progression. The benefit of regular, scheduled follow-up MRI on patient management and outcomes is unclear.
MATERIAL AND METHODS
In this multi-centre, retrospective observational cohort study we included patients with a histopathologically confirmed glioblastoma, operated between August 31, 2018 and February 1, 2019 who received any adjuvant oncological treatment. Follow-up MRI schedules, indications, and clinical outcomes were collected. The primary objective was to investigate the follow-up MRI surveillance practice after surgery for glioblastoma and assess compliance with recommendations from the National Institute for Health and Care Excellence (NICE) (Post-operative scan <72 hrs, MRI every 3-6 months). The secondary objectives were to determine indications for MRI scans and the association on overall survival (OS) and progression-free survival (PFS).
RESULTS
754 patients, with a median age of 63 years (range: 21-84) from 26 neuro-oncology centres were included. Most patients had post-operative MRI within 72 hours of surgery (88.1%, N=407/462). The median number of subsequent follow-up MRI was 1 (Interquartile range 0-4). 28.1% of patients had follow-up MRI in accordance with NICE recommendations (N=212/754). Patients in this group were more likely to receive second-line chemotherapy (28.6% vs 19.5%, P=0.009). The median follow-up period was 10.5 months (IQR 5.3-19.4 months). Median overall survival was 15.1 months (95% CI 12.9-17.3) in the scheduled MRI group and 9.1 months (95% CI 7.8-10.4) in the non-compliant group. On multivariable cox regression analysis, regular, scheduled MRI was independently associated with longer overall survival (HR 1.67, 95% CI 1.33-2.10, P<0.001), but not PFS (HR 1.20, 95% CI 0.98-1.47, P=0.074). Patients with progression first detected on scheduled imaging had a significantly longer OS (18.4 vs 15.6 months, P=0.013) and PFS (9.9 months vs 7.9 months, P=0.041).
CONCLUSION
Following regular scheduled surveillance follow-up MRI for glioblastoma is associated with longer overall survival. Prospective trials are needed to determine whether regular or symptom-directed MRI influences survival outcomes and quality of life.
Context. Over the past 20 yr, the quietest areas of the solar surface have revealed a weak but extremely dynamic magnetism occurring at small scales (<500 km), which may provide an important ...contribution to the dynamics and energetics of the outer layers of the atmosphere. Understanding this magnetism requires the inference of physical quantities from high-sensitivity spectro-polarimetric data with high spatio-temporal resolution. Aims. We present high-precision spectro-polarimetric data with high spatial resolution (0.4′′) of the very quiet Sun at 1.56 μm obtained with the GREGOR telescope to shed some light on this complex magnetism. Methods. We used inversion techniques in two main approaches. First, we assumed that the observed profiles can be reproduced with a constant magnetic field atmosphere embedded in a field-free medium. Second, we assumed that the resolution element has a substructure with either two constant magnetic atmospheres or a single magnetic atmosphere with gradients of the physical quantities along the optical depth, both coexisting with a global stray-light component. Results. Half of our observed quiet-Sun region is better explained by magnetic substructure within the resolution element. However, we cannot distinguish whether this substructure comes from gradients of the physical parameters along the line of sight or from horizontal gradients (across the surface). In these pixels, a model with two magnetic components is preferred, and we find two distinct magnetic field populations. The population with the larger filling factor has very weak (~150 G) horizontal fields similar to those obtained in previous works. We demonstrate that the field vector of this population is not constrained by the observations, given the spatial resolution and polarimetric accuracy of our data. The topology of the other component with the smaller filling factor is constrained by the observations for field strengths above 250 G: we infer hG fields with inclinations and azimuth values compatible with an isotropic distribution. The filling factors are typically below 30%. We also find that the flux of the two polarities is not balanced. From the other half of the observed quiet-Sun area ~50% are two-lobed Stokes V profiles, meaning that 23% of the field of view can be adequately explained with a single constant magnetic field embedded in a non-magnetic atmosphere. The magnetic field vector and filling factor are reliable inferred in only 50% based on the regular profiles. Therefore, 12% of the field of view harbour hG fields with filling factors typically below 30%. At our present spatial resolution, 70% of the pixels apparently are non-magnetised.
•NK cell KIR2DL4 interacts with HLA-G on OLs, leading to IFN-γ production by NK cells.•IFN-γ from NK cells reduces myelin protein content from OLs in vitro.•KIR2DL4+ and CD56bright NK cells are ...higher in number in MS patients.•Patient NK cell-OL conjugates are high in IFN-γ but low in myelin protein content.
Interactions between germline-encoded natural killer (NK) cell receptors and their respective ligands on tumorigenic or virus-infected cells determine NK cell cytotoxic activity and/or cytokine secretion. NK cell cytokine responses can be augmented in and can potentially contribute to multiple sclerosis (MS), an inflammatory disease of the central nervous system focused upon the oligodendrocytes (OLs). To investigate mechanisms by which NK cells may contribute to MS pathogenesis, we developed an in vitro human model of OL-NK cell interaction. We found that activated, but not resting human NK cells form conjugates with, and mediate cytotoxicity against, human oligodendrocytes. NK cells, when in conjugate with OLs, rapidly synthesize and polarize IFN-γ toward the OLs. IFN-γ is capable of reducing myelin oligodendrocyte and myelin associated glycoproteins (MOG and MAG) content. This activity is independent of MHC class-I mediated inhibition via KIR2DL1, but dependent upon the interaction between NK cell-expressed KIR2DL4 and its oligodendrocyte-expressed ligand, HLA-G. NK cells from patients with MS express higher levels of IFN-γ following conjugation to OLs, more actively promote in vitro reduction of MOG and MAG and have higher frequencies of the KIR2DL4 positive population. These data collectively suggest a mechanism by which NK cells can promote pathogenic effects upon OLs.
We assessed the influence of inclusion (method 1) and exclusion (method 2) of intratumoral vessels when determining maximum relative cerebral blood volume (rCBVmax) in 3 types of low-grade gliomas ...(LGGs): astrocytomas, oligoastrocytomas, and oligodendrogliomas. Method 1 yielded significantly higher mean rCBVmax than method 2. However, only method 2 demonstrated a significant (P = .026) association between rCBVmax and membership of a differently ranked histologic category. Exclusion of intratumoral vessels appears, therefore, preferable when determining rCBVmax in LGGs.
Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be ...possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics.
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with a high risk of colorectal cancer. This increased cancer risk is thought to result from the cellular damage ...induced by the inflammatory field. The aim of this study was to determine the pattern and time course of genomic instability occurring in UC-related neoplasia. Sites of cancer, dysplasia, and nondysplasia from 14 UC colectomy cases containing cancer were analyzed for chromosomal alterations by comparative genomic hybridization (CGH) and for microsatellite instability using a series of 10 microsatellite markers. Clonal chromosomal alterations were present in 85% of cancer sites, 86% of dysplasia sites, and 36% of nondysplasia sites. Losses of chromosome 18 or 18q and chromosome 5 or 5q were common in cancer and dysplasia and were occasionally detected in nondysplasia. High-level microsatellite instability was detected in the cancer and dysplasia of two cases. Samples that demonstrated high-level microsatellite instability were unlikely to have chromosomal alterations demonstrable by CGH. These studies suggest that the predominant type of genomic instability in UC-related neoplasia is associated with chromosomal alterations and that this type of genomic instability frequently occurs before the development of histologically defined dysplasia.
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