Glioblastomas represent the most aggressive glioma grade and are associated with a poor patient prognosis. The current standard of care, consisting of surgery, radiation and chemotherapy, only ...results in a median survival of 14 months, underscoring the importance of developing effective new therapeutic strategies. Among the challenges in treating glioblastomas are primary resistance and the rapid emergence of recurrent disease, which can result from tumor cell-intrinsic mechanisms in addition to tumor microenvironment (TME)-mediated extrinsic resistance. Using a PDGF-B-driven proneural glioma mouse model, we assessed a panel of tyrosine kinase inhibitors with different selectivity profiles. We found that PLX3397, an inhibitor of colony stimulating factor-1 receptor (CSF-1R), blocks glioma progression, markedly suppresses tumor cell proliferation and reduces tumor grade. By contrast, the multi-targeted tyrosine kinase inhibitors dovitinib and vatalanib, which directly target tumor cells, exert minimal anti-tumoral effects in vivo, despite killing glioma cells in vitro, suggesting a TME-mediated resistance mechanism may be involved. Interestingly, PLX3397 interferes with tumor-mediated education of macrophages and consequently restores the sensitivity of glioma cells to tyrosine kinase inhibitors in vivo in preclinical combination trials. Our findings thus demonstrate that microenvironmental alteration by CSF-1R blockade renders tumor cells more susceptible to receptor tyrosine kinase inhibition in a preclinical glioblastoma model, which may have important translational relevance.
Cell transplantation is a potential strategy for treating blindness caused by the loss of photoreceptors. Although transplanted rod-precursor cells are able to migrate into the adult retina and ...differentiate to acquire the specialized morphological features of mature photoreceptor cells, the fundamental question remains whether transplantation of photoreceptor cells can actually improve vision. Here we provide evidence of functional rod-mediated vision after photoreceptor transplantation in adult Gnat1−/− mice, which lack rod function and are a model of congenital stationary night blindness. We show that transplanted rod precursors form classic triad synaptic connections with second-order bipolar and horizontal cells in the recipient retina. The newly integrated photoreceptor cells are light-responsive with dim-flash kinetics similar to adult wild-type photoreceptors. By using intrinsic imaging under scotopic conditions we demonstrate that visual signals generated by transplanted rods are projected to higher visual areas, including V1. Moreover, these cells are capable of driving optokinetic head tracking and visually guided behaviour in the Gnat1−/− mouse under scotopic conditions. Together, these results demonstrate the feasibility of photoreceptor transplantation as a therapeutic strategy for restoring vision after retinal degeneration.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metal nanoshells are a class of nanoparticles with tunable optical resonances. In this article, an application of this technology to thermal ablative therapy for cancer is described. By tuning the ...nanoshells to strongly absorb light in the near infrared, where optical transmission through tissue is optimal, a distribution of nanoshells at depth in tissue can be used to deliver a therapeutic dose of heat by using moderately low exposures of extracorporeally applied near-infrared (NIR) light. Human breast carcinoma cells incubated with nanoshells in vitro were found to have undergone photothermally induced morbidity on exposure to NIR light (820 nm, 35 W/cm2), as determined by using a fluorescent viability stain. Cells without nanoshells displayed no loss in viability after the same periods and conditions of NIR illumination. Likewise, in vivo studies under magnetic resonance guidance revealed that exposure to low doses of NIR light (820 nm, 4 W/cm2) in solid tumors treated with metal nanoshells reached average maximum temperatures capable of inducing irreversible tissue damage (ΔT = 37.4 ± 6.6° C) within 4-6 min. Controls treated without nanoshells demonstrated significantly lower average temperatures on exposure to NIR light (ΔT < 10° C). These findings demonstrated good correlation with histological findings. Tissues heated above the thermal damage threshold displayed coagulation, cell shrinkage, and loss of nuclear staining, which are indicators of irreversible thermal damage. Control tissues appeared undamaged.
Since the start of the Wide-angle Search for Planets (WASP) program, more than 160 transiting exoplanets have been discovered in the WASP data. In the past, possible transit-like events identified by ...the WASP pipeline have been vetted by human inspection to eliminate false alarms and obvious false positives. The goal of this paper is to assess the effectiveness of machine learning as a fast, automated, and reliable means of performing the same functions on ground-based wide-field transit-survey data without human intervention. To this end, we have created training and test data sets made up of stellar light curves showing a variety of signal types including planetary transits, eclipsing binaries, variable stars, and non-periodic signals. We use a combination of machine-learning methods including Random Forest Classifiers (RFCs) and convolutional neural networks (CNNs) to distinguish between the different types of signals. The final algorithms correctly identify planets in the test data ∼90 per cent of the time, although each method on its own has a significant fraction of false positives. We find that in practice, a combination of different methods offers the best approach to identifying the most promising exoplanet transit candidates in data from WASP, and by extension similar transit surveys.
To investigate the origin of the features discovered in the exoplanet population, the knowledge of exoplanets' mass and radius with a good precision (≲10%) is essential. To achieve this purpose the ...discovery of transiting exoplanets around bright stars is of prime interest. In this paper, we report the discovery of three transiting exoplanets by the SuperWASP survey and the SOPHIE spectrograph with mass and radius determined with a precision better than 15%. WASP-151b and WASP-153b are two hot Saturns with masses, radii, densities and equilibrium temperatures of 0.31−0.03+0.04 MJ$0.31_{-0.03}^{+0.04}\,{M_{\textrm{J}}}$0.31−0.03+0.04 MJ, 1.13−0.03+0.03 RJ$1.13_{-0.03}^{+0.03}\,{R_{\textrm{J}}}$1.13−0.03+0.03 RJ, 0.22−0.02+0.03 ρJ$0.22_{-0.02}^{+0.03}\,\rho_{\mathrm{J}}$0.22−0.02+0.03 ρJ and 1290−10+20 K$1290_{-10}^{+20}~\mathrm{K}$1290−10+20 K, and 0.39−0.02+0.02 MJ$0.39_{-0.02}^{+0.02}\,{M_{\textrm{J}}}$0.39−0.02+0.02 MJ, 1.55−0.08+0.10 RJ$1.55_{-0.08}^{+0.10}\,{R_{\textrm{J}}}$1.55−0.08+0.10 RJ, 0.11−0.02+0.02 ρJ$0.11_{-0.02}^{+0.02}\,\rho_{\mathrm{J}}$0.11−0.02+0.02 ρJ and 1700−0.40+0.40 K$1700_{-40}^{+40}~\mathrm{K}$1700−40+40 K, respectively. Their host stars are early G type stars (with mag V ~ 13) and their orbital periods are 4.53 and 3.33 days, respectively. WASP-156b is a super-Neptune orbiting a K type star (mag V = 11.6). It has a mass of $0.128_{-0.009}^{+0.010}\,{M_{\rm J}}$0.128−0.009+0.010 MJ0.128-0.009+0.010MJ, a radius of $0.51_{-0.02}^{+0.02}\,{R_{\rm J}}$0.51−0.02+0.02 RJ0.51-0.02+0.02RJ, a density of 1.0−0.1+0.1 ρJ$1.0_{-0.1}^{+0.1}\,\rho_{\mathrm{J}}$1.0−0.1+0.1 ρJ, an equilibrium temperature of 970−20+30 K$970_{-20}^{+30}~\mathrm{K}$970−20+30 K and an orbital period of 3.83 days. The radius of WASP-151b appears to be only slightly inflated, while WASP-153b presents a significant radius anomaly compared to a recently published model. WASP-156b, being one of the few well characterized super-Neptunes, will help to constrain the still debated formation of Neptune size planets and the transition between gas and ice giants. The estimates of the age of these three stars confirms an already observed tendency for some stars to have gyrochronological ages significantly lower than their isochronal ages. We propose that high eccentricity migration could partially explain this behavior for stars hosting a short period planet. Finally, these three planets also lie close to (WASP-151b and WASP-153b) or below (WASP-156b) the upper boundary of the Neptunian desert. Their characteristics support that the ultra-violet irradiation plays an important role in this depletion of planets observed in the exoplanet population.
No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors ...associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge.
The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing.
2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 25·5% of 1965) and 1 year (232 28·9% of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 95% CI 0·46–0·99), obesity (0·50 0·34–0·74) and invasive mechanical ventilation (0·42 0·23–0·76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 IQR 0·74–1·00), at 5 months (0·74 0·64–0·88) to 1 year (0·75 0·62–0·88), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters.
The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.
UK Research and Innovation and National Institute for Health Research.
Mutations in bone morphogenetic protein receptor type 2 (BMPR2) cause familial pulmonary arterial hypertension (FPAH), but the penetrance is reduced and females are significantly overrepresented. In ...addition, gene expression data implicating the oestrogen-metabolising enzyme CYP1B1 suggests a detrimental role of oestrogens or oestrogen metabolites. We examined genetic and metabolic markers of altered oestrogen metabolism in subjects with a BMPR2 mutation. Genotypes for CYP1B1 Asn453Ser (N453S) were determined for 140 BMPR2 mutation carriers (86 females and 54 males). Nested from those subjects, a case-control study of urinary oestrogen metabolite levels (2-hydroxyoestrogen (2-OHE) and 16alpha-hydroxyoestrone (16alpha-OHE(1))) was conducted in females (five affected mutation carriers versus six unaffected mutation carriers). Among females, there was four-fold higher penetrance among subjects homozygous for the wild-type genotype (N/N) than those with N/S or S/S genotypes (p = 0.005). Consistent with this finding, the 2-OHE/16alpha-OHE(1) ratio was 2.3-fold lower in affected mutation carriers compared to unaffected mutation carriers (p = 0.006). Our findings suggest that variations in oestrogens and oestrogen metabolism modify FPAH risk. Further investigation of the role of oestrogens in this disease with profound sex bias may yield new insights and, perhaps, therapeutic interventions.
We are entering an era of unprecedented quantities of data from current and planned survey telescopes. To maximize the potential of such surveys, automated data analysis techniques are required. Here ...we implement a new methodology for variable star classification, through the combination of Kohonen Self-Organizing Maps (SOMs, an unsupervised machine learning algorithm) and the more common Random Forest (RF) supervised machine learning technique. We apply this method to data from the K2 mission fields 0–4, finding 154 ab-type RR Lyraes (10 newly discovered), 377 δ Scuti pulsators, 133 γ Doradus pulsators, 183 detached eclipsing binaries, 290 semidetached or contact eclipsing binaries and 9399 other periodic (mostly spot-modulated) sources, once class significance cuts are taken into account. We present light-curve features for all K2 stellar targets, including their three strongest detected frequencies, which can be used to study stellar rotation periods where the observed variability arises from spot modulation. The resulting catalogue of variable stars, classes, and associated data features are made available online. We publish our SOM code in python as part of the open source pymvpa package, which in combination with already available RF modules can be easily used to recreate the method.
ABSTRACT
We report the results of optical follow-up observations of 29 gravitational-wave (GW) triggers during the first half of the LIGO–Virgo Collaboration (LVC) O3 run with the Gravitational-wave ...Optical Transient Observer (GOTO) in its prototype 4-telescope configuration (GOTO-4). While no viable electromagnetic (EM) counterpart candidate was identified, we estimate our 3D (volumetric) coverage using test light curves of on- and off-axis gamma-ray bursts and kilonovae. In cases where the source region was observable immediately, GOTO-4 was able to respond to a GW alert in less than a minute. The average time of first observation was 8.79 h after receiving an alert (9.90 h after trigger). A mean of 732.3 square degrees were tiled per event, representing on average 45.3 per cent of the LVC probability map, or 70.3 per cent of the observable probability. This coverage will further improve as the facility scales up alongside the localization performance of the evolving GW detector network. Even in its 4-telescope prototype configuration, GOTO is capable of detecting AT2017gfo-like kilonovae beyond 200 Mpc in favourable observing conditions. We cannot currently place meaningful EM limits on the population of distant ($\hat{D}_L = 1.3$ Gpc) binary black hole mergers because our test models are too faint to recover at this distance. However, as GOTO is upgraded towards its full 32-telescope, 2 node (La Palma & Australia) configuration, it is expected to be sufficiently sensitive to cover the predicted O4 binary neutron star merger volume, and will be able to respond to both northern and southern triggers.
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