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Interplay among immune activation and cancer pathogenesis provides the framework for a novel subspecialty known as immunooncology. In the rapidly evolving field of immunooncology, understanding the tumor-specific immune response enhances understanding of cancer resistance. This review highlights the fundamentals of incorporating precision medicine to discover new immune biomarkers and predictive signatures. Using a personalized approach may have a significant, positive impact on the use of oncolytics to better guide safer and more effective therapies.

In addition to its established contribution to innate immunity, recent studies have suggested novel roles for the complement system in the development of various lung diseases. Several studies have demonstrated that complement may serve as a key link between innate and adaptive immunity in a variety of pulmonary conditions. However, the specific contributions of complement to lung diseases based on innate and adaptive immunity are just beginning to emerge. Elucidating the role of complement-mediated immune regulation in these diseases will help to identify new targets for therapeutic interventions.

The LOw Frequency ARray (LOFAR) radio telescope possesses the unique capability to measure ultra‐high energy cosmic rays as well as image lightning discharges. This study presents a comparison between the inferred thunderstorm charge structures derived from cosmic‐ray measurements and from lightning flashes. Our results show a basic triple‐layered distribution: a positive upper layer, a main negative layer, and a positive lower layer. However, our cosmic‐ray measurement shows a bottom‐heavy structure, where the charge in the upper positively charged layer is smaller than that in the lower one. This is consistent with practically all lightning observations with LOFAR, showing well‐developed negative leader structures at altitudes below those where positive leaders are seen. This is very different from the vast majority of thundercloud charge structures seen around the world. Plain Language Summary The LOw Frequency ARray radio telescope can measure radio signals from extensive air showers induced by cosmic rays during thunderstorms, helping us understand the charge distribution within thunderclouds. It can also capture images of lightning to study the charge structures. In this study, we compared the charge structures as determined by cosmic‐ray measurements and lightning flashes. For one event, both methods show a general agreement in the heights of the charge layers. In addition, the suspicion is confirmed that the charge structure of Dutch thunderstorms is different from the majority seen around the world. Usually the charge is distributed in three layers: a large positive charge at the top, a negative charge in the middle, and another weak positive charge at the bottom, referred to as a top‐heavy charge distribution. However, our measurements indicate that Dutch thunderstorms are generally bottom‐heavy, where the upper positive charge is weaker than the lower one. Key Points LOw Frequency ARray has the unique ability to simultaneously perform cosmic‐ray and lightning imaging observations to use for atmospheric science The general agreement between the charge structure heights from two observations confirms the consistency of these two independent methods A triple‐layer charge structure is found with a dominant lower positive charge, in contrast to typical thunderstorms

Ultra-high-energy (UHE) cosmic neutrinos interacting with the Moon’s regolith generate particle showers that emit Askaryan radiation. This radiation can be observed from the Earth using ground-based radio telescopes like LOFAR. We simulate the effective detection aperture for UHE neutrinos hitting the Moon. Under the same assumptions, results from this work are in good agreement with previous analytic parameterizations and Monte Carlo codes. The dependence of the effective detection aperture on the observing parameters, such as observing frequency and minimum detection threshold, and lunar characteristics like surface topography have been studied. Using a Monte Carlo simulation, we find that the detectable neutrino energy threshold is lowered when we include a realistic treatment of the inelasticity, transmission coefficient, and surface roughness. Lunar surface roughness at large scales enhances the total aperture for higher observation frequencies ( ν ≥ 1 GHz ) but has no significant effect on the LOFAR aperture. However, roughness at scales small compared to the wavelength reduces the aperture at all frequencies.

Fast propagation of sawtooth induced heat pulse is observed in the magnetohydrodynamic (MHD) active plasmas of ADITYA tokamak. The sawtooth crash deposits heat beyond the inversion radius, which gets transported to the edge region of the plasma, and is reflected as inverted sawtooth modulation in the edge channels of electron cyclotron emission (ECE) and H α spectral line emission. The time-lag analysis on ECE signal reveals the propagation time from plasma core to edge of ∼150 µ s. From this analysis, the estimated transient electron heat diffusivity χ e hp is found to be ∼50–60 m 2 s −1 , which is ten times higher than that of power balance heat diffusivity χ e pb , in the MHD active discharges of ADITYA. It has been observed that the presence of MHD ( m / n = 2/1, 3/1) activity in the intermediate region between the q = 1 and the edge radii, significantly influences the heat transport from the plasma core to the edge region. Stochastic magnetic field region formation with overlapping m / n = 2/1 and 3/1 MHD islands facilitates the fast heat-pulse propagation during a sawtooth crash in ADITYA tokamak. The disparity between the measured and the power-balance estimated diffusivity is significantly reduced by considering the electron heat diffusivity due to stochastization of magnetic field in the intermediate region.

Present paper deals with the composition and modelling of compact dense astrophysical bodies under the framework of f(R) gravity. The model is employed on various observed strange stars viz., SMC X-1, SAX J1808.4-3658, Swift J1818.0-1607, PSR J1614-2230 and PSR J0348+0432. Upon setting the appropriate value of dimensionless coupling parameter λ, the physical parameters such as the density, the radial and tangential pressures were obtained. Mass-Radius relation without presuming any equation of state is capable enough to accommodate all strange stars nearly having solar mass up to 2.5. The physical viability of the model is examined for all the aforementioned stars and it is found that all the regularity and stability conditions are satisfied.

ABSTRACT Purpose Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients. Methods A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. ‘Dried Blood Spot’ samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach. Results A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL PNA<21 days 0.57 versus CL PNA>21days 0.88 L/h. Conclusions Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Intravenous salbutamol is commonly used to treat children with severe asthma unresponsive to inhaled β2-agonist therapy. However, in this setting, there is little clinical trial data demonstrating its effectiveness. Additionally, there are significant concerns that intravenous salbutamol-dosing recommendations for children with acute asthma are excessive, and unnecessarily raise the potential for adverse reactions, such as lactic acidosis and tachycardia which, by increasing respiratory workload, exacerbate respiratory failure. Here, we review salbutamol clinical pharmacology and toxicology, evidence relating to its use in acute asthma and highlight gaps in the evidence base.

The common phenomenon of lightning still harbors many secrets such as what are the conditions for lightning initiation and what is driving the discharge to propagate over several tens of kilometers through the atmosphere forming conducting ionized channels called leaders. Since lightning is an electric discharge phenomenon, there are positively and negatively charged leaders. In this work we report on measurements made with the LOFAR radio telescope, an instrument primarily build for radio-astronomy observations. It is observed that a negative leader rather suddenly changes, for a few milliseconds, into a mode where it radiates 100 times more VHF power than typical negative leaders after which it spawns a large number of more typical negative leaders. This mode occurs during the initial stage, soon after initiation, of all lightning flashes we have mapped (about 25). For some flashes this mode occurs also well after initiation and we show one case where it is triggered twice, some 100 ms apart. We postulate that this is indicative of a small (order of 5 km 2 ) high charge pocket. Lightning thus appears to be initiated exclusively in the vicinity of such a small but dense charge pocket.

Background While most pediatric sarcomas respond to front-line therapy, some bone sarcomas do not show radiographic response like soft-tissue sarcomas (rhabdomyosarccomas) but do show 90% necrosis. Though, new therapies are urgently needed to improve survival and quality of life in pediatric patients with sarcomas. Complex chromosomal aberrations such as amplifications and deletions of DNA sequences are frequently observed in pediatric sarcomas. Evaluation of copy number variations (CNVs) associated with pediatric sarcoma patients at the time of diagnosis or following therapy offers an opportunity to assess dysregulated molecular targets and signaling pathways that may drive sarcoma development, progression, or relapse. The objective of this study was to utilize publicly available data sets to identify potential predictive biomarkers of chemotherapeutic response in pediatric Osteosarcoma (OS), Rhabdomyosarcoma (RMS) and Ewing’s Sarcoma Family of Tumors (ESFTs) based on CNVs following chemotherapy (OS n  = 117, RMS n  = 64, ESFTs n  = 25 tumor biopsies). Methods There were 206 CNV profiles derived from pediatric sarcoma biopsies collected from the public databases TARGET and NCBI-Gene Expression Omnibus (GEO). Through our comparative genomic analyses of OS, RMS, and ESFTs and 22,255 healthy individuals called from the Database of Genomic Variants (DGV), we identified CNVs (amplifications and deletions) pattern of genomic instability in these pediatric sarcomas. By integrating CNVs of Cancer Cell Line Encyclopedia (CCLE) identified in the pool of genes with drug-response data from sarcoma cell lines ( n  = 27) from Cancer Therapeutics Response Portal (CTRP) Version 2, potential predictive biomarkers of therapeutic response were identified. Results Genes associated with survival and/recurrence of these sarcomas with statistical significance were found on long arm of chromosome 8 and smaller aberrations were also identified at chromosomes 1q, 12q and x in OS, RMS, and ESFTs. A pool of 63 genes that harbored amplifications and/or deletions were frequently associated with recurrence across OS, RMS, and ESFTs. Correlation analysis of CNVs from CCLE with drug-response data of CTRP in 27 sarcoma cell lines, 33 CNVs out of 63 genes correlated with either sensitivity or resistance to 17 chemotherapies from which actionable CNV signatures such as IGF1R, MYC, MAPK1, ATF1, and MDM2 were identified. These CNV signatures could potentially be used to delineate patient populations that will respond versus those that will not respond to a particular chemotherapy. Conclusions The large-scale analyses of CNV-drug screening provides a platform to evaluate genetic alterations across aggressive pediatric sarcomas. Additionally, this study provides novel insights into the potential utilization of CNVs as not only prognostic but also as predictive biomarkers of therapeutic response. Information obtained in this study may help guide and prioritize patient-specific therapeutic options in pediatric bone and soft-tissue sarcomas.