Validation of the Human Ozone Challenge Model as a Tool for Assessing Anti-Inflammatory Drugs in Early Development

This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, doubledummy, double-blind, placebo-controlled 3-period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2mg), oral prednisolone (oral corticosteroids, 50mg), ormatched placebo. At a 2-week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3-hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean [95% confidence interval]) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti-inflammatory compounds in early development

Developing Core Sets for Persons With Traumatic Brain Injury Based on the International Classification of Functioning, Disability, and Health

The authors outline the process for developing the International Classification of Functioning, Disability, and Health (ICF) Core Sets for traumatic brain injury (TBI). ICF Core Sets are selections of categories of the ICF that identify relevant categories of patients affected by specific diseases. Comprehensive and brief ICF Core Sets for TBI should become useful for clinical practice and for research. The final definition of the ICF Core Sets for TBI will be determined at an ICF Core Sets Consensus Conference, which will integrate evidence from preliminary studies. The development of ICF Core Sets is an inclusive and open process and rehabilitation professionals are invited to participate

Respiratory pathogen colonisation of dental plaque, the lower airways and endotracheal tube biofilms during mechanical ventilation

Purpose In mechanically ventilated patients, the endotracheal tube is an essential interface between the patient and ventilator, but inadvertently, it also facilitates the development of ventilator-associated pneumonia (VAP) by subverting pulmonary host defenses. A number of investigations suggest that bacteria colonizing the oral cavity may be important in the etiology of VAP. The present study evaluated microbial changes that occurred in dental plaque and lower airways of 107 critically ill mechanically ventilated patients. Materials and Methods Dental plaque and lower airways fluid was collected during the course of mechanical ventilation, with additional samples of dental plaque obtained during the entirety of patients' hospital stay. Results A “microbial shift” occurred in dental plaque, with colonization by potential VAP pathogens, namely, Staphylococcus aureus and Pseudomonas aeruginosa in 35 patients. Post-extubation analyses revealed that 70% and 55% of patients whose dental plaque included S aureus and P aeruginosa, respectively, reverted back to having a predominantly normal oral microbiota. Respiratory pathogens were also isolated from the lower airways and within the endotracheal tube biofilms. Conclusions To the best of our knowledge, this is the largest study to date exploring oral microbial changes during both mechanical ventilation and after recovery from critical illness. Based on these findings, it was apparent that during mechanical ventilation, dental plaque represents a source of potential VAP pathogens

[12CII] and [13CII] 158 mum emission from NGC 2024: Large column densities of ionized carbon

Context: We analyze the NGC 2024 HII region and molecular cloud interface using [12CII] and [13CII] observations. Aims: We attempt to gain insight into the physical structure of the interface layer between the molecular cloud and the HII region. Methods. Observations of [12CII] and [13CII] emission at 158 {\mu}m with high spatial and spectral resolution allow us to study the detailed structure of the ionization front and estimate the column densities and temperatures of the ionized carbon layer in the PDR. Results: The [12CII] emission closely follows the distribution of the 8 mum continuum. Across most of the source, the spectral lines have two velocity peaks similar to lines of rare CO isotopes. The [13CII] emission is detected near the edge-on ionization front. It has only a single velocity component, which implies that the [12CII] line shape is caused by self-absorption. An anomalous hyperfine line-intensity ratio observed in [13CII] cannot yet be explained. Conclusions: Our analysis of the two isotopes results in a total column density of N(H)~1.6\times10^23 cm^-2 in the gas emitting the [CII] line. A large fraction of this gas has to be at a temperature of several hundred K. The self-absorption is caused by a cooler (T<=100 K) foreground component containing a column density of N(H)~10^22 cm^-2

LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons

The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. We show here that the serine/threonine kinase LKB1, previously implicated in the establishment of epithelial polarity and control of cell growth, is required for axon specification during neuronal polarization in the mammalian cerebral cortex. LKB1 polarizing activity requires its association with the pseudokinase Stradalpha and phosphorylation by kinases such as PKA and p90RSK, which transduce neurite outgrowth-promoting cues. Once activated, LKB1 phosphorylates and thereby activates SAD-A and SAD-B kinases, which are also required for neuronal polarization in the cerebral cortex. SAD kinases, in turn, phosphorylate effectors such as microtubule-associated proteins that implement polarization. Thus, we provide evidence in vivo and in vitro for a multikinase pathway that links extracellular signals to the intracellular machinery required for axon specification

Distinct transcriptional programs stratify ovarian cancer cell lines into the five major histological subtypes.

From Europe PMC via Jisc Publications RouterHistory: epub 2021-09-01, ppub 2021-09-01Publication status: PublishedFunder: Cancer Research UK; Grant(s): C147/A25254, C1422/A19842Funder: Manchester Biomedical Research Centre; Grant(s): R120700/CAA070107BackgroundEpithelial ovarian cancer (OC) is a heterogenous disease consisting of five major histologically distinct subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), endometrioid (ENOC), clear cell (CCOC) and mucinous (MOC). Although HGSOC is the most prevalent subtype, representing 70-80% of cases, a 2013 landmark study by Domcke et al. found that the most frequently used OC cell lines are not molecularly representative of this subtype. This raises the question, if not HGSOC, from which subtype do these cell lines derive? Indeed, non-HGSOC subtypes often respond poorly to chemotherapy; therefore, representative models are imperative for developing new targeted therapeutics.MethodsNon-negative matrix factorisation (NMF) was applied to transcriptomic data from 44 OC cell lines in the Cancer Cell Line Encyclopedia, assessing the quality of clustering into 2-10 groups. Epithelial OC subtypes were assigned to cell lines optimally clustered into five transcriptionally distinct classes, confirmed by integration with subtype-specific mutations. A transcriptional subtype classifier was then developed by trialling three machine learning algorithms using subtype-specific metagenes defined by NMF. The ability of classifiers to predict subtype was tested using RNA sequencing of a living biobank of patient-derived OC models.ResultsApplication of NMF optimally clustered the 44 cell lines into five transcriptionally distinct groups. Close inspection of orthogonal datasets revealed this five-cluster delineation corresponds to the five major OC subtypes. This NMF-based classification validates the Domcke et al. analysis, in identifying lines most representative of HGSOC, and additionally identifies models representing the four other subtypes. However, NMF of the cell lines into two clusters did not align with the dualistic model of OC and suggests this classification is an oversimplification. Subtype designation of patient-derived models by a random forest transcriptional classifier aligned with prior diagnosis in 76% of unambiguous cases. In cases where there was disagreement, this often indicated potential alternative diagnosis, supported by a review of histological, molecular and clinical features.ConclusionsThis robust classification informs the selection of the most appropriate models for all five histotypes. Following further refinement on larger training cohorts, the transcriptional classification may represent a useful tool to support the classification of new model systems of OC subtypes

TGF-β Signaling Specifies Axons during Brain Development

In the mammalian brain, the specification of a single axon and multiple dendrites occurs early in the differentiation of most neuron types. Numerous intracellular signaling events for axon specification have been described in detail. However, the identity of the extracellular factor(s) that initiate neuronal polarity in vivo is unknown. Here, we report that transforming growth factor-β (TGF-β) initiates signaling pathways both in vivo and in vitro to fate naïve neurites into axons. Neocortical neurons lacking the type II TGF-β receptor (TβR2) fail to initiate axons during development. Exogenous TGF-β is sufficient to direct the rapid growth and differentiation of an axon, and genetic enhancement of receptor activity promotes the formation of multiple axons. Finally, we show that the bulk of these TGF-β-dependent events are mediated by site-specific phosphorylation of Par6. These results define an extrinsic cue for neuronal polarity in vivo that patterns neural circuits in the developing brain