Investigation of atovaquone-induced spatial changes in tumour hypoxia assessed by hypoxia PET/CT in non-small cell lung cancer patients

Background Tumour hypoxia promotes an aggressive tumour phenotype and enhances resistance to anticancer treatments. Following the recent observation that the mitochondrial inhibitor atovaquone increases tumour oxygenation in NSCLC, we sought to assess whether atovaquone affects tumour subregions differently depending on their level of hypoxia. Methods Patients with resectable NSCLC participated in the ATOM trial (NCT02628080). Cohort 1 (n = 15) received atovaquone treatment, whilst cohort 2 (n = 15) did not. Hypoxia-related metrics, including change in mean tumour-to-blood ratio, tumour hypoxic volume, and fraction of hypoxic voxels, were assessed using hypoxia PET imaging. Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. Results Atovaquone-induced reduction in tumour hypoxia mostly occurred in the inner and outer tumour subregions, and to a lesser extent in the centre subregion. Atovaquone did not seem to act in the edge subregion, which was the only tumour subregion that was non-hypoxic at baseline. Notably, the most intensely hypoxic tumour voxels, and therefore the most radiobiologically resistant areas, were subject to the most pronounced decrease in hypoxia in the different subregions. Conclusions This study provides insights into the action of atovaquone in tumour subregions that help to better understand its role as a novel tumour radiosensitiser. Trial registration: ClinicalTrials.gov, NCT0262808. Registered 11th December 2015, https://clinicaltrials.gov/ct2/show/NCT0262808

A perspective from extinct radionuclides on a Young Stellar Object: The Sun and its accretion disk

Meteorites, which are remnants of solar system formation, provide a direct glimpse into the dynamics and evolution of a young stellar object (YSO), namely our Sun. Much of our knowledge about the astrophysical context of the birth of the Sun, the chronology of planetary growth from micrometer-sized dust to terrestrial planets, and the activity of the young Sun comes from the study of extinct radionuclides such as 26Al (t1/2 = 0.717 Myr). Here we review how the signatures of extinct radionuclides (short-lived isotopes that were present when the solar system formed and that have now decayed below detection level) in planetary materials influence the current paradigm of solar system formation. Particular attention is given to tying meteorite measurements to remote astronomical observations of YSOs and modeling efforts. Some extinct radionuclides were inherited from the long-term chemical evolution of the Galaxy, others were injected into the solar system by a nearby supernova, and some were produced by particle irradiation from the T-Tauri Sun. The chronology inferred from extinct radionuclides reveals that dust agglomeration to form centimeter-sized particles in the inner part of the disk was very rapid (<50 kyr), planetesimal formation started early and spanned several million years, planetary embryos (possibly like Mars) were formed in a few million years, and terrestrial planets (like Earth) completed their growths several tens of million years after the birth of the Sun.Comment: 49 pages, 9 figures, 1 table. Uncorrected preprin

Can programme theory be used as a 'translational tool’ to optimise health service delivery in a national early years’ initiative in Scotland: a case study

Background Theory-based evaluation (TBE) approaches are heralded as supporting formative evaluation by facilitating increased use of evaluative findings to guide programme improvement. It is essential that learning from programme implementation is better used to improve delivery and to inform other initiatives, if interventions are to be as effective as they have the potential to be. Nonetheless, few studies describe formative feedback methods, or report direct instrumental use of findings resulting from TBE. This paper uses the case of Scotland’s, National Health Service, early years’, oral health improvement initiative (Childsmile) to describe the use of TBE as a framework for providing feedback on delivery to programme staff and to assess its impact on programmatic action.&lt;p&gt;&lt;/p&gt; Methods In-depth, semi-structured interviews and focus groups with key stakeholders explored perceived deviations between the Childsmile programme 'as delivered’ and its Programme Theory (PT). The data was thematically analysed using constant comparative methods. Findings were shared with key programme stakeholders and discussions around likely impact and necessary actions were facilitated by the authors. Documentary review and ongoing observations of programme meetings were undertaken to assess the extent to which learning was acted upon.&lt;p&gt;&lt;/p&gt; Results On the whole, the activities documented in Childsmile’s PT were implemented as intended. This paper purposefully focuses on those activities where variation in delivery was evident. Differences resulted from the stage of roll-out reached and the flexibility given to individual NHS boards to tailor local implementation. Some adaptations were thought to have diverged from the central features of Childsmile’s PT, to the extent that there was a risk to achieving outcomes. The methods employed prompted national service improvement action, and proposals for local action by individual NHS boards to address this.&lt;p&gt;&lt;/p&gt; Conclusions The TBE approach provided a platform, to direct attention to areas of risk within a national health initiative, and to agree which intervention components were 'core’ to its hypothesised success. The study demonstrates that PT can be used as a 'translational tool’ to facilitate instrumental use of evaluative findings to optimise implementation within a complex health improvement programme.&lt;p&gt;&lt;/p&gt

Getting inside acupuncture trials - Exploring intervention theory and rationale

<p>Abstract</p> <p>Background</p> <p>Acupuncture can be described as a complex intervention. In reports of clinical trials the mechanism of acupuncture (that is, the process by which change is effected) is often left unstated or not known. This is problematic in assisting understanding of how acupuncture might work and in drawing together evidence on the potential benefits of acupuncture. Our aim was to aid the identification of the assumed mechanisms underlying the acupuncture interventions in clinical trials by developing an analytical framework to differentiate two contrasting approaches to acupuncture (traditional acupuncture and Western medical acupuncture).</p> <p>Methods</p> <p>Based on the principles of realist review, an analytical framework to differentiate these two contrasting approaches was developed. In order to see how useful the framework was in uncovering the theoretical rationale, it was applied to a set of trials of acupuncture for fatigue and vasomotor symptoms, identified from a wider literature review of acupuncture and early stage breast cancer.</p> <p>Results</p> <p>When examined for the degree to which a study demonstrated adherence to a theoretical model, two of the fourteen selected studies could be considered TA, five MA, with the remaining seven not fitting into any recognisable model. When examined by symptom, five of the nine vasomotor studies, all from one group of researchers, are arguably in the MA category, and two a TA model; in contrast, none of the five fatigue studies could be classed as either MA or TA and all studies had a weak rationale for the chosen treatment for fatigue.</p> <p>Conclusion</p> <p>Our application of the framework to the selected studies suggests that it is a useful tool to help uncover the therapeutic rationale of acupuncture interventions in clinical trials, for distinguishing between TA and MA approaches and for exploring issues of model validity. English language acupuncture trials frequently fail to report enough detail relating to the intervention. We advocate using this framework to aid reporting, along with further testing and refinement of the framework.</p

Restricting Microbial Exposure in Early Life Negates the Immune Benefits Associated with Gut Colonization in Environments of High Microbial Diversity

Background: Acquisition of the intestinal microbiota in early life corresponds with the development of the mucosal immune system. Recent work on caesarean-delivered infants revealed that early microbial composition is influenced by birthing method and environment. Furthermore, we have confirmed that early-life environment strongly influences both the adult gut microbiota and development of the gut immune system. Here, we address the impact of limiting microbial exposure after initial colonization on the development of adult gut immunity. Methodology/Principal Findings: Piglets were born in indoor or outdoor rearing units, allowing natural colonization in the immediate period after birth, prior to transfer to high-health status isolators. Strikingly, gut closure and morphological development were strongly affected by isolator-rearing, independent of indoor or outdoor origins of piglets. Isolator-reared animals showed extensive vacuolation and disorganization of the gut epithelium, inferring that normal gut closure requires maturation factors present in maternal milk. Although morphological maturation and gut closure were delayed in isolatorreared animals, these hard-wired events occurred later in development. Type I IFN, IL-22, IL-23 and Th17 pathways were increased in indoor-isolator compared to outdoor-isolator animals during early life, indicating greater immune activation in pigs originating from indoor environments reflecting differences in the early microbiota. This difference was less apparent later in development due to enhanced immune activation and convergence of the microbiota in all isolator-reared animals. This correlated with elevation of Type I IFN pathways in both groups, although T cell pathways were still more affected in indoor-reared animals. Conclusions/Significance: Environmental factors, in particular microbial exposure, influence expression of a large number of immune-related genes. However, the homeostatic effects of microbial colonization in outdoor environments require sustained microbial exposure throughout development. Gut development in high-hygiene environments negatively impacts on normal succession of the gut microbiota and promotes innate immune activation which may impair immune homeostasis

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Does the cognitive reflection test measure cognitive reflection? A mathematical modeling approach

We used a mathematical modeling approach, based on a sample of 2,019 participants, to better understand what the cognitive reflection test (CRT; Frederick In Journal of Economic Perspectives, 19, 25–42, 2005) measures. This test, which is typically completed in less than 10 min, contains three problems and aims to measure the ability or disposition to resist reporting the response that first comes to mind. However, since the test contains three mathematically based problems, it is possible that the test only measures mathematical abilities, and not cognitive reflection. We found that the models that included an inhibition parameter (i.e., the probability of inhibiting an intuitive response), as well as a mathematical parameter (i.e., the probability of using an adequate mathematical procedure), fitted the data better than a model that only included a mathematical parameter. We also found that the inhibition parameter in males is best explained by both rational thinking ability and the disposition toward actively open-minded thinking, whereas in females this parameter was better explained by rational thinking only. With these findings, this study contributes to the understanding of the processes involved in solving the CRT, and will be particularly useful for researchers who are considering using this test in their research

IL-10-dependent partial refractoriness to Toll-like receptor stimulation modulates gut mucosal dendritic cell function

The default response of the intestinal immune system to most antigens is the induction of immunological tolerance, which is difficult to reconcile with the constant exposure to ligands for TLR and other pattern recognition receptors. We showed previously that dendritic cells (DC) from the lamina propria of normal mouse intestine may be inherently tolerogenic and here we have explored how this might relate to the expression and function of Toll-like receptors (TLR). Lamina propria (LP) DC showed higher levels of TLR 2, 3, 4 and 9 protein expression than spleen and MLN DC, with most TLR-expressing DC in the gut being CD11clo, class II MHClo, CD103–, CD11b– and F4/80–. TLR expression by lamina propria DC was low in the upper small intestine and higher in distal small intestine and colon. Freshly isolated lamina propria DC expressed some CD40, CD80, CD86 and functional CCR7. These were up-regulated on CD11clo, but not on CD11chi LP DC by stimulation via TLR. However, there was little induction of IL-12 by either subset in response to TLR ligation. This was associated with constitutive IL-10 production and was reversed by blocking IL-10 function. Thus, IL-10 may maintain LP DC in a partially unresponsive state to TLR ligation, allowing them to have a critical role in immune homeostasis in the gut

Office Space Bacterial Abundance and Diversity in Three Metropolitan Areas

People in developed countries spend approximately 90% of their lives indoors, yet we know little about the source and diversity of microbes in built environments. In this study, we combined culture-based cell counting and multiplexed pyrosequencing of environmental ribosomal RNA (rRNA) gene sequences to investigate office space bacterial diversity in three metropolitan areas. Five surfaces common to all offices were sampled using sterile double-tipped swabs, one tip for culturing and one for DNA extraction, in 30 different offices per city (90 offices, 450 total samples). 16S rRNA gene sequences were PCR amplified using bar-coded “universal” bacterial primers from 54 of the surfaces (18 per city) and pooled for pyrosequencing. A three-factorial Analysis of Variance (ANOVA) found significant differences in viable bacterial abundance between offices inhabited by men or women, among the various surface types, and among cities. Multiplex pyrosequencing identified more than 500 bacterial genera from 20 different bacterial divisions. The most abundant of these genera tended to be common inhabitants of human skin, nasal, oral or intestinal cavities. Other commonly occurring genera appeared to have environmental origins (e.g., soils). There were no significant differences in the bacterial diversity between offices inhabited by men or women or among surfaces, but the bacterial community diversity of the Tucson samples was clearly distinguishable from that of New York and San Francisco, which were indistinguishable. Overall, our comprehensive molecular analysis of office building microbial diversity shows the potential of these methods for studying patterns and origins of indoor bacterial contamination. “[H]umans move through a sea of microbial life that is seldom perceived except in the context of potential disease and decay.” – Feazel et al. (2009)