Development of a Core Outcome Set and Minimum Reporting Set for intervention studies in growth restriction in the NEwbOrN (COSNEON): study protocol for a Delphi study.

BACKGROUND: Growth restriction in the newborn (GRN) can predispose to severe complications including hypoglycemia, sepsis, and necrotizing enterocolitis. Different interventions and treatments, such as feeding strategies, for GRN have specific benefits and risks. Comparing results from studies investigating intervention studies in GRN is challenging due to the use of different baseline and study characteristics and differences in reported study outcomes. In order to be able to compare study results and to allow pooling of data, uniform reporting of study characteristics (minimum reporting set [MRS]) and outcomes (core outcome set [COS]) are needed. We aim to develop both an MRS and a COS for interventional and treatment studies in GRN. METHODS/DESIGN: The MRS and COS will be developed according to Delphi methodology. First, a scoping literature search will be performed to identify study characteristics and outcomes in research focused on interventions/treatments in the GRN. An international group of stakeholders, including experts (clinicians working with GRN, and researchers who focus on GRN) and lay experts ([future] parents of babies with GRN), will be questioned to rate the importance of the study characteristics and outcomes in three rounds. After three rounds there will be two consensus meetings: a face-to-face meeting and an electronic meeting. During the consensus meetings multiple representatives of stakeholder groups will reach agreement upon which study characteristics and outcomes will be included into the COS and MRS. The second electronic consensus meeting will be used to test if an electronic meeting is as effective as a face-to-face meeting. DISCUSSION: In our opinion a COS alone is not sufficient to compare and aggregate trial data. Hence, to ensure optimum comparison we also will develop an MRS. Interventions in GRN infants are often complicated by coexisting preterm birth. A COS already has been developed for preterm birth. The majority of GRN infants are born at term, however, and we therefore chose to develop a separate COS for interventions in GRN, which can be combined (with expected overlap) in intervention studies enrolling preterm GRN babies. TRIAL REGISTRATION: Not applicable. This study is registered in the Core Outcome Measures for Effectiveness ( COMET ) database. Registered on 30 June 2017

Evaluating Promotional Approaches for Citizen Science Biological Recording: Bumblebees as a Group Versus Harmonia axyridis as a Flagship for Ladybirds

Over the past decade, the number of biological records submitted by members of the public have increased dramatically. However, this may result in reduced record quality, depending on how species are promoted in the media. Here we examined the two main promotional approaches for citizen science recording schemes: flagship-species, using one charismatic species as an umbrella for the entire group (here, Harmonia axyridis (Pallas) for Coleoptera: Coccinellidae), and general-group, where the group is promoted as a whole and no particular prominence is given to any one species (here, bumblebees, genus Bombus (Hymenoptera: Apidae)). Of the two approaches, the general-group approach produced data that was not biased towards any one species, but far fewer records per year overall. In contrast, the flagship-species approach generated a much larger annual dataset, but heavily biased towards the flagship itself. Therefore, we recommend that the approach for species promotion is fitted to the result desired

Control of amino-acid transport coordinates metabolic reprogramming in T cell malignancy

This study explores the regulation and importance of System L amino acid transport in a murine model of T cell acute lymphoblastic leukemia (T-ALL) caused by deletion of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). There has been a strong focus on glucose transport in leukemias but the present data show that primary T-ALL cells have increased transport of multiple nutrients. Specifically, increased leucine transport in T-ALL fuels mammalian target of rapamycin complex 1 (mTORC1) activity which then sustains expression of hypoxia inducible factor-1α (HIF1α) and c-Myc; drivers of glucose metabolism in T cells. A key finding is that PTEN deletion and phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) accumulation is insufficient to initiate leucine uptake, mTORC1 activity, HIF1α or c-Myc expression in T cells and hence cannot drive T-ALL metabolic reprogramming. Instead, a key regulator for leucine transport in T-ALL is identified as NOTCH. Mass spectrometry based proteomics identifies SLC7A5 as the predominant amino acid transporter in primary PTEN(-/-) T-ALL cells. Importantly, expression of SLC7A5 is critical for the malignant transformation induced by PTEN deletion. These data reveal the importance of regulated amino acid transport for T cell malignancies, highlighting how a single amino acid transporter can play a key role.Leukemia accepted article preview online, 26 May 2017. doi:10.1038/leu.2017.160.</p

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Intracellular lumen extension requires ERM-1-dependent apical membrane expansion and AQP-8-mediated flux

SUMMARY Many unicellular tubes such as capillaries form lumens intracellularly, a process that is not well understood. Here we show that the cortical membrane organizer ERM-1 is required to expand the intracellular apical/lumenal membrane and its actin undercoat during single-cell C.elegans excretory canal morphogenesis. We characterize AQP-8, identified in an ERM-1 overexpression (ERM-1[++]) suppressor screen, as a canalicular aquaporin that interacts with ERM-1 in lumen extension in a mercury-sensitive manner, implicating water-channel activity. AQP-8 is transiently recruited to the lumen by ERM-1, co-localizing in peri-lumenal cuffs interspaced along expanding canals. An ERM-1[++]-mediated increase in the number of lumen-associated canaliculi is reversed by AQP-8 depletion. We propose that the ERM-1-AQP-8 interaction propels lumen extension by translumenal flux, suggesting a direct morphogenetic effect of water-channel-regulated fluid pressure

The development of compassionate engagement and action scales for self and others

Background Studies of the value of compassion on physical and mental health and social relationships have proliferated in the last 25 years. Although, there are several conceptualisations and measures of compassion, this study develops three new measures of compassion competencies derived from an evolutionary, motivational approach. The scales assess 1. the compassion we experience for others, 2. the compassion we experience from others, and 3. self-compassion based on a standard definition of compassion as a ‘sensitivity to suffering in self and others with a commitment to try to alleviate and prevent it’. We explored these in relationship to other compassion scales, self-criticism, depression, anxiety, stress and well-being. Methods Participants from three different countries (UK, Portugal and USA) completed a range of scales including compassion for others, self-compassion, self-criticism, shame, depression, anxiety and stress with the newly developed ‘The Compassionate Engagement and Actions’ scale. Results All three scales have good validity. Interestingly, we found that the three orientations of compassion are only moderately correlated to one another (r < .5). We also found that some elements of self-compassion (e.g., being sensitive to, and moved by one’s suffering) have a complex relationship with other attributes of compassion (e.g., empathy), and with depression, anxiety and stress. A path-analysis showed that self-compassion is a significant mediator of the association between self-reassurance and well-being, while self-criticism has a direct effect on depressive symptoms, not mediated by self-compassion. Discussion Compassion evolved from caring motivation and in humans is associated with a range of different socially intelligent competencies. Understanding how these competencies can be inhibited and facilitated is an important research endeavour. These new scales were designed to assess these competencies. Conclusions This is the first study to measure the three orientations of compassion derived from an evolutionary model of caring motivation with specified competencies. Our three new measures of compassion further indicate important complex relationships between different potentiation’s of compassion, well-being, and vulnerability to psychopathologies.N/

Amyloid Plaques Beyond Aβ: A Survey of the Diverse Modulators of Amyloid Aggregation

Aggregation of the amyloid-β (Aβ) peptide is strongly correlated with Alzheimer’s disease (AD). Recent research has improved our understanding of the kinetics of amyloid fibril assembly and revealed new details regarding different stages in plaque formation. Presently, interest is turning toward studying this process in a holistic context, focusing on cellular components which interact with the Aβ peptide at various junctures during aggregation, from monomer to cross-β amyloid fibrils. However, even in isolation, a multitude of factors including protein purity, pH, salt content, and agitation affect Aβ fibril formation and deposition, often producing complicated and conflicting results. The failure of numerous inhibitors in clinical trials for AD suggests that a detailed examination of the complex interactions that occur during plaque formation, including binding of carbohydrates, lipids, nucleic acids, and metal ions, is important for understanding the diversity of manifestations of the disease. Unraveling how a variety of key macromolecular modulators interact with the Aβ peptide and change its aggregation properties may provide opportunities for developing therapies. Since no protein acts in isolation, the interplay of these diverse molecules may differentiate disease onset, progression, and severity, and thus are worth careful consideration

Heavy Ion Carcinogenesis and Human Space Exploration

Prior to the human exploration of Mars or long duration stays on the Earth s moon, the risk of cancer and other diseases from space radiation must be accurately estimated and mitigated. Space radiation, comprised of energetic protons and heavy nuclei, has been show to produce distinct biological damage compared to radiation on Earth, leading to large uncertainties in the projection of cancer and other health risks, while obscuring evaluation of the effectiveness of possible countermeasures. Here, we describe how research in cancer radiobiology can support human missions to Mars and other planets

An increased abundance of tumor-infiltrating regulatory t cells is correlated with the progression and prognosis of pancreatic ductal adenocarcinoma

CD4+CD25+Foxp3+ regulatory T cells (Tregs) can inhibit cytotoxic responses. Though several studies have analyzed Treg frequency in the peripheral blood mononuclear cells (PBMCs) of pancreatic ductal adenocarcinoma (PDA) patients using flow cytometry (FCM), few studies have examined how intratumoral Tregs might contribute to immunosuppression in the tumor microenvironment. Thus, the potential role of intratumoral Tregs in PDA patients remains to be elucidated. In this study, we found that the percentages of Tregs, CD4+ T cells and CD8+ T cells were all increased significantly in tumor tissue compared to control pancreatic tissue, as assessed via FCM, whereas the percentages of these cell types in PBMCs did not differ between PDA patients and healthy volunteers. The percentages of CD8 + T cells in tumors were significantly lower than in PDA patient PBMCs. In addition, the relative numbers of CD4+CD25+Foxp3+ Tregs and CD8+ T cells were negatively correlated in the tissue of PDA patients, and the abundance of Tregs was significantly correlated with tumor differentiation. Additionally, Foxp3+ T cells were observed more frequently in juxtatumoral stroma (immediately adjacent to the tumor epithelial cells). Patients showing an increased prevalence of Foxp3+ T cells had a poorer prognosis, which was an independent factor for patient survival. These results suggest that Tregs may promote PDA progression by inhibiting the antitumor immunity of CD8+ T cells at local intratumoral sites. Moreover, a high proportion of Tregs in tumor tissues may reflect suppressed antitumor immunity. Copyright: © 2014 Tang et al

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers