Therapeutic targeting of tumor associated macrophages.

Previous studies on the mechanistic induction of anti-tumor responses by IL-12 cytokine therapy have focused on the adaptive immune response, specifically the activation NK cells and T cells as the primary targets of IL-12 treatment. In contrast, little attention has been given to the potential role of macrophages in the initiation of anti-tumor responses by IL-12 therapy despite reports that macrophages play a major role in promoting tumor growth and metastasis and in suppressing anti-tumor immune responses. Based on the functional adaptivity hypothesis, which is the concept that macrophages functionally adapt, rather than differentiate into specific mature subsets, in response to environmental stimuli, we hypothesized that tumor infiltrating (TIMs) as well as tumor-associated macrophages (TAMs) could be converted from tumor supportive activities to pro-immunogenic activities by IL-12 therapy. We examined the functional activities displayed by TIMs and TAMs after treatment with IL-12. Our data demonstrate (1) that tumor cells and tumor exosomes activate TIMs and TAMs by cell-contact dependent mechanisms involving ligation of CD40 and/or NKG2D, (2) that IL-12 treatment both in vivo and in vitro induces a rapid reduction of tumor supportive activities and a concomitant increase in pro-inflammatory activities in TIMs as well as TAMs, (3) that IL-12 induces a rapid release of cytoplasmic IL-I5 from the in situ activated tumor associated macrophages and (4) the release of IL-15 in essential to the recruitment of lymphocytes to the tumor and the metastatic lung, and to the destruction of the tumor and clearance of metastasis. It is concluded that macrophages in the tumor environment are activated and functionally modulated by the tumor. TIMs and TAMs respond to IL-12 treatment by rapidly converting from suppressive, tumor supportive activities to inflammatory, pro-immunogenic activities. Tumor associated macrophages thus are a critical target of IL-12 therapy and may orchestrate the subsequent NK and T cell cytotoxic response against the tumor

A validated food frequency questionnaire to determine dietary intake of vitamin D

This article has been accepted for publication and will appear in a revised form, subsequent to peer review and/or editorial input by Cambridge University Press, in Public Health Nutrition published by Cambridge University Press. Copyright Cambridge University Press.Objective The aim of the present study was to develop and validate a vitamin D food frequency questionnaire (FFQ) for assessment of dietary vitamin D intake in healthy adults in England, UK. Design: The current study assessed the agreement between a four-day food diary (4d-FD) and a new vitamin D FFQ to measure dietary intake of vitamin D. Dietary intake was estimated using Nutritics dietary analysis software and Spearman’s and Bland-Altman tests were utilised to assess correlation and agreement, respectively. Participants also provided a blood sample for plasma analysis of vitamin D concentrations. Setting: Home setting. Participants: Fifty participants were recruited to the study from the University of Chester and vicinity. Results: Results showed a strong correlation between vitamin D intake recorded by the FFQ and the 4d-FD (r = 0.609; P < 0.0001) within 95% limits of agreement. Furthermore, a significant correlation between plasma 25(OH)D concentrations and vitamin D intake measured by the FFQ (r = 0.290, P = 0.041) and the 4d-FD (r = 0.360, P = 0.01) was observed. Conclusion: Our analysis suggests this FFQ is a useful and rapid tool for researchers and health professionals to assess vitamin D dietary intakes in healthy adults in the UK

FOXO3: A master switch for regulating tolerance and immunity in dendritic cells

Recent findings demonstrate that dendritic cells in prostate tumors induce immune tolerance in tumor antigen-specific CD8+ T cells. We propose that DC tolerogenicity can be regulated by expression of Foxo3; silencing Foxo3 expression enhances anti-tumor immune responses and renders FOXO3 a potential target for immunotherapy

Interventional Physical and Occupational Therapy Services and Motor Coordination among Low Birth Weight Infants

Introduction: Children born very low birth weight (VLBW) have an increased risk of impaired preschool motor coordination, which may have negative effects on the child's mental and physical health. Physical and occupational therapy services are suggested to attenuate the negative effects of poor preschool coordination. We estimated the effect of physical and occupational therapy services delivered in early childhood on preschool motor coordination among VLBW children. To control for confounding, we implemented propensity score (PS) methods estimated using traditional logistic regression (LR) and tree based methods. Methods: Using the Early Childhood Longitudinal Study Birth Cohort (ECLS-B) we estimated the effect of therapy on: skipping eight consecutive steps, hopping five times, standing on one leg for ten seconds, walking backwards six steps on a line, jumping distance, and change in jumping distance from preschool to kindergarten. We estimated the PS using random forest classification, bagging, and a single tree using the R statistical program and with LR in SAS 9.2. Using linear regression, we modeled the estimated effect of therapy on the distance that the child jumped. We weighted the adjusted models using inverse probability of treatment weights estimated from all four methods. We modeled all other end points as stated using LR. Results: Approximately 500 children were VLBW. RF and Bagging produced the best covariate balance between treatment groups (MSD 0.07, 0.03). The single classification tree produced the worst covariate balance (MDS 0.18). When estimating the PS with RF, treated VLBW children were 2.39 times as likely to successfully skipping eight steps (OR: 2.39, 95% CI: 0.75, 7.51) compared to the untreated group. Treated children jumped an additional 1.79 inches (95% CI: -2.21-5.79) further and were also 52% (OR: 1.52, 95% CI: 0.51, 4.54) more likely to successfully complete the backwards walking task. There was little effect of therapy on other endpoints. Effect estimates were similar among models weighted with RF, bagging, and LR. Conclusion: Providing therapy to VLBW children, may improve the child's school age motor coordination. RF is a useful method to improve covariate balance when estimating the PS and to potentially reduce bias in observational studies.Doctor of Philosoph

Clinical academic research internships for nurses, midwives and allied health professionals: a qualitative evaluation

Background: Nurses, midwives and allied health professionals are integral to research, yet rarely engage simultaneously in research and clinical practice. Clinical academic internships offer a route to access academic research training. This study aimed to elucidate facilitators and barriers to participation and engagement, and suggest improvements for future programmes. Method: The experiences of 10 health professional research interns were explored, using a method based on a synthesis between grounded theory and content analysis. Findings: Four categories emerged: 1) integrating clinical and research aspirations; 2) Support – or lack of it; 3) The hidden curriculum; 4) The legacy effect. Within these categories, respondents identified a variety of facilitators and barriers to engagement, including unforeseen challenges. Conclusion: Formal support is necessary but not sufficient to foster engagement and maximise benefits. Participation must be supported by colleagues and enabled by institutional structures. The potential impact of internships on engagement with research is considerable but requires collaboration between all stakeholders. Implications for Practice: Deeper institutional engagement is needed so that internship opportunities are fully supported by all colleagues and practically enabled by institutional structures. Future schemes should attempt to promote opportunities to collaborate via group projects to reduce researcher isolation

Diving into our digital future: defining IAMSLIC's digital architecture

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Bacteriophages isolated from Lake Michigan demonstrate broad host-range across several bacterial phyla

BACKGROUND: The study of bacteriophages continues to generate key information about microbial interactions in the environment. Many phenotypic characteristics of bacteriophages cannot be examined by sequencing alone, further highlighting the necessity for isolation and examination of phages from environmental samples. While much of our current knowledge base has been generated by the study of marine phages, freshwater viruses are understudied in comparison. Our group has previously conducted metagenomics-based studies samples collected from Lake Michigan - the data presented in this study relate to four phages that were extracted from the same samples. FINDINGS: Four phages were extracted from Lake Michigan on the same bacterial host, exhibiting similar morphological characteristics as shown under transmission electron microscopy. Growth characteristics of the phages were unique to each isolate. Each phage demonstrated a host-range spanning several phyla of bacteria - to date, such a broad host-range is yet to be reported. Genomic data reveals genomes of a similar size, and close similarities between the Lake Michigan phages and the Pseudomonas phage PB1, however, the majority of annotated genes present were ORFans and little insight was offered into mechanisms for host-range. CONCLUSIONS: The phages isolated from Lake Michigan are capable of infecting several bacterial phyla, and demonstrate varied phenotypic characteristics despite similarities in host preference, and at the genomic level. We propose that such a broad host-range is likely related to the oligotrophic nature of Lake Michigan, and the competitive benefit that this characteristic may lend to phages in nature

Early Breastfeeding Experience and Postpartum Depression: a Longitudinal Study

Objective: We measured the association between early breastfeeding experience and maternal mood at two months postpartum. Methods: We used logistic regression to evaluate the association between early breastfeeding experience and maternal mood, quantified with the Edinburgh Postnatal Depression Scale (EPDS), among women who initiated breastfeeding in the Infant Feeding Practices Survey II. Women reported their early breastfeeding experiences at 1 month, and they completed the EPDS at 2 months. Results: In the neonatal period, 2586 women reported ever breastfeeding, among whom 223 (8.6%) met criteria for major depression (EPDS ≥13) at 2 months postpartum. Women who reported disliking breastfeeding in the first week were more likely to meet criteria for major depression at 2 months (OR 1.42, 95% CI 1.04-1.93), adjusting for maternal age, parity, education, ethnicity, and postnatal WIC participation. We also found that women who were depressed were more likely to report severe breastfeeding pain in the first day (adjusted OR 1.96, 95% CI 1.17-3.29, vs. no pain), the first week, (adjusted OR 2.13, 95% CI 0.74-6.15, vs no pain), and in the second week (adjusted OR 2.24, 95% CI 1.18-4.26, vs. no pain). Conclusions: Women who disliked breastfeeding or experienced severe pain in the neonatal period were more likely to have depressive symptoms at 2 months postpartum. Early breastfeeding difficulties may identify a subgroup of women at high risk for postpartum depression

Comparison of cellular responses to TGF-β1 and BMP-2 between healthy and torn tendons

Background: Tendons heal by fibrotic repair, increasing the likelihood of reinjury. Animal tendon injury and overuse models have identified transforming growth factor beta (TGF-β) and bone morphogenetic proteins (BMPs) as growth factors actively involved in the development of fibrosis, by mediating extracellular matrix synthesis and cell differentiation. Purpose: To understand how TGF-β and BMPs contribute to fibrotic processes using tendon-derived cells isolated from healthy and diseased human tendons. Study Design: Controlled laboratory study. Methods: Tendon-derived cells were isolated from patients with a chronic rotator cuff tendon tear (large to massive, diseased) and healthy hamstring tendons of patients undergoing anterior cruciate ligament repair. Isolated cells were incubated with TGF-β1 (10 ng/mL) or BMP-2 (100 ng/mL) for 3 days. Gene expression was measured by real-time quantitative polymerase chain reaction. Cell signaling pathway activation was determined by Western blotting. Results: TGF-β1 treatment induced ACAN mRNA expression in both cell types but less in the diseased compared with healthy cells (P < .05). BMP-2 treatment induced BGN mRNA expression in healthy but not diseased cells (P < .01). In the diseased cells, TGF-β1 treatment induced increased ACTA2 mRNA expression (P < .01) and increased small mothers against decapentaplegic (SMAD) signaling (P < .05) compared with those of healthy cells. Moreover, BMP-2 treatment induced ACTA2 mRNA expression in the diseased cells only (P < .05). Conclusion: Diseased tendon–derived cells show reduced expression of the proteoglycans aggrecan and biglycan in response to TGF-β1 and BMP-2 treatments. These same treatments induced enhanced fibrotic differentiation and canonical SMAD cell signaling in diseased compared with healthy cells. Clinical Relevance: Findings from this study suggest that diseased tendon–derived cells respond differently than healthy cells in the presence of TGF-β1 and BMP-2. The altered responses of diseased cells may influence fibrotic repair processes during tendon healing