TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target.

Chronic lymphocytic leukemia (CLL) remains incurable despite B-cell receptor-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate that is activated by unmethylated cytosine guanine dinucleotide-DNA. Here, we show that plasma from patients with CLL contains significantly more unmethylated DNA than plasma from healthy control subjects (P < .0001) and that cell-free DNA levels correlate with the prognostic markers CD38, ß2-microglobulin, and lymphocyte doubling time. Furthermore, elevated cell-free DNA was associated with shorter time to first treatment (hazard ratio, 4.0; P = .003). We also show that TLR9 expression was associated with in vitro CLL cell migration (P < .001), and intracellular endosomal TLR9 strongly correlated with aberrant surface expression (sTLR9; r = 0.9). In addition, lymph node-derived CLL cells exhibited increased sTLR9 (P = .016), and RNA-sequencing of paired sTLR9hi and sTLR9lo CLL cells revealed differential transcription of genes involved in TLR signaling, adhesion, motility, and inflammation in sTLR9hi cells. Mechanistically, a TLR9 agonist, ODN2006, promoted CLL cell migration (P < .001) that was mediated by p65 NF-κB and STAT3 transcription factor activation. Importantly, autologous plasma induced the same effects, which were reversed by a TLR9 antagonist. Furthermore, high TLR9 expression promoted engraftment and rapid disease progression in a NOD/Shi-scid/IL-2Rγnull mouse xenograft model. Finally, we showed that dual targeting of TLR9 and Bruton's tyrosine kinase (BTK) was strongly synergistic (median combination index, 0.2 at half maximal effective dose), which highlights the distinct role for TLR9 signaling in CLL and the potential for combined targeting of TLR9 and BTK as a more effective treatment strategy in this incurable disease.

Targeting of low ALK antigen density neuroblastoma using AND logic-gate engineered CAR-T cells.

BACKGROUND AIMS: The targeting of solid cancers with chimeric antigen receptor (CAR) T cells faces many technological hurdles, including selection of optimal target antigens. Promising pre-clinical and clinical data of CAR T-cell activity have emerged from targeting surface antigens such as GD2 and B7H3 in childhood cancer neuroblastoma. Anaplastic lymphoma kinase (ALK) is expressed in a majority of neuroblastomas at low antigen density but is largely absent from healthy tissues. METHODS: To explore an alternate target antigen for neuroblastoma CAR T-cell therapy, the authors generated and screened a single-chain variable fragment library targeting ALK extracellular domain to make a panel of new anti-ALK CAR T-cell constructs. RESULTS: A lead novel CAR T-cell construct was capable of specific cytotoxicity against neuroblastoma cells expressing low levels of ALK, but with only weak cytokine and proliferative T-cell responses. To explore strategies for amplifying ALK CAR T cells, the authors generated a co-CAR approach in which T cells received signal 1 from a first-generation ALK construct and signal 2 from anti-B7H3 or GD2 chimeric co-stimulatory receptors. The co-CAR approach successfully demonstrated the ability to avoid targeting single-antigen-positive targets as a strategy for mitigating on-target off-tumor toxicity. CONCLUSIONS: These data provide further proof of concept for ALK as a neuroblastoma CAR T-cell target.

Social Rank and Rejection Sensitivity as Mediators of the Relationship between Insecure Attachment and Disordered Eating.

AIM: The current study assessed a new interpersonal model for eating disorders (EDs), in which interpersonal rejection sensitivity (RS), appearance-based RS and social rank were hypothesised to mediate the relationship between insecure attachment and disordered eating. METHOD: The sample comprised a clinical ED group (N = 122) and a control group (N = 622). Participants were asked to complete a number of self-report measures related to the variables of interest. RESULTS: Invariance testing indicated that the model was structurally non-invariant (different across groups). For the ED group, appearance-based RS and social rank were significant mediators of the relationship between insecure attachment and disordered eating. For the controls, the relationship between insecure attachment and disordered eating was mediated through multiple pathways involving interpersonal RS, appearance-based RS and social rank. CONCLUSION: These findings may inform existing therapies such as interpersonal psychotherapy for EDs, by emphasising the role of sensitivity to rejection in the development and maintenance of disordered eating. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

More than Just Child's Play?: An Experimental Investigation of the Impact of an Appearance-Focused Internet Game on Body Image and Career Aspirations of Young Girls.

In recent years, elements of the modern environment (such as television, Internet, toys and clothes) have been criticized for having an increasingly sexualized or appearance focus, which has been suggested to be detrimental to girls' development. The current study examined the impact of an appearance-focused Internet game on young girls' body image and career cognitions and aspirations. Eighty British girls aged 8-9 years were randomly assigned to play an appearance-focused or a non-appearance focused game for 10 minutes. Girls in the appearance-focused game condition displayed greater body dissatisfaction compared to the control condition. Type of game did not impact girls' perceived capacity to do various jobs. However, girls who played the appearance-focused game reported a greater preference for feminine careers compared to the control group. This provides preliminary evidence that appearance-focused Internet games may be detrimental to young girls' body image and aspirations. Internet games should be included in our consideration of influential messages for young girls.

More than my appearance: a pilot evaluation of the expand your Horizon Online functionality-based writing programme for adults with visible differences.

Background: Adults with conditions that affect their appearance, known as visible differences, can experience appearance concerns, social anxiety, and depression. Interventions have been developed for this population to facilitate adjustment and coping skills; however, they have limited evidence of efficacy. The Expand Your Horizon [Alleva, J. M., Martijn, C., Van Breukelen, G. J., Jansen, A., & Karos, K. (2015). Expand Your Horizon: A programme that improves body image and reduces self-objectification by training women to focus on body functionality. Body Image, 15, 81-89. https://doi.org/10.1016/j.bodyim.2015.07.001] online functionality-based writing programme was adapted for adults with visible differences. Method: A pilot randomised controlled trial with a wait-list control group was carried out to assess preliminary intervention efficacy and gain information about the acceptability and feasibility of the programme. Forty-four adults aged 21-63 years (M = 40.21; SD = 12.05) with visible differences took part. Various facets of body image (i.e. functionality appreciation and body appreciation) as well as depression and anxiety were assessed immediately pre- and post-intervention and at three-months. Results: Participants reported enjoying the programme, felt that the format was acceptable, and it significantly increased functionality appreciation, which was maintained at three-months. However, there were no improvements in body appreciation, depression, and anxiety. Conclusions: In future, a full trial should be carried out with an active control group.

Optimising the use of cell salvage in revision hip arthroplasty.

BACKGROUND: Intraoperative cell salvage is an established method to reduce the requirement for and the volume of allogenic blood transfusion but adds to the financial cost of performing surgery. AIMS: The primary aim of this study was to determine which patients and what type of revision hip surgery benefit most from intraoperative cell salvage. METHODS: This observational study included patients who underwent revision hip surgery performed by the senior author at a single orthopaedic unit. The cohort was divided into single and two-component revision groups; then, the transfusion requirement combined with analysis of patient factors was used to create a decision-making protocol. FINDINGS: The two-component group had a significantly higher number of cases using cell salvage and a higher total transfusion volume. Patients who required postoperative allogenic blood transfusions had a higher mean age, were less likely to have received tranexamic acid and had a lower preoperative haemoglobin level. CONCLUSION: Based on these results, a decision-making protocol was developed for when to use cell salvage in revision hip surgery.

A systematic review of interventions aiming to promote positive body image in children and adolescents.

Evidence shows interventions can improve positive body image in adult women. This systematic review examined the evidence of efficacy of interventions that aimed to increase positive body image in children and young people aged under 18 years. The authors followed PRISMA guidelines for the review. Searches of CINAHL Plus, Medline, PsychINFO, Wiley Online Library, SCOPUS and grey literature were conducted up to February 2021 and identified 4171 papers. Thirteen studies evaluating 12 interventions, designed for children/adolescents aged 9-18 years, were eligible and evaluated using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool. The studies evaluated body appreciation, body-esteem, and embodiment. Studies using cognitive dissonance, peer support, and psychoeducation had evidence of improving body appreciation and body-esteem in adolescent girls. However, evidence of efficacy for younger children and boys was lacking and the studies ranged in methodological quality. Further research should rigorously evaluate positive body image interventions using second-generation measures that assess specific components of positive body image and consider how to promote positive body image in young children and boys.

"I didn't want to say something and them to go outside and tell everyone": The acceptability of a dissonance-based body image intervention among adolescent girls in the UK.

Cognitive dissonance-based interventions (CDIs) have been well established as effective programs for the prevention of eating disorders. However, limited research has qualitatively explored adolescent girls experience of such interventions. The present study examined the acceptability of a cognitive dissonance-based body image intervention among adolescent girls in UK secondary schools. Adolescent girls aged 14-18 years (N = 99; Mage = 14.87, SD = 0.97) who opted to participate in the intervention were invited to provide intervention feedback via open-ended questions and small focus groups. The findings suggest that the intervention was largely acceptable among adolescent girls. Peers played an important role. Despite initial concerns about sharing within the group, the groups provided a sense of belonging and participants no longer felt alone in their experience of body dissatisfaction. Participants discussed a transition from negative to positive body image following the intervention. Although acceptability was generally high, the data provides some interesting insights into potential considerations and modifications which may be advantageous in future CDIs. These include enhancing authenticity through reduced reliance on the script, inclusion of more personal content from the peer-leaders, and more interactive activities and physical movement.

Does body appreciation or satisfaction buffer against idealised functionality-focused images of models?

Research suggests that greater levels of body appreciation and body satisfaction may protect women from negative outcomes when viewing media images of the thin-ideal. In this study, we compared the effectiveness of body appreciation and body satisfaction in ameliorating negative effects from viewing images of the traditional thin-ideal and the newer functional-ideal (i.e., models presented in active stances with a focus on the function of their body). A sample of 122 women (Mage = 24.43 years) from a regional university and the general community was recruited to complete an online study. Participants were randomly allocated to view images of models presented in either an active or posed stance, or images of scenery. Participants completed pre- and post-test measures of appearance and functionality satisfaction, as well as trait measures of body appreciation and satisfaction. Results showed that women had poorer outcomes after viewing the active but not the posed or scenery images. Neither body appreciation nor body satisfaction moderated effects. Active, functional images may be particularly insidious and further research is needed to identify effective protective strategies.

Quantifying the sources of variation in eosinophilia among Scottish blackface lambs with mixed, predominantly Teladorsagia circumcincta nematode infection.

Eosinophils play a key role in defence against gastrointestinal nematodes. There is considerable variation among animals in the intensity of eosinophilia following nematode infection. However, the statistical distribution of eosinophils among animals has still to be determined. A better description of the variation among animals could provide biological insight and determine the most appropriate way to analyse the effect of eosinophils. We estimated blood eosinophil numbers in a flock of Scottish Blackface sheep that were naturally exposed to mixed, predominantly Teladorsagia circumcincta infection. Three of the four eosinophil counts were better described by a gamma distribution than by a lognormal distribution. The scale and shape parameters of the gamma distribution varied over time. Eosinophil counts differed among animals kept on separate fields before weaning and between singletons and twins but were not significantly different between years and genders. Eosinophil counts also differed among offspring from different sires and dams. The parameters of the gamma distribution were used to enable a power analysis. Large numbers of animals were required to reliably detect even large differences between two groups. These results indicate that methods appropriate for gamma distributions, such as generalized linear mixed models, will provide more reliable inferences than traditional methods of analysis and experimental design.

Engineering Solutions for Mitigation of Chimeric Antigen Receptor T-Cell Dysfunction.

The clinical successes of chimeric antigen receptor (CAR)-T-cell therapy targeting cell surface antigens in B cell leukaemias and lymphomas has demonstrated the proof of concept that appropriately engineered T-cells have the capacity to destroy advanced cancer with long term remissions ensuing. Nevertheless, it has been significantly more problematic to effect long term clinical benefit in a solid tumour context. A major contributing factor to the clinical failure of CAR-T-cells in solid tumours has been named, almost interchangeably, as T-cell "dysfunction" or "exhaustion". While unhelpful ambiguity surrounds the term "dysfunction", "exhaustion" is canonically regarded as a pejorative term for T-cells. Recent understanding of T-cell developmental biology now identifies exhausted cells as vital for effective immune responses in the context of ongoing antigenic challenge. The purpose of this review is to explore the critical stages in the CAR-T-cell life-cycle and their various contributions to T-cell exhaustion. Through an appreciation of the predominant mechanisms of CAR-T-cell exhaustion and resultant dysfunction, we describe a range of engineering approaches to improve CAR-T-cell function.

Investigating the role of attachment in social comparison theories of eating disorders within a non-clinical female population.

OBJECTIVE: The present study aimed to integrate attachment theory and sociocultural theory as predictors of disordered eating, thereby combining two previously distinct literatures in order to provide a more comprehensive model of eating disorder development. It was specifically proposed that women's attachment style may influence their tendency to socially compare themselves to idealized others. METHOD: Participants (N = 213) were non-clinical female undergraduates. Sociocultural attitudes to appearance, social comparison, attachment and eating disorder symptomatology were assessed using self-report questionnaires. RESULTS: Consistent with the hypothesis, social comparison was found to mediate the relationship between attachment anxiety and disordered eating. In addition, attachment avoidance, was not significantly associated with either internalisation of cultural ideals or social comparison but was significantly related to eating psychopathology. CONCLUSION: The findings suggest that attachment anxiety and avoidance influence disordered eating via different pathways, with attachment anxiety specifically being implicated in sociocultural models of disordered eating.

A randomized experimental evaluation of a yoga-based body image intervention.

Recent literature argues that body image interventions need to become more embodied. This paper evaluates a brief yoga-based body image intervention which incorporates themes specifically tailored to focus on positive body image. Young women (Mage = 20.21, SDage = 2.15) were randomly allocated to a four-session yoga intervention (n = 22) or a control condition (n = 22). Compared to controls, participants in the yoga condition reported significant increases in body appreciation, body connectedness, body satisfaction, and positive mood at posttest and at 4-week follow-up. There were no significant changes in negative mood or body surveillance. These findings add to existing evidence that yoga can improve women's body image and positive mood. In addition, they suggest that a strong thematic focus on positive body image can achieve benefits at relatively low yoga doses. These findings are important as intervention length impacts the potential for dissemination.

Cognitive-behavioral roots of body image therapy and prevention.

The existing array of evidence-based body image prevention and intervention approaches has evolved over time. However, the majority originated directly or indirectly from a cognitive-behavioral conceptualisation of body image pioneered by Thomas F. Cash. In this way, it is difficult to overstate the impact Tom Cash has had on body image intervention research and practice. His ground-breaking work, building on the work of Schilder and Fisher, was the first to provide a comprehensive model of body image that reflected the broad range of influences and consequences of body image. His differentiation of the components of body image as a construct and between body image traits and states allowed us to identify and influence targets for intervention. Moreover, the intervention strategies that Tom Cash employed are still used today and laid the foundations for contemporary intervention programs. There is a gap of more than 15 years between the first and last of us receiving our PhDs, yet Cash's work has been an important influence on us all. We are extremely grateful for the theoretical and practical tools that he has given to our field. In this paper, we will outline how Cash's work has informed contemporary body image intervention and prevention. We will describe Cash's theory and intervention tools before discussing how this work paved the way for subsequent research and practice.

The effectiveness of interventions aiming to promote positive body image in adults: A systematic review.

Theory suggests promoting positive body image (PBI) through interventions would have a significant impact on health and well-being. However, little is known about the effectiveness of existing interventions. This review aimed to identify and assess the evidence of effectiveness of interventions to increase PBI in adults. Database searches were conducted using CINAHL Plus, Medline, PsychINFO, Wiley Online Library, and SCOPUS. Application of inclusion criteria and data extraction were conducted by two reviewers. Methodological quality was assessed using the Effective Public Health Practice Project Quality Assessment Tool, and narrative synthesis was conducted. Fifteen studies, evaluating 13 interventions, were included. Three studies, evaluating one online writing-based functionality intervention, were judged to have strong methodological quality and had evidence of improving body appreciation, body esteem, and functionality satisfaction. Six moderate quality studies found interventions using intuitive eating, CBT, self-compassion, and exercise improved PBI. There was limited evidence of effectiveness of interventions for men, suggesting future research is needed to better understand PBI mechanisms in men. Lack of heterogeneity of outcome measures is discussed as a limitation. Findings suggest existing interventions are effective at increasing aspects of PBI among women and support the development of interventions that target multiple components of PBI.

Can big business foster positive body image? Qualitative insights from industry leaders walking the talk.

The fashion, beauty, and advertising industries have been positioned as key contributors to body dissatisfaction through the promotion of unrealistic and homogenous appearance ideals. Recently, some businesses within these industries have started to disrupt the status quo by taking actions that can be seen to be fostering positive body image (e.g., through representative and diverse imagery, body acceptance messages, and inclusive product ranges). The aim of this study was to explore the opportunities and challenges to foster positive body image from a business perspective. Participants were purposively selected based on their experience of leading business actions to foster positive body image in fashion, beauty, and/or advertising. In total, 45 individuals (82% women) took part in semi-structured interviews, which were transcribed and then analysed using thematic analysis. Four themes were identified: (1) Personal motivations for championing change, (2) Industry ingrained appearance standards, (3) Business barriers to fostering positive body image, and (4) Fostering positive body image as an effective corporate social responsibility (CSR) strategy. This study provides future directions for research aimed at creating healthier body image environments in addition to considerations for businesses seeking to foster positive body image.

Evaluating the impact of a brief yoga intervention on preadolescents' body image and mood.

Yoga is an embodying activity that promotes body awareness, body connection, body responsiveness, and appreciation of body functionality, and it therefore may be a beneficial school-based intervention for children's body image. The present study examined the impact of a 4-week yoga intervention on pre-adolescent girls' and boys' body image (body appreciation, body esteem, and body surveillance) and mood (positive and negative affect) 1-week post-intervention and at 6-week follow-up. British children (N = 344; 54.4% female) aged 9-11 years were recruited from four schools, two of which were randomly assigned to the yoga intervention and two to a physical education control condition. Overall, girls reported greater body image concern and negative mood than boys. Unexpectedly, both groups reported increased body appreciation, body esteem, and positive mood, and decreased body surveillance and negative affect from baseline to post-intervention and/or follow-up. Both girls and boys in the yoga intervention evaluated the sessions very favourably; the majority desired to participate in more lessons. Potential explanations for these findings are discussed.

Young men's minimisation of their body dissatisfaction.

OBJECTIVE: To examine men's body dissatisfaction qualitatively. DESIGN: Forty-two British men aged 18-45 years took part in a two-session group intervention across 12 groups. The intervention was designed to improve body dissatisfaction by engaging them in a critique of the appearance ideal through written and behavioural exercises. Main outcome measures/results: Analysis of the topics discussed during the intervention generated two core themes. Theme 1 showed that, in general, men minimised the existence of their own body dissatisfaction while (somewhat surprisingly) outlining the ubiquity and potency of the appearance ideal for men in general. Theme 2 involved men reporting the problematic impact of body dissatisfaction in their lives (despite earlier minimisation), such as social avoidance, strict eating and supplement regimes, or difficulty in situations where the body was exposed. CONCLUSION: The results stress the need to acknowledge that men experience a range of impacts of body dissatisfaction beyond clinical presentations (such as disordered eating) that influence their everyday lives, while also recognising that they tend to minimise this dissatisfaction in conversation. These findings have important implications for advocacy and interventions to improve men's body dissatisfaction.

A randomised-controlled trial investigating potential underlying mechanisms of a functionality-based approach to improving women's body image.

Focusing on body functionality is a promising technique for improving women's body image. This study replicates prior research in a large novel sample, tests longer-term follow-up effects, and investigates underlying mechanisms of these effects (body complexity and body-self integration). British women (N = 261) aged 18-30 who wanted to improve their body image were randomised to Expand Your Horizon (three online body functionality writing exercises) or an active control. Trait body image was assessed at Pretest, Posttest, 1-week, and 1-month Follow-Up. To explore whether changes in body complexity and body-self integration 'buffer' the impact of negative body-related experiences, participants also completed beauty-ideal media exposure. Relative to the control, intervention participants experienced improved appearance satisfaction, functionality satisfaction, body appreciation, and body complexity at Posttest, and at both Follow-Ups. Neither body complexity nor body-self integration mediated intervention effects. Media exposure decreased state body satisfaction among intervention and control participants, but neither body complexity nor body-self integration moderated these effects. The findings underscore the value of focusing on body functionality for improving body image and show that effects persist one month post-intervention.

More than my RA: A randomized trial investigating body image improvement among women with rheumatoid arthritis using a functionality-focused intervention program.

OBJECTIVE: Negative body image is prevalent in women with rheumatoid arthritis and can affect other areas of well-being. Patients have expressed desire for body image to be addressed in treatment. Yet, it is not routinely addressed and no experimental intervention research has been conducted, until now. This randomized trial evaluated a brief online body image intervention for women with rheumatoid arthritis, with a focus on body functionality (everything the body is capable of doing) as the primary technique. METHOD: Women with rheumatoid arthritis and who wanted to feel better about their body (N = 84; Mage = 44.82) were randomized to the Expand Your Horizon intervention (comprising 3 writing exercises focusing on body functionality) or a waitlist control group. Primary outcomes concerned body image and secondary outcomes related to rheumatoid arthritis; these outcomes were assessed at pretest, posttest, and at 1-week and 1-month follow-up. RESULTS: Multilevel modeling analyses showed that, relative to control, participants in the intervention experienced improvements in various aspects of body image (functionality appreciation, body appreciation, body satisfaction, body-self alienation) and decreases in depression, with effects persisting at 1-week and 1-month follow-up. No intervention effects were found for body-self harmony, rheumatoid arthritis-specific disability, pain-related disability, and anxiety. CONCLUSIONS: Focusing on body functionality can improve body image and reduce depression in women with rheumatoid arthritis. The intervention technique is easy and affordable to deliver and could be a fruitful addition to extant treatments for rheumatoid arthritis. (PsycINFO Database Record