Tumor-associated mesenchymal stromal cells modulate macrophage phagocytosis in stromal-rich colorectal cancer via PD-1 signaling.

CMS4 colorectal cancer (CRC), based on the consensus molecular subtype (CMS), stratifies patients with the poorest disease-free survival rates. It is characterized by a strong mesenchymal stromal cell (MSC) signature, wound healing-like inflammation and therapy resistance. We utilized 2D and 3D in vitro, in vivo, and ex vivo models to assess the impact of inflammation and stromal cells on immunosuppression in CMS4 CRC. RNA sequencing data from untreated stage II/III CRC patients showed enriched TNF-α signatures in CMS1 and CMS4 tumors. Secretome from TNF-α treated cancer cells induced an immunomodulatory and chemotactic phenotype in MSC and cancer-associated fibroblasts (CAFs). Macrophages in CRC tumours migrate and preferentially localise in stromal compartment. Inflammatory CRC secretome enhances expression of PD-L1 and CD47 on both human and murine stromal cells. We demonstrate that TNF-α-induced inflammation in CRC suppresses macrophage phagocytosis via stromal cells. We show that stromal cell-mediated suppression of macrophage phagocytosis is mediated in part through PD-1 signaling. These data suggest that re-stratification of CRC by CMS may reveal patient subsets with microsatellite stable tumors, particularly CMS4-like tumors, that may respond to immunotherapies.

How do the guideline recommendations work for you? Patients' perceived effectiveness of therapeutic approaches in arterial hypertension.

Blood pressure remains in the hypertensive range in nearly half of those affected by arterial hypertension despite it being an extremely modifiable risk factor, whereby morbidity decreases significantly upon implementation of lifestyle-based therapeutic approaches. There are significant discrepancies between the S3 guideline's recommendations and its implementation. In this cross-sectional study sampling 160 inpatients with arterial hypertension, we assessed patients' perceptions of secondary prevention therapeutic approaches recommended to them within treatment guidelines. Additionally, we used psychometric questionnaires to assess prevention factors. We conducted a latent class analysis to identify patterns in patients' views, and tested for group differences regarding gender, age, education years, body mass index, psychopathology, and blood pressure. Two latent classes could be identified: Class 1 tended to perceive all recommended therapeutic approaches as helpful and reflected individuals with high-normal blood pressure. Class 2 tended to view recommendations regarding weight reduction, and cessation of nicotine and alcohol use, as less effective and included those with mild hypertension. There were no statistically significant class differences regarding the socio-demographic parameters. We further examined the evaluation of therapeutic approaches independent of classes, with social support reported to be the most effective approach. In conclusion, persistently-elevated blood pressure may be linked to poorer perceptions of therapeutic approaches which are then not implemented. Furthermore, patient-centered treatment planning and concepts such as shared decision-making appear to be central in treating this population regarding secondary prevention.

Usability of the BigO system in pediatric obesity treatment: A mixed-methods evaluation of clinical end-users.

Objective: To assess technical usability of the BigO app and clinical portal among diverse participants and explore the overall user experiences of both. Methods: Methods included technical usability testing by measuring the relative user efficiency score (RUS) for the app and measuring Relative User Efficiency (RUE) using the 'think aloud' method with the clinical portal. Qualitative approaches involved focus groups with adolescent app users and semi-structured one-to-one interviews with clinician participants. Thematic analysis was applied to analyze qualitative data. Participants: Clinical participants consisted of adolescents seeking treatment for severe obesity and were invited via telephone/face to face to attend technical usability testing and a focus group. Healthcare professionals (HCPs) and researchers using the BigO clinical portal interface were invited to participate in usability testing and semi-structured interviews. Results: From 14 families invited to attend, seven consented to join the study and four adolescents (mean age=13.8 (SD 0.8) years) participated. Additionally, six HCPs and one pediatric obesity researcher took part. RUS for adolescents indicated that the tasks required of them via myBigO app were feasible, and technically efficient. No user-related errors were observed during tasks. Technical barriers reported by adolescents included notifications of battery optimization, misunderstanding image annotation language, and compatibility challenges with certain phone models. RUS for the HCPs and researcher indicated that basic technical skills are a potential barrier for clinical portal use and qualitative findings revealed that clinical users wanted a logging option for monitoring goals and providing feedback on the portal. Conclusion: Our study provided valuable formative findings from clinical end-users in Ireland indicating that adolescents being treated for obesity rated myBigO app as usable, acceptable and that it may assist other key stakeholders to understand food marketing and to monitor dietary and physical activity behaviors. Several key suggestions for future iterations of the clinical portal were provided to enhance its value in pediatric obesity treatment.

Providing a common language for obesity: the European Association for the Study of Obesity obesity taxonomy.

BACKGROUND: The basis for a high-performing and resilient healthcare system is having a common, precise, and scientifically accurate language used across all stakeholder groups. However, such a common language is lacking for obesity. Therefore, the European Association for the Study of Obesity undertook a taxonomy initiative to provide standardised language for obesity as commonly used from policy to practice for other major policy-prioritised non-communicable diseases (NCDs). METHODS: An online Delphi consensus study was conducted, involving a panel of experts representing stakeholder groups of policymakers, healthcare professionals, people with lived experience, and researchers. Based on the understanding of obesity as an adiposity-based chronic disease, 54 statements demarcated into definition, scope and contextual usage were developed across six themes: Definition of obesity, Causes, onset and progression, Obesity prevention, Screening and early diagnosis, Treatment and management, Obesity consequences. RESULTS: Of the 194 invited experts, 70 (36%), 63 (33%), and 58 (30%) experts participated in rounds one, two, and three, respectively. Consensus was achieved on 70% of the proposed definitions, scope, and contextual usage after round one, 94% after round two and 100% after round three. The Definition of Obesity theme included distinctions between population-level indicators and individual-level signs of obesity, and how pre-obesity was defined. The Causes, Onset and Progression theme characterised the timing of obesity development. The Obesity Prevention theme explicitly differentiated between health promotion and primary prevention. Both the Screening and Early Diagnosis, and the Treatment and Management themes defined concepts supporting a continuum of care model. The Consequences of Obesity theme encompassed health and socio-economic outcomes. CONCLUSION: The taxonomy provides a contemporary evidence-based language about obesity that aligns with language used for policy-prioritised NCDs. The taxonomy is useful for education, advocacy, and communication and can be used by policymakers, healthcare professionals, people living with obesity, researchers, and health system users.

Addressing child and adolescent obesity management in Ireland: identifying facilitators and barriers in clinical practice.

Background: Ireland's Model of Care for the Management of Overweight and Obesity outlines a plan for treating adolescent and child obesity (CO). However, engagement with key stakeholders is required to support its implementation and improve health services. Aim: This study aims to map the perceived barriers and facilitators related to CO management across healthcare settings, professional disciplines, and regions in the Republic of Ireland (ROI). Materials and methods: An online cross-sectional survey of registered healthcare professionals (HPs), designed to adhere to the Consolidated Framework for Implementation Research (CFIR), was co-developed by a project team consisting of researchers, healthcare professionals, and patient advocates. The survey was pilot tested with project stakeholders and distributed online to professional groups and via a social media campaign, between September 2021 and May 2022, using "SurveyMonkey." Data were summarised using descriptive statistics and thematic analyses. Themes were mapped to the CFIR framework to identify the type of implementation gaps that exist for treating obesity within the current health and social care system. Results: A total of 184 HPs completed the survey including nurses (18%), physicians (14%), health and social care professionals (60%), and other HPs (8%). The majority were female (91%), among which 54% reported conducting growth monitoring with a third (32.6%) giving a diagnosis of paediatric/adolescent obesity as part of their clinical practice. Nearly half (49%) of the HPs reported having the resources needed for clinical assessment. However, 31.5% of the HPs reported having enough "time," and almost 10% of the HPs reported having no/limited access to suitable anthropometric measurement tools. Most HPs did not conduct obesity-related clinical assessments beyond growth assessment, and 61% reported having no paediatric obesity training. CFIR mapping identified several facilitators and barriers including time for clinical encounters, suitable materials and equipment, adequate training, perceived professional competency and self-efficacy, human equality and child-centredness, relative priorities, local attitudes, referral protocols, and long waiting times. Conclusions: The findings provide actionable information to guide the implementation of the Model of Care for the Management of Overweight and Obesity in Ireland. Survey findings will now inform a qualitative study to explore implementation barriers and facilitators and prioritise actions to improve child and adolescent obesity management.

Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment.

Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8+ PD1+ and CD8+ Siglec-7+/Siglec-9+ T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8+ T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

A qualitative study exploring the perceptions of health among pre-teen girls from disadvantaged communities in Dublin.

There are disparities in health outcomes between youth from higher and lower socioeconomic backgrounds, and girls are especially vulnerable to changes in health-related behaviours as they develop. Therefore, this study explored how girls from disadvantaged communities in Dublin, Ireland, make sense of 'being healthy.' A phenomenological qualitative design was implemented. Three focus groups were conducted (n = 22, 10-12 years) and data were analysed using thematic analysis. Food and physical appearance featured prominently within the girls' definitions of health. Girls and their families from low-SES backgrounds may experience more difficulties with time scarcity as well as environmental barriers to a healthy lifestyle.

In vivo Assessment of the Impact of Molecular Weight on Constructs of 68Ga-DOTA-Manocept in a Syngeneic Mouse Tumor Model.

PURPOSE: Manocept™ constructs are mannosylated amine dextrans (MADs) that bind with high affinity to the mannose receptor, CD206. Tumor-associated macrophages (TAMs) are the most numerous immune cells in the tumor microenvironment and a recognized target for tumor imaging and cancer immunotherapies. Most TAMs express CD206, suggesting utility of MADs to deliver imaging moieties or therapeutics to TAMs. The liver Kupffer cells also express CD206, making them an off-target localization site when targeting CD206 on TAMs. We evaluated TAM targeting strategies using two novel MADs differing in molecular weight in a syngeneic mouse tumor model to determine how varying MAD molecular weights would impact tumor localization. Increased mass dose of the non-labeled construct or a higher molecular weight (HMW) construct were also used to block liver localization and enhance tumor to liver ratios. PROCEDURES: Two MADs, 8.7 kDa and 22.6 kDa modified with DOTA chelators, were synthesized and radiolabeled with 68Ga. A HMW MAD (300 kDa) was also synthesized as a competitive blocking agent for Kupffer cell localization. Balb/c mice, with and without CT26 tumors, underwent dynamic PET imaging for 90 min followed by biodistribution analyses in selected tissues. RESULTS: The new constructs were readily synthesized and labeled with 68Ga with ≥ 95% radiochemical purity in 15 min at 65 °C. When injected at doses of 0.57 nmol, the 8.7 kDa MAD provided 7-fold higher 68Ga tumor uptake compared to the 22.6 kDa MAD (2.87 ± 0.73%ID/g vs. 0.41 ± 0.02%ID/g). Studies with increased mass of unlabeled competitors showed reduced liver localization of the [68Ga]MAD-8.7 to varying degrees without significant reductions in tumor localization, resulting in enhanced tumor to liver signal ratios. CONCLUSION: Novel [68Ga]Manocept constructs were synthesized and studied in in vivo applications, showing that the smaller MAD localized to CT26 tumors more effectively than the larger MAD and that the unlabeled HMW construct could selectively block liver binding of [68Ga]MAD-8.7 without diminishing the localization to tumors. Promising results using the [68Ga]MAD-8.7 show a potential path to clinical applications.