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Cannabinoid (CB) receptors (CB 1 and CB 2 ) are expressed on cancer cells and their expression influences carcinogenesis in various tumor entities. Cells of the tumor microenvironment (TME) also express CB receptors, however, their role in tumor development is still unclear. We, therefore, investigated the role of TME-derived CB 1 and CB 2 receptors in a model of non-small cell lung cancer (NSCLC). Leukocytes in the TME of mouse and human NSCLC express CB receptors, with CB 2 showing higher expression than CB 1 . In the tumor model, using CB 1 - (CB 1 -/- ) and CB 2 -knockout (CB 2 -/- ) mice, only deficiency of CB 2 , but not of CB 1 , resulted in reduction of tumor burden vs. wild type (WT) littermates. This was accompanied by increased accumulation and tumoricidal activity of CD8 + T and natural killer cells, as well as increased expression of programmed death-1 (PD-1) and its ligand on lymphoid and myeloid cells, respectively. CB 2 -/- mice responded significantly better to anti-PD-1 therapy than WT mice. The treatment further increased infiltration of cytotoxic lymphocytes into the TME of CB 2 -/- mice. Our findings demonstrate that TME-derived CB 2 dictates the immune cell recruitment into tumors and the responsiveness to anti-PD-1 therapy in a model of NSCLC. CB 2 could serve as an adjuvant target for immunotherapy.

The G protein-coupled receptor 55 (GPR55) is part of an expanded endocannabinoid system (ECS), and plays a pro-tumorigenic role in different cancer models, including pancreatic cancer. Next to cancer cells, various cells of the immune tumor microenvironment (TME) express receptors of the ECS that critically determine tumor growth. The role of GPR55 in cancer cells has been widely described, but its role in the immune TME is not well understood. We intended to uncover the role of GPR55 in tumor immunity in a model of pancreatic ductal adenocarcinoma (PDAC). To this end, a KPCY tumor cell line or a GPR55-overexpressing KPCY cell line (KPCY55) from murine PDAC were subcutaneously injected into wildtype (WT) and GPR55 knockout (KO) mice, and immune cell populations were evaluated by flow cytometry. Deficiency of GPR55 in the TME led to reduced tumor weight and volume, and altered the immune cell composition of tumors, favoring an anti-tumorigenic environment by increasing the number of CD3 T cells, particularly CD8 T cells, and the expression of PDL1 on macrophages. RNA-seq pathway analysis revealed higher T cell activity in KPCY55 tumors of GPR55 KO vs. WT mice. In addition, tumors from GPR55 KO mice displayed increased levels of T cell chemokines Cxcl9 and Cxcl10. Migration of T cells from GPR55 KO mice towards CXCL9 was increased in comparison to T cells from WT mice, suggesting that a CXCR3/CXCL9 axis was involved in T cell influx into tumors of GPR55 KO mice. Notably, anti-PD-1 immunotherapy increased tumor burden in WT mice, while this effect was absent in the GPR55 KO mice. Our study indicates that GPR55 in TME cells may drive tumor growth by suppressing T cell functions, such as migration, in a model of PDAC, making it an interesting target for immunotherapies.

Eosinophilic esophagitis (EoE) is a chronic, inflammatory, antigen-driven disease of the esophagus. Tissue EoE pathology has previously been extensively characterized by novel transcriptomics and proteomic platforms, however the majority of surface marker determination and screening has been performed in blood due to mucosal tissue size limitations. While eosinophils, CD4 T cells, mast cells and natural killer (NK) T cells were previously investigated in the context of EoE, an accurate picture of the composition of peripheral blood mononuclear cells (PBMC) and their activation is missing. In this study, we aimed to comprehensively analyze the composition of peripheral blood mononuclear cells and their activation using surface marker measurements with multicolor flow cytometry simultaneously in both blood and mucosal tissue of patients with active EoE, inactive EoE, patients with gastroesophageal reflux disease (GERD) and controls. Moreover, we set out to validate our data in co-cultures of PBMC with human primary esophageal epithelial cells and in a novel inducible mouse model of eosinophilic esophagitis, characterized by extensive IL-33 secretion in the esophagus. Our results indicate that specific PBMC populations are enriched, and that they alter their surface expression of activation markers in mucosal tissue of active EoE. In particular, we observed upregulation of the immunomodulatory molecule CD38 on CD4 T cells and on myeloid cells in biopsies of active EoE. Moreover, we observed significant upregulation of PD-1 on CD4 and myeloid cells, which was even more prominent after corticosteroid treatment. With co-culture experiments we could demonstrate that direct cell contact is needed for PD-1 upregulation on CD4 T cells. Finally, we validated our findings of PD-1 and CD38 upregulation in an inducible mouse model of EoE. Herein we show significant alterations in the PBMC activation profile of patients with active EoE in comparison to inactive EoE, GERD and controls, which could have potential implications for treatment. To our knowledge, this study is the first of its kind expanding the multi-color flow cytometry approach in different patient groups using and translational models.

Apolipoprotein C3 (apoC3) is a key regulator of triglyceride metabolism and has emerged as a potential therapeutic target for reducing the risk of cardiovascular disease. However, its broader physiological functions are not fully understood. This study investigates the role of apoC3 in platelet function and thrombus formation. Interestingly, human apoC3 was found to rapidly inhibit platelet activation over the tested concentration range of 0.1–10 µg/mL, with significant effects observed at low concentrations and brief pre-incubation times (from 1 min). At a concentration of 10 µg/mL, apoC3 suppressed platelet activation by approximately 70% in response to ADP and by approximately 40% in response to collagen stimulation. Depleting apoC3 from human serum enhanced platelet aggregation by more than 25 % (1.28 ± 0.19 vs. vehicle), indicating an endogenous regulatory function of apoC3. Mechanistically, apoC3 binding to platelets reduced both GPIIb/IIIa activation and P-selectin expression by around 20%. ApoC3 binding to platelets increased when platelets were activated by ADP and was partially mediated by GPIIb/IIIa, implicating this integrin as a functionally relevant receptor. Taken together, these findings reveal a novel link between apoC3 and platelet biology with potential implications for thrombotic risk and vascular homeostasis.

The tumor microenvironment (TME) is pivotal in cancer progression and the response to immunotherapy. A “hot” tumor typically contains immune cells that promote anti-tumor immunity, predicting positive prognosis. “Cold” tumors lack immune cells, suggesting a poor outlook across various cancers. Recent research has focused on converting “cold” tumors into “hot” tumors to enhance the success of immunotherapy. A prerequisite for the studies of the TME is an accurate knowledge of the cell populations of the TME. This study aimed to describe the immune TME of lung and colorectal cancer and melanoma, focusing on lymphoid and myeloid cell populations. We induced heterotopic immunocompetent tumors in C57BL/6 mice, using KP and LLC (Lewis lung carcinoma) cells for lung cancer, MC38 cells for colorectal cancer, and B16-F10 cells for melanoma. Immune cell infiltration was analyzed using multicolor flow cytometry in single-cell suspensions after tumor excision. KP cell tumors showed an abundance of neutrophils and eosinophils; however, they contained much less adaptive immune cells, while LLC cell tumors predominated in monocytes, neutrophils, and monocyte-derived dendritic cells. Monocytes and neutrophils, along with a significant T cell infiltration, were prevalent in MC38 tumors. Lastly, B16-F10 tumors were enriched in macrophages, while showing only moderate T cell presence. In conclusion, our data provide a detailed overview of the immune TME of various heterotopic tumors, highlighting the variabilities in the immune cell profiles of different tumor entities. Our data may be a helpful basis when investigating new immunotherapies, and thus, this report serves as a helpful tool for preclinical immunotherapy research design.

Passive acoustic monitoring (PAM) is a key technology for studying marine mammal populations. PAM typically generates large volumes of data that contain signals from multiple overlapping sources. To extract meaningful information from these data, automated tools are required that can cope with multiple sources, missed detections, and false alarms. This paper presents the Multiple-Animal Model-Based Acoustic Tracking (MAMBAT) framework, which integrates model-based localization with Bayesian multi-target tracking to automatically track multiple sound sources using acoustic data from wide baseline arrays. MAMBAT leverages a “Track-before-Localize” strategy followed by a “Localize-then-Track” strategy that does not require detection, classification, or association steps. The framework’s effectiveness is demonstrated through application to real-world datasets that contain multiple sperm whales from two ocean basins. MAMBAT advances our ability to monitor marine mammal distribution, abundance, and behavior, with potential to provide valuable information for conservation and management efforts.

The role of last-mile delivery professionals is becoming increasingly vital in modern urban logistics, driven by the rapid expansion of e-commerce and rising consumer expectations for fast and reliable services. This study aimed to analyse the decision-making patterns of last-mile delivery professionals through stated preference data. To achieve this, a stated-preference questionnaire was conducted with 333 riders aged 18–65 from Croatia, Cyprus, Greece, Italy and Slovenia. A random parameter logit (RPL) model was applied to evaluate the influence of factors such as driving behaviour, delivery time and salary type on decision-making in hypothetical scenarios. Results showed that driving behaviour, trip duration and salary type significantly affected respondents’ preferences. Participants displayed a strong preference for flat salaries, indicating the importance of income stability over performance-based pay. Driving behaviour was also crucial, as respondents favoured legal and safe practices. Interestingly, while shorter delivery times were generally preferred, several scenarios revealed a tolerance for longer durations, possibly reflecting perceived benefits such as safer routes or reduced stress. Comparative analyses also revealed regional differences in vehicle use, work patterns and safety perceptions. The study highlights the need for tailored training programs on safety compliance, route optimization and time management, alongside hybrid salary structures balancing stability and productivity.

INTRODUCTION:Patients with type 2 diabetes mellitus (T2DM) are at increased risk of metabolic dysfunction-associated steatotic liver disease, advanced liver fibrosis, and metabolic dysfunction-associated steatohepatitis (MASH). We evaluated the prevalence and severity of metabolic dysfunction-associated steatotic liver disease among patients with T2DM at their first referral to diabetes clinics and assessed the effectiveness of the 2-tier screening approach by Fibrosis-4 (FIB-4) and vibration-controlled transient elastography (VCTE).METHODS:Consecutive patients with T2DM from 6 different diabetes clinics were prospectively enrolled. Liver stiffness measurement (LSM) was assessed by VCTE, whereas liver steatosis by controlled attenuation parameter (Fibroscan, Echosens, France). “At-risk MASH” was assessed by FibroScan-aspartate aminotransferase score.RESULTS:Eight hundred patients (median age: 59, 53–65 years; males: 485, 60.6%) met the inclusion criteria. Prevalence of liver steatosis (controlled attenuation parameter ≥ 248 db/m) was 73.6%. The proportion of patients at medium/high risk of advanced liver fibrosis (LSM ≥ 8.0 kPa) was 16.9%. Patients with “at-risk MASH” (FibroScan-aspartate aminotransferase > 0.67) were 12.0%. A 2-tier screening for advanced liver fibrosis by FIB-4 and VCTE would have led to 70 patients (8.8%) referred to liver clinics with a false-negative rate of 9.6% (n = 77; patients with FIB-4 < 1.3 and LSM ≥ 8.0 kPa). At multivariate analysis, overweight/obesity (odds ratio = 3.13, 95% confidence interval 1.23–7.97) and elevated alanine aminotransferase (odds ratio = 1.91, 95% confidence interval 1.17–3.10) were independently associated with LSM ≥ 8.0 kPa in patients with FIB-4 < 1.3.DISCUSSION:In diabetes clinics, the 2-tier screening using FIB-4 and VCTE is effective for the identification of patients with T2DM to be referred to hepatologists. VCTE referral may be considered for patients with overweight/obesity and elevated alanine aminotransferase classified as at low risk of advanced liver fibrosis by FIB-4.

Patients with type 2 diabetes mellitus (T2DM) are at increased risk for metabolic dysfunction-associated steatotic liver disease (MASLD), advanced liver fibrosis, and metabolic dysfunction-associated steatohepatitis (MASH). We evaluated the prevalence and severity of MASLD among patients with T2DM at their first referral to diabetes clinics, and assessed the effectiveness of the 2-tier screening approach by Fibrosis-4 (FIB-4) and vibration-controlled transient elastography (VCTE).BACKGROUND AIMSPatients with type 2 diabetes mellitus (T2DM) are at increased risk for metabolic dysfunction-associated steatotic liver disease (MASLD), advanced liver fibrosis, and metabolic dysfunction-associated steatohepatitis (MASH). We evaluated the prevalence and severity of MASLD among patients with T2DM at their first referral to diabetes clinics, and assessed the effectiveness of the 2-tier screening approach by Fibrosis-4 (FIB-4) and vibration-controlled transient elastography (VCTE).Consecutive patients with T2DM from six different diabetes clinics were prospectively enrolled. Liver stiffness measurement (LSM) was assessed by VCTE, while liver steatosis by controlled attenuation parameter (CAP) (Fibroscan, Echosens, France). \"At risk MASH\" was assessed by FibroScan-AST (FAST) score.METHODSConsecutive patients with T2DM from six different diabetes clinics were prospectively enrolled. Liver stiffness measurement (LSM) was assessed by VCTE, while liver steatosis by controlled attenuation parameter (CAP) (Fibroscan, Echosens, France). \"At risk MASH\" was assessed by FibroScan-AST (FAST) score.800 patients (median age: 59, 53-65 years; males: 485, 60.6%) met the inclusion criteria. Prevalence of liver steatosis (CAP ≥ 248 db/m) was 73.6%. The proportion of patients at medium/high risk of advanced liver fibrosis (LSM ≥ 8.0 kPa) was 16.9%. Patients with \"at risk MASH\" (FAST > 0.67) were 12.0%.A 2-tier screening for advanced liver fibrosis by FIB-4 and VCTE would have led to 70 (8.8%) patients referred to liver clinics with a false-negative rate of 9.6% (n = 77; patients with FIB-4 < 1.3 and LSM ≥ 8.0 kPa). At multivariate analysis, overweight/obesity (OR = 3.13, 95%CI 1.23-7.97) and elevated ALT (OR = 1.91, 95%CI 1.17-3.10) were independently associated with LSM ≥ 8.0 kPa in patients with FIB-4 < 1.3.RESULTS800 patients (median age: 59, 53-65 years; males: 485, 60.6%) met the inclusion criteria. Prevalence of liver steatosis (CAP ≥ 248 db/m) was 73.6%. The proportion of patients at medium/high risk of advanced liver fibrosis (LSM ≥ 8.0 kPa) was 16.9%. Patients with \"at risk MASH\" (FAST > 0.67) were 12.0%.A 2-tier screening for advanced liver fibrosis by FIB-4 and VCTE would have led to 70 (8.8%) patients referred to liver clinics with a false-negative rate of 9.6% (n = 77; patients with FIB-4 < 1.3 and LSM ≥ 8.0 kPa). At multivariate analysis, overweight/obesity (OR = 3.13, 95%CI 1.23-7.97) and elevated ALT (OR = 1.91, 95%CI 1.17-3.10) were independently associated with LSM ≥ 8.0 kPa in patients with FIB-4 < 1.3.In diabetes clinics, the 2-tier screening using FIB-4 and VCTE is effective for the identification of T2DM patients to be referred to hepatologists. VCTE referral may be considered for patients with overweight/obesity and elevated ALT classified as at low risk of advanced liver fibrosis by FIB-4.CONCLUSIONSIn diabetes clinics, the 2-tier screening using FIB-4 and VCTE is effective for the identification of T2DM patients to be referred to hepatologists. VCTE referral may be considered for patients with overweight/obesity and elevated ALT classified as at low risk of advanced liver fibrosis by FIB-4.

Background An “obesity paradox” for mortality has been shown in chronic disorders such as diabetes, and attributed to methodological bias, including the use of body mass index (BMI) for obesity definition. This analysis investigated the independent association of BMI versus surrogate measures of central adiposity with all-cause mortality in individuals with type 2 diabetes. Methods The Renal Insufficiency And Cardiovascular Events Italian Multicentre Study is a prospective cohort study that enrolled 15,773 patients in 19 Italian centres in 2006–2008. Exposures were BMI and the surrogate measures of central adiposity waist circumference (WC), waist-to-height ratio (WHtR), and A Body Shape Index (ABSI). Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%), Results Age- and sex-adjusted hazard ratios and 95% confidence intervals were significantly higher in BMI-based underweight (1.729 [1.193–2.505), P  = 0.004), moderately obese (1.214 [1.058–1.392), P  = 0.006) and severely obese (1.703 [1.402–2.068), P  < 0.0001), lower in overweight (0.842 [0.775–0.915), P  < 0.0001) and similar in mildly obese (0.950 [0.864–1.045), P  = 0.292), compared to normal-weight individuals. When further adjusting for smoking, physical activity (PA), and comorbidities, risk was lower also in mildly obese versus normal-weight patients. The BMI-mortality relationship did not change after sequentially excluding ever smokers, individuals with comorbidities, and those died within two years from enrollment and when analyzing separately participants below and above the median age. Conversely, a paradox relationship was observed among inactive/moderately inactive, but not moderately/highly active patients. Mortality risk adjusted for age, gender, smoking, PA and comorbidities was significantly higher in the highest tertile of WC (1.279 [1.089–1.501], P  = 0.003), WHtR (1.372 [1.165–1.615], P  < 0.0001), and ABSI (1.263 [1.067–1.495], P  = 0.007) versus the lowest tertile. However, risk was lower in the intermediate versus lowest tertile for WC (0.823 [0.693–0.979], P  = 0.028), similar for WHtR, and higher, though not significantly, for ABSI. Conclusions An “overweight paradox” remained after controlling for age, smoking, and comorbidities, arguing against a collider bias or reverse causation. However, it could be partly explained by confounding from PA level, possibly through its impact on lean mass and cardiorespiratory fitness. No obesity paradox was observed with WHtR and especially ABSI, which predicted mortality risk associated with central adiposity better than WC. Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008