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Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast-activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD8+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD8+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.

The purpose of the present study was to investigate the impact of an intervention on primary school students’ construction of knowledge on ocean acidification and the development of their systems thinking. Eighty-five 11 to 12-year-old students from five different classes of two public primary schools in Greece participated in the 8-h intervention. The intervention included inquiry-based and knowledge-integration activities, and students worked in groups during all activities. Rich pictures, made by the groups at the beginning and the end of the intervention, were used to evaluate their progress in their knowledge concerning the carbon cycle, as well as in their systems thinking. Our findings showed that the intervention contributed to primary students’ conceptual knowledge of the carbon cycle and the inclusion of ocean acidification in the carbon cycle. It also helped them improve their systems thinking, indicating that students’ systems thinking at this age could be developed through formal instruction with interventions which emphasize content knowledge and use an earth systems approach. Moreover, our findings indicate that the systems thinking perspective can serve as an effective approach to help children better understand and critically engage with complex environmental issues, such as ocean acidification.

Myeloproliferative Neoplasms (MPN) are malignancies of hematopoietic stem and progenitor cells (HSPCs) that lead to the overproduction of mature blood cells. These disorders include Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (PMF), primarily driven by somatic mutations such as JAK2V617F. Research indicates that mesenchymal stromal cells (MSCs) support fibrosis in PMF, though their role in ET and PV remains less clear. Furthermore, in vivo studies of ET/PV HSPCs remain a challenge due to low engraftment levels in xenograft models. We employed a 3D scaffold model to create an MPN humanized xenograft mouse model, enabling in vivo functional studies of primary MPN progenitor cells and the supportive role of human MSCs. Using this model, we first demonstrated robust hematopoietic support of healthy (HD) HSPCs by PV and ET MSCs. We then investigated the role of MSCs in sustaining JAK2V617F mutant cells by using a CRISPR‐Cas9 editing model, along with primary PV and ET HSPCs. Our results showed consistent engraftment of CRISPR‐edited JAK2V617F mutant HSPCs and PV and ET patient‐derived HSPCs in scaffolds seeded with HD, PV, and ET stroma, providing the first in vivo evidence that PV and ET MSCs can sustain both healthy and MPN‐associated hematopoiesis. Furthermore, HD MSCs were also capable of sustaining PV and ET HSPCs in vivo. Overall, we present the first humanized MPN xenograft model that offers valuable insights into how human BM MSCs interact with JAK2V617F mutant clones.

Chronic lymphocytic leukaemia (CLL) is a non-curative B cell malignancy characterised by profound T cell exhaustion and an understudied immunosuppressive tumour microenvironment (TME). Although current therapies such as targeted drugs (BTKis, BCL-2i) alone or in combination with monoclonal antibodies achieve impressive response rates, disease persists and can eventually relapse - highlighting a clinical need to identify additional treatment strategies for these patients. Pre-clinical and early clinical work utilizing immunotherapeutic approaches that harness the ability of the immune system to control disease, opened up new opportunities for cancer therapy. In CLL, the use of immunotherapy to tackle relapse is appealing, although overcoming T cell exhaustion, as well as the inhibitory TME will likely be required. However, it is first desirable in order to optimise the use of immunotherapy, to understand how current therapies like ibrutinib alter the T cell compartment in CLL (immunomodulatory effects of targeted drug therapy). The first project within this thesis investigated how ibrutinib-based therapy versus traditional chemoimmunotherapy modulated T cell subsets and their function during therapy. Analysing patient samples collected from a large Phase 3 trial with flow cytometry and functional assays identified distinct T cell changes and activities during treatment. Importantly, we identified that Ibrutinib-rituximab therapy promoted CD8+ lytic synapse function. In sharp contrast, FCR- treated T cells failed to improve their anti-CLL cytotoxic ability, even with the addition of ex vivo immunotherapy. This study also revealed novel correlations between T cell subset numbers and function and clinical outcomes for both treatment arms, providing novel insight into the role of T cells in contributing to clinical response with these therapies. Next, this thesis evaluated the ability of a novel bispecific antibody combination immunotherapy [CD20-T cell bispecific (TCB) with a CD19-4-1BBL fusion drug] to modulate anti-CLL immune function. Multiple T cell functional assays, co-culture systems, an in vivo xenograft model and organotypic cultures were used to pre-clinically model combination immunotherapy in CLL and non-Hodgkin lymphoma. The results reveal that bispecific antibody pairing induces high levels of T cell cytotoxic function and could help combat TME-mediated immunosuppression in CLL, strengthening the rationale for developing combination immunotherapy to harness the power of cytolytic T cells to deepen therapeutic responses and tackle relapsed disease.

Both clonal hematopoiesis of indeterminate potential (CHIP) and cancer are more common with age. When they coexist in the same patient, CHIP cells may migrate to the tumor and have an adverse effect on overall survival.

Myeloproliferative Neoplasms (MPN) are malignancies of hematopoietic stem and progenitor cells (HSPCs) that lead to the overproduction of mature blood cells. These disorders include Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (PMF), primarily driven by somatic mutations such as JAK2 V617F . Research indicates that mesenchymal stromal cells (MSCs) support fibrosis in PMF, though their role in ET and PV remains less clear. Furthermore, in vivo studies of ET/PV HSPCs remain a challenge due to low engraftment levels in xenograft models. We employed a 3D scaffold model to create an MPN humanized xenograft mouse model, enabling in vivo functional studies of primary MPN progenitor cells and the supportive role of human MSCs. Using this model, we first demonstrated robust hematopoietic support of healthy (HD) HSPCs by PV and ET MSCs. We then investigated the role of MSCs in sustaining JAK2 V617F mutant cells by using a CRISPR‐Cas9 editing model, along with primary PV and ET HSPCs. Our results showed consistent engraftment of CRISPR‐edited JAK2 V617F mutant HSPCs and PV and ET patient‐derived HSPCs in scaffolds seeded with HD, PV, and ET stroma, providing the first in vivo evidence that PV and ET MSCs can sustain both healthy and MPN‐associated hematopoiesis. Furthermore, HD MSCs were also capable of sustaining PV and ET HSPCs in vivo. Overall, we present the first humanized MPN xenograft model that offers valuable insights into how human BM MSCs interact with JAK2 V617F mutant clones.

Background/Objectives: Contradictory results have been reported regarding the influence of obesity on the prognosis of atrial fibrillation (AF). The present study aimed to explore the potential association of body mass index (BMI) with the clinical outcomes of hospitalized patients with AF. Methods: In this retrospective, post hoc analysis of the MISOAC-AF randomized trial, 1113 AF patients were included and stratified as the following: underweight (BMI < 18 kg/m2), normal weight (BMI 18–24.9 kg/m2), overweight (BMI 25–29.9 kg/m2), and obese (BMI ≥ 30 kg/m2). The primary outcome was all-cause mortality; the secondary composite outcome was any hospitalization related to AF, heart failure (HF), or stroke. Cox regression analysis, survival analysis, and spline curve models were utilized. Results: Of the patients (median age: 76 years (IQR: 13), male: 54.6%), the majority were overweight (41.4%), followed by obese (33%), normal weight (24%), and underweight (1.6%). During a median 31-month follow-up, 436 (39.2%) patients died and 657 (59%) were hospitalized due to AF, HF, or stroke. Underweight, overweight, and obesity groups were significantly associated with an increased risk of all-cause mortality (p-values 0.02, 0.001, and <0.001, respectively), while overweight and obesity were significantly associated with the composite endpoint (p-values 0.01, <0.001, respectively) compared to normal weight. The spline curve analyses yielded that BMIs > 26.3 and > 25 were incrementally associated with all-cause mortality and the composite endpoint, respectively. A J-shaped relationship between BMI and AF prognosis was deduced. Conclusions: In conclusion, in recently hospitalized AF patients, BMI values outside the normal range were independently associated with poorer prognosis; therefore, it is essential that AF patients maintain a normal weight.

The implications of the adult congenital heart disease anatomic and physiological classification (AP-ACHD) for risk assessment have not been adequately studied. A retrospective cohort study was conducted using data from an ongoing national, multicentre registry of patients with ACHD and atrial arrhythmias (AA) receiving apixaban (PROTECT-AR study, NCT03854149). At enrollment, patients were stratified according to Anatomic class (AnatC, range I to III) and physiological stage (PhyS, range B to D). A follow-up was conducted between May 2019 and September 2021. The primary outcome was a composite of death from any cause, any major thromboembolic event, major or clinically relevant non-major bleeding, or hospitalization. Cox proportional-hazards regression modeling was used to evaluate the risks for the outcome among AP-ACHD classes. Over a median 20-month follow-up period, 47 of 157 (29.9%) ACHD patients with AA experienced the composite outcome. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for the outcome in PhyS C and PhyS D were 1.79 (95% CI 0.69 to 4.67) and 8.15 (95% CI 1.52 to 43.59), respectively, as compared with PhyS B. The corresponding aHRs in AnatC II and AnatC III were 1.12 (95% CI 0.37 to 3.41) and 1.06 (95% CI 0.24 to 4.63), respectively, as compared with AnatC I. In conclusion, the PhyS component of the AP-ACHD classification was an independent predictor of net adverse clinical events among ACHD patients with AA.

Healthcare access and a high quality of the provided services to healthcare users are fundamental human rights according to the Alma Ata Declaration of 1978. Although 45 years have passed since then, health inequalities still exist, not only among countries but also within populations of the same country. For example, several small Greek islands have only a small Primary Healthcare Center in order to provide healthcare services to the insular population. In the current study, we investigated the level of self-reported overall, dental and mental health status and the level of satisfaction regarding the access to and the quality of the healthcare services provided by the Primary Healthcare center of Alonissos, along with registering the requirements for transportation to the mainland in order to receive such services. In this questionnaire-based cross-sectional study, 235 inhabitants of the remote Greek island of Alonissos that accounts for nearly 9% of the population participated (115 males and 120 females). The self-reported overall health status was reported to be moderate to very poor at a percentage of 31.49%, and the results were similar for dental and self-reported mental health status. Although nearly 60% of the participants reported very good/good quality of the healthcare provision, only 37.45% reported that the access to healthcare was very good/good, while around 94% had at least one visit to the mainland in order to receive proper healthcare services. Strategies for improving access to healthcare services need to be placed in remote Greek islands like Alonissos.

The prognostic value of health status metrics in patients with adult congenital heart disease (ACHD) and atrial arrhythmias is unclear. In this retrospective cohort study of an ongoing national, multicenter registry (PROTECT-AR, NCT03854149), ACHD patients with atrial arrhythmias on apixaban are included. At baseline, health metrics were assessed using the physical component summary (PCS), the mental component summary (MCS) of the Short-Form-36 (SF-36) Health Survey, and the modified European Heart Rhythm Association (mEHRA) score. Patients were divided into groups according to their SF-36 PCS and MCS scores, using the normalized population mean of 50 on the PCS and MCS as a threshold. The primary outcome was the composite of mortality from any cause, major thromboembolic events, major/clinically relevant non-major bleedings, or hospitalizations. Multivariable Cox-regression analyses using clinically relevant parameters (age greater than 60 years, anatomic complexity, ejection fraction of the systemic ventricle, and CHA₂DS₂-VASc and HAS-BLED scores) were performed to examine the association of health metrics with the composite outcome. Over a median follow-up period of 20 months, the composite outcome occurred in 50 of 158 (32%) patients. The risk of the outcome was significantly higher in patients with SF-36 PCS ≤ 50 compared with those with PCS > 50 (adjusted hazard ratio (aHR), 1.98; 95% confidence interval [CI], 1.02–3.84; p = 0.04) after adjusting for possible confounders. The SF-36 MCS ≤ 50 was not associated with the outcome. The mEHRA score was incrementally associated with a higher risk of the composite outcome (aHR = 1.44 per 1 unit increase in score; 95% CI, 1.03–2.00; p = 0.03) in multivariable analysis. In ACHD patients with atrial arrhythmias, the SF-36 PCS ≤ 50 and mEHRA scores predicted an increased risk of adverse events.