EP4 receptor stimulation down-regulates human eosinophil function

Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE2 receptor EP4, ONO AE1-329, potently attenuated the chemotaxis of human peripheral blood eosinophils, upregulation of the adhesion molecule CD11b and the production of reactive oxygen species. These effects were accompanied by the inhibition of cytoskeletal rearrangement and Ca2+ mobilization. The involvement of the EP4 receptor was substantiated by a selective EP4 antagonist, which reversed the inhibitory effects of PGE2 and the EP4 agonist. Selective kinase inhibitors revealed that the inhibitory effect of EP4 stimulation on eosinophil migration depended upon activation of PI 3-kinase and PKC, but not cAMP. Finally, we found that EP4 receptors are expressed by human eosinophils, and are also present on infiltrating leukocytes in inflamed human nasal mucosa. These data indicate that EP4 agonists might be a novel therapeutic option in eosinophilic diseases

Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases

Background: Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown. Methods: In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs. Results: Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005). Conclusions: H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB

Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed—from diagnosis to LT—with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016–2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population

Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed—from diagnosis to LT—with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016–2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population

Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed-from diagnosis to LT-with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016-2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population.Peer reviewe

Model matchmaking via the Solve-RD Rare Disease Models &amp; Mechanisms Network (RDMM-Europe)

In biomedical research, particularly for rare diseases (RDs), there is a critical need for model organisms to unravel the mechanistic basis of diseases, perform biomarker studies and develop potential therapeutic interventions. Within Solve-RD, an EU-funded research project with the aim of solving large numbers of previously unsolved RDs, the European Rare Disease Models &amp; Mechanisms Network (RDMM-Europe) has been established.</p

Physician and Patient Predictors of Evidence-Based Prescribing in Heart Failure: A Multilevel Study

BACKGROUND: The management of patients with heart failure (HF) needs to account for changeable and complex individual clinical characteristics. The use of renin angiotensin system inhibitors (RAAS-I) to target doses is recommended by guidelines. But physicians seemingly do not sufficiently follow this recommendation, while little is known about the physician and patient predictors of adherence. METHODS: To examine the coherence of primary care (PC) physicians' knowledge and self-perceived competencies regarding RAAS-I with their respective prescribing behavior being related to patient-associated barriers. Cross-sectional follow-up study after a randomized medical educational intervention trial with a seven month observation period. PC physicians (n = 37) and patients with systolic HF (n = 168) from practices in Baden-Wuerttemberg. Measurements were knowledge (blueprint-based multiple choice test), self-perceived competencies (questionnaire on global confidence in the therapy and on frequency of use of RAAS-I), and patient variables (age, gender, NYHA functional status, blood pressure, potassium level, renal function). Prescribing was collected from the trials' documentation. The target variable consisted of ≥50% of recommended RAAS-I dosage being investigated by two-level logistic regression models. RESULTS: Patients (69% male, mean age 68.8 years) showed symptomatic and objectified left ventricular (NYHA II vs. III/IV: 51% vs. 49% and mean LVEF 33.3%) and renal (GFR<50%: 22%) impairment. Mean percentage of RAAS-I target dose was 47%, 59% of patients receiving ≥50%. Determinants of improved prescribing of RAAS-I were patient age (OR 0.95, CI 0.92-0.99, p = 0.01), physician's global self-confidence at follow-up (OR 1.09, CI 1.02-1.05, p = 0.01) and NYHA class (II vs. III/IV) (OR 0.63, CI 0.38-1.05, p = 0.08). CONCLUSIONS: A change in physician's confidence as a predictor of RAAS-I dose increase is a new finding that might reflect an intervention effect of improved physicians' intention and that might foster novel strategies to improve safe evidence-based prescribing. These should include targeting knowledge, attitudes and skills