The accumulation of senescent cells promotes aging, but the molecular mechanism that senescent cells use to evade immune clearance and accumulate remains to be elucidated. Here, we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to elimination of p16, PD-L1-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of PD-L1 as a target for treating senescence-mediated age-associated diseases.

Baclgrpund/Aim. Heart transplantation is the most effective way to treat patients in the terminal stage of heart failure. Endomyocardial biopsy has proven to be a safe and appropriate technique, with little sampling error and remains to this day one of the most commonly used methods for diagnosing of acute rejection. In 1990, ISHLT defined a standardized system for grading the severity of acute transplant rejection regarding endomyocardial sampling histopathological analysis. The aim of study is assessment of morphological, immunohistochemical and immunofluorescent markers of cellular and antibody-mediated rejection of heart transplant in patients monitored during 2020. Methods. From 31 patients transplanted at the Clinic for Cardiac Surgery of the Clinical Center of Serbia, endomyocardial biopsy material was obtained, then processed and analyzed at the Institute of Pathology of the Medical Faculty, University of Belgrade. Results. The average Transplant Rejection Score (TRS) value was 0.42. Spearman 's correlation test didn?t show a statistically significant relationship between the TRS score value and the difference between the ejection fraction values three and twelve months after transplantation. Conclusion. The mean TRS score value obtained in this study suggests dominant cell graft rejection.

S33national level in England and assumed that the interventions would be achieved in 100% of patients. RESULTS: The AF register included 1,065,569 patients (prevalence 1.85%). The model estimated, however, that prevalence should be 2.50% (1.4 million patients), giving a detection gap of 25.9%. Screening of all undetected patients and improved diagnostic interventions coupled with adequate anticoagulation would cost £47.1 million. Risk assessments had not been performed in 13,592 (3.1%) patients. With 100% assessment, the reduced stroke risk would be associated with a saving of £4.4 million. Among 877 964 patients eligible for anticoagulation, 165,355 (19%) were not receiving treatment, and among the 712,609 being treated, anticoagulation was inadequate in 191,289 (30%). Starting treatment in all untreated patients would save £53.7 million and achieving adequate anticoagulation in all would save a further £136.6 million. The total achievable saving over 3 years, therefore, would be £147.7 million. CONCLUSIONS: Addressing AF diagnosis and management gaps, especially adequacy of anticoagulation, would lead to significant savings across England, even with the cost of introducing screening.