ABSTRACT
Point-of-Care Ultrasound (POCUS) is a rapid and valuable diagnostic tool available in emergency and intensive care units. In the context of cardiac arrest, POCUS application can help assess cardiac activity, identify causes of arrest that could be reversible (such as pericardial effusion or pneumothorax), guide interventions like central line placement or pericardiocentesis, and provide real-time feedback on the effectiveness of resuscitation efforts, among other critical applications. Its use, in addition to cardiovascular life support maneuvers, is advocated by all resuscitation guidelines. The purpose of this narrative review is to summarize the key applications of POCUS in cardiac arrest, highlighting, among others, its prognostic, diagnostic, and forensic potential. We conducted an extensive literature review utilizing PubMed by employing key search terms regarding ultrasound and its use in cardiac arrest. Apart from its numerous advantages, its limitations and challenges such as the potential for interruption of chest compressions during image acquisition and operator proficiency should be considered as well and are discussed herein.
ABSTRACT
Patients with acute myeloid leukemia (AML) often achieve remission after allogeneic hematopoietic cell transplantation (allo-HCT) but subsequently die of relapse driven by leukemia cells resistant to elimination by allogeneic T cells based on decreased major histocompatibility complex II (MHC-II) expression and apoptosis resistance. Here we demonstrate that mouse-double-minute-2 (MDM2) inhibition can counteract immune evasion of AML. MDM2 inhibition induced MHC class I and II expression in murine and human AML cells. Using xenografts of human AML and syngeneic mouse models of leukemia, we show that MDM2 inhibition enhanced cytotoxicity against leukemia cells and improved survival. MDM2 inhibition also led to increases in tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2 (TRAIL-R1/2) on leukemia cells and higher frequencies of CD8+CD27lowPD-1lowTIM-3low T cells, with features of cytotoxicity (perforin+CD107a+TRAIL+) and longevity (bcl-2+IL-7R+). CD8+ T cells isolated from leukemia-bearing MDM2 inhibitor-treated allo-HCT recipients exhibited higher glycolytic activity and enrichment for nucleotides and their precursors compared with vehicle control subjects. T cells isolated from MDM2 inhibitor-treated AML-bearing mice eradicated leukemia in secondary AML-bearing recipients. Mechanistically, the MDM2 inhibitor-mediated effects were p53-dependent because p53 knockdown abolished TRAIL-R1/2 and MHC-II upregulation, whereas p53 binding to TRAILR1/2 promotors increased upon MDM2 inhibition. The observations in the mouse models were complemented by data from human individuals. Patient-derived AML cells exhibited increased TRAIL-R1/2 and MHC-II expression on MDM2 inhibition. In summary, we identified a targetable vulnerability of AML cells to allogeneic T-cell-mediated cytotoxicity through the restoration of p53-dependent TRAIL-R1/2 and MHC-II production via MDM2 inhibition.
