Lyn and PECAM-1 function as interdependent inhibitors of platelet aggregation.

Inhibition of platelet responsiveness is important to control pathologic thrombus formation. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) and the Src family kinase Lyn inhibit platelet activation by the glycoprotein VI (GPVI) collagen receptor; however, it is not known whether PECAM-1 and Lyn function in the same or different inhibitory pathways. In these studies, we found that, relative to wild-type platelets, platelets derived from PECAM-1-deficient, Lyn-deficient, or PECAM-1/Lyn double-deficient mice were equally hyperresponsive to stimulation with a GPVI-specific agonist, indicating that PECAM-1 and Lyn participate in the same inhibitory pathway. Lyn was required for PECAM-1 tyrosine phosphorylation and subsequent binding of the Src homology 2 domain-containing phosphatase-2, SHP-2. These results support a model in which PECAM-1/SHP-2 complexes, formed in a Lyn-dependent manner, suppress GPVI signaling.

Immune checkpoint inhibitor toxicity and associated outcomes in older patients with cancer.

INTRODUCTION: Increased immune checkpoint inhibitor (ICI) use in various advanced cancer types has led to a parallel rise in immune-related adverse events (irAEs). Despite widespread use, ICI data in older patients remains limited. We investigate irAE prevalence in older patients receiving ICI and whether irAEs and survival are associated. MATERIALS AND METHODS: Our retrospective study included patients aged ≥65 years with advanced malignancies who had ≥1 dose of ICI from January 2011 through September 2019. We evaluated irAE cases and their respective grades and assessed oncological response by progression-free survival (PFS) and overall survival (OS). RESULTS: Mean age of 210 patients was 75.0 ± 7.2 years, 58.1% were men, and most were white. IrAE prevalence was 41.4% (n = 87); 9.5% (n = 20) developed multisystem irAE. Most irAEs were grades 1 and 2 (27.6% and 49.4%, respectively), while grades 3 and 4 accounted for 17.2% and 5.8%, respectively. No grade 5 irAE occurred. Compared with patients with no irAEs, those with irAEs had improved OS (HR [hazard ratio], 0.41; 95% CI [confidence interval], 0.282-0.597; p < 0.0001) and PFS (HR, 0.311; 95% CI: 0.213-0.453; p < 0.0001). Improved OS was seen with irAE grades 1 and 2 versus grades 3 and 4 (HR, 0.344; 95% CI: 0.171-0.694; p = 0.0029). Similarly, improved PFS was seen with lower grade irAE (HR, 0.489; 95% CI: 0.247-0.965; p = 0.0391). DISCUSSION: The irAE prevalence in older patients was similar to that in younger patients. To our knowledge, this is one of few studies that confirms a positive association of irAE on both OS and PFS in older patients with cancer, and improved OS and PFS with lower versus higher grade irAE.

Does Timing of Inferior Vena Cava Filter Retrieval Planning Impact Retrieval Rates? A Comparison of Planning Before or After Hospital Discharge.

INTRODUCTION: Indwelling inferior vena cava (IVC) filters are associated with complications, and the US Food and Drug Administration recommends their prompt removal when no longer indicated. Therefore, assessing strategies for increasing retrieval rates is warranted. OBJECTIVE: To analyze the variability of IVC filter retrieval rates within our institution based on 2 separate, pre-existing processes in which IVC retrieval is planned for before or after hospital discharge. METHODS: Retrospective chart review was completed for all IVC filters placed in adults between January 2005 and March 2015. Demographics and clinical data related to filter placement and retrieval were abstracted. Patients were classified into 2 groups: patients who had a trauma consultation trauma and nontrauma medical and surgical patients medical. The trauma group patients were subject to a 2-layer tracking process, in which retrieval planning was done before discharge, versus the medical group with a single-layer tracking process and retrieval planning done after discharge. RESULTS: Of the 588 filter placements analyzed, 236 were placed in trauma patients and 352 were placed for medical reasons. The retrieval rate of the entire cohort was 45% (262/588), with the rate among trauma patients more than double that of medical patients (155/236, 66% and 107/352, 30%; respectively, P < 0.0001). CONCLUSION: IVC filter retrieval rate was increased when filter removal was included in discharge planning versus postdischarge tracking. A systematic, multidisciplinary strategic approach to IVC filter management has great potential to improve filter utilization, resource allocation, patient safety, and filter retrieval.

Effect of combined antisense oligonucleotides against high-glucose- and diabetes-induced overexpression of extracellular matrix components and increased vascular permeability.

The effect of combined antisense oligonucleotides (AS-oligos) against overexpression of extracellular matrix (ECM) components, fibronectin, laminin, and collagen IV and on cell monolayer permeability was examined in rat microvascular endothelial cells (RMECs) grown in high glucose medium and on retinal vascular permeability in diabetic rats. RMECs grown in high glucose for 10 days and transfected with combined AS-oligos showed a significantly reduced fibronectin, laminin, and collagen IV protein level. In parallel studies, high-glucose-induced excess monolayer permeability was also reduced in RMECs transfected with the combined AS-oligos. Similarly, diabetic rats intravitreally injected with the combined AS-oligos and examined after 2 months of diabetes showed significant reduction in retinal fibronectin, laminin, and collagen IV expression. In addition, vascular permeability, as determined from extravasation of fluorescein isothiocyanate-BSA in the surrounding areas of the retinal capillaries, was partially reduced in the combined AS-oligos-treated diabetic retinas. Our results indicate that the combined AS-oligos strategy is effective in simultaneously reducing fibronectin, collagen IV, and laminin overexpression and reducing vascular leakage in the retinal capillaries of diabetic rat retinas. The findings suggest that abnormal synthesis of ECM components may contribute to vascular leakage in the diabetic retina.