NCAM180 Regulates Ric8A Membrane Localization and Potentiates β-Adrenergic Response

Cooperation between receptors allows integrated intracellular signaling leading to appropriate physiological responses. The Neural Cell Adhesion Molecule (NCAM) has three main isoforms of 120, 140 and 180 kDa, with adhesive and signaling properties, but their respective functions remains to be fully identified. Here we show that the human NCAM180 intracellular domain is a novel interactor of the human guanosine exchange factor (GEF) Ric8A using the yeast two hybrid system and immunoprecipitation. Furthermore, NCAM, Ric8A and Gαs form a tripartite complex. Colocalization experiments by confocal microscopy revealed that human NCAM180 specifically induces the recruitment of Ric8A to the membrane. In addition, using an in vitro recombinant system, and in vivo by comparing NCAM knock-out mouse brain to NCAM heterozygous and wild type brains, we show that NCAM expression dose dependently regulates Ric8A redistribution in detergent resistent membrane microdomains (DRM). Previous studies have demonstrated essential roles for Ric8 in Gα protein activity at G protein coupled receptors (GPCR), during neurotransmitter release and for asymmetric cell division. We observed that inhibition of Ric8A by siRNA or its overexpression, decreases or increases respectively, cAMP production following β-adrenergic receptor stimulation. Furthermore, in human HEK293T recombinant cells, NCAM180 potentiates the Gαs coupled β-adrenergic receptor response, in a Ric8A dependent manner, whereas NCAM120 or NCAM140 do not. Finally, in mouse hippocampal neurons expressing endogenously NCAM, NCAM is required for the agonist isoproterenol to induce cAMP production, and this requirement depends on Ric8A. These data illustrate a functional crosstalk between a GPCR and an IgCAM in the nervous system

New Cancer Diagnosis After Bleeding in Anticoagulated Patients With Atrial Fibrillation.

Background Bleeding is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulant therapy, and may be the first manifestation of underlying cancer. We sought to investigate to what extent bleeding represents the unmasking of an occult cancer in patients with AF treated with oral anticoagulants. Methods and Results Using data from CardioCHUVI-AF (Retrospective Observational Registry of Patients With Atrial Fibrillation From Vigo's Health Area), 8753 patients with AF aged ≥75 years with a diagnosis of AF between 2014 and 2017 were analyzed. Of them, 2171 (24.8%) experienced any clinically relevant bleeding, and 479 (5.5%) were diagnosed with cancer during a follow-up of 3 years. Among 2171 patients who experienced bleeding, 198 (9.1%) were subsequently diagnosed with cancer. Patients with bleeding have a 3-fold higher hazard of being subsequently diagnosed with new cancer compared with those without bleeding (4.7 versus 1.4 per 100 patient-years; adjusted hazard ratio [HR], 3.2 [95% CI, 2.6-3.9]). Gastrointestinal bleeding was associated with a 13-fold higher hazard of new gastrointestinal cancer diagnosis (HR, 13.4; 95% CI, 9.1-19.8); genitourinary bleeding was associated with an 18-fold higher hazard of new genitourinary cancer diagnosis (HR, 18.1; 95% CI, 12.5-26.2); and bronchopulmonary bleeding was associated with a 15-fold higher hazard of new bronchopulmonary cancer diagnosis (HR, 15.8; 95% CI, 6.0-41.3). For other bleeding (nongastrointestinal, nongenitourinary, nonbronchopulmonary), the HR for cancer was 2.3 (95% CI, 1.5-3.6). Conclusions In patients with AF treated with oral anticoagulant therapy, any gastrointestinal, genitourinary, or bronchopulmonary bleeding was associated with higher rates of new cancer diagnosis. These bleeding events should prompt investigation for cancers at those sites.S

Imaging in Transcatheter Mitral Valve Replacement: State-of-Art Review

Mitral regurgitation is the second-most frequent valvular heart disease in Europe and it is associated with high morbidity and mortality. Recognition of MR should encourage the assessment of its etiology, severity, and mechanism in order to determine the best therapeutic approach. Mitral valve surgery constitutes the first-line therapy; however, transcatheter procedures have emerged as an alternative option to treat inoperable and high-risk surgical patients. In patients with suitable anatomy, the transcatheter edge-to-edge mitral leaflet repair is the most frequently applied procedure. In non-reparable patients, transcatheter mitral valve replacement (TMVR) has appeared as a promising intervention. Thus, currently TMVR represents a new treatment option for inoperable or high-risk patients with degenerated or failed bioprosthetic valves (valve-in-valve); failed repairs, (valve-in-ring); inoperable or high-risk patients with native mitral valve anatomy, or those with severe annular calcifications, or valve-in-mitral annular calcification. The patient selection requires multimodality imaging pre-procedural planning to select the best approach and device, study the anatomical landing zone and assess the risk of left ventricular outflow tract obstruction. In the present review, we aimed to highlight the main considerations for TMVR planning from an imaging perspective; before, during, and after TMVR

Transcatheter Tricuspid Valve Replacement: Illustrative Case Reports and Review of State-of-Art

Tricuspid regurgitation (TR) is one of the most common heart valve diseases, associated a with poor prognosis since significant TR is associated with an increased mortality risk compared to no TR or mild regurgitation. Surgery is the standard treatment for TR, although it is associated with high morbidity, mortality, and prolonged hospitalization, particularly in tricuspid reoperation after left-sided surgery. Thus, several innovative percutaneous transcatheter approaches for repair and replacement of the tricuspid valve have gathered significant momentum and have undergone extensive clinical development in recent years, with favorable clinical outcomes in terms of mortality and rehospitalization during the first year of follow-up. We present three clinical cases of transcatheter tricuspid valve replacement in an orthotopic position with two different innovative systems along with a review of the state-of-the-art of this emergent topic

Transcatheter Tricuspid Valve Replacement: Illustrative Case Reports and Review of State-of-Art

Tricuspid regurgitation (TR) is one of the most common heart valve diseases, associated a with poor prognosis since significant TR is associated with an increased mortality risk compared to no TR or mild regurgitation. Surgery is the standard treatment for TR, although it is associated with high morbidity, mortality, and prolonged hospitalization, particularly in tricuspid reoperation after left-sided surgery. Thus, several innovative percutaneous transcatheter approaches for repair and replacement of the tricuspid valve have gathered significant momentum and have undergone extensive clinical development in recent years, with favorable clinical outcomes in terms of mortality and rehospitalization during the first year of follow-up. We present three clinical cases of transcatheter tricuspid valve replacement in an orthotopic position with two different innovative systems along with a review of the state-of-the-art of this emergent topic