Recent studies have demonstrated that kynurenic acid (KYNA), a compound produced endogenously by the interferon-␥-induced degradation of tryptophan by indoleamine 2,3-dioxygenase, activates the previously orphaned G protein-coupled receptor, GPR35. This receptor is expressed in immune tissues, although its potential function in immunomodulation remains to be explored. We determined that GPR35 was most highly expressed on human peripheral monocytes. In an in vitro vascular flow model, KYNA triggered the firm arrest of monocytes to both fibronectin and ICAM-1, via ␤ 1 integrin-and ␤ 2 integrin-mediated mechanisms, respectively. Incubation of monocytes with pertussis toxin prior to use in flow experiments significantly reduced the KYNA-induced monocyte adhesion, suggesting that adhesion is triggered by a G i -mediated process. Furthermore, KYNA-triggered adhesion of monocytic cells was reduced by short hairpin RNA-mediated silencing of GPR35. Although GPR35 is expressed at slightly lower levels on neutrophils, KYNA induced firm adhesion of these cells to an ICAM-1-expressing monolayer as well. KYNA also elicited neutrophil shedding of surface L-selectin, another indicator of leukocyte activation. Taken together, these data suggest that KYNA could be an important early mediator of leukocyte recruitment.Leukocyte recruitment into tissue compartments is a tightly regulated process orchestrated by chemokines (1). Chemokines convert leukocyte rolling or tethering on the vascular endothelium to firm arrest via the activation of leukocyte surface integrins (2, 3). As chemoattractants, chemokines subsequently play an important role in the directional migration of leukocytes through tissues.Chemoattractant receptors are a subtype of G protein-coupled receptors (GPCRs), 3 one of the largest known families of human proteins. Chemoattractant receptors bind a variety of agonists, including proteins such as interleukin-8 (IL-8, CXCL8) (4) and monocyte chemoattractant protein-1 (MCP-1, CCL2) (5), small peptides such as fMLP (6), as well as bioactive lipids including leukotriene B 4 (7). As such, chemoattractant receptors mirror the entire family of GPCRs, which can be activated by ligands ranging in size from metabolites to large proteins (8).Because GPCRs serve as targets for therapeutic intervention, considerable activity has gone into the identification of both putative GPCR genes and the ligands for the resulting receptors (8). Recently, the tryptophan metabolite kynurenic acid (KYNA) was identified as an agonist for the previously "orphaned" receptor GPR35. KYNA was shown to elicit intracellular release of Ca 2ϩ in Chinese hamster ovary cells in which GPR35 was co-expressed in the context of a chimeric G protein signaling apparatus. HEK93 cells transfected with GPR35 and G qo proteins accumulated inositol phosphate upon exposure to KYNA. KYNA also induced internalization of GPR35 on HeLa cells, which is commonly seen following the activation of GPRs with agonists such as chemokines (9).KYNA is produced endogenously as a resu...

The innovative development of cancer therapies has led to an unprecedented improvement in survival outcomes and a wide array of treatment-related toxicities, including those that are cardiovascular in nature. Aging of the population further adds to the number of patients being treated for cancer, especially those with comorbidities. Such pre-existing and developing cardiovascular diseases pose some of the greatest risks of morbidity and mortality in patients with cancer. Addressing the complex cardiovascular needs of these patients has become increasingly important, resulting in an imperative for an intersecting discipline: cardio-oncology. Over the past decade, there has been a remarkable rise of cardio-oncology clinics and service lines. This development, however, has occurred in a vacuum of standard practice and training guidelines, although these are being actively pursued. In this council perspective document, the authors delineate the scope of practice in cardio-oncology and the proposed training requirements, as well as the necessary core competencies. This document also serves as a roadmap toward confirming cardio-oncology as a subspecialty in medi

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardiooncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.