Faculty Bibliography

Anthracyclines have proved to be one of the most effective chemotherapeutic agents in the treatment of numerous solid tumors and hematologic malignancies in both adult and pediatric patients. Their clinical benefit, however, is sometimes hampered by the development of cardiotoxicity, a process that still remains elusive despite decades of investigation. It has been postulated that anthracycline-induced cardiotoxicity is mediated in part by reactive oxygen species and redox cycling. This article reviews anthracycline cardiotoxicity in terms of historical significance, epidemiology, current detection strategies, prevention strategies, and patient care after anthracycline-based chemotherapy.

The acknowledgement of cardiovascular disease as one of the leading causes of mortality and morbidity among cancer survivors is the cornerstone of the growing field of cardio-oncology. Although standardizing treatment for any given disease is often considered ideal, it is important to recognize the value of pursuing a practical and personalized approach when caring for an oncology patient to minimize the risk of treatment-related cardiotoxicity. We hereby discuss a series of cases that illustrate the ways vascular toxicity can manifest in patients with cancer and, when appropriate, provide scientific evidence that supports clinical decision making. We also raise questions about the complex management of these patients while shedding light on future research in this growing field.

Recent studies have demonstrated that kynurenic acid (KYNA), a compound produced endogenously by the interferon-gamma-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 beta(1) integrin- and beta(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.

Serum- and glucocorticoid-induced kinase 1 is a ubiquitous kinase that regulates diverse processes such as ion transport and cell survival. We report that a single SGK1 mRNA produces isoforms with different N-termini owing to alternative translation initiation. The long isoforms, 49 and 47 kDa, are the most abundant, localize to the ER membrane, exhibit rapid turnover, their expression is decreased by ER stress, activate the epithelial sodium channel (ENaC) and translocate FoxO3a transcriptional factors from the nucleus to the cytoplasm. The short isoforms, 45 and 42 kDa, localize to the cytoplasm and nucleus, exhibit long half-life and phosphorylate glycogen synthase kinase-3beta. The data indicate that activation of Sgk1 in different cellular compartments is key to providing functional specificity to Sgk1 signaling pathways. We conclude that the distinct properties and functional specialization of Sgk1 given by the N-terminus confer versatility of function while maintaining the same core kinase domain.