The Right to Write: Who “Owns” the Case Report?

In this Letter to the Editor, Agrawal et al. debate the conflicts that can arise regarding the authorship of case reports. Like all other medical journals, EJCRIM has zero tolerance for the willful undisclosed re-submission of papers that have already been published elsewhere. However, this may occasionally happen by accident, especially in large healthcare institutions in which multiple teams of physicians may care for a patient throughout their illness

Drugging Chemokine Receptors: Biased CXCR3 Agonists Differentially Regulate Chemotaxis And Inflammation

Drugging Chemokine Receptors: Biased CXCR3 Agonists Differentially Regulate Chemotaxis And Inflammation Jeffrey Smith, MD, PhD Providence Portland Medical Center – Portland, OR Additional Authors: Dylan Eiger, BS; Chia-Feng Tsai, PhD; Lowell Nicholson,MD; Rachel Glenn, BS; Priya Alagesan, BS; Amanda MacLeod, MD; John Jacobs, PhD; Tujin Shi, PhD; Sudarshan Rajagopal, MD,PhD Introduction: G protein-coupled receptors (GPCRs) are the largest class of transmembrane receptors and the target of ~30% of FDA approved drugs. It is now well established that GPCRs can signal through multiple transducers, including classical heterotrimeric G proteins but also GPCR kinases and β-arrestins (1). While these signaling pathways can be activated or blocked by ‘balanced’ agonists or antagonists, they can also be selectively activated in ‘biased’ responses. This new GPCR signaling paradigm of ‘biased signaling’ heralds drugs with increasing efficacy and fewer side effects (2). With over 50 ligands and 20 receptors, biased agonism is prominent within the chemokine system. Here, ligands and receptors bind one another with significant redundancy. For example, the GPCR CXCR3 is expressed on activated T cells and has three established endogenous ligands: CXCL9, CXCL10, and CXCL11 (3,4). Despite its role in inflammation, infectious disease, and cancer (5), no approved drugs target CXCR3. The purpose of my research is to measure biased signaling at CXCR3 and assess the therapeutic potential of selectively targeting certain CXCR3 signaling pathways with biased agonists. Methods: Utilizing state-of-the-art transcriptomic and phosphoproteomic analyses (6), we show vast differences in CXCR3-regulated intracellular signaling. Responses were compared between vehicle, CXCL9, CXCL10, or CXCL11 treatment assessing \u3e5,000 unique phosphopeptides and \u3e13,000 genes. Biased responses were assessed in both immortalized cell lines and primary human T cells. Utilizing various second messenger reporter systems and bioluminescence resonance energy transfer assays (2,3), we identify an important proximal GPCR signaling pathway, β-arrestin, and demonstrate that CXCL11 acts as a β-arrestin-biased agonist at CXCR3. Furthermore, we screened small molecules to identify a G protein-biased and a β-arrestin-biased small molecule agonist of CXCR3. We then utilized these small molecules to measure physiological readouts of inflammation and chemotaxis in both mice and patients. Results: Endogenous chemokines of CXCR3 activate divergent intracellular signaling pathways. Using both chemokines and small molecules, we show that β-arrestin pathway signaling through CXCR3 is necessary for full efficacy chemotaxis of activated T cells in both mice and patients (p\u3c0.05). In addition, a β-arrestin-biased small molecule potentiated the cutaneous inflammatory responses in wild-type mice (p\u3c0.05), but not in either β-arrestin KO (p=0.77) or CXCR3 KO (p=0.72) mice, indicating both CXCR3 and β-arrestin dependence in T cell mediated inflammatory responses. Conclusions: Here we show that CXCL9, CXCL10, and CXCL11 activate distinct CXCR3 intracellular signaling pathways with divergent physiological effects. We clearly demonstrate that the multiple CXCR3 chemokines, CXCL9, CXCL10, and CXCL11, are not redundant in their CXCR3 signaling properties. We show that non-canonical β-arrestin signaling is necessary for certain CXCR3-regulated inflammatory responses and for chemotaxis in both mice and patients. These data strongly suggest that CXCR3 biased agonists have therapeutic promise to treat inflammatory conditions. References Smith, J.S. and Rajagopal, S., 2016. The β-arrestins: multifunctional regulators of G protein-coupled receptors. Journal of Biological Chemistry, 291(17), pp.8969-8977. Smith, J.S., Lefkowitz, R.J. and Rajagopal, S., 2018. Biased signaling: from simple switches to allosteric microprocessors. Nature Reviews Drug Discovery, 17(4), p.243. Smith, J.S., Alagesan, P., Desai, N.K., Pack, T.F., Wu, J.H., Inoue, A., Freedman, N.J. and Rajagopal, S., 2017. CXC motif chemokine receptor 3 splice variants differentially activate beta-arrestins to regulate downstream signaling pathways. Molecular pharmacology, 92(2), pp.136-150. Smith, J.S., Nicholson, L.T., Suwanpradid, J., Glenn, R.A., Knape, N.M., Alagesan, P., Gundry, J.N., Wehrman, T.S., Atwater, A.R., Gunn, M.D. MacLeod, A.S., and Rajagopal, S., 2018. Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. Sci. Signal., 11(555), p.eaaq1075. Chow, M.T., Ozga, A.J., Servis, R.L., Frederick, D.T., Lo, J.A., Fisher, D.E., Freeman, G.J., Boland, G.M. and Luster, A.D., 2019. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity. Tsai, C.F.*, Smith, J.S.*, Krajewski, K., Zhao, R., Moghieb, A.M., Nicora, C.D., Xiong, X., Moore, R.J., Liu, T., Smith, R.D. and Jacobs, J.M., 2019. TMT labeling facilitates RPLC-MS analysis of hydrophilic phosphopeptides. Analytical chemistry.https://digitalcommons.psjhealth.org/ppmc_internal/1003/thumbnail.jp

Factors and outcomes associated with improved left ventricular systolic function in patients with cardiomyopathy

Background: Many patients in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) had a significant improvement (> 10%) in the left ventricular ejection fraction (LVEF) during the course of the study, but the factors and outcomes associated with such improvement are uncertain. Methods: We examined factors and rates of mortality, cause-specific mortality, and implantable cardioverter defibrillator (ICD) shocks associated with improvement in LVEF by analyzing patients in the SCD-HeFT who were randomized to placebo or an ICD and who had an LVEF checked during follow-up. Results: During a median follow-up of 3.99 years, of 837 patients who had at least two follow-up LVEF measurements, 276 (33%) patients had > 10% improvement in LVEF and 561 (67%) patients had no significant change in LVEF. Factors significantly associated with LVEF improvement included female sex, white race, history of hypertension, a QRS duration < 120 ms, and beta-blocker use. Improvement in LVEF was associated with a significant improvement in survival. There was no significant association between improvement in LVEF and cause-specific death, but there was a significant association between improvement in LVEF and reduced risk of receiving appropriate ICD shocks. Conclusions: About a third of patients in this analysis, who were randomized to placebo or an ICD in SCD-HeFT, had a significant improvement in LVEF during follow-up; improvement in LVEF was associated with improved survival but not with cause-specific death, and with decreased likelihood of receiving appropriate ICD shocks

Biased agonists of the chemokine receptor CXCR3 differentially signal through Gαi:β-arrestin complexes.

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and signal through the proximal effectors, G proteins and β-arrestins, to influence nearly every biological process. The G protein and β-arrestin signaling pathways have largely been considered separable; however, direct interactions between Gα proteins and β-arrestins have been described that appear to be part of a distinct GPCR signaling pathway. Within these complexes, Gαi/o, but not other Gα protein subtypes, directly interacts with β-arrestin, regardless of the canonical Gα protein that is coupled to the GPCR. Here, we report that the endogenous biased chemokine agonists of CXCR3 (CXCL9, CXCL10, and CXCL11), together with two small-molecule biased agonists, differentially formed Gαi:β-arrestin complexes. Formation of the Gαi:β-arrestin complexes did not correlate well with either G protein activation or β-arrestin recruitment. β-arrestin biosensors demonstrated that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We also found that Gαi:β-arrestin complexes did not couple to the mitogen-activated protein kinase ERK, as is observed with other receptors such as the V2 vasopressin receptor, but did couple with the clathrin adaptor protein AP-2, which suggests context-dependent signaling by these complexes. These findings reinforce the notion that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of the spectrum of biased agonism