Research Spotlight

Frieder, J., D. Kivelevitch, I. Haugh, I. Watson and A. Menter (2017). “Anti-il-23 and anti-il-17 biologic agents for the treatment of immune-mediated inflammatory conditions.” Clin Pharmacol Ther: 2017 Sep [Epub ahead of print].

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Advancements in the immunopathogenesis of psoriasis have identified interleukin (IL)-23 and IL-17 as fundamental contributors in the immune pathways of the disease. Leveraging these promising therapeutic targets has led to the emergence of a number of anti-IL-23 and -17 biologic agents with the potential to treat multiple conditions with common underlying pathology. The unprecedented clinical efficacy of these agents in the treatment of psoriasis has paved way for their evaluation in diseases such as psoriatic arthritis, Crohn’s disease, rheumatoid arthritis, in addition to other immune-mediated conditions. Here, we will review the IL-23/IL-17 immune pathways and discuss the key clinical and safety data of the anti-IL-23 and anti-IL-17 biologic agents in psoriasis and other immune-mediated diseases.

Choi, S., C. Cui, Y. Luo, S. H. Kim, J. K. Ko, X. Huo, J. Ma, L. W. Fu, R. F. Souza, I. Korichneva and Z. Pan (2017). “Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through orai1.” Faseb j: 2017 Sep [Epub ahead of print].

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Zinc, an essential micronutrient, has a cancer preventive role. Zinc deficiency has been shown to contribute to the progression of esophageal cancer. Orai1, a store-operated Ca2+ entry (SOCE) channel, was previously reported to be highly expressed in tumor tissues removed from patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis, and elevation of its expression contributes to both hyperactive intracellular Ca2+ oscillations and fast cell proliferation in human ESCC cells. However, the molecular basis of cancer preventive functions of zinc and its association with Orai1-mediated cell proliferation remains unknown. The present study shows that zinc supplementation significantly inhibits proliferation of ESCC cell lines and that the effect of zinc is reversible with N,N,N’,N’-Tetrakis (2-pyridylmethyl) ethylenediamine, a specific Zn2+ chelator, whereas nontumorigenic esophageal epithelial cells are significantly less sensitive to zinc treatment. Fluorescence live cell imaging revealed that extracellular Zn2+ exerted rapid inhibitory effects on Orai1-mediated SOCE and on intracellular Ca2+ oscillations in the ESCC cells. Knockdown of Orai1 or expression of Orai1 mutants with compromised zinc binding significantly diminished sensitivity of the cancer cells to zinc treatment in both SOCE and cell proliferation analyses. These data suggest that zinc may inhibit cell proliferation of esophageal cancer cells through Orai1-mediated intracellular Ca2+ oscillations and reveal a possible molecular basis for zinc-induced cancer prevention and Orai1-SOCE signaling pathway in cancer cells.-Choi, S., Cui, C., Luo, Y., Kim, S.-H., Ko, J.-K., Huo, X., Ma, J., Fu, L.-W., Souza, R. F., Korichneva, I., Pan, Z. Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1.

Froehler, M. T., J. L. Saver, O. O. Zaidat, R. Jahan, M. A. Aziz-Sultan, R. P. Klucznick, D. C. Haussen, F. R. Hellinger, Jr., D. R. Yavagal, T. L. Yao, D. S. Liebeskind, A. P. Jadhav, R. Gupta, A. E. Hassan, C. O. Martin, H. Bozorgchami, R. Kaushal, R. G. Nogueira, R. H. Gandhi, E. C. Peterson, S. R. Dashti, C. A. Given, 2nd, B. P. Mehta, V. Deshmukh, S. Starkman, I. Linfante, S. H. McPherson, P. Kvamme, T. J. Grobelny, M. S. Hussain, I. Thacker, N. Vora, P. R. Chen, S. J. Monteith, R. D. Ecker, C. M. Schirmer, E. Sauvageau, A. Abou-Chebl, C. P. Derdeyn, L. Maidan, A. Badruddin, A. H. Siddiqui, T. M. Dumont, A. Alhajeri, M. A. Taqi, K. Asi, J. S. Carpenter, A. Boulos, G. Jindal, A. S. Puri, R. Chitale, E. M. Deshaies, D. H. Robinson, D. F. Kallmes, B. W. Baxter, M. A. Jumaa, P. Sunenshine, A. Q. Majjhoo, J. D. English, S. Suzuki, R. D. Fessler, J. E. Delgado Almandoz, J. C. Martin and N. H. Mueller-Kronast (2017). “Interhospital transfer prior to thrombectomy is associated with delayed treatment and worse outcome in the stratis registry.” Circulation: 2017 Sep [Epub ahead of print].

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Background -Endovascular treatment with mechanical thrombectomy (MT) is beneficial for acute stroke patients suffering a large vessel occlusion, though treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared to direct presentation. Methods -STRATIS was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke due to anterior-circulation large vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without IV-tPA, and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed 1) real-world time metrics of stroke care delivery, 2) outcome differences between direct and transfer patients undergoing MT, and 3) the potential impact of local hospital bypass. Results -A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct vs. 311.5 minutes for transfer patients (p<0.001). Clinical outcomes were better in the direct group with 60.0% (299/498) achieving functional independence, compared to 52.2% (213/408) in the transfer group (odds ratio 1.38, 95%CI 1.06-1.79; p=0.02). Likewise, excellent outcome (modified Rankin Score 0-1) was achieved in 47.4% (236/498) of direct patients vs. 38.0% (155/408) of transfer patients (odds ratio 1.47, 95%CI 1.13-1.92; p=0.005). Mortality did not differ between the two groups (15.1% for direct, 13.7% for transfer; p=0.55). IV-tPA did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that IV-tPA would be delayed by 12 minutes but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then IV-tPA would be delayed by 7 minutes and MT performed 94 minutes earlier. Conclusions -In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large vessel occlusion and direct routing to endovascular-capable centers for severe stroke patients may improve outcomes.

Gottlieb, R. L., T. Sam, S. Y. Wada, J. F. Trotter, S. K. Asrani, B. Lima, S. M. Joseph, G. V. Gonzalez-Stawinski and S. A. Hall (2017). “Rational heart transplant from a hepatitis c donor: New antiviral weapons conquer the trojan horse.” J Card Fail 23(10): 765-767.

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BACKGROUND: Donors with hepatitis C (HCV) viremia are rarely used for orthotopic heart transplantation (HT) owing to post-transplantation risks. New highly effective HCV antivirals may alter the landscape. METHODS: An adult patient unsuitable for bridging mechanical support therapy accepted a heart transplant offer from a donor with HCV viremia. On daily logarithmic rise in HCV viral load and adequate titers to ensure successful genotyping, once daily sofosbuvir (400 mg)-velpatasvir (100 mg) (Epclusa; Gilead) was initiated empirically pending HCV genotype (genotype 3a confirmed after initiation of therapy). RESULTS: We report the kinetics of acute hepatitis C viremia and therapeutic response to treatment with a new pangenotypic antiviral agent after donor-derived acute HCV infection transmitted incidentally with successful cardiac transplantation to an HCV-negative recipient. Prompt resolution of viremia was noted by the 1st week of a 12 week course of antiviral therapy. Sustained virologic remission continued beyond 12 weeks after completion of HCV therapy (SVR-12). CONCLUSIONS: The availability of effective pangenotypic therapy for HCV may expand donor availability. The feasibility of early versus late treatment of HCV remains to be determined through formalized protocols. We hypothesize pharmacoeconomics to be the greatest limitation to widespread availability of this promising tool.

Grimaldi, M., V. Swarup, B. DeVille, J. Sussman, P. Jais, F. Gaita, M. Duytschaever, G. A. Ng, E. Daoud, D. D. Lakkireddy, R. Horton, A. Wickliffe, C. Ellis and L. Geller (2017). “Importance of anticoagulation and postablation silent cerebral lesions: Subanalyses of revolution and remarqable studies.” Pacing Clin Electrophysiol: 2017 Sep [Epub ahead of print].

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BACKGROUND: Silent cerebral lesions (SCLs) are a potential complication of left atrial radiofrequency ablation (RFA) procedures for paroxysmal atrial fibrillation (PAF). We aimed to compare the incidence of SCLs in patients treated with irrigated RFA multielectrode catheters (nMARQ(R) Catheter group) and irrigated focal RFA catheters (NAVISTAR(R) THERMOCOOL(R) Catheter; TC group) after PAF ablation from subpopulation neurological assessment (SNA) cohorts of the REVOLUTION and reMARQable studies. METHODS: Data from SNA cohorts in the prospective, nonrandomized REVOLUTION study (March 2011 to September 2013) and the prospective, randomized, controlled reMARQable study (October 2013 to November 2015) were included. The incidence of SCLs was assessed pre- and post-ablation using magnetic resonance imaging. Neurological deficits were assessed using the National Institutes of Health Stroke Scale, modified Rankin Scale, and Montreal Cognitive Assessment. RESULTS: A total of 37 patients from REVOLUTION and 76 patients from reMARQable were included in the SNA cohort of each study. In the REVOLUTION SNA cohort, the incidence of SCLs was 21.1% (4/19) in the nMARQ(R) Catheter group and 5.9% (1/17) in the TC group. Findings from REVOLUTION helped inform the reMARQable study protocol’s stringent anticoagulation regimen. SCL incidence was subsequently reduced in both groups (nMARQ(R) Catheter, 7.9%; TC, 3.3%). No permanent neurological deficits were observed. CONCLUSION: Adherence to a stringent anticoagulation regimen prior to and during ablation procedures appears to be an important factor in minimizing the risk of SCL.