Research Spotlight

He, L., S. Wu, Q. Hao, E. M. Dioum, K. Zhang, C. Zhang, W. Li, W. Zhang, Y. Zhang, J. Zhou, Z. Pang, L. Zhao, X. Ma, M. Li and Q. Zhang (2017). “Local blockage of self-sustainable erythropoietin signaling suppresses tumor progression in non-small cell lung cancer.” Oncotarget 8(47): 82352-82365.

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Functional significance of co-expressed erythropoietin (EPO) and its receptor (EPOR) in non-small cell lung cancer (NSCLC) had been under debate. In this study, co-overexpression of EPO/EPOR was confirmed to be positively associated with poor survival in NSCLC. The serum EPO in 14 of 35 enrolled NSCLC patients were found elevated significantly and decreased to normal level after tumor resection. With primary tumor cell culture and patient-derived tumor xenograft (PDX) mouse model, the EPO secretion from the tumors of these 14 patients was verified. Then, we proved the patient derived serum EPO was functionally active and had growth promotion effect in EPO/EPOR overexpressed but not in EPO/EPOR under-expressed NSCLC cells. We also illustrated EPO promoted NSCLC cell proliferation through an EPOR/Jak2/Stat5a/cyclinD1 pathway. In xenograft mouse model, we proved local application of EPO neutralizing antibody and short hairpin RNA (shRNA) against EPOR effectively inhibited the growth of EPO/EPOR overexpressed NSCLC cells and prolonged survivals of the mice. Finally, EPO/EPOR/Jak2/Stat5a/cyclinD1 signaling was found to be a mediator of hypoxia induced growth in EPO/EPOR overexpressed NSCLC. Our results illustrated a subgroup of NSCLC adapt to hypoxia through self-sustainable EPO/EPOR signaling and suggest local blockage of EPO/EPOR as potential therapeutic method in this distinct NSCLC population.

Bixler, G. M., G. C. Powers, R. H. Clark, M. W. Walker and V. N. Tolia (2017). “Changes in the diagnosis and management of patent ductus arteriosus from 2006 to 2015 in united states neonatal intensive care units.” J Pediatr 189: 105-112.

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OBJECTIVE: To identify changes in the diagnosis, pharmacotherapy, and surgical ligation of patent ductus arteriosus (PDAs) in infants born premature and report on temporal changes in mortality and morbidity from a large volume of neonatal intensive care units (NICUs) in the US. STUDY DESIGN: We queried the Pediatrix Clinical Data Warehouse for all inborn infants without major anomalies born between 23 and 30 weeks’ gestation from 2006 to 2015 for a diagnosis of PDA, use of indomethacin or ibuprofen, history of ductal ligation, mortality, and major morbidities. RESULTS: There were 829 091 infants entered in the Clinical Data Warehouse; 61 520 infants from 280 NICUs met our inclusion criteria. The diagnosis of PDA declined from 51% to 38% (P < .001), use of indomethacin or ibuprofen decreased from 32% to 18%, and PDA ligation decreased from 8.4% to 2.9% (both P < .001). During the study period, mortality decreased with no increase in any measured morbidity. Of the 163 sites with data for both periods, 128 (79%) showed a decrease in the diagnosis of PDA, and 132 (81%) showed a decrease in the use indomethacin and/or ibuprofen when 2011-2015 was compared with 2006-2010. Of 103 sites with at least 1 PDA ligation, 85 (83%) showed a decrease in PDA ligation in a similar comparison. CONCLUSIONS: In this large population of infants <30 weeks' gestation from 280 NICUs across the US, there were significant decreases in the diagnosis and treatment of the PDA. Although there was no evidence of increased morbidities, it remains uncertain how these changes may directly affect infant outcomes.

Chang, C. A., M. C. Lawrence and B. Naziruddin (2017). “Current issues in allogeneic islet transplantation.” Curr Opin Organ Transplant 22(5): 437-443.

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PURPOSE OF REVIEW: Transplantation of allogenic pancreatic islets is a minimally invasive treatment option to control severe hypoglycemia and dependence on exogenous insulin among type 1 diabetes (T1D) patients. This overview summarizes the current issues and progress in islet transplantation outcomes and research. RECENT FINDINGS: Several clinical trials from North America and other countries have documented the safety and efficacy of clinical islet transplantation for T1D patients with impaired hypoglycemia awareness. A recently completed phase 3 clinical trial allows centres in the United States to apply for a Food and Drug Administration Biologics License for the procedure. Introduction of anti-inflammatory drugs along with T-cell depleting induction therapy has significantly improved long-term function of transplanted islets. Research into islet biomarkers, immunosuppression, extrahepatic transplant sites and potential alternative beta cell sources is driving further progress. SUMMARY: Allogeneic islet transplantation has vastly improved over the past two decades. Success in restoration of glycemic control and hypoglycemic awareness after islet transplantation has been further highlighted by clinical trials. However, lack of effective strategies to maintain long-term islet function and insufficient sources of donor tissue still impose limitations to the widespread use of islet transplantation. In the United States, wide adoption of this technology still awaits regulatory approval and, importantly, a financial mechanism to support the use of this technology.

Chiruvolu, A., H. Qin, E. T. Nguyen and R. W. Inzer (2017). “The effect of delayed cord clamping on moderate and early late-preterm infants.” Am J Perinatol: 2017 Sep [Epub ahead of print].

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Objective: This study aims to evaluate the clinical consequences of protocol-driven delayed umbilical cord clamping (DCC) implementation in moderate and early latepreterm (MELP) infants born between 320/7 and 346/7 weeks gestation. Study Design: We conducted a prospective cohort study with a historic control cohort comparison. The prospective study period was 1 year when DCC was performed for 60 seconds duration (DCC cohort, n ¼ 106). The study period for historic control cohort with no DCC was also 1 year before DCC implementation (historic cohort, n ¼ 137). Results: The mean hematocrit at birth was significantly higher in the DCC cohortcompared with the historic cohort (49.1 14.9 vs. 45.7 15.7; p ¼ 0.01). Fewer infants in the DCC cohort were admitted to neonatal intensive care unit (NICU) on respiratory support compared with the historic cohort (17.9 vs. 29.9%; p ¼ 0.04). The incidence of respiratory distress syndrome was significantly lower in the DCC cohort compared with the historic cohort (2.8 vs. 14.6%; p ¼ 0.002). There were no differences in the incidence of phototherapy or NICU length of stay (LOS) between groups. Conclusion: In MELP infants, DCC was associated with increased hematocrit and better respiratory transition at birth. DCC was not associated with increased phototherapy or NICU LOS.

Filardo, G., B. D. Pollock, B. da Graca, T. K. Phan, D. M. Sass, G. Ailawadi, V. Thourani and R. Damiano (2017). “Underestimation of the incidence of new-onset post-coronary artery bypass grafting atrial fibrillation and its impact on 30-day mortality.” J Thorac Cardiovasc Surg 154(4): 1260-1266.

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OBJECTIVE: Inconsistent definitions of atrial fibrillation after coronary artery bypass grafting have caused uncertainty about its incidence and risk. We examined the extent to which limiting the definition to post-coronary artery bypass grafting atrial fibrillation events requiring treatment underestimates its incidence and impact on 30-day mortality. METHODS: We assessed in-hospital atrial fibrillation and 30-day mortality in 9268 consecutive patients without preoperative atrial fibrillation who underwent isolated coronary artery bypass grafting at 5 US hospitals (2004-2010). Patients who experienced 1 or more episode of post-coronary artery bypass grafting atrial fibrillation detected via continuous in-hospital electrocardiogram/telemetry monitoring were divided into those for whom Society of Thoracic Surgeons data (applying the definition “atrial fibrillation/flutter requiring treatment”) also indicated atrial fibrillation versus those for whom it did not. Risk-adjusted 30-day mortality was compared between these 2 groups and with patients without post-coronary artery bypass grafting atrial fibrillation. RESULTS: Risk-adjusted incidence of post-coronary artery bypass grafting atrial fibrillation incidence was 33.4% (27.0% recorded in Society of Thoracic Surgeons data, 6.4% missed). Patients with post-coronary artery bypass grafting atrial fibrillation missed by Society of Thoracic Surgeons data had a significantly greater risk of 30-day mortality (odds ratio, 2.08, 95% confidence interval, 1.17-3.69) than those captured. By applying the significant underestimation of post-coronary artery bypass grafting atrial fibrillation incidence we observed (odds ratio [Society of Thoracic Surgeons vs missed], 0.78; 95% confidence interval, 0.72-0.83) to the approximately 150,000 patients undergoing isolated coronary artery bypass grafting in the United States each year estimates this increased risk of mortality is carried by 9600 patients (95% confidence interval, 9420-9780) annually. CONCLUSIONS: Defining post-coronary artery bypass grafting atrial fibrillation as episodes requiring treatment significantly underestimates incidence and misses patients at a significantly increased risk for mortality. Further research is needed to determine whether this increased risk carries over into long-term outcomes and whether it is mediated by differences in treatment and management.