Research Spotlight

Saravanan, P. B., S. Vasu, G. Yoshimatsu, C. M. Darden, X. Wang, J. Gu, M. C. Lawrence and B. Naziruddin (2019). “Differential expression and release of exosomal miRNAs by human islets under inflammatory and hypoxic stress.” Diabetologia Aug 1. [Epub ahead of print].

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AIMS/HYPOTHESIS: Pancreatic islets produce non-coding microRNAs (miRNAs) that regulate islet cell function and survival. Our earlier investigations revealed that human islets undergo significant damage due to various types of stresses following transplantation and release miRNAs. Here, we sought to identify and validate exosomal miRNAs (exo-miRNAs) produced by human islets under conditions of cellular stress, preceding loss of cell function and death. We also aimed to identify islet stress signalling pathways targeted by exo-miRNAs to elucidate potential regulatory roles in islet cell stress. METHODS: Human islets were subjected to proinflammatory cytokine and hypoxic cell stress and miRNA from exosomes was isolated for RNA sequencing and analysis. Stress-induced exo-miRNAs were evaluated for kinetics of expression and release by intact islets for up to 48 h exposure to cytokines and hypoxia. A subset of stress-induced exo-miRNAs were assessed for recovery and detection as biomarkers of islet cell stress in a diabetic nude mouse xenotransplant model and in patients undergoing total pancreatectomy with islet auto-transplantation (TPIAT). Genes and signalling pathways targeted by stress-induced exo-miRNAs were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and direct interactions of miRNAs with downstream signalling targets were validated in human islet cells using the miRNA Tests for Read Analysis and Prediction (MirTrap) system. RESULTS: Global exo-miRNA sequencing revealed that 879 miRNA species were released from human islets and 190 islet exo-miRNAs were differentially expressed in response to proinflammatory cytokines, hypoxia or both. Release of exo-miRNAs hsa-miR-29b-3p and hsa-miR-216a-5p was detected within 6 h of exposure to cytokines and hypoxia. The remaining subset of stress-induced exo-miRNAs, including hsa-miR-148a-3p and islet cell damage marker hsa-miR-375, showed delayed release at 24-48 h, correlating with apoptosis and cell death. Stress and damage exo-miRNAs were significantly elevated in the circulation in human-to-mouse xenotransplant models and in human transplant recipients. Elevated blood exo-miRNAs negatively correlated with post-transplant islet function based on comparisons of stress and damage exo-miRNA indices with Secretory Unit of Islet Transplant Objects (SUITO) indices. KEGG analysis and further validation of exo-miRNA targets by MirTrap analysis revealed significant enrichment of islet mRNAs involved in phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signalling pathways. CONCLUSIONS/INTERPRETATION: The study identifies exo-miRNAs differentially expressed and released by islets in response to damage and stress. These exo-miRNAs could serve as potential biomarkers for assessing islet damage and predicting outcomes in islet transplantation. Notably, exo-miRNAs 29b-3p and 216a-5p could be detected in islets prior to damage-released miRNAs and indicators of cellular apoptosis and death. Thus, these stress-induced exo-miRNAs may have potential diagnostic value for detecting early islet stress prior to progressive loss of islet cell mass and function. Further investigations are warranted to investigate the utility of these exo-miRNAs as early indicators of islet cell stress during prediabetic conditions.

Roberts, W. C., A. Y. Lee, S. R. Lander, C. S. Roberts and B. L. Hamman (2019). “Libman-Sacks Endocarditis Involving a Bioprosthesis in the Aortic Valve Position in Systemic Lupus Erythematosus.” Am J Cardiol 124(2): 316-318.

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Described herein is a 39-year-old man with systemic lupus erythematosus not receiving corticosteroid therapy who developed Libman-Sacks endocarditis causing stenosis of a bioprosthesis in the aortic valve position.

Reichard, C. A., Y. A. Nyame, D. Sundi, J. Tosoian, L. Wilkins, R. Alam, M. F. Achim, X. Wang, A. J. Stephenson, E. A. Klein, A. E. Ross, J. W. Davis and B. F. Chapin (2019). “Does time from diagnosis to treatment of high- or very-high-risk prostate cancer affect outcome?” BJU Int 124(2): 282-289.

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OBJECTIVE: To determine whether time from diagnosis to treatment impacted outcomes in a multicentre cohort of high- and very-high-risk (VHR) patients with prostate cancer undergoing radical prostatectomy (RP). PATIENTS AND METHODS: In all, 1392 patients from three tertiary centres who underwent RP for either high-risk or VHR disease, from 2005 to 2015, were identified. The cohort was divided into tertiles based on time from diagnostic biopsy to RP. Cumulative incidence of biochemical recurrence (BCR), metastasis, and prostate cancer-specific mortality (PCSM) were calculated for each tertile. The Kaplan-Meier method was used to evaluate for differences in all-cause mortality (ACM) amongst tertiles. Competing risks regression models, as well as Cox proportional hazards regression models, were fitted to assess the association between time-to-event outcomes and patient characteristics. RESULTS: The median (interquartile range [IQR]) time from biopsy to RP was 68 (50-94) days. The median (IQR) follow-up was 31 (12.1-55.7) months. The cumulative incidence of BCR (P = 0.14), metastasis (P = 0.15), and PCSM (P = 0.69) did not differ amongst time-to-treatment tertiles of VHR patients. Also, Kaplan-Meier estimates of ACM (P = 0.53) did not differ amongst time-to-treatment tertiles. Similarly, BCR, metastasis, PCSM, and ACM did not significantly differ amongst time-to-treatment tertiles in multivariable modelling. CONCLUSION: In this pooled meta-dataset of patients with high-risk or VHR prostate cancer, time from diagnosis to RP did not appear to significantly contribute to differences in clinical outcomes. This finding supports the safety of enrollment of such patients into neoadjuvant clinical trials.

Ramsay, M. A. (2019). “Postoperative Pain Management: Is the Surgical Team Approach Finally Getting It Right?” Ann Surg 270(2): 209-210.

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The concerns that many physicians have with the management of epidural anesthesia for open liver surgery include the increased risk of a neuraxial hematoma resulting from a postoperative coagulopathy. In some centers this has resulted in the reluctance to using the modality and in others to withholding of venous thromboembolism (VTE) prophylaxis until the prothrombin time-derived international normalized ratio (PT-INR) has returned to less than 1.5. This, in some centers leads to the administration of fresh frozen plasma to correct the PT-INR. A review of the National Surgical Quality Improvement Program data for extended hepatic resections, the VTE rate has been reported as high as 5.8%. This exceeds the rate for most major abdominal surgeries including colectomy. It has now been well established that many of these patients with an increased PT-INR have normal or increased coagulable states and do need VTE protection. The success of epidural anesthesia to provide optimal pain management for open liver surgery requires the formation of a surgical team. An experienced team approach leads to greater success, including the reduction of complications, early mobilization and discharge home, and thereby increased patient safety. Postoperative analgesia still continues to be inadequately managed in many centers. However, Kehlet and Wilmore, have developed enhanced recovery pathways (ERPs) after surgery that have resulted in early mobility and discharge, good pain management with multimodal analgesia and reduced or opioid-free therapy, and reduced morbidity and mortality. Protocols that promote ERPs have become more frequently used and the evidence to support these protocols is getting stronger. Randomized clinical trials have shown that ERPs are effective as long as each member of the perioperative team is well versed in the protocols, carries them out effectively, and the data are collected and monitored. These protocols are not just reliant on 1 anesthetic technique but rather rely on the experience of all team participants to be expert in the techniques used. The team must consist of the surgeon, anesthesiologist, perioperative nurses, pharmacy staff, physical and respiratory therapists, and the patient, together with a coordinator who collects the data and helps to demonstrate what is or is not working. This will enable the team and the hospital to track progress, provide education, and more importantly to learn where they are having success and what areas need improvement. The surgical team should have regular meetings to discuss patient management. (Excerpt from text, p. 209; no abstract available.)

Rajiah, P., Y. Tanabe, S. Partovi and A. Moore (2019). “State of the art: utility of multi-energy CT in the evaluation of pulmonary vasculature.” Int J Cardiovasc Imaging 35(8): 1509-1524.

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Multi-energy computed tomography (MECT) refers to acquisition of CT data at multiple energy levels (typically two levels) using different technologies such as dual-source, dual-layer and rapid tube voltage switching. In addition to conventional/routine diagnostic images, MECT provides additional image sets including iodine maps, virtual non-contrast images, and virtual monoenergetic images. These image sets provide tissue/material characterization beyond what is possible with conventional CT. MECT provides invaluable additional information in the evaluation of pulmonary vasculature, primarily by the assessment of pulmonary perfusion. This functional information provided by the MECT is complementary to the morphological information from a conventional CT angiography. In this article, we review the technique and applications of MECT in the evaluation of pulmonary vasculature.