Baylor Scott and White Research Institute

Kumano, K., M. C. Lawrence, N. Onaca, M. F. Levy and B. Naziruddin (2019). “Successful allogeneic islet transplantation after total pancreatectomy with islet autotransplantation to restore normoglycemia: a case report.” Acta Diabetol Nov 26. [Epub ahead of print].

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Total pancreatectomy with islet autotransplantation (TPIAT) has been recognized as a treatment option for patients with refractory chronic pancreatitis (CP) who experience debilitating pain and impaired quality of life. Restoring as much endocrine function as possible is crucial to prevent postsurgical diabetes and reduce the risk of brittle diabetes and hypoglycemic unawareness. However, obtaining sufficient islet yield from CP pancreata remains a technical challenge due to chronic inflammation, which damages the morphology of the pancreas. A previous report showed that approximately 20% of TPIAT patients receive a low islet yield (< 2500 IEQ/kg), and those patients have poor metabolic outcomes compared to patients who receive a high islet yield (> 5000 IEQ/kg). Therefore, salvage therapy is considered for CP patients who develop postsurgical brittle diabetes. Whole-pancreas allogeneic transplantation after TP has been reported to restore both endocrine function and exocrine function. To date, there has been one case report of islet allogeneic transplantation after TP in acute pancreatitis, as islet allogeneic transplantation has largely been restricted to type 1 diabetic patients with severe hypoglycemia and glycemic lability. Thus, it remains unknown if islet allogeneic transplantation could be used as salvage therapy to restore endocrine function after TPIAT following islet graft dysfunction. Here, we report a novel case of allogeneic islet transplantation in a CP patient who had postsurgical diabetes and multiple episodes of hypoglycemic unawareness after TPIAT. (Excerpt from text, p. 1; no abstract available.)

Cedars, A., L. Burchill, S. L. Roche, J. Menachem, K. Axsom and K. Tecson (2019). “Impact of durable ventricular assist devices on post-transplant outcomes in adults with congenital heart disease.” Congenit Heart Dis Oct 18. [Epub ahead of print].

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BACKGROUND: There are no published data on post-transplant outcomes in durable ventricular assist device (VAD)-supported adult congenital heart disease (ACHD) patients. METHODS: We compared post-transplant outcomes in VAD-supported vs non-VAD-supported ACHD patients using the Scientific Registry of Transplant Recipients. RESULTS: At 1 year, there was no difference in post-transplant mortality between VAD-supported (12 patients) and non-VAD-supported (671 patients) ACHD patients. CONCLUSIONS: In appropriate ACHD patients, VAD use as a bridge to transplant is a reasonable strategy.

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 62(10): 1901-1914.

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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.

Culp, B. L., J. W. Roden-Foreman, E. V. Thomas, E. E. McShan, M. M. Bennett, K. R. Martin, M. B. Powers, M. L. Foreman, L. B. Petrey and A. M. Warren (2019). “Better with age? A comparison of geriatric and non-geriatric trauma patients’ psychological outcomes 6 months post-injury.” Cognitive Behaviour Therapy 48(5): 406-418.

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This is the first study to compare both physical and psychological outcomes in geriatric and non-geriatric patients (n = 268) at baseline and 6 months post-trauma. Demographic, clinical, and psychological data, including screens for alcohol use, depressive symptoms, and post-traumatic stress symptoms (PTSS) were collected from 67 geriatric patients (70.7 +/- 8.0 years) and 201 non-geriatric patients (40.2 +/- 12.8 years) admitted to a Level I trauma center for >/= 24 h. Geriatric patients were significantly less likely to screen positive for alcohol use at baseline, and depression, PTSS, and alcohol use at follow-up. When not controlling for discharge to rehabilitation or nursing facility, geriatric patients had significantly lower odds of alcohol use at follow-up. There was no significant difference in injury severity, resilience, or pre-trauma psychological status between the two groups. Results indicate that geriatric trauma patients fare better than their younger counterparts at 6 months post-trauma on measures of alcohol use, depression, and PTSS. Screenings and interventions for both age groups could improve psychological health post-trauma, but younger patients may require additional attention.

Chan, J., X. Wang, J. A. Turner, N. E. Baldwin and J. Gu (2019). “Breaking the paradigm: Dr Insight empowers signature-free, enhanced drug repurposing.” Bioinformatics 35(16): 2818-2826.

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MOTIVATION: Transcriptome-based computational drug repurposing has attracted considerable interest by bringing about faster and more cost-effective drug discovery. Nevertheless, key limitations of the current drug connectivity-mapping paradigm have been long overlooked, including the lack of effective means to determine optimal query gene signatures. RESULTS: The novel approach Dr Insight implements a frame-breaking statistical model for the ‘hand-shake’ between disease and drug data. The genome-wide screening of concordantly expressed genes (CEGs) eliminates the need for subjective selection of query signatures, added to eliciting better proxy for potential disease-specific drug targets. Extensive comparisons on simulated and real cancer datasets have validated the superior performance of Dr Insight over several popular drug-repurposing methods to detect known cancer drugs and drug-target interactions. A proof-of-concept trial using the TCGA breast cancer dataset demonstrates the application of Dr Insight for a comprehensive analysis, from redirection of drug therapies, to a systematic construction of disease-specific drug-target networks. AVAILABILITY AND IMPLEMENTATION: Dr Insight R package is available at https://cran.r-project.org/web/packages/DrInsight/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.