A M James Shapiro

University of Alberta, Edmonton, Alberta, Canada

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Publications (266)1247.19 Total impact

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    ABSTRACT: There are potential advantages to the low-temperature (-196°C) banking of isolated islets, including the maintenance of viable islets for future research. We therefore assessed the in vitro and in vivo function of islets cryopreserved for nearly 20 years. Human islets were cryopreserved from 1991 to 2001 and thawed between 2012 and 2014. These were characterised by immunostaining, patch-clamp electrophysiology, insulin secretion, transcriptome analysis and transplantation into a streptozotocin (STZ)-induced mouse model of diabetes. The cryopreservation time was 17.6 ± 0.4 years (n = 43). The thawed islets stained positive with dithizone, contained insulin-positive and glucagon-positive cells, and displayed levels of apoptosis and transcriptome profiles similar to those of freshly isolated islets, although their insulin content was lower. The cryopreserved beta cells possessed ion channels and exocytotic responses identical to those of freshly isolated beta cells. Cells from a subset of five donors demonstrated similar perifusion insulin secretion profiles pre- and post-cryopreservation. The transplantation of cryopreserved islets into the diabetic mice improved their glucose tolerance but did not completely normalise their blood glucose levels. Circulating human insulin and insulin-positive grafts were detectable at 10 weeks post-transplantation. We have demonstrated the potential for long-term banking of human islets for research, which could enable the use of tissue from a large number of donors with future technologies to gain new insight into diabetes.
    Diabetologia 05/2015; DOI:10.1007/s00125-015-3598-4 · 6.88 Impact Factor
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    ABSTRACT: Blood group ABH(O) carbohydrate antigens are carried by precursor structures denoted type I-IV chains, creating unique antigen epitopes that may differ in expression between circulating erythrocytes and vascular endothelial cells. Characterization of such differences is invaluable in many clinical settings including transplantation. Monoclonal antibodies were generated and epitope specificities were characterized against chemically synthesized type I-IV ABH and related glycans. Antigen expression was detected on endomyocardial biopsies (n = 50) and spleen (n = 11) by immunohistochemical staining and on erythrocytes by flow cytometry. On vascular endothelial cells of heart and spleen, only type II-based ABH antigens were expressed; type III/IV structures were not detected. Type II-based ABH were expressed on erythrocytes of all blood groups. Group A1 and A2 erythrocytes additionally expressed type III/IV precursors, whereas group B and O erythrocytes did not. Intensity of A/B antigen expression differed among group A1 , A2 , A1 B, A2 B and B erythrocytes. On group A2 erythrocytes, type III H structures were largely un-glycosylated with the terminal "A" sugar α-GalNAc. Together, these studies define qualitative and quantitative differences in ABH antigen expression between erythrocytes and vascular tissues. These expression profiles have important implications that must be considered in clinical settings of ABO-incompatible transplantation when interpreting anti-ABO antibodies measured by hemagglutination assays with reagent erythrocytes. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
    American Journal of Transplantation 05/2015; DOI:10.1111/ajt.13328 · 6.19 Impact Factor
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    ABSTRACT: Transplantation of donor-derived islets into the liver is a successful cellular replacement therapy for individuals with diabetes. However, the hepatic vasculature is not an optimal transplant site for several reasons, including graft attrition and the inability to retrieve or image the islets. Here we describe islet transplantation into a prevascularized, subcutaneous site created by temporary placement of a medically approved vascular access catheter. In mice with streptozotocin (STZ)-induced diabetes, transplantation of ∼500 syngeneic islets into the resulting 'device-less' space reversed diabetes in 91% of mice and maintained normoglycemia for >100 days. The approach was also effective in mice with pre-existing diabetes, in another mouse strain that mounts a more vigorous inflammatory response, and across an allogeneic barrier. These results demonstrate that transient priming of a subcutaneous site supports diabetes-reversing islet transplantation in mouse models without the need for a permanent cell-encapsulation device.
    Nature Biotechnology 04/2015; 33(5). DOI:10.1038/nbt.3211 · 39.08 Impact Factor
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    ABSTRACT: We report a unique first case of benign heterotopic pancreas arising within the proximal hepatic bile duct, containing a focus of intraductal papillary mucinous neoplasm (IPMN). The condition was diagnosed on pathological explant after left hepatic lobectomy with total extrahepatic bile duct excision.
    01/2015; 2015:1-4. DOI:10.1155/2015/816960
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    ABSTRACT: Objective The spectrum of the surgeon-scientist ranges from a clinician who participates in the occasional research collaboration to the predominantly academic scientist with no involvement in clinical work. Training surgeon-scientists can involve resource-intense and lengthy training programs, including Masters and PhD degrees. Despite high enrollment rates in such programs, limited data exist regarding their outcome. The aim of the study was to investigate the scientific productivity of general surgeons who completed Masters or PhD graduate training compared with those who completed clinical residency training only. Design A retrospective cohort study of graduates of general surgery residency was conducted over 2 decades. Data regarding graduation year, dedicated research training type, as well as publication volume, authorship role, and publication impact of surgeons during and after training, were analyzed. Setting The study was conducted in 2 general surgery residency training programs in Canada (University of Alberta and University of Toronto). Participants A cohort of 323 surgeons who completed general surgery residency between 1998 and 2012. Results Overall, 25% of surgeons obtained graduate-level research degrees. Surgeons with graduate degrees were proportionately more likely to participate in research publications both during training (100% of PhD, 82% of Masters, and 38% of clinical-only graduates, p < 0.05) and after training (91% of PhD, 81% of Masters, and 44% of clinical-only graduates, p < 0.05). Among surgeons involved in publication, the individual publication volume and impact of publication were highest among those with PhD degrees, as compared with clinical-only or Masters training. Conclusions The volume and impact of research publication of PhD-trained surgeon-scientists are significantly higher than those having clinical-only and Masters training. The additional 1 or 2 years of training to obtain a PhD over a Masters degree significantly nurtures trainees to hone research skills within a supervised environment and should be encouraged for research-inclined residents.
    Journal of Surgical Education 11/2014; 71(6). DOI:10.1016/j.jsurg.2014.05.007 · 1.39 Impact Factor
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    ABSTRACT: Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (K ATP) channels, sulfonylureas boost insulin release from the pancreatic beta cell mass to restore glucose homeostasis. A limitation of these compounds is the elevated risk of developing hypoglycemia and cardio-vascular disease, both potentially fatal complications. Here, we describe the design and development of a photoswitchable sulfonylurea, JB253, which reversibly and repeatedly blocks K ATP channel activity following exposure to violet-blue light. Using in situ imaging and hormone assays, we further show that JB253 bestows light sensitivity upon rodent and human pancreatic beta cell function. Thus, JB253 enables the optical control of insulin release and may offer a valuable research tool for the interrogation of K ATP channel function in health and T2DM.
    Nature Communications 10/2014; 5:5116. DOI:10.1038/ncomms6116 · 10.74 Impact Factor
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    ABSTRACT: Islet transplantation is an effective means of treating severe type 1 diabetes in patients with life-threatening hypoglycemia. Improvements in glycemic control with correction of HbA1C enhance quality of life irrespective of insulin independence. By antagonizing the Natural Killer Group 2, member D (NKG2D) receptor expression on NK and CD8+ T cells, in combination with blocking CTLA-4 binding sites, we demonstrate a significant delay of graft rejection in islet allotransplant. Anti-NKG2D combined with CTLA-4 Ig (n = 15) results in prolonged allograft survival, with 84.6 ± 10% of the recipients displaying insulin independence compared to controls (n = 10, p < 0.001). The effect of combination therapy on graft survival is superior to treatments alone (CTLA-4 Ig vs. combination p = 0.024, anti-NKG2D vs. combination p < 0.001) indicating an interaction between these pathways. In addition, combination treatment also improves glucose tolerance when compared to controls (n = 10, p = 0.018). Histologically, NKG2D+ cells were significantly decreased within the allograft after 7 days of combination treatment (n = 6, p = 0.029). T cell proliferation was significantly reduced with anti-NKG2D therapy and CD8+ T cell daughter fractions were also significantly decreased with mAb and combination treatment when measured by in vitro mixed lymphocyte reaction (n = 5, p = 0.015, p = 0.005 and p = 0.048). These results demonstrate that inhibition of NKG2D receptors and costimulatory pathways enhance islet allograft survival.
    American Journal of Transplantation 08/2014; 14(10). DOI:10.1111/ajt.12838 · 6.19 Impact Factor
  • A.M. James Shapiro, Camillo Ricordi
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    ABSTRACT: Remarkable progress has occurred in clinical islet transplantation, and with over 1000 patients treated in the past 12 years, this therapy has moved from status of curiosity to realistic treatment for selected patients with type 1 diabetes complicated by refractory glycemic lability. The current chapter discusses indications for the procedure, provides a practical approach to optimal immunosuppressive and adjunctive management, discusses potential risks, long-term outcomes and advances in post-transplant treatment aimed at further moving this treatment closer to a potential cure, or at the very least, more widely available therapy, for diabetes.
    Textbook of Organ Transplantation, 07/2014: pages 1314-1333; , ISBN: 9781118870143
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    ABSTRACT: Human islet allotransplantation for the treatment of type 1 diabetes is in phase III clinical trials in the U.S. and is the standard of care in several other countries. Current islet product release criteria include viability based on cell membrane integrity stains, glucose-stimulated insulin release, and islet equivalent (IE) dose based on counts. However, only a fraction of patients transplanted with islets that meet or exceed these release criteria become insulin independent following 1 transplant. Measurements of islet oxygen consumption rate (OCR) have been reported as highly predictive of transplant outcome in many models.
    Transplantation Proceedings 07/2014; 46(6):1985-8. DOI:10.1016/j.transproceed.2014.06.001 · 0.95 Impact Factor
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    ABSTRACT: Islet transplantation is a recognized treatment option for select patients with type I diabetes mellitus. However, islet infusions from multiple donors are often required to achieve insulin independence. Ideally, insulin independence would be achieved routinely with only a single donor. Identification of factors associated with insulin independence after single-donor islet transplantation may help to select recipient-donor combinations with the highest probability of success.
    Transplantation 06/2014; 98(9). DOI:10.1097/TP.0000000000000217 · 3.78 Impact Factor
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    Boris L. Gala-Lopez, Andrew R. Pepper, A. M. James Shapiro
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    ABSTRACT: The optimal endocrine transplant that should follow a successful kidney transplant in patients with type 1 diabetes is currently open to debate. Ideally, a combined kidney and pancreas transplant is carried out simultaneously from an optimal donor as there is clear immunological benefit. However, when a living donor kidney transplant occurs initially, either a pancreas after kidney or islet after kidney transplant may be considered. A pancreas after kidney transplant carries more surgical risk but provides more robust endocrine reserve compared to the alternative option of islet after kidney transplantation. Furthermore, islet transplantation is not universally available, requires specialized manufacturing facilities, and the costs associated with islet manufacture may not be reimbursable by healthcare. From a patient’s perspective, however, islet after kidney transplantation is a highly attractive option to avoid further surgical risk and recovery. This paper discusses the merits and demerits of these alternative transplant options, and debates both competitive aspects and complementarity. We discuss current outcomes and ongoing clinical trials.
    06/2014; 1(2). DOI:10.1007/s40472-014-0016-7
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, the mechanisms underlying the effects of these polymorphic variants at the level of pancreatic beta cells remain unclear. Here, we show firstly that ADCY5 mRNA expression in islets is lowered by the possession of risk alleles at rs11708067. Next, we demonstrate that ADCY5 is indispensable for coupling glucose, but not GLP-1, to insulin secretion in human islets. Assessed by in situ imaging of recombinant probes, ADCY5 silencing impaired glucose-induced cAMP increases and blocked glucose metabolism towards ATP at concentrations of the sugar >8 mM. However, calcium transient generation and functional connectivity between individual human beta cells were sharply inhibited at all glucose concentrations tested, implying additional, metabolism-independent roles for ADCY5. In contrast, calcium rises were unaffected in ADCY5-depleted islets exposed to GLP-1. Alterations in beta cell ADCY5 expression and impaired glucose signalling thus provide a likely route through which ADCY5 gene polymorphisms influence fasting glucose levels and T2D risk, while exerting more minor effects on incretin action.
    Diabetes 04/2014; DOI:10.2337/db13-1607 · 8.47 Impact Factor
  • Tatsuya Kin, A M James Shapiro
    JOP: Journal of the pancreas 01/2014; 15(1):2063.
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    ABSTRACT: In new generation medical therapies for type 1 diabetes mellitus (DM), cell-based approaches using pancreatic islets have attracted significant attention worldwide. In particular, dispersed islet cells obtained from isolated pancreatic islets have been a valuable source in the cell biology and tissue engineering fields. Our experimental approach to the development of new islet-based DM therapies consisted of creating a monolithic islet cell sheet format using dispersed islet cells. In this experiment, we explored the potential of internationally transporting human islets from Alberta, Canada to Tokyo, Japan and obtaining viable dispersed islet cells. A total of 34 batches of isolated and purified human islets were transported using a commercial air courier service. Prior to shipping, the human islets had been in culture for 0‐108 h at the University of Alberta. The transportation period from Alberta to Tokyo was 2‐5 days. The transported human islet cells were enzymatically dispersed as single cells in Tokyo. The number of single islet cells decreased as the number of transportation days increased. In contrast, cell viability was maintained regardless of the number of transportation days. The preshipment culture time had no effect on the number or viability of single cells dispersed in Tokyo. When dispersed single islet cells were plated on laminin-5-coated temperature-responsive polymer-grafted culture dishes, the cells showed favorable attachment followed by extension as a monolithic format. The present study demonstrated that long-distance transported human islets are a viable cell source for experiments utilizing dispersed human islet cells.
    12/2013; 6(1):33-38. DOI:10.3727/215517913X674243
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    ABSTRACT: Since the initial reporting of the successful reversal of hyperglycemia through the transplantation of pancreatic islets, significant research efforts have been conducted in elucidating the process of revascularization and the influence of engraftment site on graft function and survival. During the isolation process the intrinsic islet vascular networks are destroyed, leading to impaired revascularization after transplant. As a result, in some cases a significant quantity of the beta cell mass transplanted dies acutely following the infusion into the portal vein, the most clinically used site of engraftment. Subsequently, despite the majority of patients achieving insulin independence after transplant, a proportion of them recommence small, supplemental exogenous insulin over time. Herein, this review considers the process of islet revascularization after transplant, its limiting factors, and potential strategies to improve this critical step. Furthermore, we provide a characterization of alternative transplant sites, analyzing the historical evolution and their role towards advancing transplant outcomes in both the experimental and clinical settings.
    Clinical and Developmental Immunology 09/2013; 2013:352315. DOI:10.1155/2013/352315 · 2.93 Impact Factor
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    Oliver J Ziff, A M James Shapiro
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    ABSTRACT: Colonoscopy is widely accepted as the gold-standard screening technique for detecting malignancies in the distal gastrointestinal tract in patients with symptoms suggestive of colon cancer. However, this procedure is not without risk, including colonic perforation. We report a patient who was managed conservatively after colonoscopy induced perforation. Eighteen months after appearing to make a full recovery, he presented with an upper gastrointestinal bleed. Oesophago-gastro-duodenoscopy (OGD) revealed large gastric fundal varices and computed tomography (CT) revealed splenic vein thrombosis. The ensuing left-sided (sinistral) hypertension explains the development of the fundal varices in the presence of normal liver function. At surgery, a persistent abscess cavity was identified and cultures from this site grew Streptococcus anginosus. Curative splenectomy was performed and the patient made a full recovery. We advocate more prompt operative intervention in selected cases of iatrogenic colonic perforation with primary repair to prevent late complications.
    08/2013; 2013:695318. DOI:10.1155/2013/695318
  • Boris Gala-Lopez, Andrew R Pepper, A M James Shapiro
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    ABSTRACT: Islet transplantation is today an accepted modality for treating selected patients with frequent hypoglycemic events or severe glycemic lability. Despite tremendous progress in islet isolation, culture, and preservation, clinical use is still restricted to a limited subset, and lifelong immunosuppression is required. Issues surrounding limited islet revascularization and immune destruction remain. One of the major challenges is to prevent alloreactivity and recurrence of autoimmunity against β-cells. These two hurdles can be effectively reduced by immunosuppressive therapy combining induction and maintenance treatments. The introduction of highly potent and selective biologic agents has significantly reduced the frequency of acute rejection and has prolonged graft survival, while minimizing the complications of this therapeutic scheme. This review will address the most important biological agents used in islet transplantation. We provide a historical perspective of their introduction into clinical practice and their role in current clinical protocols, aiming at improved engraftment efficiency, increased long-term survival, and better overall results of clinical islet transplantation.
    Current Diabetes Reports 08/2013; 13(5). DOI:10.1007/s11892-013-0414-8 · 3.38 Impact Factor

Publication Stats

9k Citations
1,247.19 Total Impact Points

Institutions

  • 1995–2015
    • University of Alberta
      • • Department of Medicine
      • • Department of Surgery
      • • Alberta Diabetes Institute (ADI)
      • • Surgical Medical Research Institute (SMRI)
      Edmonton, Alberta, Canada
  • 2011
    • Fred Hutchinson Cancer Research Center
      • Division of Clinical Research
      Seattle, WA, United States
  • 2007
    • University of Oxford
      Oxford, England, United Kingdom
    • Fujita Health University
      • Department of Surgery
      Toyohashi, Aichi-ken, Japan
  • 2004
    • Kyoto University
      • Graduate School of Medicine / Faculty of Medicine
      Kioto, Kyōto, Japan
  • 1997–2000
    • University of British Columbia - Vancouver
      • Department of Surgery
      Vancouver, British Columbia, Canada