A M J Shapiro

• MD PhD FRCS(Eng) FRCSC MSM FRSC
• University of Alberta

Background: Despite ongoing efforts to improve the pancreaticoduodenectomy technique and perioperative care, surgical site infection (SSI) remains a contributor to morbidity. Efforts to reduce SSI include the use of negative pressure wound therapy (NPWT), but studies and meta-analyses have been met with conflicting results. We aimed to provide an u...

The matricellular protein Fibulin-5 (Fbln5) is a secreted protein that is essential for elastic fiber formation, and pancreatic islets are usually surrounded by the extracellular matrix (ECM), which includes elastic fibers. However, much uncertainty remains regarding the function of the ECM and its components in β-cells. Here, we describe the role...

Background Recurrent disease after liver transplant is well recognized for many diseases. Metabolic dysfunction–associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are leading indications for liver transplant, and there is scarce knowledge about recurrence-related end outcomes such as retransplant and mortality. This project aims...

Background Total pancreatectomy (TP) offers a surgical option for refractory pancreatitis, yet confers substantial long-term morbidity associated with resultant diabetes. While total pancreatectomy with islet autotransplantation (TPIAT) offers an intuitive solution, data evaluating its safety have been limited to single-center studies. The aim of t...

Backgrounds/Aims: Pancreatic texture is difficult to predict without palpation. Soft pancreatic texture is associated with increased post-operative complications, including postoperative pancreatic fistula (POPF), cardiac, and respiratory complications. We aimed to develop a calculator predicting pancreatic texture using patient factors and to illu...

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell function. Here, we show that an lncRNA-transcribed antisense to Pax6, annotated as Pax6os1/PAX6-AS1, was upregulated by high glucose concentrations in human as well as murine beta cell lines and islets. Elevated expression was also observed in islets from mice on a high-...

Background/Objectives: Efforts to preoperatively risk stratify and optimize patients before liver resection allow for improvements in postoperative outcomes, with hypoalbuminemia being increasingly researched as a surrogate for nutrition, overall health and functional status. Given the paucity of studies examining the relationship between hypoalbum...

Human islets from deceased organ donors have made important contributions to our understanding of pancreatic endocrine function and continue to be an important resource for research studies aimed at understanding, treating, and preventing diabetes. Understanding the impacts of isolation and culture upon the yield of human islets for research is imp...

Background. Induced pluripotent stem cells (iPSCs) offer the potential to generate autologous iPSC-derived islets (iPSC islets), however, remain limited by scalability and product safety. Methods. Herein, we report stagewise characterization of cells generated following a bioreactor-based differentiation protocol. Cell characteristics were asses...

Background Efforts to preoperatively risk stratify and optimize patients before pancreaticoduodenectomy continue to improve outcomes. This study aims to determine the impact of hypoalbuminemia on outcomes following pancreaticoduodenectomy and outline optimal hypoalbuminemia cut-off values in this population. Methods The ACS-NSQIP (2016–2021) datab...

Human islets from deceased organ donors have made important contributions to our understanding of pancreatic endocrine function and continue to be an important resource for research studies aimed at understanding, treating, and preventing diabetes. Understanding the impacts of isolation and culture upon the yield of human islets for research is imp...

Background Limited information is available regarding outcomes of islet cell isolation (ICI) and transplantation (ITx) using medical assistance in dying (MAiD) donors. We aimed to assess the feasibility and outcomes of ICI and ITx in MAiD donors. Methods ICI and ITx from MAiD were compared with donation after circulatory death (DCD) type III betwe...

Islet transplantation (ITx) is an established treatment for recurrent, severe hypoglycemia in type 1 diabetes, however, requires lifelong immunosuppression (IS) which can be nephrotoxic. We conducted a risk regression to identify factors associated with progression to Stage 3 CKD (S3CKD) or worse post-ITx. We used data from adults undergoing ITx al...

Background Biliary obstruction before liver resection is a known risk factor for post-operative complications. The aim of this study was to determine the impact of persistent hyperbilirubinemia following preoperative biliary drainage before liver resection. Methods The ACS-NSQIP (2016–2021) database was used to extract patients with cholangiocarci...

There has been a steady expansion in islet isolation and transplantation activity worldwide. In addition to preparing human islets for transplantation, we have been providing human islets to basic researchers. The aim of this study was to review the activity of distribution of human islets to basic researchers in North America, Europe, and Asia, an...

Background and aim The liver is susceptible to ischemia-reperfusion injury (IRI) during hepatic surgery, when the vessels are compressed to control bleeding, or liver transplantation, when there is an obligate period of ischemia. The hallmark of IRI comprises mitochondrial dysfunction, which generates reactive oxygen species, and cell death through...

Pancreatic islet transplantation (ITx) established proof of concept that cellular therapies are feasible options to manage intractable severe and recurrent hypoglycemia, but that they can also provide optimal glycemic control and insulin independence in a large proportion of patients. Long-term evidence is consolidating ITx as a safe and effective...

Ex vivo normothermic machine perfusion (NMP) preserves donor organs and permits real-time assessment of allograft health, but the most effective indicators of graft viability are uncertain. Mitochondrial DNA (mtDNA), released consequent to traumatic cell injury and death, including the ischemia-reperfusion injury inherent in transplantation, may me...

Background In solid organ transplantation, HLA matching between donor and recipient is associated with superior outcomes. In islet transplantation, an intervention for Type 1 diabetes, HLA matching between donor and recipient is not performed as part of allocation. Susceptibility to Type 1 diabetes is associated with the presence of certain HLA typ...

Background Ischemia/reperfusion injury (IRI) is an inherent problem in organ transplantation, owing to the obligate period of ischemia that organs must endure. Cyclosporine A (CsA), though better know as an immunosuppressant, has been shown to mitigate warm IRI in a variety of organ types, including the liver. However, there is little evidence for...

Cellular therapies for type-1 diabetes can leverage cell encapsulation to dispense with immunosuppression. However, encapsulated islet cells do not survive long, particularly when implanted in poorly vascularized subcutaneous sites. Here we show that the induction of neovascularization via temporary controlled inflammation through the implantation...

Generation of pure pancreatic progenitor (PP) cells is critical for clinical translation of stem cell-derived islets. Herein, we performed PP differentiation with and without AKT/P70 inhibitor AT7867 and characterized the resulting cells at protein and transcript level in vitro and in vivo upon transplantation into diabetic mice. AT7867 treatment i...

Mitochondria are the powerhouse of the cell and dynamically control fundamental biological processes including cell reprogramming, pluripotency, and lineage specification. Although remarkable progress in induced pluripotent stem cell (iPSC)-derived cell therapies has been made, very little is known about the role of mitochondria and the mechanisms...

Type 1 Diabetes (T1D) is an autoimmune destruction of pancreatic beta cells. The development of the Edmonton Protocol for islet transplantation in 2000 revolutionized T1D treatment and offered a glimpse at a cure for the disease. In 2022, the 20-year follow-up findings of islet cell transplantation demonstrated the long-term safety of islet cell tr...

Background: Induced pluripotent stem cells (iPSCs) offer potential to revolutionize regenerative medicine as a renewable source for islets, dopaminergic neurons, retinal cells, and cardiomyocytes. However, translation of these regenerative cell therapies requires cost-efficient mass manufacturing of high-quality human iPSCs. This study presents an...

Induced pluripotent stem cells (iPSCs) offer the potential to generate autologous iPSC-derived islets (iPSC islets). Differentiation protocol optimization with stage-wise characterization, off-target evaluation, and cell yield assessment are necessary to inform clinical implementation. Herein, we report stage-wise characterization of cells generate...

Historically, only patients with brittle diabetes or severe recurrent hypoglycemia have been considered for islet transplantation (ITx). This population has been selected to optimize the risk-benefit profile considering risks of long-term immunosuppression and limited organ supply. However, with the advent of stem cell-derived ITx and the potential...

Generation of pure pancreatic progenitor cells (PPs) is critical for clinical translation of stem cell derived islets. Herein, we performed PP differentiation with and without AKT/P70 inhibitor AT7867 and characterized the resulting cells at protein and transcript level in vitro and in vivo upon transplantation into diabetic mice. AT7867 treatment...

Normothermic machine perfusion (NMP) has emerged as a valuable tool in the preservation of liver allografts before transplantation. Randomized trials have shown that replacing static cold storage (SCS) with NMP reduces allograft injury and improves graft utilization. The University of Alberta's liver transplant program was one of the early adopters...

Background: Allogeneic islet transplantation is a validated therapy in type 1 diabetes; however, there is decline of transplanted islet graft function over time and the mechanisms underlying this decline are unclear. We evaluated the distinct association between primary graft function (PGF) and 5-year islet transplantation outcomes. Methods: In...

The proportion of general surgeons with graduate degrees in Canada is increasing. We sought to evaluate the types of graduate degree held by surgeons in Canada, and whether differences in publication capacity exist. We evaluated all general surgeons working at English-speaking Canadian academic hospitals to determine the types of degrees achieved,...

The COVID-19 pandemic is an unforgettable healthcare challenge of the twenty-first century; still, the world is struggling to recover from the aftermath. COVID-19 is associated with a hypercoagulable state and can cause end organ ischemia leading to morbidity and mortality. The solid organ transplant recipients who are on immunosuppressive therapy...

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissue...

Objective: To provide the largest single-centre analysis of islet (ITx) and pancreas (PTx) transplantation. Summary Background Data: Studies describing long-term outcomes with ITx and PTx are scarce. Methods: We included adults undergoing ITx (n=266) and PTx (n=146) at the University of Alberta from January 1999-October 2019. Outcomes include...

The year 2022 has been notable for game-changing early progress in clinical trials with stem cell islets; durable and promising 20-year data with long-term outcomes in clinical islet transplantation; and the development of locally protective or gene-editing-based approaches to avoid long-term immunosuppression. ViaCyte Inc.’s PEC-01 trials with sub...

Background Hepato-pancreatico-biliary (HPB) patients experience competing risk of venous thromboembolism (VTE) and bleeding. We sought to evaluate the effect of anti-Xa levels on VTE and bleeding, and to characterize factors associated with subprophylaxis. Methods This prospective cohort study evaluated adult HPB surgical patients; cohorts were de...

Background: Preliminary studies show promise for extrahepatic islet transplantation (ITx). However, clinical comparisons with intraportal ITx outcomes remain limited. We aimed to compare short-term glycemic outcomes for patients receiving extrahepatic and intraportal ITx. Methods: This single-centre cohort study evaluates patients receiving extrahe...

Background . C-peptide levels are a key measure of beta-cell mass following islet transplantation, but threshold values required to achieve clinically relevant patient-centered outcomes are not yet established. Methods . We conducted a cross-sectional retrospective cohort study evaluating patients undergoing islet transplantation at a single cen...

Background. ABO-incompatible transplantation has improved accessibility of kidney, heart, and liver transplantation. Pancreatic islet transplantation continues to be ABO-matched, yet ABH antigen expression within isolated human islets or novel human embryonic stem cell (hESC)-derived islets remain uncharacterized. Methods. We evaluated ABH glyca...

The delivery of encapsulated islets or stem cell-derived insulin-producing cells (i.e., bioartificial pancreas devices) may achieve a functional cure for type 1 diabetes, but their efficacy is limited by mass transport constraints. Modeling such constraints is thus desirable, but previous efforts invoke simplifications which limit the utility of th...

Acute liver failure (ALF) is a rare but devastating disease associated with substantial morbidity and a mortality rate of almost 45%. Medical treatments, apart from supportive care, are limited and liver transplantation may be the only rescue option. Large animal models, which most closely represent human disease, can be logistically and technicall...

Prevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 tha...

Background: Though best known for its immunosuppressant effects, cyclosporine A (CsA) has also been studied as a treatment to mitigate ischemia-reperfusion injury (IRI) by its inhibition of the mitochondria permeability transition pore (mPTP). Despite numerous preclinical studies supporting its benefit in reducing infarct size following myocardial...

Recapitulation of embryonic pancreatic development has enabled development of methods for in vitro islet cell differentiation using human pluripotent stem cells (hPSCs), which have the potential to cure diabetes. Advanced methods for optimal generation of stem-cell-derived islets (SC-islets) has enabled successful diabetes reversal in rodents and s...

Progress in human pluripotent stem cells has opened up an opportunity to autologous β-cell replacement therapies in patients with diabetes. Such an approach could render immunologically compatible islets from an unconstrained source without requirement for chronic immune suppression. Several proof-of-concept studies have generated stem cell-derived...

Little is known about how early islet graft function evolves in the clinical setting. The BETA-2 score is a validated index of islet function that can be calculated from a single blood sample and lends itself to frequent monitoring of graft function. In this study, we characterized early graft function by calculating weekly BETA-2 score in recipien...

Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by...

Islet transplantation is a highly effective treatment for select patients with type 1 diabetes. Unfortunately, current use is limited to those with brittle disease due to donor limitations and immunosuppression requirements. Discovery of factors for induction of pluripotent stem cells from adult somatic cells into a malleable state has reinvigorate...

Background. Preliminary studies show promise for extrahepatic islet transplantation (ITx). However, clinical comparisons with intraportal ITx outcomes remain limited. Methods. This single-center cohort study evaluates patients receiving extrahepatic or intraportal ITx between 1999 and 2018. Primary outcome was stimulated C-peptide level. Seconda...

Background: For academic hiring committees and surgical trainees, the benefits of a graduate degree are unclear. We sought to identify if graduate degrees or professorship status were associated with increased research productivity among Canadian academic surgeons. Methods: We included general surgeons from the largest hospitals associated with ac...

Background Islet transplantation offers an effective treatment for selected people with type 1 diabetes and intractable hypoglycaemia. Long-term experience, however, remains limited. We report outcomes from a single-centre cohort up to 20 years after islet transplantation. Methods This cohort study included patients older than 18 years with type...

Islet cell transplant (ITx) continues to improve, with recently published long-term outcomes suggesting nearly 80% graft survival, leading to improvements in glycemic control, reductions in insulin doses, and near-complete abrogation of severe hypoglycemia. Unfortunately, access to ITx remains limited by immunosuppression requirements and donor sup...

Background & aims: Association between sarcopenia and mortality in cirrhosis is well recognised; however, little is known about the clinical implications of adipose tissue radiodensity, indicative of biological features. This study aimed to determine an association between high subcutaneous adipose tissue (SAT) radiodensity and survival, compare t...

Incidental premalignant pancreatic cystic lesions (pPCLs) are increasingly being detected in patients undergoing orthotopic liver transplantation (OLT). The impact of chronic immunosuppression upon pPCLs may elevate risk of progression to pancreatic cancer. This systematic review assesses prevalence, outcome, and management of pPCLs in patients und...

DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 207 healthy tissue samples. Replicates o...

Regulatory T cells (Tregs) modulate alloimmune responses and may facilitate minimization or withdrawal of immunosuppression post-transplant. Current approaches, however, rely on complex ex vivo Treg expansion protocols. Herein, we explore endogenous in vivo Treg expansion through antibody-mediated agonistic stimulation of the tumor necrosis factor...

Acute liver failure is marked by the rapid deterioration of liver function in a previously well patient over period of days to weeks. Though relatively rare, it is associated with high morbidity and mortality. This makes it a challenging disease to study clinically, necessitating reliance on preclinical models as means to explore pathophysiology an...

These preliminary data from an ongoing first-in-human phase 1/2, open-label study provide proof-of-concept that pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) engrafted in type 1 diabetes patients become islet cells releasing insulin in a physiologically regulated fashion. In this study of 17 subjects aged 22-57 with type 1 diabet...

Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of primary islets from human donors and identified de novo glutathione synthesis as a prominent gluco...

The discovery of insulin a century ago changed the lives of millions of individuals suffering from diabetes, paving the way for long-term survival. While the availability of recombinant insulin for hormone replacement therapy has served extremely well to help control blood glucose in diabetes, there remains significant room for further improvements...

The effects of imeglimin, a novel anti-diabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expressi...

To estimate the incremental cost‐effectiveness of a liver transplant program that utilizes normothermic machine perfusion (NMP) alongside static cold storage (SCS) compared to SCS alone (control). A Markov model compared strategies (NMP vs control) using 1‐year cycle lengths over a 5‐year time horizon from the public healthcare payer perspective. P...

Background Simultaneous kidney-pancreas transplantation (SPK) has benefits for patients with kidney failure and type I diabetes mellitus, but is associated with greater perioperative risk compared with kidney-alone transplantation. Postoperative care settings for SPK recipients vary across Canada and may have implications for patient outcomes and h...

Background: Hepatic artery thrombosis represents a potentially fatal complication following liver transplantation. Rates of hepatic artery thrombosis are significantly higher in children, with mortality reported up to 80 percent. Microsurgical anastomosis has been shown to decrease the rate of hepatic artery thrombosis and now represents the stand...

Purpose of review: Chronic diabetes-related complications continue to exert a rapidly growing and unsustainable pressure on healthcare systems worldwide. In type 1 diabetes, glycemic control is particularly challenging, as intensive management substantially increase the risk of severe hypoglycemic episodes. Alternative approaches to address this i...

Acute recurrent and chronic pancreatitis in children carries high morbidity and burden. Compared to adults, ~75% of the cases of chronic pancreatitis in children are associated with underlying genetic mutations. The decision to intervene and the optimal timing poses unique challenges. Total pancreatectomy and islet cell autotransplantation (TPIAT)...

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin‐8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independen...

Over the last century, diabetes has been treated with subcutaneous insulin, a discovery that enabled patients to forego death from hyperglycemia. Despite novel insulin formulations, patients with diabetes continue to suffer morbidity and mortality with unsustainable costs to the health care system. Continuous glucose monitoring, wearable insulin pu...

Total pancreatectomy with autologous islet cell transplant (TPAIT) is a treatment option for patients suffering from chronic or recurrent acute pancreatitis, providing benefits of pain relief, enhanced quality of life, and prevention of brittle type 3c diabetes [1]. While surgical procedure requires extensive dissection and elevates risk of bleedin...

Background: Undifferentiated embryonal cell sarcoma (UESL) of the liver is the third most common malignant liver disease of childhood presenting as a rapidly enlarging intraabdominal mass. This systematic review explores the practicality of liver transplantation as a viable option in the treatment armamentarium for locally advanced undifferentiate...

Islet transplantation (IT) is now a robust treatment for selected patients with type 1 diabetes suffering from recurrent hypoglycemia and impaired awareness of hypoglycemia. A global soar of clinical islet transplant programs attests to the commitment of many institutions and researchers to advance IT as a potential cure for this devastating diseas...

Background Islet isolation is an essential process in every human islet transplantation protocol. Intraductal enzyme delivery followed by adequate distention of the pancreas is the most critical step in islet isolation. Anomalies of the pancreatic duct system can significantly affect this process. Thus, identification and characterization of ductal...

Background Despite the significant advancement in islet transplantation over the past three decades, our understanding of infectious complications post islet transplant remains limited. Methods This is a single center retrospective review of Islet transplant recipients at the University of Alberta between February 2006 and December 2015. All infec...

Regulatory T cells (Tregs) have become highly relevant in the pathophysiology and treatment of autoimmune diseases, such as type 1 diabetes (T1D). As these cells are known to be defective in T1D, recent efforts have explored ex vivo and in vivo Treg expansion and enhancement as a means for restoring self-tolerance in this disease. Given their capac...

Background Liver transplantation is an effective treatment for end-stage liver disease. However, waiting lists continue to lengthen as demand exceeds supply. Use of extended criteria donors has helped but is associated with increased rates of complications. The application of normothermic machine perfusion (NMP) has been shown to be protective, esp...

Aim/Hypothesis Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell development and function. Here, we investigate roles for an antisense lncRNA expressed from the Pax6 locus (annotated as Pax6os1 in mice and PAX6-AS1 in humans) in beta cell identity and functionality. Methods Pax6os1 expression was silenced in MIN6 cells...

It has been proposed that unmethylated insulin promoter fragments in plasma derive exclusively from β-cells, reflect their recent demise and can be used to assess β-cell damage in type 1 diabetes. Herein we describe an ultrasensitive assay for detection of a β-cell-specific DNA methylation signature, by simultaneous assessment of six DNA methylatio...

Background: Pancreas and islet transplantation can achieve optimal glycemic control in patients type 1 diabetes (T1DM) and persistent problematic hypoglycemia. We describe our experience with these two therapies over a 20-yr period. Methods: Patients with T1DM undergoing pancreas (PT) or islet (IT) allotransplantation from January 1st 1999 to May 1...

Background: The BETA-2 score is a validated composite measure of beta cell function in islet transplantation. It is calculated from a fasting sample and lends itself to regular monitoring of islet graft function. To determine whether changes in the BETA-2 score are significant, it is important to understand inherent variability of the score. The ai...

Machine perfusion (MP) is at the forefront of innovation in modern liver transplantation. Several approaches, mainly varying in the temperature at which the graft is perfused, have shown benefit in preclinical models and non-randomized clinical trials. Given the recent randomized controlled trial by Nasralla et al. demonstrating the efficacy of nor...

Chronic inflammation is linked to diverse disease processes, but the intrinsic mechanisms that determine cellular sensitivity to inflammation are incompletely understood. Here, we show the contribution of glucose metabolism to inflammation-induced changes in the survival of pancreatic islet β-cells. Using metabolomic, biochemical and functional ana...