Technical optimization of spatially resolved single-cell transcriptomic datasets to study clinical liver disease.

Single cell and spatially resolved 'omic' techniques have enabled deep characterization of clinical pathologies that remain poorly understood, providing unprecedented insights into molecular mechanisms of disease. However, transcriptomic platforms are costly, limiting sample size, which increases the possibility of pre-analytical variables such as tissue processing and storage procedures impacting RNA quality and downstream analyses. Furthermore, spatial transcriptomics have not yet reached single cell resolution, leading to the development of multiple deconvolution methods to predict individual cell types within each transcriptome 'spot' on tissue sections.

Review of pediatric combined heart-liver transplantation: A roadmap to success.

Background: Combined heart-liver transplantation (CHLT) is a promising technique to address end stage organ failure in patients with concomitant heart failure and chronic liver disease. While most experience with CHLT has involved adult patients, the expanding population of children born with univentricular congenital heart disease who underwent the Fontan procedure and develop Fontan-associated liver disease (FALD) has emerged as a growing indication for pediatric CHLT.

Methods: Currently, CHLT is performed at a select subset of experienced transplant centers, especially in the pediatric population.

Technical optimization of spatially resolved single-cell transcriptomic datasets to study clinical liver disease.

Single cell and spatially resolved 'omic' techniques have enabled deep characterization of clinical pathologies that remain poorly understood, providing unprecedented insights into molecular mechanisms of disease. However, transcriptomic platforms are costly, limiting sample size, which increases the possibility of pre-analytical variables such as tissue processing and storage procedures impacting RNA quality and downstream analyses. Furthermore, spatial transcriptomics have not yet reached single cell resolution, leading to the development of multiple deconvolution methods to predict individual cell types within each transcriptome 'spot' on tissue sections.

Living Donor Liver Transplantation for Hepatocellular Carcinoma Within and Outside Traditional Selection Criteria: A Multicentric North American Experience.

Objective: To evaluate long-term oncologic outcomes of patients post-living donor liver transplantation (LDLT) within and outside standard transplantation selection criteria and the added value of the incorporation of the New York-California (NYCA) score.

Background: LDLT offers an opportunity to decrease the liver transplantation waitlist, reduce waitlist mortality, and expand selection criteria for patients with hepatocellular carcinoma (HCC).

Methods: Primary adult LDLT recipients between October 1999 and August 2019 were identified from a multicenter cohort of 12 North American centers.

Impact of gut microbiota on liver transplantation.

The gut microbiota has been gaining attention due to its interactions with the human body and its role in pathophysiological processes. One of the main interactions is the "gut-liver axis," in which disruption of the gut mucosal barrier seen in portal hypertension and liver disease can influence liver allograft function over time. For example, in patients who are undergoing liver transplantation, preexisting dysbiosis, perioperative antibiotic use, surgical stress, and immunosuppressive use have each been associated with alterations in gut microbiota, potentially impacting overall morbidity and mortality.

Potential association between public medical insurance, waitlist mortality, and utilization of living donor liver transplantation: An analysis of the Scientific Registry of Transplant Recipients.

Background: The Affordable Care Act (ACA) and subsequent Medicaid expansion has increased utilization of public health insurance. Living donor liver transplantation (LDLT) increases access to transplant and is associated with improved survival but consistently represents < 5% of LT in the United States.

Study Design: National registry data were analyzed to evaluate the impact of insurance payor on waitlist mortality and LDLT rates at LDLT centers since implementation of the ACA.

HCV Eradication with Direct-Acting Antivirals Does Not Impact HCC Progression on the Waiting List or HCC Recurrence after Liver Transplantation.

Background: The introduction of direct-acting antivirals (DAA) for HCV has led to high rates of HCV eradication. Treatment of patients awaiting liver transplantation (LT) has been controversial. Recent data suggests that DAA treatment may accelerate recurrent HCC.

Case series and systematic review of acquired diaphragmatic hernia after liver transplantation.

Background: ADH is a rare and potentially fatal complication following LT. In this study, a systematic review was completed to identify risk factors which may contribute to ADH.

Methods: Transplant databases at three LT programs were reviewed.

Hepatic Epithelioid Hemangioendothelioma Presenting as an Enlarging Vascular Lesion within the Spleen.

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm with variable malignant potential that most often presents within the liver. Many patients present with bilobar or extrahepatic disease, and the current treatment paradigm involves liver transplantation, with favorable long term results. Up to 25% of patients are diagnosed incidentally following imaging for other indications, and confirmation of diagnosis requires histologic analysis, as there are no classical imaging features to distinguish hepatic EHE (HEHE) from other solid hepatic lesions.

AEB071 (sotrastaurin) does not exhibit toxic effects on human islets in vitro, nor after transplantation into immunodeficient mice.

AEB071 (AEB, sotrastaurin), a specific inhibitor of protein kinase C, reduces T-lymphocyte activation and cytokine release. AEB delays islet allograft rejection in rats and prevents rejection when combined with cyclosporine. Since many immunosuppressive agents have toxic effects on the function of transplanted islets, we investigated whether this was also the case with AEB.

Caspase inhibitor therapy synergizes with costimulation blockade to promote indefinite islet allograft survival.

Objective: Costimulation blockade has emerged as a selective nontoxic maintenance therapy in transplantation. However, these drugs must be combined with other immunomodulatory agents to ensure long-term graft survival.

Research Design And Methods: Recent work has demonstrated that caspase inhibitor therapy (EP1013) prevents engraftment phase islet loss and markedly reduces the islet mass required to reverse diabetes.

Vascular endothelial growth factor expression in hepatic epithelioid hemangioendothelioma: Implications for treatment and surgical management.

Epithelioid hemangioendothelioma (EHE) is a low-grade, malignant vascular tumor that most commonly presents within the liver. Patients with hepatic EHE are often candidates for liver transplantation as the disease is usually multifocal at diagnosis. Although these patients achieve excellent early outcomes post-transplant, there are very few data regarding tumor markers that can further direct chemotherapy in hepatic EHE to prevent recurrent disease.

Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice.

Objective: The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear.

Porcine marginal mass islet autografts resist metabolic failure over time and are enhanced by early treatment with liraglutide.

Although insulin independence is maintained in most islet recipients at 1 yr after transplant, extended follow-up has revealed that many patients will eventually require insulin therapy. Previous studies have shown that islet autografts are prone to chronic failure in large animals and humans, suggesting that nonimmunological events contribute to islet graft functional decay. Early intervention with therapies that promote graft stability should provide a measurable benefit over time.

The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice.

Objective: Clinical islet transplantation can provide insulin independence in patients with type 1 diabetes, but chronic graft failure has been observed. This has been attributed in part to loss of >or=60% of the transplanted islets in the peritransplant period, resulting in a marginal implant mass. Strategies designed to maximize survival of the initial islet mass are likely to have major impact in enhancing long-term clinical outcomes.

Belatacept and basiliximab diminish human antiporcine xenoreactivity and synergize to inhibit alloimmunity.

Background: Maintenance immunosuppression with calcineurin inhibitor therapy has improved survival rates in solid organ transplantation over the past decade. However, these drugs are associated with negative side effects, including nephrotoxicity and new-onset diabetes. Selective immunomodulatory agents such as belatacept and basiliximab have shown great promise in promoting allograft survival.

Factors influencing the loss of beta-cell mass in islet transplantation.

Recent advances in clinical islet transplantation have clearly demonstrated that this procedure can provide excellent glycemic control and often insulin independence in a population of patients with type 1 diabetes. A key limitation in the widespread application of clinical islet transplantation is the requirement of 10,000 islet equivalents/kg in most recipients, generally derived from two or more cadaveric donors. It has been determined that a majority of the transplanted islets fail to engraft and become fully functional.

Caspase inhibitor therapy enhances marginal mass islet graft survival and preserves long-term function in islet transplantation.

Islet transplantation can provide insulin independence in patients with type 1 diabetes, but islets derived from two or more donors are often required. A significant fraction of the functional islet mass is lost to apoptosis in the immediate posttransplant period. The caspase inhibitor N-benzyloxycabonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-FMK) has been used therapeutically to prevent apoptosis in experimental animal models of ischemic injury, autoimmunity, and degenerative disease.

Factors Influencing the Loss of β-Cell Mass in Islet Transplantation.

Recent advances in clinical islet transplantation have clearly demonstrated that this procedure can provide excellent glycemic control and often insulin independence in a population of patients with type 1 diabetes. A key limitation in the widespread application of clinical islet transplantation is the requirement of 10,000 islet equivalents/kg in most recipients, generally derived from two or more cadaveric donors. It has been determined that a majority of the transplanted islets fail to engraft and become fully functional.

Neonatal porcine islets exhibit natural resistance to hypoxia-induced apoptosis.

Background: Despite the success of the Edmonton protocol for human islet transplantation, an alternate source of islet tissue must be developed if beta-cell replacement therapy is to see widespread application. Neonatal porcine islets (NPI) represent one potential source of tissue. When human or rodent islets are transplanted, the majority of cells undergo hypoxia-induce apoptosis soon after the grafts are placed in the recipient.