The Current State of Liver Transplantation for Colorectal Liver Metastases in the United States: A Call for Standardized Reporting.

BACKGROUND: Current success in transplant oncology for select liver tumors, such as hepatocellular carcinoma, has ignited international interest in liver transplantation (LT) as a therapeutic option for nonresectable colorectal liver metastases (CRLM). In the United States, the CRLM LT experience is limited to reports from a handful of centers. This study was designed to summarize donor, recipient, and transplant center characteristics and posttransplant outcomes for the indication of CRLM. METHODS: Adult, primary LT patients listed between December 2017 and March 2022 were identified by using United Network Organ Sharing database. LT for CRLM was identified from variables: "DIAG_OSTXT"; "DGN_OSTXT_TCR"; "DGN2_OSTXT_TCR"; and "MALIG_TY_OSTXT." RESULTS: During this study period, 64 patients were listed, and 46 received LT for CRLM in 15 centers. Of 46 patients who underwent LT for CRLM, 26 patients (56.5%) received LTs using living donor LT (LDLT), and 20 patients received LT using deceased donor (DDLT) (43.5%). The median laboratory MELD-Na score at the time of listing was statistically similar between the LDLT and DDLT groups (8 vs. 9, P = 0.14). This persisted at the time of LT (8 vs. 12, P = 0.06). The 1-, 2-, and 3-year, disease-free, survival rates were 75.1, 53.7, and 53.7%. Overall survival rates were 89.0, 60.4, and 60.4%, respectively. CONCLUSIONS: This first comprehensive U.S. analysis of LT for CRLM suggests a burgeoning interest in high-volume U.S. transplant centers. Strategies to optimize patient selection are limited by the scarce oncologic history provided in UNOS data, warranting a separate registry to study LT in CRLM.

Long-Term Financial, Psychosocial, and Overall Health-Related Quality of Life After Living Liver Donation.

BACKGROUND: To assess the impact of living liver donation (LD) in a diverse and aging population up to 20 y after donation, particularly with regard to medical, financial, psychosocial, and overall health-related quality of life (HRQOL). METHODS: Patients undergoing LD between 1999 and 2009 were recruited to respond to the Short-Form 36 and a novel Donor Quality of Life Survey at two time points (2010 and 2018). RESULTS: Sixty-eight living liver donors (LLDs) completed validated surveys, with a mean follow-up of 11.5 ± 5.1 y. Per Donor Quality of Life Survey data, physical activity or strength was not impacted by LD in most patients. All respondents returned to school or employment, and 82.4% reported that LD had no impact on school or work performance. LD did not impact health insurability in 95.6% of donors, and only one patient experienced difficulty obtaining life insurance. Overall, 97.1% of respondents did not regret LD. Short-Form 36 survey-measured outcomes were similar between LLDs and the general U.S. POPULATION: LLDs who responded in both 2010 and 2018 were followed for an overall average of 15.4 ± 2.4 y and HRQOL outcomes in these donors also remained statistically equivalent to U.S. population norms. CONCLUSIONS: This study represents the longest postdonation follow-up and offers unique insight related to HRQOL in a highly diverse patient population. Although LLDs continue to maintain excellent HRQOL outcomes up to 20 y after donation, continued lifetime follow-up is required to accurately provide young, healthy potential donors with an accurate description of the risks that they may incur on aging.

Immunologic benefit of maternal donors in pediatric living donor liver transplantation.

PURPOSE OF REVIEW: Long-term follow-up has suggested that pediatric LDLT may have superior outcomes compared to deceased donor recipients. In this review, we describe the subset of LDLT recipients with maternal donors that have lower reported rates of rejection and improved allograft survival. RECENT FINDINGS: Pediatric LDLT recipients, particularly those with a primary diagnosis of biliary atresia who receive grafts from their mothers, have been reported to have lower rates of acute cellular rejection post-transplant and graft failure. Maternal-fetal microchimerism and the persistence of regulatory T cells may be related to improved outcomes observed in recipients with maternal donors. Further, recent studies have shown that up to 60% of pediatric LDLT recipients can undergo intentional withdrawal of immunosuppression and achieve long-term operational tolerance. The impact of graft type on operational tolerance has not been thoroughly investigated; however, investigation of tolerant pediatric LDLT patients with maternal donors may provide key insights into the mechanisms of immune tolerance. SUMMARY: While excellent outcomes can be achieved in pediatric LDLT, there is still a measurable decrease in graft and patient survival over time post-transplant. Recipients of maternal donor liver transplants are a subset of patients who may be advantaged toward improved outcomes by means of immune tolerance.

Myogenic Akt signaling attenuates muscular degeneration, promotes myofiber regeneration and improves muscle function in dystrophin-deficient mdx mice.

Duchenne muscular dystrophy, the most common form of childhood muscular dystrophy, is caused by X-linked inherited mutations in the dystrophin gene. Dystrophin deficiencies result in the loss of the dystrophin-glycoprotein complex at the plasma membrane, which leads to structural instability and muscle degeneration. Previously, we induced muscle-specific overexpression of Akt, a regulator of cellular metabolism and survival, in mdx mice at pre-necrotic (<3.5 weeks) ages and demonstrated upregulation of the utrophin-glycoprotein complex and protection against contractile-induced stress. Here, we found that delaying exogenous Akt treatment of mdx mice after the onset of peak pathology (>6 weeks) similarly increased the abundance of compensatory adhesion complexes at the extrasynaptic sarcolemma. Akt introduction after onset of pathology reverses the mdx histopathological measures, including decreases in blood serum albumin infiltration. Akt also improves muscle function in mdx mice as demonstrated through in vivo grip strength tests and in vitro contraction measurements of the extensor digitorum longus muscle. To further explore the significance of Akt in myofiber regeneration, we injured wild-type muscle with cardiotoxin and found that Akt induced a faster regenerative response relative to controls at equivalent time points. We demonstrate that Akt signaling pathways counteract mdx pathogenesis by enhancing endogenous compensatory mechanisms. These findings provide a rationale for investigating the therapeutic activation of the Akt pathway to counteract muscle wasting.

Differential Function and Maturation of Human Stem Cell-Derived Islets After Transplantation.

Insulin-producing stem cell-derived islets (SC-islets) provide a virtually unlimited cell source for diabetes cell replacement therapy. While SC-islets are less functional when first differentiated in vitro compared to isolated cadaveric islets, transplantation into mice has been shown to increase their maturation. To understand the effects of transplantation on maturation and function of SC-islets, we examined the effects of cell dose, transplantation strategy, and diabetic state in immunocompromised mice. Transplantation of 2 and 5, but not 0.75 million SC-islet cells underneath the kidney capsule successfully reversed diabetes in mice with pre-existing diabetes. SQ and intramuscular injections failed to reverse diabetes at all doses and had undetectable expression of maturation markers, such as MAFA and FAM159B. Furthermore, SC-islets had similar function and maturation marker expression regardless of diabetic state. Our results illustrate that transplantation parameters are linked to SC-islet function and maturation, providing ideal mouse models for preclinical diabetes SC therapy research.

Myogenic Akt signaling upregulates the utrophin-glycoprotein complex and promotes sarcolemma stability in muscular dystrophy.

Duchenne muscular dystrophy is caused by dystrophin mutations that lead to structural instability of the sarcolemma membrane, myofiber degeneration/regeneration and progressive muscle wasting. Here we show that myogenic Akt signaling in mouse models of dystrophy promotes increased expression of utrophin, which replaces the function of dystrophin thereby preventing sarcolemma damage and muscle wasting. In contrast to previous suggestions that increased Akt in dystrophy was a secondary consequence of pathology, our findings demonstrate a pivotal role for this signaling pathway such that modulation of Akt can significantly affect disease outcome by amplification of existing, physiological compensatory mechanisms.

Big Data in Transplantation Practice-the Devil Is in the Detail-Fontan-associated Liver Disease.

BACKGROUND: As a result of the Fontan procedure, the prognosis of congenital single-ventricle heart disease has improved, with many affected children surviving into adulthood. However, the unanticipated consequences of chronic exposure to Fontan hemodynamics have revealed a new set of secondary noncardiac complications. Fontan-associated liver disease (FALD) is characterized by progressive hepatic fibrosis in nearly all patients post-Fontan, with the potential to develop cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. A lack of data regarding FALD-related prognosis makes consideration of indications for and timing of heart alone versus combined heart-liver transplantation challenging. METHODS: A multidisciplinary group within the American Society for Transplantation analyzed several administrative datasets to study the epidemiology of FALD. RESULTS: This approach presented several obstacles, and efforts to characterize FALD were limited by a lack of Fontan- and FALD-specific diagnostic codes and an inability to follow individual patients through multiple health systems. Several ongoing Fontan registries were also reviewed but these do not adequately capture FALD-related variables. Such barriers highlight the need for large-scale data collection in patients post-Fontan to better understand and care for this complex population. CONCLUSIONS: This study emphasizes the challenges of studying emerging transplant-related diagnoses in existing datasets and the need for mechanisms to adapt registries to appropriately identify patients with rare or emerging conditions.

Gene-edited human stem cell-derived ß cells from a patient with monogenic diabetes reverse preexisting diabetes in mice.

Differentiation of insulin-producing pancreatic ß cells from induced pluripotent stem cells (iPSCs) derived from patients with diabetes promises to provide autologous cells for diabetes cell replacement therapy. However, current approaches produce patient iPSC-derived ß (SC-ß) cells with poor function in vitro and in vivo. Here, we used CRISPR-Cas9 to correct a diabetes-causing pathogenic variant in Wolfram syndrome 1 (WFS1) in iPSCs derived from a patient with Wolfram syndrome (WS). After differentiation to ß cells with our recent six-stage differentiation strategy, corrected WS SC-ß cells performed robust dynamic insulin secretion in vitro in response to glucose and reversed preexisting streptozocin-induced diabetes after transplantation into mice. Single-cell transcriptomics showed that corrected SC-ß cells displayed increased insulin and decreased expression of genes associated with endoplasmic reticulum stress. CRISPR-Cas9 correction of a diabetes-inducing gene variant thus allows for robust differentiation of autologous SC-ß cells that can reverse severe diabetes in an animal model.

Sinomenine suppresses TNF-alpha-induced VCAM-1 expression in human umbilical vein endothelial cells.

Sinomenine (SN), an alkaloid prepared from the root of Sinomenium acutum Rehd. Et wils, is used to alleviate the symptoms of rheumatism in Chinese medicine. In the present study, the potential inhibition of TNF-alpha-induced VCAM-1 expression on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro. HUVECs were isolated from freshly collected umbilical cords. Positive controls were stimulated with TNF-alpha, omitting SN. Negative controls were cultured omitting TNF-alpha and SN. Experimental groups were co-cultured with TNF-alpha and SN at different concentrations (0.25, 0.5, and 1.0 mol/L), or TNF-alpha and Dexamethasone (Dex) at a concentration of 1.0 x 10(-6) mol/L. Cells were harvested after culturing with the above drugs for 12 h. VCAM-1 mRNA expression was detected by real-time quantitative PCR, and VCAM-1 expression was detected by flow cytometry. The experimental data indicated that VCAM-1 mRNA and VCAM-1 were induced by TNF-alpha. The relative VCAM-1 mRNA expression decreased in the experimental groups (p<0.05). Concentrations of SN at 0.5 and 1.0 mol/L inhibited expression of VCAM-1 (p<0.05). SN at concentration of 0.25 mol/L and Dex at concentration of 1.0 x 10(-6) mol/L did not show an inhibitory effect on VCAM-1 expression in TNF-alpha-induced HUVECs. Our preliminary data indicates that SN has an inhibitory effect in vitro on TNF-alpha-induced VCAM-1 expression at both mRNA level and protein level in HUVECs, and suggests that SN may be a novel method of immunotherapy for rheumatic carditis or rheumatic heart disease.

Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus.

OBJECTIVE: To study 5 type I interferon (IFN)-inducible genes (LY6E, OAS1, OASL, MX1, and ISG15) in patients with systemic lupus erythematosus (SLE) and to correlate expression levels with disease activity and/or clinical manifestations. METHODS: Peripheral blood cells were obtained from 48 SLE patients, 48 normal controls, and 22 rheumatic disease controls, and total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by real-time polymerase chain reaction, standardized to a housekeeping gene, and summed to an IFN score. Disease activity was determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) composite. RESULTS: Each gene was highly expressed in SLE patients compared with normal controls (P < or = 0.0003) or disease controls (P < or = 0.0008 except for MX1). IFN scores were positively associated with the SELENA-SLEDAI instrument score (P = 0.001), the SELENA-SLEDAI flare score (P = 0.03), and the physician's global assessment score (P = 0.005). Compared with patients without nephritis, lupus nephritis patients had higher IFN scores (overall P < 0.0001), especially during active renal disease. IFN scores were weakly associated with neurologic manifestations. Elevated IFN scores were positively associated with the current presence of anti-double-stranded DNA (anti-dsDNA) antibodies (P = 0.007) or hypocomplementemia (P = 0.007). LY6E expression levels distinguished active from inactive lupus nephritis (P = 0.02) and were positively associated with proteinuria (P = 0.009). CONCLUSION: The 5 IFN-inducible genes were highly expressed in SLE patients, and increased levels were correlated with disease activity defined by several methods. IFN scores, or LY6E levels, were elevated in lupus nephritis patients, especially during active renal disease, and in patients with anti-dsDNA antibody positivity and hypocomplementemia. IFN scores, or LY6E levels, may be useful as a biomarker for lupus nephritis therapy.