Publications by authors named "Douglas Farmer"

As important immune regulatory cells, whether innate lymphoid cells (ILCs) are involved in liver transplantation (LT) remains unclear. In a murine orthotopic LT model, we dissected roles of ILCs in liver ischemia-reperfusion injury (IRI). Wild type (WT) grafts suffered significantly higher IRI in Rag2-γc double knockout (DKO) than Rag2 KO recipients, in association with downregulation of group 1 ILCs genes, including IFN-γ.

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Dishevelled 2 (Dvl2) is a key mediator of the Wingless/Wnt signaling pathway that regulates cell proliferation, migration, and immune function. However, little is known about the role of macrophage Dvl2 in modulating NOD1-mediated pyroptosis and hepatocyte death in oxidative stress-induced inflammatory liver injury. In a mouse model of oxidative stress-induced liver inflammation, mice with myeloid-specific Dvl2 knockout (Dvl2) displayed exacerbated ischemia/reperfusion (IR) stress-induced hepatocellular damage with increased serum ALT levels, oxidative stress, and proinflammatory mediators.

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Article Synopsis
  • Innate immune activation is essential for the onset of liver inflammation in nonalcoholic steatohepatitis (NASH), with unclear mechanisms of how certain immune molecules detect signals related to fat and inflammation.
  • High-fat diets trigger oxidative stress, activating specific signaling pathways (Foxo1, YAP, Notch1) in liver macrophages, while removing Foxo1 reduced inflammation and fibrosis in the liver.
  • The study reveals that the interplay between Foxo1, YAP, and Notch1 is crucial for managing lipid metabolism and immune responses during NASH, highlighting their roles as regulatory factors in disease progression.
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The history of intestinal transplantation can be traced back to the turn of the twentieth century. Although advancements have been made, the intestine still presents a greater challenge to transplantation than does that of other solid organs, experiencing higher rates of graft rejection and lower long-term survival. Increasingly, intestinal re-transplantation (re-ITx) is seen as a viable option and is now the fourth most common indication for ITx.

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Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT.

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Sirtuin 1 (SIRT1) is a histone/protein deacetylase in the cellular response to inflammatory, metabolic, and oxidative stressors. We previously reported that myeloid SIRT1 regulates the inflamed liver's canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain.

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Background And Aims: The hallmark of NAFLD or hepatic steatosis is characterized by lipid droplet (LD) accumulation in hepatocytes. Autophagy may have profound effects on lipid metabolism and innate immune response. However, how innate immune activation may regulate the autophagic degradation of intracellular LDs remains elusive.

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Background & Aims: Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is a central player in triggering necroptotic cell death. However, whether macrophage RIPK3 may regulate NOD1-dependent inflammation and calcineurin/transient receptor potential cation channel subfamily M member 7 (TRPM7)-induced hepatocyte death in oxidative stress-induced liver inflammatory injury remains elusive.

Methods: A mouse model of hepatic ischaemia-reperfusion (IR) injury, the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific RIPK3 knockout (RIPK3) and RIPK3-proficient (RIPK3) mice.

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Although alternative splicing (AS) drives transcriptional responses and cellular adaptation to environmental stresses, its contributions in organ transplantation have not been appreciated. We have shown that carcinoembryonic antigen-related cell adhesion molecule (Ceacam1; ), a transmembrane biliary glycoprotein expressed in epithelial, endothelial, and immune cells, determines donor liver transplant quality. Here, we studied how AS of affects ischemia-reperfusion injury (IRI) in mouse and human livers.

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Background & Aims: Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) acts through homophilic and heterophilic interactions with T cell immunoglobulin domain and mucin domain-containing protein 3 (TIM-3), which regulates innate immune activation in orthotopic liver transplantation (OLT). We investigated whether cluster of differentiation (CD) 4 T cell-dependent CC1-TIM-3 crosstalk may affect OLT outcomes in mice and humans.

Methods: Wild-type (WT) and CC1-deficient (CC1 knock-out [KO]) mouse livers were transplanted into WT, CC1KO, or T-cell TIM-3 transgenic (TIM-3Tg)/CC1KO double-mutant recipients.

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Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. We previously reported that myeloid SIRT1 signaling regulates the inflamed liver's canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain.

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Article Synopsis
  • This study analyzed liver retransplantation (ReLT) data over a 35-year period at a single center, revealing that up to 40% of liver transplant recipients experience graft failure.
  • A total of 654 ReLT procedures were performed, with significant differences noted between pre- and post-model for end-stage liver disease (MELD) eras in terms of patient age, comorbidities, and causes for retransplantation.
  • Findings indicate that despite the challenges faced by post-MELD ReLT patients, survival rates have improved compared to pre-MELD patients, highlighting the effectiveness of careful patient selection in liver retransplantation.
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T-cell immunoglobulin and mucin ()4 is expressed on APCs, including macrophages, as one of the main amplifiers in the mechanism of liver ischemia-reperfusion injury (IRI) following orthotopic liver transplantation (OLT). Though donor selectively expressed on Kupffer cells serves as a checkpoint regulator of innate immune-driven IRI cascades, its role on cells outside the OLT remains unclear. To dissect the role of donor vs.

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Persistent pleural effusions (PPEf) represent a known complication of orthotopic liver transplant (OLT). However, their clinical relevance is not well described. We evaluated the clinical, biochemical, and cellular characteristics of post-OLT PPEf and assessed their relationship with longitudinal outcomes.

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Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CC1, or CD66a) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown.

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Background & Aims: The stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress.

Methods: A mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIP) and TXNIP-proficient (TXNIP) mice.

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Valve-in-valve transcatheter aortic valve replacement for degenerated surgical bioprosthesis is becoming a more common therapeutic option. Rapid-deployment valves are novel, have distinct structural differences from standard surgical valves, and are increasingly used in minimal-access surgery. We report the case of a 61-year-old man who developed severe stenosis of an Edwards INTUITY Elite rapid-deployment valve and who subsequently underwent successful valve-in-valve placement of a self-expanding transcatheter valve.

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Article Synopsis
  • Pleural effusions are a common issue after liver transplantation, and chronic cases can lead to worse health outcomes for patients.
  • A study at UCLA analyzed 1,722 liver transplant patients and found that 7% experienced persistent pleural effusions, with 21.4% of them developing a condition called "trapped lung."
  • Patients with trapped lung required more surgeries, had longer hospital stays, and faced a higher risk of mortality compared to those without this complication, indicating significant impacts on health and healthcare resources.
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Immunosuppression withdrawal can be safely performed in select liver transplantation recipients, but the long-term outcomes and sustainability of tolerance have not been well studied. We completed a 10-year prospective, observational study of 18 pediatric liver transplantation recipients with operational tolerance to (1) assess the sustainability of tolerance over time, (2) compare the clinical characteristics of patients who maintained versus lost tolerance, (3) characterize liver histopathology findings in surveillance liver biopsies; and (4) describe immunologic markers in patients with tolerance. Comparator patients from two clinical phenotype groups termed "stable" and "nontolerant" patients were used as controls.

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Background: Liver transplantation (LT) for alcohol-related liver disease has historically been reserved for patients who have been six months abstinent. Given the increasing incidence of alcohol-related hepatitis (AH) and dismal survival in patients who fail medical therapy, transplant centers are extending their acceptance criteria for patients with less than 6 months of sobriety. We sought to determine the barriers for listing.

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Background: Frailty has been implicated as a negative predictor of Liver Transplant (LT) outcomes. However, an understanding of changes in patient muscle mass peri-LT, and their effect in high-acuity patients remains lacking. We examined the impact of perioperative muscle mass changes (ΔSMI) on high-acuity (MELD ≥35) LT recipients.

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Background: Sarcopenia has gained momentum as a potential risk-stratification tool in liver transplantation (LT). While LT recipients recently have more advanced end-stage liver disease, the impact of sarcopenia in high acuity recipients with a high model for end-stage liver disease (MELD) score remains unclear.

Methods: We retrospectively assessed sarcopenia by calculating skeletal muscle index (SMI) from cross-sectional area at third lumbar vertebra (cm ) and height (m ) in 296 patients with a CT ≤ 30 days prior to LT.

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