Recipient Versus Donor CYP3A4/5 Genotypes in Adult Liver Transplant Recipients to Achieve Therapeutic Tacrolimus Concentrations Early Post-Transplant.

Tacrolimus is an immunosuppressive agent with difficult dosing due to a narrow therapeutic index and large interpatient pharmacokinetic variability, for which CYP3A5 variation plays a role. Tacrolimus/CYP3A5 pharmacogenetic guidelines exclude liver transplant patients with a donor/recipient CYP3A5 mismatch. We sought to determine the influence of donor vs.

Understanding Immune Dynamics in Liver Transplant Through Mathematical Modeling.

Liver transplant can be a life-saving procedure for patients with end-stage liver disease. With the introduction of modern immunosuppressive therapies, short-term survival has significantly improved. However, long-term survival has not substantially improved in decades.

Donor and recipient genetic variants in drug metabolizing enzymes and transporters affect early tacrolimus pharmacokinetics after liver transplantation.

This study examines the influence of single nucleotide polymorphisms in drug metabolizing enzymes CYP3A4, CYP3A5, and UGT1A4, and the transporter ABCB1 on tacrolimus dose requirements and blood trough level variability in the period immediately after liver transplantation. We analyzed genotypes for these genes in 61 adult liver transplant recipients who received tacrolimus and their respective donors. Significant findings include increased average daily deviation (ADD) from the therapeutic range in patients with: donor CYP3A4*22 GG (1.

Tacrolimus dosing in liver transplant recipients using phenotypic personalized medicine: A phase 2 randomized clinical trial.

Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing.

Soluble DNA Concentration in the Perfusate is a Predictor of Posttransplant Renal Function in Hypothermic Machine Perfused Kidney Allografts.

Background: Hypothermic machine perfusion (HMP) has greatly improved kidney allograft preservation. However, tissue damage still occurs during HMP, affecting posttransplant graft function. Therefore, better methods are needed to continuously assess organ quality and to predict posttransplant graft function and survival.

Plasma Extracellular Vesicle-derived MicroRNA Associated with Human Alpha-1 Antitrypsin Deficiency-mediated Liver Disease.

Background And Aims: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with liver disease, ranging from fibrosis to hepatocellular carcinoma. The disease remains asymptomatic until its final stages when liver transplantation is the only available therapy. Biomarkers offer an advantage for disease evaluation.

GrB-Fc-KS49, an anti-EMP2 granzyme B fusion protein therapeutic alters immune cell infiltration and suppresses breast cancer growth.

Background: Granzyme B (GrB) is a key effector molecule, delivered by cytotoxic T lymphocytes and natural killer cells during immune surveillance to induce cell death. Fusion proteins and immunoconjugates represent an innovative therapeutic approach to specifically deliver a deadly payload to target cells. Epithelial membrane protein-2 (EMP2) is highly expressed in invasive breast cancer (BC), including triple-negative BC (TNBC), and represents an attractive therapeutic target.

Analyses of mitochondrial metabolism in diseases: a review on C magnetic resonance tracers.

Metabolic diseases such as obesity, type 2 diabetes, and cardiovascular diseases have become a global health concern due to their widespread prevalence and profound impact on life expectancy, healthcare expenditures, and the overall economy. Devising effective treatment strategies and management plans for these diseases requires an in-depth understanding of the pathophysiology of the metabolic abnormalities associated with each disease. Mitochondrial dysfunction is intricately linked to a wide range of metabolic abnormalities and is considered an important biomarker for diseases.

Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation.

Objectives: Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs).

Loss of CEACAM1 in hepatocytes causes hepatic fibrosis.

Background: The role of insulin resistance in hepatic fibrosis in Metabolic dysfunction-Associated SteatoHepatitis (MASH) remains unclear. Carcinoembryonic Antigen-related Cell Adhesion Molecule1 protein (CEACAM1) promotes insulin clearance to maintain insulin sensitivity and repress de novo lipogenesis, as bolstered by the development of insulin resistance and steatohepatitis in AlbuminCre + Cc1 mice with liver-specific mouse gene encoding CEACAM1 protein (Ceacam1) deletion. We herein investigated whether these mice also developed hepatic fibrosis and whether hepatic CEACAM1 is reduced in patients with MASH at different fibrosis stages.

Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through lipophagy.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation.

Detecting Residual Chronic Salmonella Typhi Carriers on the Road to Typhoid Elimination in Santiago, Chile, 2017-2019.

Background: In Santiago, Chile, where typhoid had been hyperendemic (1977-1991), we investigated whether residual chronic carriers could be detected among household contacts of non-travel-related typhoid cases occurring during 2017-2019.

Methods: Culture-confirmed cases were classified as autochthonous (domestically acquired) versus travel/immigration related. Household contacts of cases had stool cultures and serum Vi antibody measurements to detect chronic Salmonella Typhi carriers.

Current Trends in Surgical Management of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Surgical management, including hepatic resection, liver transplantation, and ablation, offers the greatest potential for a curative approach. This review aims to discuss recent advancements in HCC surgery and identify unresolved issues in the field.

Effects of Clinical and Tumor Characteristics on Survival in Patients with Hepatocellular Carcinoma with Bone Metastasis.

Background: Advanced hepatocellular carcinoma (HCC) generally has a dismal prognosis. Bone metastases from HCC are infrequent, with a poorer prognosis. However, the survival influencing factors are not yet well understood.

Personalized Tacrolimus Dosing After Liver Transplantation: A Randomized Clinical Trial.

Background: Inter- and intra-individual variability in tacrolimus dose requirements mandates empirical clinician-titrated dosing that frequently results in deviation from a narrow target range. Improved methods to individually dose tacrolimus are needed. Our objective was to determine whether a quantitative, dynamically-customized, phenotypic-outcome-guided dosing method termed Phenotypic Personalized Medicine (PPM) would improve target drug trough maintenance.

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis.

Objectives: Hepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1 mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1 male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target.

Low vs Standard-Dose Indocyanine Green in the Identification of Biliary Anatomy Using Near-Infrared Fluorescence Imaging: A Multicenter Randomized Controlled Trial.

Background: Near-infrared fluorescence imaging using intravenous indocyanine green (ICG) facilitates intraoperative identification of biliary anatomy. We hypothesize that a much lower dose of ICG than the standard decreases hepatic and background fluorescence and improves bile duct visualization.

Study Design: In this multicenter randomized controlled trial, 55 adult patients undergoing laparoscopic cholecystectomy were randomized to low-dose (0.