Xenotransplantation: future frontiers and challenges.

Purpose Of Review: Recent advancements in genetic engineering have propelled the field of xenotransplantation from preclinical models to early compassionate use cases. As first-in-human clinical trials (FIHCTs) approach, we examine recent developments, ethical and regulatory challenges, immunological considerations, and the clinical infrastructure necessary for successful xenotransplantation trials.

Recent Findings: Expanded access transplants of pig hearts, kidneys, and livers have identified key challenges.

Clinical Outcomes and Donor-specific Antibody Rebound 5 y After Kidney Transplant Enabled by Imlifidase Desensitization.

Background: Imlifidase is an IgG-cleaving endopeptidase conditionally approved in Europe for desensitization of highly sensitized patients before kidney transplantation. We present 5-y outcomes and donor-specific antibody (DSA) levels for clinical trial participants from a single site who received imlifidase for desensitization before incompatible transplantation (NCT02790437).

Methods: Imlifidase was administered up to 24 h before living or deceased donor kidney transplantation.

Second Time Around: Increased Rate of Living Donation From Repeat Organ Donors.

Introduction: Some living organ donors will decide to donate again at a later date. Evidence has indicated that this practice may have increased in recent years. We evaluated the incidence and outcomes of this practice to inform counseling of potential repeat donors.

Evaluating Large Language Models in extracting cognitive exam dates and scores.

Ensuring reliability of Large Language Models (LLMs) in clinical tasks is crucial. Our study assesses two state-of-the-art LLMs (ChatGPT and LlaMA-2) for extracting clinical information, focusing on cognitive tests like MMSE and CDR. Our data consisted of 135,307 clinical notes (Jan 12th, 2010 to May 24th, 2023) mentioning MMSE, CDR, or MoCA.

Prophylactic 2-week Glecaprevir/Pibrentasvir in Hepatitis C positive to negative kidney transplantation.

Background And Hypothesis: Hepatitis C virus (HCV) positive-to-negative kidney transplants (KT) require direct acting antiviral therapy, but the optimal timing and duration remain unclear. We hypothesized that 14-day prophylactic course of glecaprevir/pibrentasvir 300/120 mg (GLE/PIB) would be safe and effective at treating donor-derived HCV viremia.

Methods: This was a prospective, single-center, single-arm, open-label pilot study.

Mineralocorticoid Receptor in Endothelial Cells Contributes to Vascular Endothelial Growth Factor Receptor Inhibitor-Induced Vascular and Kidney Damage.

Background: Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer patient survival by inhibiting tumor angiogenesis. However, VEGFRis induce treatment-limiting hypertension which has been associated with impaired vascular endothelial cell (EC) function and kidney damage. The mineralocorticoid receptor (MR) regulates blood pressure (BP) via its effects on the vasculature and the kidney.

ChatGPT Solving Complex Kidney Transplant Cases: A Comparative Study With Human Respondents.

Introduction: ChatGPT has shown the ability to answer clinical questions in general medicine but may be constrained by the specialized nature of kidney transplantation. Thus, it is important to explore how ChatGPT can be used in kidney transplantation and how its knowledge compares to human respondents.

Methods: We prompted ChatGPT versions 3.

Identifying mitigating strategies for endothelial cell dysfunction and hypertension in response to VEGF receptor inhibitors.

Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients.

Rapamycin Reduces Arterial Mineral Density and Promotes Beneficial Vascular Remodeling in a Murine Model of Severe Medial Arterial Calcification.

Peripheral artery disease (PAD) is the narrowing of the arteries that carry blood to the lower extremities. PAD has been traditionally associated with atherosclerosis. However, recent studies have found that medial arterial calcification (MAC) is the primary cause of chronic limb ischemia below the knee.

Endothelium as a Source of Cardiovascular Toxicity From Antitumor Kinase Inhibitors.

Kinase inhibitors (KIs) targeting oncogenic molecular pathways have revolutionized cancer therapy. By directly targeting specific tumor-driving kinases, targeted therapies have fewer side effects compared with chemotherapy. Despite the enhanced specificity, cardiovascular side effects have emerged with many targeted cancer therapies that limit long-term outcomes in patients with cancer.

Integrative multi-omics profiling in human decedents receiving pig heart xenografts.

In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity.

Development and Implementation of an Integrated Preclinical Atherosclerosis Database.

Background: Basic scientists have used preclinical animal models to explore mechanisms driving human diseases for decades, resulting in thousands of publications, each supporting causative inferences. Despite substantial advances in the mechanistic construct of disease, there has been limited translation from individual studies to advances in clinical care. An integrated approach to these individual studies has the potential to improve translational success.

Prior Exposure to Experimental Preeclampsia Increases Atherosclerotic Plaque Inflammation in Atherogenic Mice-Brief Report.

Background: Women with a history of preeclampsia have evidence of premature atherosclerosis and increased risk of myocardial infarction and stroke compared with women who had a normotensive pregnancy. Whether this is due to common risk factors or a direct impact of prior preeclampsia exposure has never been tested in a mouse atherosclerosis model.

Methods: Pregnant LDLR-KO (low-density lipoprotein receptor knockout; n=35) female mice were randomized in midgestation to sFlt1 (soluble fms-like tyrosine kinase 1)-expressing adenovirus or identical control adenovirus.

Single center utilization and post-transplant outcomes of thoracoabdominal normothermic regional perfusion deceased cardiac donor organs.

Introduction: Thoracoabdominal normothermic regional perfusion (TA-NRP) following cardiac death is an emerging multivisceral organ procurement technique. Recent national studies on outcomes of presumptive TA-NRP-procured organs are limited by potential misclassification since TA-NRP is not differentiated from donation after cardiac death (DCD) in registry data.

Methods: We studied 22 donors whose designees consented to TA-NRP and organ procurement performed at our institution between January 20, 2020 and July 3, 2022.

Mineralocorticoid Receptors in Vascular Smooth Muscle: Blood Pressure and Beyond.

After half a century of evidence suggesting the existence of mineralocorticoid receptors (MR) in the vasculature, the advent of technology to specifically knockout the MR from smooth muscle cells (SMCs) in mice has elucidated contributions of SMC-MR to cardiovascular function and disease, independent of the kidney. This review summarizes the latest understanding of the molecular mechanisms by which SMC-MR contributes to (1) regulation of vasomotor function and blood pressure to contribute to systemic and pulmonary hypertension; (2) vascular remodeling in response to hypertension, vascular injury, obesity, and aging, and the impact on vascular calcification; and (3) cardiovascular pathologies including aortic aneurysm, heart valve dysfunction, and heart failure. Data are reviewed from in vitro studies using SMCs and in vivo findings from SMC-specific MR-knockout mice that implicate target genes and signaling pathways downstream of SMC-MR.

Evaluating Large Language Models in Extracting Cognitive Exam Dates and Scores.

Importance: Large language models (LLMs) are crucial for medical tasks. Ensuring their reliability is vital to avoid false results. Our study assesses two state-of-the-art LLMs (ChatGPT and LlaMA-2) for extracting clinical information, focusing on cognitive tests like MMSE and CDR.

Inhibition of the histone methyltransferase EZH2 induces vascular stiffness.

Vascular stiffness increases with aging, obesity and hypertension and predicts cardiovascular risk. The levels of histone H3-lysine-27 methylation (H3K27me) and the histone methyltransferase EZH2 both decrease in aging vessels, driving vascular stiffness. The impact of EZH2 inhibitors on vascular stiffness is unknown.

Lipid droplets in the endothelium: The missing link between metabolic syndrome and cardiovascular disease?

The physiology of lipid droplets (LDs) has been most extensively characterized in adipocytes, but LDs also accumulate in endothelial cells lining blood vessels in response to changing levels of triglycerides. In recent issues of the JCI, two independent papers highlight a direct role of endothelial LDs in the genesis of hypertension and atherosclerosis in rodent models. Kim et al.

Evaluation of anesthetic skills acquisition in pre-graduate veterinary students with different grades of anesthetic experience using veterinary simulation exercises.

Background: Anesthetic skills are usually learned through continuous supervision by experienced trainers who observe, advise and challenge students. Current educational techniques rely less on live animal training and include the use of simulations and models for teaching and assessment of surgical and anesthetic skills.

Objective: To evaluate the development of anesthetic skills of veterinary students having different levels of previous experience using simulation.

A Novel Dual-Function Nitric Oxide Donor Therapy for Preeclampsia-A Proof-of-Principle Study in a Murine Model.

: Preeclampsia (PE) is a hypertensive disorder of pregnancy that is associated with substantial morbidity and mortality for the mother and fetus. Reduced nitric oxide bioavailability and oxidative stress contribute to the maternal and fetal pathophysiology of PE. In this study, we evaluated the efficacy of a novel dual-function nitric oxide donor/redox modulator, AKT-1005, in reducing PE symptoms in a mouse model of PE.

Differential vascular endothelial cell toxicity of established and novel BCR-ABL tyrosine kinase inhibitors.

BCR-ABL tyrosine kinase inhibitors (TKIs) have dramatically improved survival in Philadelphia chromosome-positive leukemias. Newer BCR-ABL TKIs provide superior cancer outcomes but with increased risk of acute arterial thrombosis, which further increases in patients with cardiovascular comorbidities and mitigates survival benefits compared to imatinib. Recent studies implicate endothelial cell (EC) damage in this toxicity by unknown mechanisms with few side-by-side comparisons of multiple TKIs and with no available data on endothelial impact of recently approved TKIs or novels TKIs being tested in clinical trials.

The Mineralocorticoid Receptor in the Vasculature: Friend or Foe?

Originally described as the renal aldosterone receptor that regulates sodium homeostasis, it is now clear that mineralocorticoid receptors (MRs) are widely expressed, including in vascular endothelial and smooth muscle cells. Ample data demonstrate that endothelial and smooth muscle cell MRs contribute to cardiovascular disease in response to risk factors (aging, obesity, hypertension, atherosclerosis) by inducing vasoconstriction, vascular remodeling, inflammation, and oxidative stress. Extrapolating from its role in disease, evidence supports beneficial roles of vascular MRs in the context of hypotension by promoting inflammation, wound healing, and vasoconstriction to enhance survival from bleeding or sepsis.

Development and implementation of an integrated preclinical atherosclerosis database.

Background: Basic scientists have used preclinical animal models to explore mechanisms driving human diseases for decades, resulting in thousands of publications, each supporting causative inferences. Despite substantial advances in the mechanistic construct of disease, there has been limited translation from individual studies to advances in clinical care. An integrated approach to these individual studies has the potential to improve translational success.