Normothermic cardiopulmonary bypass and beating heart surgery for renal cell cancer with tumor thrombus extension into inferior vena cava and right atrium: a less invasive strategy.

Purpose: Management of renal cell carcinoma (RCC) with inferior vena cava (IVC) extension is one of the greatest challenges in urology. The gold standard treatment includes extracorporeal circulation and deep hypothermic circulatory arrest (DHCA). However, this surgical treatment has an impact on survival and prognosis.

Repeated dosing of AAV-mediated liver gene therapy in juvenile rat and mouse models of Crigler-Najjar syndrome type I.

Crigler-Najjar syndrome is an ultra-rare monogenic recessive liver disease caused by gene mutations. Complete UGT1A1 deficiency results in severe unconjugated hyperbilirubinemia in newborns that, if not treated, may lead to brain damage and death. Treatment is based on intensive phototherapy, but its efficacy decreases with age, rendering liver transplantation the only curative option.

Combined fluorometric analysis of biliverdin and bilirubin by the recombinant protein HUG.

Biliverdin is a secondary metabolite of heme catabolism. It is formed by the reaction catalyzed by heme oxygenase, which converts the heme group contained in proteins such as hemoglobin, myoglobin, cytochromes, and catalase into biliverdin, iron (II) and CO in equimolar amounts, consuming NADPH. Biliverdin is then reduced to bilirubin by biliverdin reductase.

CRISPR-Cas9-mediated somatic correction of a one-base deletion in the Ugt1a gene ameliorates hyperbilirubinemia in Crigler-Najjar syndrome mice.

(AAV)-mediated episomal gene replacement therapy for monogenic liver disorders is currently limited in pediatric settings due to the loss of vector DNA, associated with hepatocyte duplication during liver growth. Genome editing is a promising strategy leading to a permanent and specific genome modification that is transmitted to daughter cells upon proliferation. Using genome targeting, we previously rescued neonatal lethality in mice with Crigler-Najjar syndrome.

Prognosticating Mortality of Primary Cardiogenic Shock Requiring Extracorporeal Life Support: The RESCUE Score.

We aimed to identify prognostic laboratory markers during extracorporeal life support (ECLS) in patients with primary refractory cardiogenic shock (RCS) and to create a preliminary specific mortality score. All 208 consecutive subjects admitted for primary RCS and treated with ECLS between January-2009 and December-2018 were retrospectively analyzed. Multivariate regression analysis on laboratory markers during the first nine days of ECLS was used to develop a "Refractory End-stage Shock CUred with Ecls" (RESCUE) score.

Activation of Alternative Bilirubin Clearance Pathways Partially Reduces Hyperbilirubinemia in a Mouse Model Lacking Functional Ugt1a1 Activity.

Bilirubin is a heme catabolite and Ugt1a1 is the only enzyme involved in the biological elimination of bilirubin. Partially functional or non-functional Ugt1a1 may result in neuronal damage and death due to the accumulation of unconjugated bilirubin in the brain. The understanding of the role of alternative bilirubin detoxification mechanisms that can reduce bilirubin toxicity risk is crucial for developing novel therapeutic strategies.

How to Optimize ECLS Results beyond Ventricular Unloading: From ECMO to CentriMag eVAD.

CentriMag extracorporeal VAD support could represent a more physiological choice than conventional ECMO in primary cardiogenic shock. We therefore evaluated the outcome of patients with primary cardiogenic shock who were supported with CentriMag extracorporeal VAD implantation versus conventional ECMO. We retrospectively reviewed all extracorporeal life supports implanted for primary cardiogenic shock between January 2009 and December 2018 at our institution.

Technology and technique for left ventricular assist device optimization: A Bi-Tech solution.

Background: We investigated the synergistic effect of the new cone-bearing design of Jarvik 2000 (Jarvik Heart Inc., NY) together with a minimally-invasive approach to outcomes of LVAD patients.

Methods: We retrospectively reviewed all patients from 5 institutions involved in the Jarvik 2000 Italian Registry, from October 2008 to October 2016.

Fludarabine increases nuclease-free AAV- and CRISPR/Cas9-mediated homologous recombination in mice.

Homologous recombination (HR)-based gene therapy using adeno-associated viruses (AAV-HR) without nucleases has several advantages over classic gene therapy, especially the potential for permanent transgene expression. However, the low efficiency of AAV-HR remains a major limitation. Here, we tested a series of small-molecule compounds and found that ribonucleotide reductase (RNR) inhibitors substantially enhance AAV-HR efficiency in mouse and human liver cell lines approximately threefold.

Long-Term Effects of Biliverdin Reductase a Deficiency in Mice: Impact on Redox Status and Metabolism.

Accumulation of neurotoxic bilirubin due to a transient neonatal or persistent inherited deficiency of bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising. We evaluated the impact of deficiency in neonatal and aged mice, in a background of unconjugated hyperbilirubinemia, by abolishing bilirubin production.

Low efficacy of recombinant SV40 in Ugt1a1-/- mice with severe inherited hyperbilirubinemia.

In contrast to AAV, Simian Virus 40 (rSV40) not inducing neutralizing antibodies (NAbs) allowing re-treatment seems a promising vector for neonatal treatment of inherited liver disorders. Several studies have reported efficacy of rSV40 in animal models for inherited liver diseases. In all studies the ubiquitous endogenous early promoter controlled transgene expression establishing expression in all transduced tissues.

Efficacy of AAV8-h with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients.

A clinical trial using adeno-associated virus serotype 8 (AAV8)-human uridine diphosphate glucuronosyltransferase 1A1 (h) to treat inherited severe unconjugated hyperbilirubinemia (Crigler-Najjar syndrome) is ongoing, but preclinical data suggest that long-term efficacy in children is impaired due to loss of transgene expression upon hepatocyte proliferation in a growing liver. This study aims to determine at what age long-term efficacy can be obtained in the relevant animal model and whether immune modulation allows re-treatment using the same AAV vector. Neonatal, suckling, and juvenile Ugt1a1-deficient rats received a clinically relevant dose of AAV8-h, and serum bilirubin levels and anti-AAV8 neutralizing antibodies (NAbs) in serum were monitored.

Long-term correction of ornithine transcarbamylase deficiency in Spf-Ash mice with a translationally optimized AAV vector.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked liver disorder caused by partial or total loss of OTC enzyme activity. It is characterized by elevated plasma ammonia, leading to neurological impairments, coma, and death in the most severe cases. OTCD is managed by combining dietary restrictions, essential amino acids, and ammonia scavengers.

Neoplastic Cells are the Major Source of MT-MMPs in -Mutant Glioma, Thus Enhancing Tumor-Cell Intrinsic Brain Infiltration.

Tumor-cell infiltration is a major obstacle to successful therapy for brain tumors. Membrane-type matrix metalloproteinases (MT-MMPs), a metzincin subfamily of six proteases, are important mediators of infiltration. The cellular source of MT-MMPs and their role in glioma biology, however, remain controversial.

From bench to bedside: Impact of left ventricular assist device outflow conduit anastomosis position on outcome.

Continuous flow left ventricular assist devices (LVADs) have become a valuable therapy for end-stage heart failure. In vitro research highlighted a role of outflow cannula position on the pattern of blood flow in the aorta. However, the clinical effects of the alterations of flow remain unclear.

A Quantitative Potency Assay for Adeno-Associated Virus Vectors Encoding for the Transgene.

Potency assessment of clinical-grade vector lots is crucial to support adeno-associated virus (AAV) vector release and is required for future marketing authorization. We have developed and validated a cell-based, quantitative potency assay that detects both transgenic expression and activity of an AAV8-h vector, which is currently under clinical evaluation for the treatment of Crigler-Najjar syndrome. Potency of AAV8-h was evaluated .

Percutaneous coronary intervention versus coronary artery bypass graft for left main coronary artery disease: A meta-analysis.

Background: The optimal revascularization strategy for patients with left main coronary artery disease is still controversial. This is systematic review and meta-analysis aims to evaluate the outcomes of percutaneous coronary intervention (PCI) with drug-eluting stents compared with coronary artery bypass graft (CABG) for LM disease.

Methods: Online electronic databases were systematically reviewed until January 2020 for randomized trials comparing PCI with drug-eluting stents and CABG.

Human liver stem cells express UGT1A1 and improve phenotype of immunocompromised Crigler Najjar syndrome type I mice.

Crigler Najjar Syndrome type I (CNSI) is a rare recessive disorder caused by mutations in the Ugt1a1 gene. There is no permanent cure except for liver transplantation, and current therapies present several shortcomings. Since stem cell-based therapy offers a promising alternative for the treatment of this disorder, we evaluated the therapeutic potential of human liver stem cells (HLSC) in immune-compromised NOD SCID Gamma (NSG)/Ugt1 mice, which closely mimic the pathological manifestations in CNSI patients.

Consolidated quality improvements following benchmarking with cardiothoracic surgery registries-a systematic review.

The influence of registries in medicine is large. However, there has been no systematic assessment conducted to quantify the impact of benchmarking with registries focused on cardiothoracic surgery. Numerous publications conclude that registry participation leads to improvement of outcomes for patients.

Experimental models assessing bilirubin neurotoxicity.

The molecular and cellular events leading to bilirubin-induced neurotoxicity, the mechanisms regulating liver and intestine expression in neonates, and alternative pathways of bilirubin catabolism remain incompletely defined. To answer these questions, researchers have developed a number of model systems to closely recapitulate the main characteristics of the disease, ranging from tissue cultures to engineered mouse models. In the present review we describe in vitro, ex vivo, and in vivo models developed to study bilirubin metabolism and neurotoxicity, with a special focus on the use of engineered animal models.

Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases.

Non-integrative AAV-mediated gene therapy in the liver is effective in adult patients, but faces limitations in pediatric settings due to episomal DNA loss during hepatocyte proliferation. Gene targeting is a promising approach by permanently modifying the genome. We previously rescued neonatal lethality in Crigler-Najjar mice by inserting a promoterless human uridine glucuronosyl transferase A1 (UGT1A1) cDNA in exon 14 of the albumin gene, without the use of nucleases.