A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells.

Introduction: Significant heterogeneity exists within the tumor-infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and may retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted T cell subpopulations critical to the improvement of therapeutic approaches.

Methods: To investigate mechanisms associated with terminally exhausted T cells, we sorted and performed transcriptional profiling of CD8 tumor-infiltrating lymphocytes (TILs) co-expressing the exhaustion markers PD-1 and TIM-3 from large-volume melanoma tumors.

Association of pancreatic fat on imaging with pediatric metabolic co-morbidities.

Background: The relationship between pancreatic fat on imaging and metabolic co-morbidities has not been established in pediatrics. We sought to investigate the relationship between pancreatic fat measured by MRI and endocrine/exocrine dysfunctions along with the metabolic co-morbidities in a cohort of children.

Objective: To investigate relationships between pancreatic fat quantified by MRI and endocrine and exocrine conditions and metabolic co-morbidities in a cohort of children.

Image or scope: Magnetic resonance imaging and endoscopic testing for exocrine and endocrine pancreatic insufficiency in children.

Objectives: We sought to evaluate associations between Magnetic Resonance Imaging (MRI) findings, exocrine pancreatic insufficiency (EPI) and endocrine insufficiency (prediabetes or diabetes) in children.

Methods: This was a retrospective study that included patients<21 years of age who underwent MRI and endoscopic pancreatic function testing (ePFT; reference standard for pancreatic exocrine function) within 3 months. MRI variables included pancreas parenchymal volume, secreted fluid volume in response to secretin, and T1 relaxation time.

Quantification of Hepatic Steatosis by Ultrasound: Prospective Comparison With MRI Proton Density Fat Fraction as Reference Standard.

Multiple ultrasound platforms now provide quantitative measures of hepatic steatosis. One such measure is the ultrasound-derived fat fraction (UDFF), which combines attenuation and backscatter quantification. The purpose of this study was to characterize agreement between UDFF and MRI proton-density fat fraction (PDFF) measurements.

Agreement between serum estimates of glomerular filtration rate (GFR) and a reference standard of radioisotopic GFR in children with cancer.

Background: Accurate assessment of renal function is important in the care of children with cancer because renal function has implications for anti-tumor medication dosing and eligibility for clinical trials.

Objective: To characterize agreement between serum estimates of glomerular filtration rate (GFR) and a reference standard of radioisotopic GFR in a large pediatric oncology cohort.

Materials And Methods: We conducted a retrospective cross-sectional study of children who had both radioisotopic GFR (Tc-diethylenetriaminepentaacetic acid, or Tc-DTPA) and serum labs (creatinine, cystatin C) obtained <7 days apart between January 2017 and August 2019.

A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients.

Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers.

Detection of urinary tract calculi on CT images reconstructed with deep learning algorithms.

Background: Deep learning Computed Tomography (CT) reconstruction (DLR) algorithms promise to improve image quality but the impact on clinical diagnostic performance remains to be demonstrated. We aimed to compare DLR to standard iterative reconstruction for detection of urolithiasis by unenhanced CT in children and young adults.

Methods: This was an IRB approved retrospective study involving post-hoc reconstruction of clinically acquired unenhanced abdomen/pelvis CT scans.

Comparison of 0.3-mSv CT to Standard-Dose CT for Detection of Lung Nodules in Children and Young Adults With Cancer.

. CT is the imaging modality of choice to identify lung metastasis. .

Under-reporting of Hepatic Steatosis in Children: A Missed Opportunity for Early Detection.

Objective: To determine the prevalence of underreporting of hepatic steatosis found incidentally on computed tomography (CT).

Study Design: Retrospective cross-sectional study including patients <18 years of age who had undergone unenhanced abdominal CT for evaluation of nephrolithiasis. Hepatic and splenic attenuation were measured independently by 2 reviewers.

Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress.

Key Points: Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia. We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD /NADH ratio and ATP content. During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids.

Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis.

Background & Aims: Increased skeletal muscle ammonia uptake with loss of muscle mass adversely affects clinical outcomes in cirrhosis. Hyperammonemia causes reduced protein synthesis and sarcopenia but the cellular responses to impaired proteostasis and molecular mechanism of l-leucine induced adaptation to ammonia induced stress were determined.

Methods: Response to activation of amino acid deficiency sensor, GCN2, in the skeletal muscle from cirrhotic patients and the portacaval anastomosis (PCA) rat were quantified.

Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis.

Unlabelled: Skeletal muscle loss (sarcopenia) is a major clinical complication in alcoholic cirrhosis with no effective therapy. Skeletal muscle autophagic proteolysis and myostatin expression (inhibitor of protein synthesis) are increased in cirrhosis and believed to contribute to anabolic resistance. A prospective study was performed to determine the mechanisms of sarcopenia in alcoholic cirrhosis and potential reversal by leucine.

Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet-induced NASH model.

Background/aims: Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH). As the contribution of specific caspases remains unclear, our aim was to ascertain the effect of caspase 3 suppression on liver injury and fibrogenesis.

Methods: C57BL/6 wild-type (WT) and caspase 3 knock out (Casp3 (-/-)) mice were placed on a methionine- and choline-deficient (MCD) diet for 6 weeks to induce steatohepatitis and liver fibrosis.

Alcohol-induced autophagy contributes to loss in skeletal muscle mass.

Patients with alcoholic cirrhosis and hepatitis have severe muscle loss. Since ethanol impairs skeletal muscle protein synthesis but does not increase ubiquitin proteasome-mediated proteolysis, we investigated whether alcohol-induced autophagy contributes to muscle loss. Autophagy induction was studied in: A) Human skeletal muscle biopsies from alcoholic cirrhotics and controls, B) Gastrocnemius muscle from ethanol and pair-fed mice, and C) Ethanol-exposed murine C2C12 myotubes, by examining the expression of autophagy markers assessed by immunoblotting and real-time PCR.

Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB-mediated mechanism.

Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea.

Adipocyte hypertrophy is associated with lysosomal permeability both in vivo and in vitro: role in adipose tissue inflammation.

Obesity in both humans and rodents is characterized by adipocyte hypertrophy and the presence of death adipocytes surrounded by macrophages forming "crown-like structures." However, the biochemical pathways involved in triggering adipocyte death as well as the role of death adipocytes in adipose tissue remodeling and macrophage infiltration remain poorly understood. We now show that induction of adipocyte hypertrophy by incubation of mature adipocytes with saturated fatty acids results in lysosomal destabilization and cathepsin B (ctsb), a key lysosomal cysteine protease, activation and redistribution into the cytosol.

Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is typically associated with pro-apoptotic caspase activation. A potential role for pro-inflammatory caspases remains incompletely understood. Our aims were to examine a potential role of caspase-1 in the development of liver damage and fibrosis in NASH.

Transcriptional profile of genes involved in oxidative stress and antioxidant defense in a dietary murine model of steatohepatitis.

Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic steatohepatitis (NASH). However, the relevant pathways that contribute to oxidative damage in vivo remain poorly understood. Here we explore the gene-expression patterns related to oxidative stress, antioxidant defense, and reactive oxygen metabolism in an established dietary murine model of NASH.

Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis.

Adipocyte death has been reported in both obese humans and rodents. However, its role in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity has not been studied. We now show using real-time reverse transcription-PCR arrays that adipose tissue of obese mice display a pro-apoptotic phenotype.