Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.

Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO.

Lysosomal/mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.

Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction, LMI) is, emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival.

Structural mechanism of CBR binding to peripheral and biased inverse agonists.

The cannabinoid receptor 1 (CBR) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CBR antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted their further therapeutic development. The peripherally restricted CBR inverse agonists MRI-1867 and MRI-1891 represent a new generation of compounds that retain the metabolic benefits of CBR inhibitors while sparing the negative psychiatric effects.

Chemical Synthesis and Antifibrotic Properties of (±)-Cochlearol T, (±)-Ganocochlearin A, and (±)-Cochlearol Y.

The cochlearols and ganocochlearins are natural products with unique antifibrotic and renoprotective activities in models of kidney disease. They represent compelling lead compounds for pharmacological intervention against kidney disease, often characterized by renal fibrosis. We report a four-step synthesis of (±)-cochlearol T () and the first reported syntheses of (±)-ganocochlearin A () and (±)-cochlearol Y () through a strategy that includes a Robinson annulation and unexpected oxidative aromatization.

Relationship between self-reported concussion history, cognition, and mood among former collegiate athletes.

: This study explored the relationship between concussion history and cognition/mood in former collegiate athletes in middle-to-later adulthood. : 407 former collegiate athletes aged 50+ ( = 61.4; 62.

Enhancing Ultrasound Image Quality Across Disease Domains: Application of Cycle-Consistent Generative Adversarial Network and Perceptual Loss.

Background: Numerous studies have explored image processing techniques aimed at enhancing ultrasound images to narrow the performance gap between low-quality portable devices and high-end ultrasound equipment. These investigations often use registered image pairs created by modifying the same image through methods like down sampling or adding noise, rather than using separate images from different machines. Additionally, they rely on organ-specific features, limiting the models' generalizability across various imaging conditions and devices.

There Is Significant Within-Subject Variation in the Time from Light Stimulus to Maximum Pupil Constriction Among Healthy Controls.

: Handheld quantitative pupilometers (QPs) measure each phase of the pupillary light reflex (PLR) and provide a summary score based on these values. One phase of the PLR is the period of time from the onset of light exposure to the maximum constriction of the pupil, also known as time to maximum constriction (tMC). Although tMC has been found to vary significantly among patients with neurological injury, there are no studies reporting tMC in healthy controls.

A Case-Control Study of Dietary Choline Intake and Risk of Colorectal Cancer Modified by Dietary B-Vitamin Intake.

Background/objectives: The incidence of colorectal cancer (CRC) is rising, and Western diets high in red and processed meats may be contributing. It is important to identify dietary nutrients that increase CRC risk and perhaps interventions that may modulate such risk. The relationship between dietary choline intake and CRC is still unclear.

Achieving theranostic probes targeting BRD3/BRD4 for imaging and therapy of tumor.

The BET family proteins play pleiotropic roles in the tumorigenesis and growth of various human malignancies that have aroused great interests as the cancer therapeutic targets. Therefore, it's significant to develop labeling toolkits for the dynamic monitoring of BET family proteins in living tumor cells and tissue slices. In particular, there are few small-molecule fluorescent probes based on BET family proteins developed for real-time imaging of these proteins in tumor cells and tissues and treatment of breast cancer.

Structural mechanisms of PIP activation and SEA0400 inhibition in human cardiac sodium-calcium exchanger NCX1.

Na/Ca exchangers (NCXs) transport Ca across the plasma membrane in exchange for Na and play a vital role in maintaining cellular Ca homeostasis. Our previous structural study of human cardiac NCX1 (HsNCX1) reveals the overall architecture of the eukaryotic exchanger and the formation of the inactivation assembly by the intracellular regulatory domain that underlies the cytosolic Na-dependent inactivation and Ca activation of NCX1. Here we present the cryo-EM structures of HsNCX1 in complex with a physiological activator phosphatidylinositol 4,5-bisphosphate (PIP), or pharmacological inhibitor SEA0400 that enhances the inactivation of the exchanger.

Benchmarks of Success in Radiotherapy versus Systemic Therapy National Clinical Trials Network (NCTN) Randomized Controlled Trials Sponsored by the National Cancer Institute (NCI).

Background: The National Clinical Trials Network (NCTN) is the largest government sponsored organization in the United States tasked with funding randomized controlled trials (RCTs) in oncology. It is unknown whether there are differences in study design by treatment modality. We evaluated differences in methodology between trials testing radiotherapy versus systemic therapy.

TREATMENT OF HYPOTHYROIDISM BY AGE AND SEX IN THE UNITED STATES: A NHANES AND OPTUM CLAIMS DATA ANALYSIS.

Objective: Recent data using NHANES and Optum Claims data (OCD) showed an increase in primary hypothyroidism (HT) prevalence in the United States following the 2002 NHANES III report. Using these data, we characterized treatment patterns of overt HT (OHT) in the US.

Methods: Data on adults with OHT were collected from NHANES (2009-2012) and OCD (2012-2019).

Design, Synthesis and Biological Evaluation of 2-Phenyl Indole Analogues of OXi8006 as Colchicine Site Inhibitors of Tubulin Polymerization and Vascular Disrupting Agents.

Inhibitors of tubulin polymerization represent a promising therapeutic approach for the treatment of solid tumors. Molecules that bind to the colchicine site are of interest as they can function with a dual mechanism of action as both potent antiproliferative agents and tumor-selective vascular disrupting agents (VDAs). One such example is a 2-aryl-3-aroyl-indole molecule (OXi8006) from our laboratory that demonstrates potent inhibition of tubulin polymerization and strong antiproliferative activity (cytotoxicity) against a variety of human cancer cell lines.

Cefiderocol pharmacokinetics during acute pulmonary exacerbations in hospitalized adult persons with cystic fibrosis.

Persons with CF (pwCF) present altered pharmacokinetics (PK) and are often infected with multidrug-resistant (MDR) bacteria. Herein, we describe the PK of cefiderocol, a siderophore cephalosporin with potent activity against MDR Gram-negative rods, in hospitalized adult pwCF with acute pulmonary exacerbation (APE). PwCF received ≥3 doses of 2 g cefiderocol (3 h infusion) with frequency determined according to their estimated glomerular filtration rate (eGFR).

Isosteric 3D Bicyclo[1.1.1]Pentane (BCP) Core-Based Lipids for mRNA Delivery and CRISPR/Cas Gene Editing.

Lipid nanoparticles (LNPs) are an essential component of messenger RNA (mRNA) vaccines and genome editing therapeutics. Ionizable amino lipids, which play the most crucial role in enabling mRNA to overcome delivery barriers, have, to date, been restricted to two-dimensional (2D) architectures. Inspired by improved physicochemical properties resulting from the incorporation of three-dimensionality (3D) into small-molecule drugs, we report the creation of 3D ionizable lipid designs through the introduction of bicyclo[1.

Phase 1/2 trial of XPO1 inhibitor selinexor plus docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer.

Purpose: Patients with KRAS mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated advanced KRAS mutant NSCLC.

Patients And Methods: The primary outcome of this multi-center phase 1/2 dose escalation trial of selinexor plus docetaxel was safety and tolerability.

Glucagon-like Peptide-1 receptor agonists versus dipeptidyl-peptidase 4 inhibitors in advanced chronic kidney disease and end stage kidney disease: Real world effectiveness and persistence of therapy.

Background: Atherosclerotic cardiovascular disease is the leading cause of death in people with type 2 diabetes (T2D) and chronic kidney disease (CKD) or end-stage kidney disease (ESKD). Glucagon-Like Peptide-1 receptor agonists (GLP-1RA) reduce cardiovascular events, improve glycemic control, promote weight loss, and slow progression of nephropathy. Despite these benefits and professional society treatment guidelines recommendations, GLP-1RAs remain under-utilized in people with advanced CKD and ESKD due to tolerability and safety concerns.

Classification of intrahepatic cholangiocarcinoma.

Cholangiocarcinoma is a heterogenous malignancy with various classifications based on location, morphological features, histological features, and actionable genetic mutations. Intrahepatic cholangiocarcinoma (ICC), which arises in and proximal to second order bile ducts, is the second most common primary liver malignancy after hepatocellular carcinoma. In this review, we will discuss ICC risk factors, precursor lesions, various growth, anatomic, morphologic, and histologic classifications, rare variants, and differential diagnoses.

The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice.

Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined.

Significant Disparities in Hepatocellular Carcinoma Outcomes by Race/Ethnicity and Sociodemographic Factors.

Background: Hepatocellular carcinoma (HCC) disproportionately affects racial/ethnic minorities. We evaluated the impact of income and geography on racial/ethnic disparities across the HCC care cascade in the U.S.

LI-RADS US Surveillance Version 2024 for Surveillance of Hepatocellular Carcinoma: An Update to the American College of Radiology US LI-RADS.

In 2017, the American College of Radiology introduced the US Liver Imaging Reporting and Data System (LI-RADS) as a framework for US surveillance of patients at risk for developing hepatocellular carcinoma. This has aided in the standardization of technique, clinical reporting, patient management, data collection, and research. Emerging evidence has helped inform changes to the algorithm, now released as LI-RADS US Surveillance version 2024.

Neurological Monitoring and Management for Adult Extracorporeal Membrane Oxygenation Patients: Extracorporeal Life Support Organization Consensus Guidelines.

Background: Critical care of patients on extracorporeal membrane oxygenation (ECMO) with acute brain injury (ABI) is notable for a lack of high-quality clinical evidence. Here, we offer guidelines for neurological care (neurological monitoring and management) of adults during and after ECMO support.

Methods: These guidelines are based on clinical practice consensus recommendations and scientific statements.

Donor-Derived Infections: A Journey From Evidence to Policy.

The prevalence of donor-derived Bartonella quintana infection poses an emerging issue in solid organ transplantation. Further studies are needed to validate criteria for donor screening to prevent transmission without negatively affecting organ utilization.