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 United States.

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.

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.

Implementing MATRIX acuity tool to improve nursing satisfaction on a stroke and epilepsy monitoring unit.

Purpose: Nursing satisfaction is a critical component of effective patient care. In the Acute Stroke Unit (ASU) and Epilepsy Monitoring Unit (EMU), patients have specialized needs that require critical nursing skills. The purpose of this study was to examine nurse satisfaction after implementation of the MATRIX acuity tool.

Performing liver imaging at a high level: quality and adequacy in LI-RADS.

Imaging is critical to HCC management, including surveillance, diagnosis, staging, and treatment response assessment, which requires it be performed consistently at a high level. The Liver Imaging Reporting and Data System (LI-RADS) was developed to standardize the acquisition, interpretation, and reporting of liver imaging, but until now, has not addressed the essential component of exam quality and adequacy. In this manuscript, we discuss the concepts of quality and adequacy and their clinical significance in the setting of HCC diagnostic imaging and treatment response assessment.

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.

Assessing Knowledge, Practices, and Barriers to PrEP and nPEP Prescription Among Texas Healthcare Providers.

Background: The effectiveness of pre-exposure prophylaxis (PrEP) and non-occupational post-exposure prophylaxis (nPEP) in preventing HIV is well-established, yet their use in clinical practice remains low. Healthcare providers, especially those in primary and emergency care settings, play a crucial role in adopting and implementing these prevention strategies. We conducted a statewide survey with 519 healthcare providers in Texas to assess their knowledge, practices, and barriers related to prescribing PrEP and nPEP.

TFE3 -rearranged Head and Neck Neoplasms : Twenty-two Cases Spanning the Morphologic Continuum Between Alveolar Soft Part Sarcoma and PEComa and Highlighting Genotypic Diversity.

TFE3 rearrangements characterize histogenetically, topographically, and biologically diverse neoplasms. Besides being a universal defining feature in alveolar soft part sarcoma (ASPS) and clear cell stromal tumor of the lung, TFE3 fusions have been reported in subsets of renal cell carcinoma, perivascular epithelioid cell tumor (PEComa), epithelioid hemangioendothelioma and ossifying fibromyxoid tumors. TFE3 -related neoplasms are rare in the head and neck and may pose diagnostic challenges.

The Midline Lateral Parapatellar Arthrotomy: A Safe Alternative Approach for Lateral Tibial Plateau Fractures.

Objectives: The midline lateral parapatellar (LP) approach has been shown in a cadaveric study to provide superior articular exposure compared to the anterolateral approach (AL). The purpose of this study was to report on outcomes and complications with the LP approach.

Methods: Design: Retrospective comparative cohort study and prospective cohort.