Charlottesville Medical Research

Background18-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scans have largely replaced bone marrow biopsy in the staging workup for diffuse large B-cell lymphoma (DLBCL).Purpose/MethodsHere, we highlight a pitfall of FDG PET/CT for assessing bone marrow involvement, detailing the clinical course of a patient diagnosed with otherwise limited-stage DLBCL who exhibited diffuse bone marrow FDG uptake, felt to be compatible with extensive lymphomatous infiltration. In accordance with current National Comprehensive Cancer Network guidelines, this finding circumvented the need for a formal staging bone marrow biopsy procedure.ResultsSubsequent clinical developments revealed extensive bone marrow involvement by a second, unexpected malignancy (multiple myeloma), casting doubt on the assumption that the initial diffuse marrow uptake was attributable to DLBCL.ConclusionThe presented case emphasizes the challenges of interpreting diffuse FDG uptake within the bone marrow compartment and highlights the inherent contribution of histomorphology for the accurate diagnosis and classification of hematolymphoid neoplasms.

The developments in knee orthotics discussed by Görtz et al. [1] well encapsulate the coincident innovation of bracing technology and medical understanding of knee osteoarthritis (OA). The population of OA patients is only increasing, and with it, our understanding of the disease and how best to mitigate its effects

Introduction and Objective: The Automated Insulin Delivery as an Adaptive NETwork FCL system may improve glycemic outcomes while reducing burden by eliminating meal announcement. Continuous glucose monitoring (CGM) metrics were compared in users with T1D using the FCL system who had high or low baseline A1c. Methods: Youth and adults with T1D were enrolled in a randomized crossover study with a supervised hotel stay followed by 7 days of home use in FCL compared to usual care (UC). Half were selected with baseline A1c <8% (low A1c) and half with baseline A1c 8-12% (high A1c). CGM metrics were analyzed by A1c subgroups. Results: Thirty-four participants (25.4±12.6 years, 62% female) completed the study. Those with high A1c showed non-inferiority of FCL vs UC on all CGM metrics and lower mean glucose with FCL (Table). Time in 70-180 mg/dL, in 70-140 mg/dL, >180 mg/dL, and >250 mg/dL showed significant improvement with FCL in the high A1c group. Those with low A1c had statistically equivalent mean glucose and time <54 mg/dL with FCL vs UC; other CGM metrics were inconclusive. Conclusion: Use of a FCL system results in significant improvement in CGM metrics in those with less optimal glycemic management, while not deteriorating control in those with more optimal A1c. FCL systems have the potential to make the most impact in those with challenges in meeting glycemic goals. Disclosure J.C. Wong: Research Support; Abbott, Dexcom, Inc., Tandem Diabetes Care, Inc. M. Moscoso-Vasquez: Other Relationship; Dexcom, Inc. Research Support; Tandem Diabetes Care, Inc, National Institute of Diabetes and Digestive and Kidney Diseases. L. Ekhlaspour: Other Relationship; Medtronic. Advisory Panel; Abbott, Medtronic. Consultant; Jaeb Center for Health Research. Research Support; MannKind Corporation. Speaker's Bureau; Insulet Corporation. Advisory Panel; Sequel Med Tech. Other Relationship; Tandem Diabetes Care, Inc. Research Support; Abbott. Other Relationship; Sanofi. S.A. Brown: Research Support; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc, Tolerion, Roche Diabetes Care. Other Relationship; MannKind Corporation. M.D. Breton: Speaker's Bureau; Sinocare Inc, Tandem Diabetes Care, Inc. Consultant; Roche Diabetes Care, Boydsense. G.P. Forlenza: Advisory Panel; Medtronic. Research Support; Medtronic, Dexcom, Inc. Consultant; Dexcom, Inc. Research Support; Insulet Corporation. Consultant; Insulet Corporation. Research Support; Tandem Diabetes Care, Inc. Advisory Panel; Tandem Diabetes Care, Inc. Research Support; Abbott. Advisory Panel; Sequel Med Tech. Funding Breakthrough T1D

Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes, yet established peptide-based therapies require injections and complex manufacturing. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. Here, we developed humanized GLP1R mouse models to investigate how small-molecule GLP1RAs influence feeding behavior. This approach revealed that these compounds regulate both homeostatic and hedonic feeding through parallel neural circuits. Beyond engaging canonical hypothalamic and hindbrain networks that control metabolic homeostasis, GLP1RAs recruit a discrete population of Glp1r-expressing neurons in the central amygdala, which selectively suppress the consumption of palatable foods by reducing dopamine release in the nucleus accumbens. Stimulating these central amygdalar neurons curtail hedonic feeding, whereas targeted deletion of the receptor in this cell population specifically diminishes the anorectic efficacy of GLP1RAs for reward-driven intake. These findings reveal a dedicated neural circuit through which small molecule GLP1RAs modulate reward processing, suggesting broad therapeutic potential in conditions of dysregulated dopamine signaling including substance use disorder and binge eating.

The ability of biologically active molecules to access intracellular targets remains a critical barrier in drug development. While assays for measuring cellular uptake exist, they often fail to distinguish between membrane-associated or endosomal trapped compounds and those that successfully reach the cytosol. Here, we present the Chloroalkane HaloTag Azide-based Membrane Penetration (CHAMP) Assay, a novel high-throughput method that employs a minimally disruptive azide tag to report the cytosolic accumulation of diverse molecules in mammalian cells. The CHAMP assay utilizes HaloTag-expressing cells and strain-promoted azide-alkyne cycloaddition (SPAAC) chemistry to quantify the presence of azide-tagged test compounds in the cytosol. We demonstrate the versatility of this approach by evaluating the accumulation profiles of small molecules, peptides, and proteins, revealing how structural variations and stereochemical differences influence cytosolic penetration. Our findings with cell-penetrating peptides confirm established structure-activity relationships, with longer polyarginine sequences showing enhanced accumulation. Additionally, we observed that C -terminal amidation and D-amino acid substitutions significantly impact cellular penetration. When applied to supercharged proteins and antibiotics, CHAMP successfully discriminates between compounds with varying accumulation capabilities. This method provides a robust platform for screening cytosolic accumulation while minimizing the confounding effects of large tags on molecular permeability, potentially accelerating the development of therapeutics targeting intracellular pathways.