Citations

Abstract Background and Aims The aim of the study was to assess the effect of guideline-directed medical therapy (GDMT) on cardiac function, neurohormonal activation, and mortality in adults with congenitally corrected transposition of the great arteries (cc-TGA) presenting with systemic right ventricular (RV) systolic dysfunction. The study hypothesis was that GDMT use (assessed using the GDMT score) was associated with improved cardiac function (higher RV free wall strain [RVFWS]), less neurohormonal activation (lower N-terminal pro-B-type natriuretic peptide [NT-proBNP] levels), and lower mortality. Methods GDMT score, RVFWS, and NT-proBNP levels were assessed at baseline and 1-year follow-up. GDMT uptitration was assessed using ΔGDMT (GDMT at 1-year minus GDMT at baseline). Improvements in RV systolic function and neurohormonal activation were defined as a relative increase in RVFWS of >20% and a relative decrease in NT-proBNP levels of >20%, respectively. Results Of 213 patients (age 43 ± 15 years; 54% male), baseline GDMT score was 1.97 ± 1.27, and ΔGDMT score was 0.74 ± 0.39. Baseline RVFWS was −18 ± 5%; 25% had improved RV systolic function. Baseline NT-proBNP was 369 (142, 1004) pg/mL; 56% had improved neurohormonal activation. Higher baseline GDMT score and ΔGDMT score were associated with improvement in RV systolic function and neurohormonal activation. Overall, 34 (16%) patients died, and higher baseline GDMT score and ΔGDMT score were associated with a lower risk of mortality and of the composite adverse event endpoint (heart failure hospitalization, death, and heart transplantation). Clinical benefits of GDMT use were observed only in patients with moderate/severe RV systolic dysfunction, and not in patients with mild RV systolic dysfunction. Conclusions GDMT use was associated with improved outcomes in patients with moderate/severe RV systolic dysfunction.

The bone marrow immune microenvironment (BMME) is a critical factor in multiple myeloma (MM) pathogenesis. Despite higher incidence of MM among self-identified African Americans, the relationship between African genetic similarity and the BMME remains unclear. We present the largest analysis to date assessing the impact of Ancestry on the BMME in myeloma (N=320, including 64 with ≥50% African genetic similarity, AFR-High) leveraging our recently generated Immune Atlas. AFR-High was associated with enrichment of late T-effector cells, driven by rare cytotoxic CD4⁺ T cells, suggesting a distinct adaptive BMME. AFR-High exhibited expansion of late-differentiated adaptive NK cells with high cytotoxic GNLY and GZMH expression. AFR-High depicted reduced CD14⁺ monocytes, increased CD16⁺ non-classical monocytes, and expansion of macrophage-like monocyte populations with enrichment of metabolic adaptation, efferocytosis and phagocytic clearance programs, and immunoregulatory pathways. These findings reveal a shift from an innate inflammatory immune landscape toward adaptive cytotoxic and immunoregulatory remodeling associated with African genetic similarity in MM.

Abstract Skeletal muscle is a major determinant of functional status. The impact of advanced prostate cancer (aPC) systemic therapies on body composition is unknown. We identified aPC patients with serial PET-CTs receiving androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPI), chemotherapy, and/or Lutetium-177. An artificial intelligence algorithm quantified body composition changes from PET-CT images. Linear mixed effects models examined body composition changes over time by treatment type. The algorithm examined 2,342 PET-CTs from 468 patients. On multivariable analysis, ADT was associated with a 9% reduction in muscle density (-1.91 Hounsfield units), ARPIs an additional 6% (-1.4 Hounsfield units), and Lutetium-177 a subsequent 6% (-1.3 Hounsfield units), demonstrating progressive reduction in muscle density across later stages of systemic therapy. This large longitudinal analysis of body composition in aPC patients supports the use of an automated PET-CT algorithm to identify aPC patients on systemic therapy at risk for muscle wasting.

Peripheral impairment: a novel therapeutic target in Fontan physiology? Exercise intolerance is nearly universal in adults post-Fontan procedure. This exercise catheterization study showed that two-thirds of adults with Fontan circulation exhibited peripheral limitation to exercise, alongside established central hemodynamic constraints. Moreover, peripheral oxygen extraction was an independent determinant of exercise capacity in multivariable analyses. As demonstrated in HFpEF, peripheral oxygen extraction may represent a modifiable therapeutic target in Fontan physiology.

Abstract Varlilumab is a monoclonal antibody with agonistic activity on CD27. The efficacy of single-agent PD-1 inhibitors on aggressive B-cell non-Hodkin lymphoma is limited. Preclinical and phase 1 data suggest that Varlilumab is safe and may have synergistic activity with PD-1 inhibitors. In the DIAL study, we explored whether dual immunomodulatory therapy with Varlilumab and Nivolumab in patients with relapsed/refractory aggressive B-NHL was safe and effective. We conducted a randomized phase II clinical trial on adult patients with relapsed/refractory aggressive B-NHL. Patients were randomized to receive Nivolumab monotherapy in the control group and Varlilumab combined with Nivolumab in the experimental group. Crossover to the experimental group was allowed upon progression in the control group. The primary endpoint was the overall response rate based on the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). 54 patients underwent randomization, and 51 received assigned intervention and were included in the intention-to-treat analysis. Objective response was observed in 6 out of 51 patients (ORR 12%). There were 4 responders (ORR 16%) in the Nivolumab group and 2 responders (ORR 7.6%) in the Nivolumab and Varlilumab combination group (p = 0.3). None of the 7 patients that crossed over to the experimental group responded to the addition of Varlilumab. The ORR of patients who were previously exposed to CAR-T cell therapy was 13% (5 out of 39) compared to 8.3% (1 out of 12) in the unexposed patients (p > 0.99). The rate of treatment emergent adverse events was similar between groups, and there was no fatal TEAE in the study. The addition of Varlilumab to Nivolumb did not improve outcomes in patients with aggressive B-NHL. Even though this trial was not designed to evaluate immunotherapy as a rescue therapy after CAR-T failure, most patients (76%) had previously received CAR-T therapy, and their outcomes were equally poor.

BET bromodomain inhibitors are efficacious as anti-inflammatory compounds, but clinical translation is hampered by dose-limiting toxicities from non-selective inhibition. We herein report compounds 16 and 26, based on previously reported 4-methyl-1,2,3-triazole-based inhibitor, DW34. 16 has a BRD4 BD1 Ki of 10 nM, and up to 13–38-fold selectivity for BRD4 BD1 over other BD2 domains, and an improved hERG affinity of 4.24 µM over DW34. 26, A biscyclopropyl analog of 16 showed further enhancement of BD1 selectivity over BD2 (26–203-fold), but exhibited more potent hERG inhibition. Compound 16 had improved liver and plasma clearance over DW34, with good biodistribution to the liver, and had an intracellular target-engagement affinity Ki of 92 nM, with reduction of Ccl2, Cxcl1, AST, and ALT in in vitro and in vivo mouse models of liver inflammation. 16 represents a useful lead for treating inflammatory liver diseases, with improved specificity, drug-like properties, and reduced hERG affinity.

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.