Citations

Abstract Glioblastoma is an aggressive brain cancer with poor prognosis. Recent evidence implicates metabolic reprogramming, including the hexosamine biosynthetic pathway (HBP) and pentose phosphate pathway (PPP), as critical for tumor survival, therapy resistance, and progression. HBP inhibition with a proprietary small molecule (G2Bz) reduced stemness and migration and increased apoptosis of GBM in vitro. HBP inhibition was concomitant with an accumulation of metabolites in the Pentose Phosphate Pathway (PPP). Therefore, we further inhibited HBP with G2Bz and/or PPP with 6-aminonicotinamide (6-AN) in primary patient-derived GBM lines and evaluated additive or synergistic effects. Ultrastructural and functional changes were examined by electron microscopy (EM), high content imaging of endoplasmic reticulum (ER) and lipid droplets (LD), extracellular-flux analysis, and lipid profiling. Synergism was validated in an orthotopic model receiving lipoparticle-encapsulated G2Bz via intranasal delivery and/or intraperitoneal 6-AN; tumor burden was monitored via bioluminescence. Dual inhibition of HBP/PPP revealed additive or synergistic anti-proliferative effect. EM displayed severe ultrastructural cell damage with mitochondrial disorganization, ER dilation, and cytoskeletal remodeling. These changes coincided with increased ROS generation and reduced spare respiratory capacity suggesting higher sensitivity and lower ability to fight stress. Reduced ER–mitochondria contacts accompanied by increased expression of BiP and ER expansion suggest an unfolded protein response. Loss of LDs were associated with downregulation of lipid biosynthesis regulator SREBF1 and an increase in free fatty acids with a rise in lipid peroxidation. Reduced mitochondria–LD contacts correlate with lower endogenous fatty acid oxidation and a shift to exogenous fatty acid utilization. Dual inhibition in-vivo, suppressed tumor growth compared to control. These findings support that dual inhibition of HBP/PPP synergistically disrupts tumor metabolism, promoting organelle disorganization and lipid remodeling and highlight metabolic co-targeting as a strategy to impair GBM metabolism.

Abstract Berubicin is a unique anthracycline engineered to have the ability to cross the blood-brain barrier (BBB). Herein we present the primary results from a large global trial of Berubicin vs. Lomustine randomizing patients with progressive disease after only one prior therapy, all being IDH WT and stratified for MGMT methylation. The primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), overall response rates (ORR) of complete (CR) and partial (PR) responses. Eligibility was determined radiologically by central reads based on progression of disease, and in 2.5 years 252 patients were enrolled with 168 randomized to Berubicin and 84 to Lomustine. Safety assessment showed that Berubicin was well tolerated and myelosuppressive side effects were manageable with growth factors. Importantly, although anthracyclines are known to cause cardiotoxicity, evaluation with frequent troponin measurements, ECG and ECHO testing revealed no evidence of impact on cardiac function. The primary endpoint, OS, showed Berubicin and Lomustine had similar outcomes. Median overall survival for Berubicin was 8.7 months (6.7, 9.9) and for Lomustine was 9.3 months (6.7, 10.7) with a Hazard Ratio of 1.13 (p = 0.5351). PFS of Berubicin and Lomustine were also similar (1.5 vs, 1.6 months). There were no responses in the Lomustine arm and stable disease in 35.2% of patients while Berubicin had a response rate of 5.8% (PR) and stable disease of 33.6% with a combined disease control rate (DCR) of 39.4%. Additional data will be presented and discussed. Anthracyclines are characteristically used in combination for systemic therapy (e.g. leukemia, lymphoma, certain breast cancers), so there is promise that combination therapy will be the next pertinent approach to treatment of GBM. Evaluation of activity against a range of pediatric brain tumors is being pursued and preliminary results will be presented at the time of the conference.

Abstract Background Global longitudinal strain (GLS) by 2D speckle tracking echocardiography (2D-STE) has been widely utilized to detect early underlying systolic myocardial dysfunction in patients with normal ejection fraction (EF). Reduced GLS is observed in patients with hypertrophic and amyloid cardiomyopathies. However, the impact of chronic kidney disease (CKD) on GLS remains underexplored. CKD patients present with multiple cardiovascular comorbidities, increased left ventricular mass index (LVMI), and altered cardiac remodeling which is a dynamic and adaptive physiological response. Left ventricular (LV) remodeling is classified based on relative wall thickness (RWT ≤ or > 0.42) and LVMI (≤ or > 88 g/m² for women and ≤ or > 102 g/m² for men) into four distinct categories: normal geometry (NG), concentric remodeling (CR), concentric hypertrophy (CH), and eccentric hypertrophy (EH). Purpose To assess and describe the LV-GLS values (SD) in male and female patients with CKD across different remodeling patterns and compare them to controls without comorbidities Methods A retrospective echocardiographic analysis was conducted on patients evaluated from 01/01/2008 to 12/31/2018. A total of 546 CKD patients and 1041 controls were identified and matched in a ≈2:1 ratio by age, gender, and cardiac geometry. ANOVA and Tukey-Kramer analysis compared GLS across groups, with data distributions visualized via box plots. P-values <0.05 were considered significant. Results The mean age of CKD patients and controls was 63.3 (SD 12.7) and 63.1 (SD 12.6) years, respectively. Overall, GLS values in CKD patients were comparable to controls, with significant differences in select subgroups. In females with eccentric hypertrophy, GLS was lower in CKD stage V vs. controls (-16.2 ± 2.5 vs. -20.7 ± 2.3, p < 0.05), CKD stage III (-16.2 ± 2.5 vs. -19.5 ± 2.4, p < 0.05), and CKD stage IV (-16.2 ± 2.5 vs. -20.2 ± 2.4, p < 0.05) (Table 1). Across CKD stages, GLS trended toward the lower limit of normality, particularly in advanced CKD. In males with normal geometry, GLS values for controls and CKD stages I, II, III, IV and V were -20.3 ± 1.9, -19.1 ± 2.3, -19.4 ± 2.7, -19.5 ± 2.8, -19.8 ± 3.6, and -17.7 ± 2.7 (Figure 1a). In females, corresponding values were -21.0 ± 2.2, -19.9 ± 2.7, -20.2 ± 2.0, -20.8 ± 2.5, -20.2 ± 3.4, and -18.8 ± 3.4, respectively (Figure 1b). Conclusion GLS values in CKD patients were largely comparable to controls for both genders. However, those with CKD V exhibited GLS values near the lower limit of normality, particularly in eccentric hypertrophy. These findings suggest that in this group of patients there is subclinical myocardial dysfunction, warranting further investigation. The values reported may serve as reference points for GLS assessment in CKD patients.

Importance Metabolic dysfunction–associated steatohepatitis (MASH) represents a high, underprioritized burden among noncommunicable diseases (NCDs) and people living with type 2 diabetes (T2D). Objective To identify cost-effective management approaches to prevent, detect, and treat MASH and liver fibrosis in people living with T2D. Design, Setting, and Participants This economic evaluation consisted of a generalized cost-effectiveness analysis (GCEA) that was conducted for 12 countries (Brazil, Chile, Germany, Italy, Japan, Saudi Arabia, South Africa, Spain, Sweden, Tanzania, Thailand, and the United States), across all 6 World Health Organization (WHO) regions. A cohort state-transition model simulated liver disease development and its impact on a synthetic cohort, aged 19 years and older and living with T2D, over their lifespan across 10 liver health states. Exposures Using an 80% coverage level, 14 management approaches were compared, including screening via the Fibrosis-4 (FIB-4) test and Enhanced Liver Fibrosis (ELF) test or vibration-controlled transient elastography (VCTE) as well as treatment with pharmacological and nonpharmacological interventions. Main Outcomes and Measures The main outcomes were the average cost-effectiveness ratios (ACERs) and the incremental cost-effectiveness ratios (ICERs), which were used to construct care expansion paths by ranking the management approaches in order of cost-effectiveness. The main measures were the total incremental costs and the total incremental quality-adjusted life-years (QALYs) of each intervention. Results In this GCEA, the outcomes were evaluated with respect to country-specific willingness-to-pay thresholds. The standard of care had the lowest ACERs in 8 countries (not in Chile, Germany, Saudi Arabia, or the United States). Treatment with intensive lifestyle interventions (ILIs), after screening via ELF or VCTE, was cost-effective in all countries. ILIs and treatment with semaglutide was cost-effective in 11 countries (not in Tanzania); ILIs and treatment with resmetirom was cost-effective in 8 countries (not in Brazil, South Africa, Tanzania, or Thailand). Conclusion and Relevance In this economic evaluation, screening followed by ILIs was found to be a cost-effective management approach for MASH and liver fibrosis among people living with T2D in all countries. Screening followed by pharmacological treatment was cost-effective in most countries. These results can inform health policy decision-making and further the development of WHO recommended interventions to address NCDs.

Introduction: Corticosteroid therapy has been demonstrated to improve prognosis and reduce mortality in patients with severe Coronavirus Disease 2019 (COVID-19) infection by attenuating the exaggerated inflammatory response that emerges in the late phase of infection. However, its impact on patients with pre-existing cardiovascular disease, who are at higher risk of complications, has not been specifically studied. The aim of this study is to evaluate the effect of corticosteroid therapy on mortality and long-term COVID-19 symptoms in this high-risk population. Methods: We analyzed the prospective registry HOPE-2. Patients with previous cardiovascular disease were selected, and 18-month all-cause death was defined as the primary endpoint. Long-term COVID-19 symptoms were considered as secondary endpoints. A total of 1188 patients with previous heart disease were included, of which 453 received corticosteroid treatment. Propensity score matching analysis in a 1:1 fashion was performed based on baseline variables that exhibited a p-value < 0.05 in the univariant analysis and outcome variables that defined corticosteroid use, with a final matched population of 796 patients. Results: In patients with pre-existing heart disease, corticosteroid treatment was not associated with differences in 18-month all-cause mortality (p = 0.52). However, a shorter duration of hospitalization (median: 8 days [IQR: 4–14] and 11 days [IQR: 7–18]; p < 0.001) was observed in patients who received corticosteroids. No significant differences in long-term COVID-19 symptoms were observed between the two groups. Conclusions: In patients with pre-existing heart disease, the absence of a clear harmful effect suggests that the positive effects of corticosteroids may be offset by their potential adverse effects which could contribute to the persistence of long COVID symptoms. This finding may reflect a differential response to corticosteroids in this high-risk subgroup, highlighting the need for further studies to clarify the role of this therapy in such patients.

Abstract Disclosure: E.M. Lewiecki: Amgen Inc, Kyowa Kirin, Ultragenyx, Angitia, Radius Health, Inc, Ascendis. E. Kapoor: Fresenius Kabi USA Inc., Astellas Pharma, Estetra SRL, WellFound Inc., Exeltis. S. Hurtado: None. V.M. Navarro: Bayer, Inc. M. Torres: Bayer, Inc. J. Beau: Bayer, Inc. I. Gkioni: Syneos Health LLC (providing service to Bayer), AstraZeneca. K. Genga: Bayer, Inc.. Background: The neuropeptide substance-P and its receptor neurokinin-1 (SP-NK1R pathway) play a role in bone metabolism and remodelling. Pre-clinical evidence also points to a role of this pathway in energy homeostasis. NK-1R antagonists have been proposed as potential therapies in obesity and musculoskeletal disorders like osteoporosis. Elinzanetant (EZN) is a dual neurokinin-1 and -3 receptor antagonist in late-stage development for vasomotor symptoms (hot flashes) associated with menopause. This post hoc analysis evaluates potential benefits of EZN on the skeleton, body weight, and body composition in postmenopausal women. Methods: Data were gathered from exploratory endpoints of the 52-week (wk), placebo (PL)-controlled, OASIS-3 Phase 3 EZN efficacy and safety trial. Mean percentage (%) change in total bone mass (kg) (measured indirectly by bioelectrical impedance analysis at baseline (BL), wks 4, 8, 12, 18, 24, 36, 52); mean % change in bone mineral density (BMD, measured directly by dual-energy X-ray absorptiometry at BL, wks 24 and 52) in femoral neck, total hip, and lumbar spine; and mean % change in key bone turnover markers osteocalcin (OC) and procollagen 1N-terminal propeptide (P1NP) at BL, wks 4, 8, 12, 18, 24, 36, 52 were evaluated. Weight, body mass index (BMI: weight/height2), waist circumference (WC), fat mass index (FMI; fat mass/height2), lean mass index (LMI; lean mass/height2) and body water were measured to monitor body composition at BL and wks 4, 8, 12, 18, 24, 36, 52. A sub-analysis was performed based on FMI at baseline (FMI ≤9 normal fat mass; &gt;9 excess fat mass). Descriptive statistics were used to evaluate all parameters and trends. Results: From BL to wk 52, increasing trends in bone mass were observed with EZN (mean [SD]: 2.81 [1.02] to 2.95 [1.96]) but not PL (mean [SD]: 2.87 [1.09] to 2.87 [1.13]). In parallel, lower BMD reductions were seen in EZN vs PL at all skeletal sites [EZN vs PL, mean % change from BL: femoral neck (0.00% vs -1.22%), total hip (-0.70% vs -1.37%), and lumbar spine (-0.57% vs -1.22%), with considerable variability in both groups (SD range 3.01 - 4.70)]. Lower levels of circulating OC and P1NP were consistently observed over 52 wks of EZN treatment, suggesting a lower rate of bone resorption with EZN vs PL. Trending reductions in weight, BMI, and WC, along with increases in LMI and body water were observed with EZN vs PL. Trends of higher LMI in patients with excess fat, or lower FMI in patients with normal fat at BL were observed with EZN, suggestive of a positive body re-composition with EZN. Conclusions: These data expand on EZN safety profile and further point to novel potential benefits for the skeleton and body composition of postmenopausal women. Further research is warranted to provide conclusive evidence of the benefits of EZN specifically in post-menopausal women with obesity/overweight status or osteoporosis. Sponsorship: Bayer U.S., Whippany, NJ, USA Presentation: Monday, July 14, 2025

ABSTRACT Background Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are emerging as an essential part of the standard of care for proteinuria in patients with chronic kidney disease. To date, no study has specifically evaluated the effects of body mass index (BMI) on the antiproteinuric efficacy of SGLT2is. Here we report the impact of BMI on the antiproteinuric efficacy of SGLT2is in non-diabetic patients with glomerular diseases. Methods This is a retrospective, multicentre, international observational cohort study that included non-diabetic patients with biopsy-proven glomerular disease and proteinuria &gt;0.5 g/24 h who received SGLT2is between 2016 and 2023. Laboratory values, including proteinuria and estimated glomerular filtration rate (eGFR), were obtained at baseline and after 3–6 months. Changes in laboratory values over time were analysed using the paired signed-rank test. Results A total of 300 patients met the inclusion criteria. The median age was 51.82 years [interquartile range (IQR) 41–62.65], 64.7% were male and 92.7% were white. The most common glomerular disease was immunoglobulin A nephropathy (40.3%). The median eGFR was 52.26 ml/min/1.73 m2 (IQR 36.41–74.01), the median proteinuria was 1.60 g/24 h (IQR 1.15–2.91) and the median serum albumin was 4.08 g/dl (IQR 3.80–4.30). Proteinuria reduction after SGLT2i initiation was significant only in overweight and obese patients (P &lt; .001 versus 0.18). Patients with normal BMI did not experience the expected early decrease in eGFR (P = .16). Conclusions SGLT2is are ineffective in proteinuria reduction in patients with a BMI &lt;25 kg/m2, which contrasts with the significant proteinuria reduction in overweight and obese patients with glomerulopathies.

ABSTRACT Objectives To explore the clinical impact of social determinants of health (SDoH) stress in bipolar disorder (BD) course of illness and to explore potential gender differences in SDoH stress endorsement. Methods 2280 individuals living with BD type I or II (62% women; 67.5% BD‐I) participating in the Mayo Clinic Bipolar Biobank who completed a questionnaire assessing positive and negative‐valent stressors in the 12 months prior to study enrollment were included for this analysis. Six negative stressors were used as proxies of SDoH. Generalized linear models were used to test the association between SDoH stressors and markers of illness severity as well as potential differences by sex by including an interaction term. Results After adjusting for age, sex, and recruitment site, SDoH‐related stressors were significantly associated with a more severe course of illness in both men and women. Except for unemployment rates, women reported more frequently SDoH‐related stress (i.e., lack of family support, financial problems, health coverage and access problems). Conclusions The study found significant gender differences in both the endorsement of specific SDoH stressors and in the prevalence of specific illness severity markers; however, it did not directly test the predictive relationship between gender differences in SDoH and illness severity markers. Future studies aiming to achieve health equity in mental health care should continue assessing social determinants of health stressors, incorporating a gender perspective to better understand their influence on bipolar disorder.