Citations

Abstract INTRODUCTION Glioblastoma (GBM) is a brain cancer known for its complex tumor microenvironment and ability to reprogram glucose metabolism and evade host immune responses. CAR-T cell therapy has attracted considerable attention due to its potential for high specificity and efficacy across various cancer types. However, its success in GBM has been limited due to the unique and hostile metabolic landscape of the tumor microenvironment. GBM tumor cells exhibit enhanced aerobic glycolysis, resulting in elevated glucose consumption. This restricts glucose availability for T cells, impairing activation and anti-tumor response. In our study, we enhanced the tumoricidal activity of CD70 CAR T-cells by overexpressing the glucose transporters GLUT1 and GLUT3, thereby improving their metabolic fitness and enabling them to overcome tumor-induced glucose deprivation. METHODS The CD70 CAR T-cell glucose metabolic pathway was modulated via glucose transporter overexpression. The efficacy and safety of metabolically modified CD70 CAR T-cells was investigated in in vitro and in vivo platforms. RESULTS GLUTs overexpression does not negatively affect T-cell differentiation and function but improves glucose consumption and intra-tumoral T-cell trafficking. We then used CD70 CAR-T platform and overexpress GLUT1 and GLUT3 to engineer T-cells. GLUT overexpression provided metabolic advantage to CD70CAR T-cells, which showed enhanced activation and cell avidity when co-cultured with GBM cells in both glucose enriched and restricted conditions. The metabolic modifications regulate CAR T-cell efficacy by enhancing intra-tumoral trafficking and persistence, followed by improved anti-tumor response and survival in mice. The lack of significant alterations in body weight and organ morphology in mice receiving GLUT-overexpressing CD70 CAR T-cells suggests that the adoptive transfer of these metabolically enhanced T cells does not elicit toxicity, thereby demonstrating a favorable safety profile during treatment. CONCLUSION Our study demonstrates development of immunotherapeutic strategies by incorporating core principles of tumor and immune cell metabolism, thus providing evidence that targeting immune-metabolic pathways is a potential approach to treat brain tumor.

Abstract MGMT is primarily inactivated via promoter methylation, but MGMT homozygous deletion (hmzdel) has been rarely reported as an alternative inactivating mechanism. Although functionally similar to a methylated MGMT promoter, MGMT hmzdel is associated with an unmethylated MGMT promoter test result reflecting the MGMT promoter status of the non-neoplastic cells invariably present in any tumor specimen. Thus, patients whose tumors have MGMT hmzdel (and unmethylated MGMT promoter) would be inaccurately predicted to lack benefit from alkylating chemotherapy based on MGMT promoter methylation testing alone. To evaluate the impact of this clinical scenario, we estimated the frequency and distribution of MGMT hmzdel in routine clinical testing of CNS tumors. Among 12,424 CNS tumors (3,044 with provided diagnosis of glioblastoma) tested using Oncoscan chromosomal microarray (2015-2025), 10 tumors (0.08%) had MGMT hmzdel: 8 with entire gene hmzdel and 2 with partial gene hmzdel favored to be inactivating (RNA-sequencing underway to exclude possibility of activating rearrangements). All tumors were supratentorial and non-midline. Median age at diagnosis was 58.5 years (range, 34-81), with 3:2 male:female. Of the 10 cases, 9 (of 3,044; 0.3%) had integrated diagnosis of glioblastoma, IDH-wildtype; the remaining case was a recurrent astrocytoma, IDH-mutant, CNS WHO grade 4. All 10 cases had loss of chromosome 10q and a highly unmethylated MGMT promoter by droplet digital PCR testing of downstream CpG sites 75-80/84-87, with median fraction abundance of 0.19% (range, 0-0.85). In summary, MGMT hmzdel only occurred in high-grade adult-type diffuse astrocytic gliomas, and is a rare potential pitfall for MGMT promoter methylation testing leading to inaccurate patient stratification. It is critical that laboratories performing routine CNS tumor copy number testing include MGMT in the curated list of reportable genes, and that clinicians be aware of this rare clinical scenario to accurately stratify patients despite misleading MGMT promoter test results.

Abstract BACKGROUND Understanding long-term sequelae of cancer care is critical. Cognitive impairment is a common and disabling survivorship issue. Because sex influences tumor biology, therapy exposure, and dementia risk, we examined whether cancer care for a prior malignancy alters late-life cognitive outcomes differently in males and females. METHODS We assessed adults ≥50 years, cognitively normal at study entry, from a longitudinal, population-based cohort (Mayo Clinic Study of Aging). Participants were linked to our institutional cancer registry (excluding non-melanoma skin cancers). Mild cognitive impairment (MCI) and dementia were adjudicated by consensus. We fitted multivariable Cox proportional-hazards models to estimate how prevalent cancer diagnosis influenced the risk of developing MCI/dementia. Sex-specific effects were determined by incorporating a cancer×sex interaction term and by generating separate hazard ratios. Analyses were controlled for age, APOE4 status, education, and presence of vascular/metabolic conditions. RESULTS 5793 MCSA participants (female: 49.4%, APOE4 positive: 27.5%) were included in the study, with a mean age of 73 years at study entry. Incident MCI was recorded in 866 participants, and 737 were diagnosed with incident dementia. About 20% (n=1176) of the cohort had a cancer diagnosis, most commonly prostate (n=423) and breast (n=277). There was no independent relationship between history of cancer and risk for MCI or dementia. We found that males with cancer had an increased risk for MCI (HR 1.28, 95% CI 1.04-1.57, p=0.003) and dementia (HR 1.29, 95% CI 1.04-1.6, p=0.053). Conversely, females with cancer had a lower risk for MCI (HR 0.79, 95% CI 0.61-1.01, p=0.063), although this was not statistically significant. CONCLUSIONS Our data suggests male cancer survivors may be more susceptible to cognitive impairment, independent of age, APOE4 status, education, and vascular/metabolic burden. Elucidating the hormonal, treatment-related, and systemic pathways driving this should be a priority for future mechanistic studies.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Abstract Aims We evaluated clinical outcomes with GLP-1 RA use post-TAVI in patients with T2D. GLP-1 receptor agonists (GLP1-RAs) lower cardiovascular risk in type 2 diabetes (T2D), but their impact in patients with valvular heart disease, including those undergoing transcatheter aortic-valve implantation (TAVI), remained unexplored. Methods and results We conducted a retrospective cohort study using the TriNetX network, including 25 184 adults (≥18 years) with T2D who underwent TAVI (2015–2023). Patients were stratified based on GLP1-RA initiation within 14 days post-TAVI. Baseline characteristics, comorbidities, medications, and laboratory data were balanced using 1:1 propensity score matching (PSM). Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for events from one-month post-TAVI until the most recent follow-up. PSM yielded 1101 patients per group, with a mean age of 73 years and 39% female. Mean follow-up duration was 2.2 ± 1.1 and 2.6 ± 1.8 years for GLP1-RA users and non-users, respectively. GLP1-RA use was also associated higher survival probability (HR: 0.708 [95% CI: 0.583–0.859]), and lower rates of all-cause hospitalization (HR: 0.790 [95% CI, 0.706–0.885]), major cardiovascular events (HR: 0.849 [95% CI: 0.749–0.963]), and acute heart failure exacerbation (HR: 0.785 [95% CI: 0.677–0.909]), acute kidney injury (HR: 0.843 [95% CI: 0.719–0.988]), and major kidney events (HR: 0.665 [95% CI: 0.510–0.866]). No differences were observed in acute myocardial infarction, cerebral infarction, or cardiac arrest. Conclusion In patients with T2D undergoing TAVI, GLP1-RA use is associated with significant survival benefits and improved cardiorenal outcomes. However, these findings are limited by the observational design, high comorbidity burden, lack of data on medication compliance, and specific cause of death. Prospective trials are warranted to confirm these benefits.

Despite advances in lipid-lowering and antithrombotic therapy, patients with acute coronary syndromes remain at elevated risk for recurrent events due to persistent atherosclerotic inflammation. This review evaluates inflammation as a therapeutic target in secondary prevention and discusses established, investigational, and emerging strategies. Colchicine, now FDA-approved for cardiovascular risk reduction, lowered major adverse cardiovascular events in COLCOT and LoDoCo2. Canakinumab (IL-1β inhibition) reduced recurrent events in proportion to IL-6 and hsCRP suppression, while ziltivekimab (IL-6 inhibition) achieved profound biomarker reductions but remains investigational. Early-phase studies of anakinra (IL-1 receptor antagonist) and dapansutrile (oral NLRP3 inhibitor) showed anti-inflammatory effects in early trials, whereas varespladib and darapladib illustrated the challenges of targeting lipid-associated pathways. Beyond direct immunomodulators, GLP-1 receptor agonists and SGLT2 inhibitors provide both cardioprotective and anti-inflammatory benefits, reinforcing their expanding role post-ACS. Additional emerging avenues include triptolidiol, dasatinib, and BTK or JAK/STAT inhibitors, while novel approaches, such as nanozyme delivery systems and CRISPR-based editing, extend the therapeutic horizon. This review highlights the potential of inflammation-targeted therapies to advance secondary prevention in ACS by integrating current evidence and perspectives on future therapeutic developments.

Abstract Purpose: Relapse is a major cause of failure in human papillomavirus–independent head and neck squamous cell carcinoma. Clinicopathologic criteria for adjuvant treatment remain imprecise and have not changed for decades. We investigated whether ctDNA in lymphatic exudate collected via surgical drains (“lymph”) 24 hours after surgery identified molecular residual disease (MRD) and compared its performance with time-matched plasma. Experimental Design: Using an ultra-sensitive tumor-informed sequencing approach, tumor variants were called in lymph and plasma to classify patients as ctDNA positive or ctDNA negative, trained in an initial cohort of 36 patients, and replicated in an independent cohort of 37 patients. Progression-free survival was compared in ctDNA(+) versus ctDNA(–) patients. Results: Lymph identified MRD in two independent multi-site cohorts (initial cohort sensitivity = 76% and specificity = 63%; log-rank P = 0.01; replication cohort sensitivity = 65% and specificity = 70%; log-rank P = 0.04). Lymph performance was enhanced in locoregional relapse (sensitivity = 78% and specificity = 67%; log-rank P = 0.0004) and generalized to early-stage patients. Analysis of matched plasma collected at this early timepoint was not predictive of recurrence (sensitivity = 35% and specificity = 72%; log-rank P = 0.7). In patients with intermediate-risk pathology, lymph ctDNA was associated with recurrence (sensitivity = 88% and specificity = 67%; log-rank P = 0.0008), suggesting an opportunity for improved stratification of patients who may benefit from additional adjuvant treatment. Conclusions: Postoperative lymph is a novel, proximal, and early source of MRD with the potential to introduce more precision into adjuvant therapy decision-making and improve outcomes, especially for patients with intermediate-risk human papillomavirus–independent head and neck squamous cell carcinoma.

Background: Paroxysmal atrial fibrillation (AF) is a common arrhythmogenic complication in the intensive care unit (ICU) associated with significant costs and morbidity. AF detection models in the literature have utilized entropic analyses of telemetry to diagnose AF, but they have not been utilized to forecast its onset. Hypothesis: Deep learning techniques applied to high-frequency telemetry data can be utilized to forecast AF with clinically significant lead time. Methods: Telemetry data were collected from 72 ICU monitored beds in a tertiary care center from 4/2018-12/2023. Coefficient of sample entropy (COSEn), a metric of heart rate variability complexity, was calculated on successive 1-minute windows and utilized to identify areas of AF initiation as well as control windows without AF. ECG lead II (256Hz) and beat-to-beat (B2B) measurements were analyzed by the MOMENT time-series foundational model to generate representation embeddings. A binary classification multilayer perceptron (MLP) was trained on these embeddings to forecast AF onset 5m in advance. All results were reported on separate test sets. Group-based trajectory modelling (GBTM) was performed on risk score trajectories from the 20m before AF onset or absence. Results: Over 230,000 hours of B2B data from 2263 patients was analyzed using COSEn to identify 287 transitions to AF from 136 patients. The same number of AF-absent windows were randomly selected. COSEn alone as a forecaster produced an area under the receiver operating characteristic curve (AUC) of 0.65 (95% CI: 0.61-0.69). The MOMENT + MLP model (MMM) achieved an AUC of 0.81 (0.78-0.83) (Fig. 1). COSEn and MMM were subsequently applied to the two hours preceding AF onset or absence. For COSEn, the mean risk trajectory dipped in the baseline period whereas the MMM risk trajectory sustained a high level through the baseline, highlighting its capacity to forecast AF (Fig. 2). For AF patients, GBMT yielded two types of trajectories: one with elevated risk throughout, and another with a rising trend 5 minutes prior to AF onset (Fig. 3). Conclusions: Deep learning techniques can forecast the onset of AF with up to 5 minutes of lead-time and GBTM allowed for the identification of different pre-AF risk trajectory phenotypes.The ability to forecast AF onset has potential to clinically prevent poor outcomes in the ICU, though further refinements to augment the amount of lead time are warranted.

Background: The arteriovenous fistula (AVF) is a requirement for hemodialysis therapy in end-stage kidney disease (ESKD) patients. A consequence of AVF creation is compensatory cardiovascular hemodynamics, which are subsequently associated with cardiac remodeling. Relatedly, cardiovascular mortality and morbidity are elevated in ESKD patients, which worsens in dialysis patients. Currently, no suitable uremic large animal models exist to investigate the underlying mechanisms of AVF-induced cardiac remodeling. Research Question: This study aims to characterize cardiovascular changes secondary to AVF creation, supported by percutaneous transluminal angioplasty (PTA), in a uremic pig model. Methods: Chronic kidney disease (CKD) was induced via renal embolization, followed by AVF creation 28 days later. The AVF was created by anastomosis of the left common carotid artery to the left external jugular vein. AVF stenosis was alleviated 28 days thereafter via PTA, and cardiac MRI was performed at 14-, 28-, and 42-days post-PTA. Results: Increased end-diastolic volumes were observed in the left and right ventricles at day 42 vs 14 (200.8ml to 249.5ml, p=0.0457, and 204.6ml to 260.0ml, p=0.0268 respectively), while systolic function was preserved. Left ventricle (LV) stroke volume and blood flow through the aorta, pulmonary artery, and vena cava were also increased. In perivascular areas of the free wall of the LV at day 42 vs control, senescence markers showed increased p16 expression (fold change 10.21, p=0.0086) and decreased p21 expression (fold change 0.07, p=0.0357). The LV showed perivascular fibrosis (0.2% to 0.59%, p=0.021), via picrosirius red, reduced collagen-type IV expression (fold change 0.81, p=0.0089), and increased MMP2 levels (fold change 14.33, p=0.0213). Cardiomyocyte cross-sectional area was increased (from 800.9 µm 2 to 1250.0 µm 2 , p=0.0296), without CD4+ or CD68+ cell LV infiltration. Conclusion: In conclusion, AVF creation leads to modified left and right ventricular function and increased peripheral flow, potentially mediated by cellular senescence and fibrosis, resulting in progressive cardiac remodeling. This model of uremic kidney disease can now be used to evaluate mechanisms of AVF induced cardiac disease and test the efficacy of therapeutics like senolytics and anti-fibrotic agents.

Introduction: In patients with type 2 diabetes (T2D) at high cardiovascular risk, glucagon-like peptide-1 receptor agonists (GLP1-RAs) have been shown to reduce major adverse cardiovascular events. However, patients with valvular heart disease, including those undergoing transcatheter aortic-valve implantation (TAVI), have been largely excluded from randomized trials. Hypothesis: We investigated whether GLP1-RA use is associated with improved one-year cardiovascular outcomes in patients with T2D undergoing TAVI. Methods: We conducted a retrospective cohort study using the TriNetX network. Adults (≥18 years) with T2D who underwent TAVI between 2015 and 2023 were included and stratified based on GLP1-RA initiation within 14 days post-TAVI. Baseline characteristics, comorbidities, medications, and laboratory data were balanced using 1:1 propensity score matching (PSM). The primary outcome was a composite of all-cause mortality or hospitalization at 1 year. Secondary outcomes included acute heart failure (HF) exacerbation, acute myocardial infarction (AMI), cardiac arrest, and ischemic stroke. Outcomes were assessed from 1 month to 1 year after TAVI. Survival probabilities were estimated using Kaplan-Meier analysis, and hazard ratios (HRs) were calculated with Cox proportional hazards models. Results: Among 20,454 patients with T2D undergoing TAVI from 2015-2023, 937 received GLP1-RAs. After PSM, 930 patients were included in each cohort, with a mean age of 73 years and 37% female. The mean follow-up duration was 342 days for GLP1-RA users and 325 days for non-users. GLP1-RA cohort exhibited a higher 1-year survival probability (93.8%) compared to non-users (89.5%) (HR 0.573 [95% CI, 0.410-0.801]; p=0.001). GLP1-RA use was also associated lower rates of all-cause hospitalization (HR 0.762 [95% CI, 0.652-0.891]; p=0.001), acute HF exacerbation (HR 0.687 [95% CI, 0.566-0.834]; p<0.001), and cardiac arrest (HR 0.452 [95% CI, 0.213-0.960]; p=0.034). No differences were observed in AMI (HR 1.033 [95% CI, 0.750-1.423]; p=0.844), or ischemic stroke (HR 0.875 [95% CI, 0.659-1.162]; p=0.356). Conclusions: In patients with T2D undergoing TAVI, GLP1-RA use is associated with significant survival benefits and improved cardiovascular outcomes, including reductions in acute HF exacerbation, all-cause hospitalization, and cardiac arrest. These findings highlight the need for prospective clinical trials to confirm these results.