Citations

Abstract High-grade gliomas represent the most common type of primary adult malignant brain tumor. IDH1/2 mutations are linked to lower-grade gliomas and better patient outcomes; however, molecular profiling has revealed additional alterations that drive aggression. CDKN2A/B loss in IDH-mutant astrocytoma is recognized as a key marker of grade 4 tumor biology, yet there remain no effective targeted therapies in aggressive gliomas. Here, we analyzed a cohort of patient-derived IDH-mutant astrocytoma with whole-exome and RNA sequencing data and identified several candidate genes and pathways concurrently regulated with CDKN2A/B loss, revealing an enhanced signature related to vascular processes. We sought to elucidate the angiogenic mechanisms and functional outcomes associated with high-grade behavior following CDKN2A/B loss in IDH-mutant astrocytoma to inform future therapeutic strategies. We used grade 4 IDH-mutant astrocytoma patient-derived xenograft (PDX) and established cell lines harboring homozygous CDKN2A/B deletion. We re-expressed the cell cycle regulators p14, p15, and p16 using a Tet-inducible lentiviral system and confirmed reduced proliferation compared to parental lines. Re-expression of p14, p15, or p16 also resulted in decreased glioma cell migration and invasion. Intriguingly, re-expressing these regulators reduced VEGF secretion. HUVEC cells cultured with conditioned media (CM) from the re-expression glioma lines decreased canonical activation of PI3K/Akt and Stat3 signaling and a diminished capacity to promote endothelial migration, invasion, and tube formation. Furthermore, in vivo Matrigel plug assays using CM from the re-expression lines showed a decreased ability to recruit endothelial cells, pericytes, and form vascular organized structures. We identified the WT1 transcription factor as an upstream regulator of angiogenesis. WT1 expression was inversely correlated with CDKN2A/B expression in patient data, and knockdown of WT1 in astrocytoma cells reduced VEGF secretion and impaired ability to promote endothelial migration. Taken together, our findings reveal a novel role for WT1 in VEGF-driven angiogenesis in IDH-mutant astrocytoma with CDKN2A/B homozygous deletion.

Abstract INTRODUCTION While TERT promoter mutation (TPM) has been established as a marker of clinically aggressive meningiomas, this alteration is rare and found in less than 5% of all cases. However, a larger subset of meningiomas may exhibit aberrant TERT expression in the absence of TPMs. This study investigated the effect of TERT gene expression on clinical outcome in meningioma patients. METHODS Clinical and molecular data were retrospectively collected on 1241 meningiomas, split into a Toronto discovery cohort and a multi-institutional validation cohort. Sanger sequencing and bulk RNA sequencing were used to determine TPM status and TERT gene expression. The effect of TERT expression on progression-free survival (PFS) was assessed using Kaplan-Meier and Cox regression analysis. RESULTS While meningiomas with TPM showed expectedly higher TERT gene expression compared to wildtype (TP-WT) cases (p<0.0001), TERT expression was still detected in 28.7% (157/547) of TP-WT meningiomas. Meningiomas with TERT expression showed significantly worse PFS compared to meningiomas without any TERT expression. In fact, WHO grade 1 meningiomas with TERT expression had PFS outcomes resembling WHO grade 2 meningiomas lacking TERT expression (p=0.59). In turn, WHO grade 2 meningiomas with TERT expression had clinical outcomes similar to WHO grade 3 meningiomas without TERT expression (p=0.42). Furthermore, the proportion of meningiomas expressing TERT as well as overall TERT expression levels increased with increasing WHO grade. Multivariable analysis showed that TERT expression was significantly associated with worse PFS even when controlling for other known predictors of clinical outcome including TPM, CDKN2A/B loss, 1p/22q status and WHO grade (HR 1.85 [95% CI 1.33-2.57], p=0.00024). CONCLUSION TERT expression is a novel independent biomarker of outcome for meningiomas identifiable in up to one-third of cases that may be utilized to reclassify tumours to a higher WHO grade.

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 INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Abstract Background and Aims Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. Methods The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter–defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. Results A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62–0.72] and 0.59 (95% CI 0.48–0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68–0.80) and 0.60 (95% CI 0.47–0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59–1.41) for AE and 1.00 (95% CI 0.69–1.32) for nf/fAE. Conclusions These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Abstract Advocacy has long been at the core of the infectious diseases (ID) field, with clinicians and researchers advocating to ensure patients can access the care they need on an individual and global scale. The Infectious Diseases Society of America Training Program Directors’ (PD) Committee met in 2024 and discussed ways that advocacy is and should be incorporated into fellowship training, as well as highlighted the role PDs play in advocating for their trainees. Policies with a negative impact on ID clinical care, public health, and research underscore the importance of mobilizing the field of ID to advocate for the patients and communities we serve, as well as for ourselves. This paper presents ideas generated at this meeting and is meant to serve as a reference for ID PDs, as well as the wider ID community, as a call to action for teaching and participating in advocacy work.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Objective: An endoscopically placed duodenal-jejunal bypass liner (DJBL) may provide a safe adjunctive therapy for those with poorly controlled type 2 diabetes mellitus (T2DM) and obesity. Background: Although some endoscopic therapies have been shown to improve glycemic indices secondary to weight loss, small bowel interventions may have direct metabolic effects. A meta-analysis of observational studies demonstrated reduction in HbA1c by 1.3% at 1 year after DJBL in patients with T2DM and obesity. Methods: This was a multicenter, double-blind, randomized, sham-controlled trial comparing DJBL to sham procedure with medical management and lifestyle modification. Primary endpoints included mean difference in changes in HbA1c at 12 months between arms, and device-related serious adverse events (SAEs). Secondary endpoints included percent total weight loss (%TWL) and subjects achieving HbA1c≤7% and TWL≥5% at 12 months. Results: Three hundred twenty subjects were randomized to DJBL (n=212) and sham (n=108). Baseline HbA1c and BMI were 8.79±0.92% and 38.45±5.75 kg/m 2 . On modified intent-to-treat analysis, change in HbA1c at 12 months was −1.10±1.45% and −0.28±1.54% for DJBL and sham groups, respectively ( P =0.0004). Rate of device-related SAEs was 9.4% including intolerance (3.7%), hemorrhage (2.8%), and hepatic abscess (2.3% stopping study early). At 12 months, DJBL group experienced greater weight loss compared with sham (7.7±9.6% TWL and 2.1±5.4% TWL, respectively; P <0.0001), with significantly more patients achieving HbA1c ≤ 7% (28.3% vs. 9.4%; P <0.0003) and TWL ≥ 5% (60.4% vs. 21.3%; P <0.0001). Conclusions: DJBL met primary glycemic control efficacy and primary safety endpoints, while providing clinically significant weight loss, and comorbidity improvement.