Citations

ABSTRACT Transformed follicular lymphoma (tFL) is typically associated with chemotherapy resistance and a poor prognosis. There are limited data regarding outcomes after CD19‐directed chimeric antigen receptor T‐cell (CAR T) therapy in relapsed/refractory (R/R) tFL. A total of 923 adult patients with R/R tFL who received commercial CD19 CAR T therapy between 2017 and 2023 were identified in the Center for International Blood and Marrow Transplant Research registry. Median age was 64 years (range: 30–86) and median prior lines of therapy was 4 (range: 1–18). Most patients (78%) received axicabtagene ciloleucel, with 67% of patients having resistant disease at the time of CAR T infusion. At a median follow‐up of 25 months (range: 1–72) from CAR T infusion, the 2‐year overall survival (OS) was 57% (95% CI: 53–60) and progression‐free survival (PFS) was 43% (95% CI: 40–47). The 2‐year cumulative incidences of relapse or progression (rel/prog) and non‐relapse mortality (NRM) were 47% (95% CI: 44–51) and 9% (95% CI: 7–11), respectively. The overall response rate to CAR T was 76%, with a complete response rate of 63%. Grade ≥ 3 cytokine release syndrome (CRS) was observed in 7.1% and grade ≥ 3 immune effector cell–associated neurologic syndrome (ICANS) in 21.6% of patients. Multivariable analysis suggested that resistant disease status at the time of CAR T, use of bridging therapy, and high comorbidity index ≥ 3 were associated with inferior PFS and OS. Older age ≥ 60 significantly increased the risk of NRM. Our study suggests that CD19 CAR T is effective and safe for tFL.

Abstract The external globus pallidus (GPe) has traditionally been viewed as a relay nucleus within the basal ganglia (BG), but accumulating evidence indicates a more dynamic role in reinforcement learning (RL). One key characteristic of GPe activity—transient pauses in high-frequency discharge (HFD) neurons—is preserved across species, yet its potential implications in RL remains unclear. Here, we developed a neurophysiologically grounded computational model to investigate the origin and role of GPe pauses in RL. Our model successfully replicated a range of empirical observations, including pause dynamics during learning and cue-related activity modulation. We demonstrated that the GPe-subthalamic nucleus (STN) circuit functions analogously to a denoising autoencoder, modulating baseline excitability in downstream BG circuits and that GPe pauses emerge as circuit-level consequences of strong, convergent inhibition from the GPe to STN. Simulations and in vivo recordings revealed that the activity of GPe-STN projecting neurons increases following sudden environmental changes, promoting adaptive exploration by disrupting action value contrast. Intriguingly, this same configuration impairs performance with extended training, suggesting that habitual behavior may benefit from weakened GPe-to-STN projections. These findings provide a unifying framework for understanding GPe pause dynamics and highlight circuit-level distinctions supporting the balance between flexibility and proficiency in RL.

Background/Objectives: High-risk percutaneous coronary interventions (HR-PCIs) often require mechanical circulatory support (MCS) to maintain hemodynamic stability. Intra-aortic balloon pump (IABP) and percutaneous left ventricular assist device (PLVAD) are two commonly used MCS devices that differ in their mechanisms. We aimed to evaluate and compare the clinical outcomes associated with IABP and PLVAD use in HR-PCIs without cardiogenic shock. Methods: We conducted a search of PubMed, Scopus, Cochrane, Mendeley, Web of Science, and Embase to identify relevant randomized controlled trials and cohort studies, and we included 13 studies for the systematic review and meta-analysis. The primary goal was to define the difference in early mortality (in-hospital and 30-day mortality), major bleeding, and major adverse cardiovascular event (MACE) components (cardiogenic shock, acute kidney injury (AKI), and stroke/TIA) in IABP and PLVAD. We used a random-effects model with the Mantel–Haenszel statistical method to estimate odds ratios (ORs) and 95% confidence intervals. Results: Among 1 trial and 12 cohort studies (35,554 patients; 30,351 IABP and 5203 PLVAD), HR-PCI with IABP was associated with a higher risk of early mortality (OR = 1.53, 95% CI [1.21, 1.94]) and cardiogenic shock (OR = 2.56, 95% CI [1.98, 3.33]) when compared to PLVAD. No significant differences were found in the rates of arrhythmia, major bleeding, AKI, stroke/TIA, or hospital length of stay. Conclusions: In high-risk PCIs, PLVAD use is associated with lower early mortality and cardiogenic shock risk compared to IABP, with no significant differences in other major outcomes.

ABSTRACTIntroductionConventional weight‐loss strategies often result in inadequate fat loss, poor sustainability, and unintended lean mass loss. Prolonged water‐only fasting followed by dietary change may offer an effective alternative, but its impact on body composition remains underexplored.MethodsThis secondary analysis utilized dual‐energy X‐ray absorptiometry (DXA) to assess changes in fat‐free mass (FFM), fat mass (FM), and bone mineral content (BMC) in adults [median (IQR) age: 62 (15) years with overweight or obesity. Participants underwent a median (IQR) of 14 (6) days of water‐only fasting, followed by 6 (3) days of food reintroduction with a whole‐plant‐food diet and a subsequent maintenance period of 45 (5) days. Study visits occurred at baseline and at the end of each period.ResultsAt end of fasting, FFM accounted for 74% of total BW lost during fasting. However, at the follow‐up visit, the median (IQR) percentage change in total BW, FFM, FM, and visceral adipose tissue (VAT) mass from baseline was −8.2 (5.2), −4.4 (5.6), −14.7 (8.9), −15.8 (12.8) %, respectively. At follow‐up, FM loss accounted for 67% of the total BW lost. BMC remained unchanged across all study visits.ConclusionsThis protocol produced sustained FM loss, specifically VAT mass, and FFM recovery, suggesting it may support effective weight management.

ABSTRACT T‐cell receptor (TCR) signaling plays a crucial role in various biological processes and is usually studied using global mass spectrometry‐based phosphoproteomic studies. Despite advancements in targeted mass spectrometry‐based assays for protein quantification, their application in studying signaling processes, for example, reproducible measurements of post‐translational modifications (PTMs) such as phosphorylation, remains limited. Tyrosine phosphorylation is critical for many signaling pathways but presents challenges due to the low abundance of phosphotyrosine‐containing peptides. Conventional untargeted methods often encounter data gaps when analyzing large sample sets, particularly for low‐abundance peptides. To address this issue, a targeted proteomics method called “SureQuant” was employed, which relies on triggered data acquisition with heavy isotope‐labeled peptides. This method has been shown to provide sensitive and reproducible quantification of low‐abundance peptides. Here we describe the development of a SureQuant‐based method to quantify phosphotyrosine peptides that are involved in the TCR signaling pathway. To monitor the change in phosphotyrosine signals upon activation, the T‐cells were stimulated with anti‐CD3/CD28 antibodies. We successfully quantified changes in important phosphotyrosine peptides in primary T‐cells upon stimulation with anti‐CD3/CD28 antibodies. This study showcases the ability of the SureQuant approach to accurately quantify low‐abundance phosphotyrosine peptides, highlighting its broader potential to study a diverse set of PTMs in physiological or clinical settings. Summary T‐cell receptor (TCR) signaling plays a fundamental role in immune responses, regulating T‐cell activation, differentiation, and function. While tyrosine phosphorylation is a key regulatory mechanism in this pathway, the low abundance of phosphotyrosine peptides presents a major challenge for their detection and quantification in complex biological samples. By employing the SureQuant targeted mass spectrometry approach, we achieved highly sensitive and reproducible quantification of key phosphotyrosine sites involved in T‐cell activation. This study provides a systematic view of TCR signaling dynamics, revealing distinct phosphorylation patterns across different activation timepoints. Our findings demonstrate the effectiveness of SureQuant in quantifying low‐abundance, post‐translationally modified peptides, offering a valuable tool for studying signaling pathways with greater precision. Additionally, this methodological framework can be extended to investigate other signaling networks, immune cell functions, and disease‐associated phosphotyrosine modifications.

Abstract The landscape of Alzheimer's disease (AD) and related dementias (ADRD) diagnosis is evolving rapidly, driven by advances in disease understanding, biomarker tools, and disease‐modifying therapies. Modern diagnostic approaches emphasize biological precision, early detection, and dynamic frameworks that adapt to treatment‐induced changes in disease biology. These frameworks enable opportunities for personalized interventions—encompassing pharmacological and non‐pharmacological strategies—and for enhanced clinical trial design. However, implementing these advancements globally is influenced by diverse cultural, infrastructural, and regulatory factors. The 2024 Alzheimer's Association International Conference Advancements: Modernizing Diagnosis, held in Japan, provided a unique platform to explore these global dynamics, particularly from an Asian perspective. This article highlights key discussions from the conference, exploring the role of biomarker‐based diagnostic frameworks in shaping the future of AD/ADRD research, diagnosis, and treatment. We highlight regional challenges and successes and emphasize ethical considerations and practical strategies needed to ensure equitable access to diagnostic and therapeutic innovations. Highlights Advances in biomarkers are reshaping Alzheimer's disease diagnosis and treatment. Modern diagnostic frameworks highlight biological precision, early detection, and dynamic frameworks. The 2024 Alzheimer's Association International Conference Advancements: Modernizing Diagnosis explored challenges and opportunities in global biomarker implementation. The conference explored geographic‐specific impacts, focusing on Asia.

ABSTRACT In response to the World Health Organization's (WHO) Global Initiative on Artificial Intelligence (AI) for Health, the World Endoscopy Organization (WEO) highlights the unique challenges and opportunities AI presents for gastrointestinal endoscopy, particularly in resource‐limited settings. While AI technologies have shown promise in improving diagnostic accuracy and efficiency in high‐resource environments, their implementation in low‐ and middle‐income countries is hindered by infrastructural, economic, regulatory, and training barriers. This commentary explores how these challenges may exacerbate existing healthcare disparities, emphasizing the need for localized datasets, affordable AI models, simplified regulatory frameworks, and workforce capacity building. The WEO supports WHO's call for equitable AI deployment and advocates for region‐specific solutions, including mobile and offline AI tools, public‐private partnerships, locally developed algorithms aligned with prevalent disease patterns, and a flexibly adapted regulatory framework. By leveraging WEO's training networks and fostering collaboration among governments, clinicians, and industry, the integration of AI into endoscopy can become more accessible and relevant to underserved populations. The commentary underscores that AI should not be seen as a luxury but as a tool to bridge global disparities in care quality. Ensuring responsible and inclusive AI integration requires both global coordination and context‐specific adaptations to truly benefit all healthcare systems.

Abstract Artificial intelligence (AI) and mucosal exposure devices like Endocuff have independently improved the adenoma detection rate (ADR) during colonoscopy. This meta-analysis evaluated the combined effect of Endocuff and AI versus AI alone on colorectal neoplasia detection rates. We searched PubMed, Embase, and Web of Science for randomized controlled trials (RCTs) comparing the impact of Endocuff+AI versus AI alone on colorectal neoplasia detection. Primary outcome was ADR; secondary outcomes included advanced adenoma detection rate (AADR), sessile serrated lesion detection rate (SSLDR), cecal intubation time, and withdrawal time. Pooled risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Three RCTs with 2404 subjects were included (n = 1198 Endocuff+AI vs. n = 1206 AI alone). ADR was significantly higher in the Endocuff+AI group than in the AI alone group (54% vs. 48%, respectively) (RR 1.12, 95% CI 1.03–1.21, P = 0.01, I2 = 0%). There was a trend toward higher AADR (12.3% vs. 10%, RR 1.23, 95% CI 0.96–1.59, P = 0.10, I2 = 17%) and SSLDR (17.6% vs. 15.5%, RR 1.16, 95% CI 0.96–1.40, P = 0.13, I2 = 0%) in the Endocuff+AI group compared with the AI alone group, but it did not reach statistical significance. Both cecal intubation time (MD -0.61 minutes; 95% CI -1.54–0.33; P = 0.20; I2 = 87%) and withdrawal time (MD -0.42 minutes; 95% CI -1.01–0.17; P = 0.17, I2 = 60%) were similar between the two groups. Endocuff combined with AI was superior to AI alone in improving the adenoma detection rate without increasing intubation or withdrawal times.