Citations

Abstract BACKGROUND: Tumor-specific T cells are often characterized by reduced TCR signaling due to central and peripheral tolerance pathways that limit their responsiveness. These signals are further weakened by insufficient co-stimulation and active co-inhibitory pathways, collectively establishing a high threshold for activation. The integration of antigen recognition with co-stimulatory and inhibitory cues ultimately determines whether a T cell becomes activated or remains tolerant. Early TCR signaling must therefore be precisely regulated to prevent autoreactivity while still supporting protective immunity. Although phosphorylation and ubiquitination are well-established regulators of proximal TCR signaling, additional post-translational mechanisms remain less defined. SIRT2, a cytosolic NAD+-dependent deacetylase with emerging roles in immune regulation, has not been examined in the context of TCR signaling. METHODS: We evaluated proximal TCR signaling events in wild-type and SIRT2-deficient T cells using flow cytometry, immunoblotting, calcium flux assays, and RNA-sequencing. SIRT2-associated pathways were defined by mapping its interactome and acetylated substrates through mass spectrometry and immunoprecipitation. We screened LCK post-translational modifications by mass spectrometry and assessed SIRT2 enzymatic activity using an HPLC-based deacetylase assay. Conformational effects of LCK modification were examined using fluorescence-polarization binding assays and AlphaFold structural modeling. SIRT2 was deleted in human tumor infiltrating lymphocytes (TILs) via CRISPR/Cas9, and the impact of SIRT2 targeting was tested in lung cancer patient-derived xenograft models reconstituted with autologous TILs. RESULTS: SIRT2 deficiency amplified proximal TCR signaling, leading to elevated phosphorylation of early signaling mediators and increased calcium flux in both naïve and anergic T cells. Loss of SIRT2 also altered thymic selection dynamics and expanded TCR repertoire diversity. Mechanistically, SIRT2 interacted with and deacetylated LCK, the initiating kinase of proximal TCR signaling. Mass spectrometry identified lysine K228 in the LCK linker region as a SIRT2-regulated deacetylation site that governs LCK conformation and kinase activity. Functionally, SIRT2 inhibition in exhausted mouse and human TILs restored TCR signaling capacity and improved anti-tumor responses. CONCLUSION: Here we identify SIRT2-regulated deacetylation of LCK as a previously unrecognized mechanism that sets the strength and threshold of proximal TCR signaling. Accordingly, SIRT2 targeting reverses the exhausted phenotype of tumor-reactive T cells. Citation Format: Imene Hamaidi, Pingyan Cheng, Soo Young Jun, Min-Hsuan Wang, Min Zhang, Odesha Taylor, Luis Lopez-bailon, Ismail Can, Bin Fang, Anders Berglund, Bradford Perez, Ben Creelan, Andriy Marusyk, Virginia Shapiro, Haitao Ji, Jose R. Conejo-Garcia, Sungjune Kim. Sirt2 dictates TCR activation thresholds through post-translational control of LCK conformational state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4250.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

BACKGROUND: Catheter ablation for atrial fibrillation is a widely used rhythm-control strategy, yet its role in reducing thromboembolic risk and enabling oral anticoagulation (OAC) discontinuation remains uncertain. This meta-analysis aims to comprehensively synthesize and evaluate randomized controlled trial evidence supporting long-term antithrombotic strategies in patients with atrial fibrillation undergoing catheter ablation. METHODS: A systematic literature search was performed in MEDLINE/PubMed, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials evaluating antithrombotic strategies after catheter ablation for atrial fibrillation. The primary outcome was ischemic stroke. A frequentist network meta-analysis comparing reported treatment arms, along with a pooled incidence meta-analysis for outcomes of interest, was conducted. RESULTS: Four randomized controlled trials, including 3924 patients, met the inclusion criteria. Three trials compared long-term OAC continuation versus OAC discontinuation, and 1 compared OAC continuation with left atrial appendage occlusion after catheter ablation. No significant differences in stroke incidence were observed when comparing OAC or left atrial appendage occlusion with no antithrombotic therapy (incidence rate ratio, 0.90 [95% CI, 0.02–33.85]; P =0.95; incidence rate ratio, 0.79 [95% CI, 0.00–241.01]; P =0.94, respectively). Among patients who discontinued antithrombotic therapy without undergoing left atrial appendage occlusion (n=1161), with 2864 cumulative person-years of follow-up, the pooled incidence of stroke was 0.23 events per 100 person-years (95% CI, 0.02–2.43; I 2 =0%). CONCLUSIONS: This analysis reinforces that, across randomized data, the incidence of thromboembolic events in patients who discontinued OAC after successful ablation remained low. However, the evaluation of net clinical benefit is limited by the low number of events across all treatment arms, underscoring the need for larger studies with prolonged follow-up to further validate the safety of this strategy, particularly in higher-risk populations.

Abstract Cellular senescence is a dynamic, multistage biological program that exerts context-dependent effects on tumor initiation, progression, and overall carcinogenesis. Our laboratory has previously demonstrated that the early accumulation of p16Ink4a-expressing (representing strong cyclin-dependent kinase inhibition) senescent alveolar macrophages during tumorigenesis actively facilitates tumor formation and progression by inhibiting the infiltration of cytotoxic T lymphocytes. However, considering the dynamic nature of cellular senescence, distinct senescent cell populations could express high amounts of the alternative cell cycle inhibitor p21Waf1/Cip1 independently of p16Ink4a to potentially catalyze distinct functions. To test this, we have employed transgenic p21-ATTAC (p21-driven apoptosis through targeted activation of caspase 8) mice to investigate the role of p21-expressing cells during Kras-driven adenoma formation. In agreement with our previous observations following clearance of p16-expressing senescent cells, we found that removal of p21+ cells attenuates early tumor development. Western blot and immunofluorescence analyses corroborates a reduction in p21, p16, and multiple members of a putative senescence-associated secretory phenotype (SASP). Although senescent alveolar macrophages remain a critical therapeutic target, here we found that senescent endothelial cells also exhibited elevated expression of p21, p16, and SASP with a high senolytic response. Future studies will include identifying the predominant p21-expressing senescent endothelial subpopulations and elucidating the mechanisms by which endothelial senescence contributes to lung tumorigenesis. Collectively, our findings have unveiled additional senescent cell populations with the potential to drive lung tumorigenesis. Citation Format: Yuanning Du, Luis I. Prieto, Karthikbabu Jeganathan, Cheng Zhang, Hu Li, Darren Baker. Elucidating the role of p21 + senescent cells in early-stage lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2268.

Introduction Increasing publication of fraudulent clinical trials poses a serious threat to evidence-based medicine. In the VITALITY Study I, we demonstrated that contamination by retracted trials significantly distorts evidence synthesis. The upcoming VITALITY Study II will take a step further and investigate how such problematic evidence undermines the credibility of guideline recommendations. Methods and analyses The VITALITY Study II will adopt a retrospective cohort design and will be structured as three work packages (WPs). To start with, a cohort of clinical practice guidelines (CPGs) that were contaminated by retracted trials and/or meta-analyses that included retracted trials will be established based on forward citation searching (WP1). Then, recommendations from these CPGs that used evidence from retracted trials and/or meta-analyses that synthesised these retracted trials will be re-evaluated after removing such problematic evidence, in terms of both the direction and strength of effect sizes (WP2). Finally, the subsequent impact on patient outcomes attributable to distorted recommendations will be estimated on a hypothetical population, measured by the number of expected benefit loss and the number of expected harm increment per 100 000 patients (WP3). Ethics and dissemination Formal ethical approval is not necessary for this study as it does not involve human or animal participants, nor does it involve the collection of primary data. We will disseminate the findings through publication in peer-reviewed journals and, whenever possible, presentations at academic conferences.

Abstract Background and Aims Stroke and systemic embolism are recognized but poorly characterized complications of atrial fibrillation (AF) and left atrial flutter (AFL) catheter ablation. Their incidence, outcomes, and procedural associations remain insufficiently defined. Methods Retrospective global registry was initiated by the European Heart Rhythm Association Scientific Committee. A secure database captured data from ablation centres worldwide on general AF and left AFL ablation activity, as well as detailed information on patients with symptomatic embolic events between 2017 and 2024. Results Overall, 204 centres reported 335 743 ablation procedures and 550 embolic events (incidence 0.16%). Centre-level rate ranged from 0% to 3.1%. Most events were cerebral (94%), followed by peripheral (5%), and combined (1%). Coronary air embolism accounted for 62% of all peripheral events. Intraprocedural events occurred in 93 patients (17%), within 72 h in 357 (78%) and beyond 72 h in 100 (22%); 128 cases (23%) were diagnosed after hospital discharge. Nonparoxysmal AF (0.23% vs 0.15%; P < .001), centre experience, and ablation energy source (radiofrequency, 0.16%; cryoballoon, 0.16%; pulsed field ablation, 0.25%; laserballoon, 0.88%; P < .001) were associated with embolic risk. Median NIHSS score after stroke was 4 (interquartile range, 2–9). Three-month follow-up was available for 518 patients with embolism (95%): 181 (35%) had sequelae and 16 (3%) died. Conclusions Symptomatic embolic events are infrequent but associated with significant morbidity and mortality. Most events occur early, though a substantial proportion arise later. Higher event rates were observed with laser and possibly with pulsed field ablation. A greater centre experience was associated with a lower embolism incidence.

ABSTRACT Electrocardiography (ECG) is a critical diagnostic tool for identifying cardiac conditions. While standard lead positions are widely used to ensure diagnostic accuracy, alternative lead placements have been developed to address specific clinical scenarios. These alternative configurations can overcome physical or technical challenges, enhance rhythm assessment, improve signal quality, and provide greater specificity for certain conditions, ultimately enabling more personalized diagnostic strategies. This paper examines the clinical significance of alternative ECG lead positions, highlighting their advantages, limitations, and potential applications in various clinical settings.

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.

This is a concise literature-based delineation of dignity and its connections with important mental health issues in the Latin American continent. This review examines the relationship between dignity and mental health in Latin America, focusing mostly on Peruvian socio-cultural studies and clinical perspectives. Drawing on published literature, an introductory geographic description and a historical narrative supported by socio-demographic data and cultural realities of the region, the review explores how dignity is shaped by cultural identity and by the mestizaje process as a decisive ontological feature. A series of seven cases covering different aspects of the impact of clinical events on the dignity of the protagonists is presented. Dignity is explored from the perspective of native healers, mothers and human rights principles, as well as its fragility in the face of socio-political, racism-induced conflicts, and sectarian/religious deformations. The difficulties faced in overcoming reductionistic and alienating influences, as well as social inequalities affecting dignity, are discussed. The review emphasizes, in turn, its consideration as one of the central issues of psychotherapeutic approaches and much-needed investigation projects.