Citations

Abstract Objective VEXAS syndrome is a severe systemic haemato-inflammatory disease with heterogeneous clinical presentations. Most patients experience recurrent inflammatory flares despite anti-inflammatory therapy. The lack of accepted definitions of flare in these patients is preventing development of disease activity tools that are essential for conducting clinical trials. We aimed to develop a consensus definition of a VEXAS flare for use in clinical trials. Methods A nine-member international expert advisory committee established a consensus definition of VEXAS flare using modified Delphi methodology. Clinical inflammatory manifestations of VEXAS syndrome were identified through a systematic literature review. Committee members developed a conceptual framework for flare definition, proposed revisions and voted on changes until consensus (≥75% concurrence) was reached. Results Consensus defined VEXAS flare as active inflammatory manifestation(s) of VEXAS syndrome requiring escalation in glucocorticoid therapy. Three flare categories were established: (i) recurrence of a prior documented VEXAS manifestation; (ii) development of a new VEXAS-defining inflammatory manifestation; or (iii) emergence of a new inflammatory manifestation not meeting criteria for A or B. The panel endorsed an independent adjudication committee to assess Category C flares in clinical trials. Conclusions This study proposes a standardized definition of VEXAS flare, providing uniform criteria for identifying VEXAS disease activity. Future research will evaluate its performance in clinical trials.

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.

Abstract Description Sequencing antigen-specific T cell receptors (TCR) remains a major technologic challenge, requiring labor- and cost-intensive single-cell approaches. We have developed a rapid and economical method for sequencing TCR mRNA from antigen stimulated peripheral blood mononuclear cells using targeted long-read nanopore sequencing with Oxford Nanopore Technologies’ (ONT) Minion sequencer. Targeted PCR amplification of TCR alpha and beta cDNA was performed with a template switching oligo (TSO). Dual unique molecular identifiers (UMI) were used for single cell, oligoclonal, or bulk cell sample specific sequence identification followed by nanopore sequencing. The reads were demultiplexed by UMIs and aligned to germline V,D, and J gene sequences from the IMGT database for identification. Error corrected sequences were then used to determine the non-templated complementarity determining region 3 (CDR3) sequence for the TCRs. From bulk PBMCs, TCR Beta Chain had 796 unique TRBV-TRBJ combination and TCR Alpha Chain had 2053 unique TRAV-TRAJ combinations. Human PBMC samples were spiked with 10% Jurkat cells and sequenced using this method for 12 hours resulting in 200K reads. After read demultiplexing, filtering (Q > 25), and alignment, it was found that 8.8% of TCR beta and 7.0% TCR alpha reads matched the Jurkat TCR sequence in the 10% spiked sample. This method provides a fast and cost-effective approach to generating antigen specific TCR sequences for downstream functional studies. Funding Sources Supported by NIH/NCI 5U01CA281660 Topic Categories Technological Innovations in Immunology (TECH)

ABSTRACT Background Proton beam therapy (PBT) offers dosimetric advantages in pediatric radiotherapy by reducing radiation exposure to healthy tissues. However, broad implementation raises important ethical, logistical, and equity considerations, especially in settings with limited access to advanced technologies. Procedure This position paper by the Paediatric Radiation Oncology Society (PROS) reviews the clinical rationale for selecting radiotherapy modalities in children, with a specific focus on ethical utilization of PBT. The document synthesizes evidence on the benefits and limitations of modern photon and proton therapies, explores disparities in access, outlines the role of local pediatric radiation oncologists, and addresses the impact of industry‐driven messaging on family decision‐making. Results While PBT offers clinical benefit in selecting pediatric cancers, high‐quality photon‐based treatments such as IMRT and VMAT remain effective and widely accessible alternatives. The referral and evaluation process for PBT is complex and may introduce treatment delays. Travel and financial burdens can exacerbate disparities. PROS underscores the critical role of local pediatric radiation oncologists in counseling families, and calls for balanced, evidence‐based communication from providers and industry stakeholders. Conclusions PROS advocates for an ethical, equitable, and evidence‐informed approach to radiotherapy modality selection in children, reflecting holistic considerations beyond dosimetry. Proton therapy should be pursued when clinically indicated and accessible without compromising timely care. Investment in a comprehensive radiation therapy infrastructure, including professional education, collaborative research, and responsible public messaging, is essential to optimize pediatric cancer outcomes globally.

Abstract Background Distinguishing physiological cardiac adaptation from pathological remodeling in endurance athletes is challenging. While the athletic heart typically demonstrates balanced biventricular enlargement, extreme exercise may rarely trigger disproportionate right ventricular (RV) changes that challenge diagnostic classification. Case Summary A 47-year-old male ultra-endurance athlete presented with exertional symptoms three months after recovery from a pulmonary embolism (PE). Initial post-PE echocardiography was normal. After resuming extreme training, he developed severe RV dilation (basal diameter 5.7 cm on echocardiography; RV volume index 92 cc/m² on cardiac magnetic resonance imaging) disproportionate to the left ventricle, with preserved systolic function and no late gadolinium enhancement. Cardiopulmonary exercise testing revealed significant chronotropic incompetence with below-expected peak oxygen uptake for his elite training status. Symptoms and ventricular ectopy improved with detraining, but severe RV dilation persisted. Evaluation excluded arrhythmogenic cardiomyopathy and significant pulmonary vascular sequelae. Discussion This case illustrates disproportionate RV remodeling precipitated by the resumption of extreme exercise in a susceptible athlete post-PE. The temporal dissociation from the PE and absence of residual clot burden implicate exercise-related hemodynamic stress as the primary driver, challenging the boundary between physiological adaptation and maladaptation. These findings highlight a potential maladaptive response to extreme exercise, possibly potentiated by a prior vascular insult, and underscore the value of integrated functional assessment and monitored detraining in athletes with borderline findings.