Citations

Effective translation relies on high performance teams integrating diverse disciplines to bring new drugs, medical devices, diagnostics or behavioral interventions into improved health. Despite substantial advancements informed by the Science of Team Science (SciTS), challenges remain in effective translational team (TT) operations, while limited institutional, scholarly, and practitioner legitimacy of team science expertise constrains efforts to address them. Here, we describe an essential member of the TT, the Team Science Professional (TSP). Serving as a team educator and facilitator of team interventions, the TSP plays a pivotal role in facilitating effective team performance. Current challenges faced by this nascent profession are defining career pathways and establishing competencies needed for expert performance. To address these challenges, the authors, representing a spectrum of academic universities organized as a special interest group (SIG) of the Association of Clinical and Translational Science (ACTS), propose a suite of individualized, standardized and pathway-selective micro-credentials (digital badges). Digital badges in “Team Science (TS) Fundamentals,” “TS Practitioner,” “TT Trainer” and “TT Intervention Expert” are described, along with preliminary feasibility and usability evaluations of the submission process. These stackable credentials provide a customizable, portable recognition of skills and help advance career pathways for TSPs. In so doing, the Digital Badge Initiative will enhance the capacity of translational science “Hubs” such as those supported by Clinical and Translational Science Awards to conduct effective and rigorous translation. Moving forward, the ACTS TSP SIG will be examining the impact of digital badging on standardization and its effect on career recognition and retention.

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 Introduction Urinary tract infections (UTIs) are the most common infectious complication in kidney transplant (KT) recipients. UTI risk is associated with frailty in older adults, and UTIs may exacerbate frailty. However, this relationship has not been described in KT recipients who are at both greater risk of frailty and UTIs. Methods We conducted a retrospective chart review of 90 KT recipients aged ≥ 50 years who underwent KT between January and July 2021 and had ≥ 12 months of post‐transplant follow‐up. UTIs were identified at the time of each occurrence. Frailty was assessed at baseline using the modified Rockwood‐20 frailty index (mFI); scores ≥ 0.25 were considered frail, 0.08–0.24 pre‐frail, and < 0.08 non‐frail. The primary outcome was cumulative UTI occurrence based on frailty status, analyzed using Cox proportional hazards regression. Results Among 90 KT recipients, 33 (37%) developed ≥ 1 UTI. Notably, 45% of KT recipients with UTIs were frail, compared to 25% of KT recipients without UTIs. Compared to non‐frail KT recipients, frail KT recipients had a significantly higher risk of UTIs (HR 8.13, 95% CI 1.89, 34.91; p = 0.005), as did pre‐frail KT recipients (HR 4.51, 95% CI 1.02, 19.92; p = 0.047). Frail KT recipients also experienced earlier UTI onset, with 12 out of 21 total UTIs (57%) occurring within the first 30 days post‐KT. Conclusion Frailty and prefrailty are associated with increased UTI risk in KT recipients. These findings highlight the importance of frailty assessment in post‐transplant care and suggest the need for targeted interventions to reduce UTI risk in this vulnerable population. image

Abstract Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.

382 Background: Androgen receptor signaling drives prostate cancer (PC) progression, and genes involved in androgen production, uptake, and conversion (APUC) are key therapeutic targets. We previously defined a 6-APUC gene set ( HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, and CYP17A1 ), that identified metastatic PC with favorable prognosis and predict docetaxel benefit. However, the expression landscape and clinical relevance of APUC genes have not been interrogated in localized PC. Methods: We analyzed the expression of 21 APUC genes in 55,329 radical prostatectomy tumor samples that underwent Decipher prostate genomic classifier (GC) testing (Veracyte Inc) between 2016-2024. Baseline clinical/pathologic factors were retrieved from Decipher GRID database (NCT02609269). Associations between gene expression quartiles with PathoGenomic Risk Factors (PGRF) including Very High Decipher score >0.85 (VHD), Grade Group (GG) 4-5, LNI and SVI were examined. Associations with distant metastatic (DM) outcomes and metastasis free survival (MFS) were evaluated using logistic regression in Mayo545 and Cox regression in Meta855 RP cohorts, respectively. Results: High expression of SRD5A2 was associated with favorable PGRF (lower odds ratio (OR), p<0.0001), lower rate of development of DM (OR 0.36, p<0.05), and longer MFS (Hazard ratio (HR) 0.51, p<0.05). HSD17B6 showed similar results for PGRF (lower OR, p<0.0001), DM (OR 0.58, p<0.05) and longer MFS (HR 0.39, p<0.05) despite being associated with GG4-5 and SVI+ in samples with VHD. In contrast, high expression of SRD5A3 and HSD17B10 had high OR for PGRFs (p<0.0001). High expression of SLCO2B1 , an androgen uptake gene, had the strongest association with GG4-5 and SVI/LNI (p<0.001 for both). We noted that SRD5A2 lacked correlation with SRD5A1 and SRD5A3 , which instead correlated with each other. Compared to all APUC genes, SRD5A2 had limited correlations with almost all APUC genes, including ones that exhibited robust cross correlation with each other . Similar to our prior finding, most APUC genes demonstrated negative correlation with AR expression and AR activity signatures. Key outcomes were validated based on transcriptomic data from 492 samples from TCGA database. Conclusions: Comprehensive analysis of 21 APUC genes in over 55,000 PC identified distinct, context-dependent associations with metastatic outcomes and clinical and molecular risk factors. Notably, high SRD5A2 expression was associated with lower odds of high-risk features and metastatic outcomes, whereas SRD5A1 and SRD5A3 linked to adverse outcomes, suggesting critical yet divergent roles among 5-alpha-reductase family members. These findings underscoring androgen-metabolic heterogeneity and highlighting SRD5A2 as a potential biomarker of indolent biology in localized prostate cancer.

Abstract Background: Estrogen receptor (ER) positive breast cancer is commonly treated with endocrine therapy, yet resistance to estrogen deprivation remains a significant clinical challenge. Using custom FISH probes designed to detect tumor-specific genomic alterations, we identified circulating tumor cells (CTCs) of true tumor origin in early-stage luminal breast cancer patients. Longitudinal analysis revealed that 80% of patients had FISH-positive CTCs after completing therapy and while on antiestrogen treatment, despite no clinical evidence of disease. This finding suggests that standard endocrine therapy is insufficient to eradicate all malignant clones, indicating the persistence of therapy-resistant tumor cells. Methods: Primary tumor DNA was analyzed using the Oncoscan microarray platform to identify somatic copy-number alterations (SCNAs). Custom FISH probes targeting these alterations were applied to peripheral blood samples before and after therapy. Immunofluorescence characterization of CTCs was performed to assess epithelial and mesenchymal phenotypes as well as ER expression status. Genomic profiling focused on identifying drivers of proliferation, known ER resistance genes, and ER transcriptional regulators. Results: Immunofluorescence revealed that CTCs were highly heterogeneous, displaying both epithelial and mesenchymal phenotypes. ER expression among CTCs was variable: while some CTCs were ER-positive, a significant proportion showed reduced or absent ER staining. This heterogeneity suggests that loss or downregulation of ER is a key mechanism of resistance, allowing tumor cells to persist despite antiestrogen therapy. Genomic profiling of parent tumors demonstrated multiple, overlapping mechanisms supporting both proliferation and endocrine resistance. All tumors harbored several genomic alterations known to drive proliferation, most commonly involving MCL1, NTRK1, SDHC, SDHD, CHEK1, ATM, and BCL6. Every tumor exhibited at least one established mechanism of ER resistance, with frequent alterations in ATM and PIK3CA, and additional recurrent changes in AKT3, MTOR, and ARID1A. Several tumors also had alterations in genes directly involved in ER transcriptional regulation, notably ARID1A and SPEN. Conclusions: The persistence of FISH-positive CTCs in the majority of patients after therapy—despite no clinical evidence of disease—highlights the insufficiency of current endocrine regimens. The underlying genomic complexity, characterized by multiple drivers of proliferation, redundant ER resistance mechanisms, and disruption of ER regulatory pathways, underpins the survival and persistence of CTCs. These findings underscore the need for therapeutic strategies that address the multifaceted and overlapping nature of endocrine resistance in luminal breast cancer. Citation Format: K. Baldwin, K. von Maltzan, A. Zulli, M. Richard, J. Abdulsattar, D. Maroni, P. T. Greipp, R. Knudson, Mayo Cytogenetics Core, S. P. Thayer. Fish-positive circulating tumor cells persist after effective therapy in estrogen receptor positive breast cancer: insights into genomic mechanisms of endocrine resistance [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-03.

Importance As gender-affirming care expands, hysterectomies for gender dysphoria are increasing, but data comparing outcomes to benign hysterectomies remain limited. Objectives The objectives of this study were to compare perioperative characteristics and 30-day outcomes between transgender and gender diverse individuals (TGDI) undergoing gender-affirming hysterectomy (GAH) and patients undergoing hysterectomy for benign indications, by surgical approach. Study Design This was a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program data (October 2015–December 2022). TGDI undergoing GAH were identified by gender dysphoria diagnosis and hysterectomy Current Procedural Terminology codes. Approaches included abdominal hysterectomy (AH), laparoscopic/robotic hysterectomy (L/RH), laparoscopically assisted vaginal hysterectomy (LAVH), and vaginal hysterectomy (VH). A matched cohort was created based on demographics and comorbidities. Primary outcomes were operative time, length of stay (LOS), and 30-day complications. Results A total of 975 TGDI undergoing GAH were included; 82% of GAHs were minimally invasive, mostly L/RH. GAH represented 0.7% of all benign hysterectomies, increasing over time ( P <0.001). TGDI (970) were matched to controls. In L/RH, TGDI had longer operative times (113 vs 97 min, P <0.001) but shorter LOS (0 vs 1 d, P <0.001). Similar patterns were seen in VH: longer operative times (103 vs 62 min, P <0.001) and shorter LOS (0 vs 1 d, P =0.018). In AH, TGDI had shorter LOS (1 vs 2 d, P =0.006) with similar operative times. No significant differences were found in LAVH or complications across groups. Conclusion GAH is safe with perioperative outcomes comparable to benign hysterectomy. TGDI experience shorter hospital stays and low complication rates. Promoting minimally invasive and vaginal approaches can enhance equitable, high-quality care for TGDI.

Abstract Purpose: Prostate-specific membrane antigen (PSMA)–directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule. Experimental Design: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc–EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc–EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging. Results: 99mTc–EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc–EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer–like morphology. Conclusions: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.

Traumatic brain injury (TBI) is one of the leading causes of death and neurological disability worldwide. The search for biomarkers that indicate TBI severity and prognosis with greater accuracy is ongoing. This study aimed to evaluate the significance of several neuroinflammatory cytokines and chemokines, assessing their potential as biomarkers in pediatric TBI (pTBI). This was an exploratory analysis of inflammatory cytokines and chemokines measured in a subset of 26 children aged 0–18 years with TBI and 21 controls. TBI severity was determined by GCS. The functional outcome was measured via the GOS-E score at 6 weeks and 3, 6, 9, and 12 months post-injury. Serum samples were analyzed for ICAM-1, VCAM-1, SAA, CRP, IFN-g, IL-10, IL-12p70, IL-13, IL-1b, IL-2, IL-4, IL-6, IL-8, TNF-a, TNF-b, eotaxin, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1a, MIP-1b and TARC. Levels of IL-6, IL-10, IL-13, IL-16, MDC, and GM-CSF were increased, and IFN-γ, IL-5, IL-8, and eotaxin-3 were decreased at enrollment when compared with controls. Elevated IL-6 and IL-10 at enrollment were associated with severe TBI (AUC of 1, p = 0.0002 and p = <0.0001, respectively). IL-6, IL-10, IL-16, and TNF-β at enrollment and IL-5 at 24 h were elevated in children with unfavorable outcomes, with an AUC > 0.8, suggesting biomarker potential. Our data indicate that several cytokines and chemokines measured after TBI may aid in the assessment of pTBI severity and prognosis. IL-6, IL-10, and IL-16 may show potential as biomarkers for pTBI severity and outcomes.