Citations

ABSTRACT Background Chronic obstructive pulmonary disease (COPD) is associated with musculoskeletal comorbidities, including cachexia. Weight loss (WL) is the major criterion for cachexia and increases risk for mortality in COPD. Risk factors for WL in COPD are incompletely understood. We performed this whole genome sequencing (WGS) analysis to identify genetic risk variants for WL in COPD. Methods We studied 16 972 participants from the Trans‐Omics for Precision Medicine (TOPMed) Initiative and All of Us Research Program. COPD was diagnosed using spirometry in TOPMed, while diagnosis codes were used in All of Us. WL was defined as WL ≥ 5% or a final body mass index (BMI) < 20 kg/m 2 . WGS data came from white blood cells in all cohorts. Single‐variant testing was conducted on both race‐ and study‐stratified cohorts and in a cosmopolitan, ancestry‐independent manner using GENESIS in TOPMed and SAIGE in All of Us. SAIGE‐GENE+ gene‐based analyses were performed on race‐stratified and cosmopolitan cohorts. Single variant meta‐analyses were conducted using METAL within (B/AA and NHW analyses of Black/African–American and non‐Hispanic white participants, respectively) and across racial groups (COSMO). Rare variant gene‐based results were combined using Fisher's method. Transcriptomic effects were predicted using MetaXcan. We used the GWAS Catalogue to analyse for colocalization with other related traits. Results Two single variants were associated with WL in COPD among All of Us participants: one intronic variant in HCN1 in Black/African–American participants (chr5:45271359:TACACAC:T, odds ratio with 95% confidence interval (OR (CI 95 )) = 2.43(1.78–3.31), p = 1.95 × 10 −8 ) and one intergenic variant between PPP4R2 and PDZRN3 in the cosmopolitan and NHW cohorts (chr3:73345901:A:G, OR (CI 95 ) = 0.21(0.12–0.35), p = 8.84 × 10 −9 in cosmopolitan and OR (CI 95 ) = 0.18(0.10–0.33), p = 9.44 × 10 −9 in NHW). Single‐variant meta‐analysis identified two loci associated with WL in COPD: five variants within DRAIC in the B/AA meta‐analysis (lead variant chr15:69571341:A:G, OR (CI 95 ) = 1.37(1.23–1.51), p = 1.29 × 10 −9 ) and two intronic variants within RFX3 in the cosmopolitan meta‐analysis (lead variant chr9:3390983:T:C, OR (CI 95 ) = 1.50(1.31–1.73), p = 1.06 × 10 −8 ). Rare variants within RNU6‐565P (NHW analysis in All of Us; p = 2.83 × 10 −7 ) and LOC339298 (B/AA analysis in All of Us, p = 1.85 × 10 −6 ) were associated with WL in COPD. The RNU‐565P signal remained significant after combination with TOPMed results (p combined = 1.23 × 10 −6 ). MetaXcan predicted differential expression of LNC00959 in visceral adipose tissue ( p = 1.16 × 10 −6 in COSMO analysis). Colocalization analyses identified genomic associations between BMI and variants in or near DRAIC , RFX3 , PDZRN3 , and LINC00959 . Conclusions In the first WGS analysis of WL in COPD, we have identified seven novel loci. Further characterization of these loci will validate our findings and improve our understanding of the molecular pathophysiology of this condition.

53BP1 nuclear bodies are dynamic structures with properties resembling biomolecular condensates, but the molecular determinants that govern 53BP1 higher-order assembly at DNA double-strand breaks (DSBs) remain to be established. Here, we show that 53BP1 condensation is stimulated by phosphatidylinositol 3-phosphate (PI(3)P) in vitro through a highly specific interaction with its C-terminal tandem BRCT domain (tBRCT). Consequently, mutational inactivation of the 53BP1 tBRCT domain compromised PI(3)P binding and suppressed 53BP1 optodroplet formation in vivo. We further show that rapid 53BP1 clustering following DNA damage precedes its stable assembly on DSB-flanking chromatin, requires its tBRCT, and is suppressed by sequestration of nuclear PI(3)P. Taken together, our findings identify PI(3)P binding as a mechanism that promotes the formation and maturation of 53BP1 condensate-like assemblies on damaged chromatin.

Abstract Background Anti‐M antibodies were described as rarely eliciting hemolytic disease of the fetus and newborn (HDFN) in pregnancy. More recent literature, primarily from Asia, reports severe HDFN attributed to maternal anti‐M. The objective of this study is to determine if there is a difference in the frequency and/or severity of anti‐M HDFN among subjects who self‐report as Asian compared to non‐Asian. Methods Retrospective data were collected from 18 sites. Fetuses/neonates affected by HDFN were categorized as unaffected, mild, moderate, or severe based on clinical management and outcomes. Results Anti‐M was identified in 557 obstetric patients. Among 332 neonates with complete data for analysis, anti‐M was detected in isolation during the pregnancies of 210 (63.3%) neonates; 198 (94.3%) were unaffected by HDFN. The overall frequency of HDFN was 6.5% (2/31) in Asian patients and 5.6% (10/179) in non‐Asian patients. The frequency of severe HDFN was 6.5% (2/31) among Asian patients and 0.6% (1/179) among non‐Asian patients. Among non‐Asian patients, eight (4.5%) were mild and one (0.6%) was moderate. Of 63 pregnancies with anti‐M and ABO incompatibility, 6 (9.5%) were associated with mild HDFN and 57 (90.5%) were unaffected. Of 49 pregnancies with anti‐M and non‐ABO antibody(s), 6 (12.2%) were associated with mild HDFN and 43 (87.8%) were unaffected. One case (10.0%) of HDFN (mild) occurred in the presence of anti‐M, additional antibody(s), and ABO incompatibility. Conclusion In this study, severe anti‐M HDFN was rare in non‐Asian subjects. There is a signal that Asian patients are at greater risk for severe anti‐M HDFN.

Abstract Background X‐ray Induced Acoustic Computed Tomography (XACT) is an emerging imaging technique that provides 3D volumetric images from a single projection by detecting X‐ray‐induced acoustic (XA) waves with ultrasound (US) transducers. Unlike MRI or CT, XACT enables real‐time 3D imaging without long acquisition times, 2D limitations, or motion artifacts from mechanical rotation. Furthermore, when integrated with conventional pulse‐echo US through time‐sequenced operation, XACT provides complementary soft‐tissue contrast, establishing it as a promising platform for dynamic interventional radiology (IR) guidance. Purpose This study aims to evaluate the feasibility of XACT as a novel imaging tool for IR, specifically for guiding needle placement and monitoring contrast agent dynamics. Methods We developed a 3D XACT imaging system equipped with a 256‐element 2D matrix array and a portable X‐ray tube to visualize needle insertion and contrast agent dynamics. To capture both needle position and soft tissue anatomy, we integrated a dual‐modality system combining XACT with pulse‐echo US using a 128‐element linear US array. Experiments were conducted on both tissue‐mimic phantoms and soft tissue samples. GPU‐accelerated algorithm has been developed for 3D XACT image reconstruction. Results The results demonstrate the 3D capabilities of XACT imaging for interventional procedures, including monitoring of needle placement and tracking of contrast agent dynamics. The imaging speed reached up to 3∼4 s per frame, constrained by the repetition rate of the X‐ray source and signal to noise ratio. The dual‐modality approach provided clear visualization of the needle's position and the surrounding soft tissue structures, achieving imaging resolution around 2 mm. Conclusions This study demonstrates that XACT imaging is feasible to be used for IR. Its 3D imaging capability with faster imaging speed would be an alternative to cone beam CT and its capability to combine US imaging will provide richer information for soft tissue

Abstract Introduction: Black prostate cancer (CaP) survivors experience unique quality-of-life (QoL) and recovery challenges after treatment compared with their White counterparts. Smartphone-delivered mobile health interventions offer promising avenues for symptom tracking and lifestyle changes; but their feasibility, user engagement, and acceptability in this population remain unclear. This study assessed the feasibility, engagement, and preliminary impact of the Survivorship App for Ethnically Diverse Black Prostate Cancer Survivors (SAFE-CaPS), designed to improve self-monitoring behaviors and health outcomes. Methods: Nine Black CaP survivors (seven U.S.-born, one African-born, and one Caribbean-born) participated in a 12-week pilot study of SAFE-CaPS. The app provided daily prompts for symptoms (pain, sleep, fatigue, sexual function, anxiety, depression) and behavior tracking (physical activity, diet), brief self-management support, and physician alerts for severe symptom reports. Mental health (GAD-7 and PHQ-9) and QoL (FACT-P) were assessed at baseline and after 12 weeks. Feasibility was evaluated based on adherence rates (i.e., ≥70% of daily diary entries). Engagement and acceptability were assessed via app analytics and qualitative interviews on usability and cultural relevance. Participants were compensated up to $125 via Greenphire ClinCard. Surveys were analyzed with SPSS v29, and interviews with Atlas.ti v23. Results: Participants’ median age at diagnosis was 56 years; six had a positive family history of CaP, and four had undergone radical prostatectomy. Four participants met the feasibility threshold, and eight completed the study. Most daily entries reflected mild pain, fatigue, bowel and urinary issues, and generally good sleep. Several participants frequently reported severe sexual dysfunction, and most diary responses indicated &lt;20 minutes of physical activity per day. Fruit/vegetable intake was low, with about half of daily responses showing 1-2 servings. At baseline, eight participants had minimal anxiety, while five had moderate depression. Overall, QoL improved from week 1 to week 12 in physical, emotional, and functional well-being, while social well-being declined over time. Interviews emphasized the app’s user-friendly design, ease of navigation, and acceptability as key strengths, with several participants highlighting its simplicity and ease of use, with recommendations to reduce repetitive items and address minor technical issues. Conclusions: SAFE-CaPS was feasible and well accepted. Sexual dysfunction, low physical activity, and moderate depression emerged as key concerns, heightening the need for integrated mental health, activity support, and stronger engagement strategies in future mHealth interventions. Citation Format: Gaurav Kumar, Parisa Ghasemi, Yan D. Zhao, Zsolt Nagykaldi, Kathleen A. Dwyer, Andrew G. McIntosh, Ernie Kaninjing, Mary E. Young, Dickey Sabrina, Daniel Morton, Opeyemi Bolajoko, Darla E. Kendzor, Motolani Ogunsanya. Feasibility of a survivorship app for black prostate cancer survivors: Results from a 12-week mHealth pilot study [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 6307.

Abstract Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of B-cell malignancies. Despite the clinical success of CD19-targeted approaches, relapsed/refractory (R/R) disease—often driven by antigen loss or immune escape—remains a major challenge. To overcome this, we developed a novel CAR-T cell therapy targeting BAFF-R, a receptor consistently expressed in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. We developed a new anti-BAFF-R monoclonal antibody and engineered the MC10029 CAR construct using its scFv. Antigen-specific cytotoxicity was validated in both in vitro and in vivo models, including Nalm-6 (leukemia) and Z138 (lymphoma), and CD19-knockout tumor cells to model (R/R) disease. MC10029 CAR-T cells were generated from healthy donors and CLL patients, and their cytotoxicity was evaluated against MEC-1, a CLL cell line, as well as autologous CLL patient tumor samples. These studies demonstrated potent and specific antitumor efficacy. We transitioned to clinical-grade production, using GMP-compliant lentivirus to manufacture MC10029 CAR-T cells under regulatory guidelines. With FDA IND approval, we initiated a Phase 1 clinical trial to evaluate safety and dosing. Our first patient, treated with a low-dose, single infusion, achieved a complete metabolic response within 2 months. The therapy is well tolerated, with no severe advent events such as cytokine release syndrome or neurotoxicity, supporting both the safety and efficacy of the therapy. Conclusion: This study represents Mayo Clinic’s first homegrown CAR-T cell therapy, developed entirely in-house—from antibody discovery and CAR design to GMP manufacturing and clinical trial—marking a significant step toward personalized, next-generation immunotherapy for B-cell malignancies. Citation Format: Yan Luo, Shaohua Guo, Yaqing Qie, Martha E. Gadd, Tanya Hundal, Hemant S. Murthy, Mohamed A. Kharfan-Dabaja, Hong Qin. From gene to bedside: Mayo Clinic’s first-in-house BAFF-R CAR-T [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 3719.

Abstract Introduction: Fibroblast growth factor receptor 2 and 3 (FGFR2 and FGFR3) are metabolic genes overexpressed in malignant epithelia. In colorectal cancer (CRC), intimate crosstalk between FGFR2/3 and epidermal growth factor receptor (EGFR) pathways has been suggested but is not fully elucidated. As a result, this study investigated associations between FGFR2/3 expression levels and clinical outcomes in patients with metastatic CRC (mCRC) enrolled in the phase III clinical trial CALGB /SWOG 80405. Methods: Data from 433 patients with mCRC enrolled in the CALGB/SWOG 80405 trial were analyzed. Patients received either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) plus chemotherapy as first-line treatment. Tumor RNA was extracted from FFPE samples and processed through the HiSeq 2500 (Ilumina) platform. Median overall survival (OS) and progression-free survival (PFS) curves were evaluated in all treatment subgroups and stratified according to high (H), medium (M), and low (L) FGFR 2 and 3 gene expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using Cox proportional hazards multivariate models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, consensus molecular subtypes, and treatment arm. Results: Both FGFR2 and FGFR3 expression levels were associated with outcomes in patients treated with cetuximab. FGFR2-L tumors showed significantly longer OS compared to the M (HR = 1.04; 95%CI 0.71-1.51) and H (HR = 1.56; 95%CI 1.06-2.28) expression groups (35.7 vs. 31.2 vs. 23.7 months, p = 0.017). In contrast, FGFR3-L tumors were associated with shorter OS compared to the M (HR = 0.63; 95%CI 0.44-0.92) and H (HR = 0.59; 95%CI 0.41-0.85) expression groups (24.7 vs 32.4 vs 37.1 months, p = 0.0009). Significant differences in PFS were not observed. A nominally significant interaction was found between treatment and FGFR3 expression for both PFS (p = 0.02) and OS (p = 0.0003), but no interaction with FGFR2 expression. No significant associations were detected in patients treated with bev. Neither FGFR2 nor FGFR3 suggested to be prognostic markers after multivariate adjustment analyses. Conclusions: Our findings suggest a predictive role of FGFR3 in patients with mCRC undergoing anti-EGFR treatment. Differences in survival within the cet subgroup suggest that EGFR inhibitor efficacy may be modulated by FGFR2/3 signaling activity. Interestingly, FGFR2 and FGFR3 expressions were inversely and positively correlated with improved OS. The findings suggest that FGFR2 signaling minimizes the specific effects of cetuximab, while FGFR3 signaling amplifies its therapeutic effects. Further studies should determine whether these associations are seen in other anti-EGFR inhibitors and detail the mechanistic interaction between FGFR and EGFR pathways. Citation Format: Steve Soto Trujillo, Yan Yang, Michela Bartolini, Shivani Soni, Pooja Mittal, Fang-Shu Ou, Lesly Torres-Gonzalez, Unnati Hemant Shah, Jae Ho Lo, Yitzhar Goretsky, Wu Zhang, Alan Venook, Sandra Algaze, Joshua Millstein, Heinz-Josef Lenz. Differences in survival outcomes among metastatic colorectal cancer patients across fibroblast growth factor receptor 2 and 3 expression levels [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 6751.

Abstract Several allogeneic CAR T-cell therapies are in clinical trials to evaluate safety, many of which rely on CRISPR/Cas-based genome editing. However, the Cas enzyme’s random repair mechanism elevates the risk of undesired, off-target effects, posing a challenge for safe allogeneic CAR T-cell generation. To mitigate the risk of therapy-related oncogenesis, we sought to pursue an alternative safe strategy to manufacture allogeneic CAR T-cells distinct from the preexisting ones in the clinic. We have developed a CRISPR RNA (crRNA) targeting T-cell receptor beta constant (TRBC) gene, which in conjunction with AsCas12a Ultra enzyme, causes site-specific editing by eliciting a predictable microhomology-mediated end joining (MMEJ) DNA repair pathway, which mitigates off-targeting risk. Targeted amplicon sequencing was employed to evaluate off-targeting and repair mechanisms. Graft versus host alloreactivity as well as CAR T persistence was evaluated using immunocompromised mice. In vivo tumor challenge study was conducted for over 3 months. Engraftment confirmation was done using immunohistochemistry and flow cytometry. Interestingly while evaluating the edited T-cells, we sequestered a unique T-cell population that showed TCR disruption yet remained CD3-positive and did not cause in vivo alloreactivity. These CD3-Retained, Allogeneically Functioning T-cells (CRAFT-cells) showed a similar growth rate as unedited T-cells and were then used as a platform to produce CD19-targeted CAR T-cells and BAFF-R-targeted CAR T-cells. When compared to the standard CD3-disrupted allogeneic CAR T-cells, CRAFT CAR T-cells displayed an equally robust cytotoxicity while possessing a safer genomic profile. CRAFT CAR T-cells could function as effector cells for bispecific T-cell engager (BiTE) and induce CD3-dependent cytotoxicity against tumor cells. Pertinently, CRAFT CAR T-cells as opposed to CD3-disrupted CAR T-cells, were present in mouse xenografts without alloreactivity. Having the onset of MMEJ-directed repair and minimal off-targeting, positions this CRAFT crRNA to generate safer allogeneic CAR T-cells with an overall reduced genotoxic profile in a clinical setting. This unique CRAFT CAR T-cell population displays in vivo persistence. Additionally, CRAFT CAR T can be combined with BiTE therapy, offering a promising and potentially more durable alternative to preexisting ex vivo allogeneic CAR T-cell therapies. Citation Format: Tanya Hundal, Yan Luo, Yaqing Qie, Martha E. Gadd, Shaohua Guo, Mohamed A. Kharfan-Dabaja, Hong Qin. CD3-positive allogeneic CAR T-cells: A novel platform with persistence, BiTE-capture, and no alloreactivity [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 4283.

Abstract Background: CLL incidence differs by ancestry, with higher rates in individuals of European ancestry (EA) than African ancestry (AA). The contribution of epigenetic variation to these disparities remains unclear. We investigated chromatin accessibility, histone modifications, and gene expression in CLL patients of EA and AA to identify ancestry-associated epigenetic signatures. Methods: ATAC-seq was performed on blood clonal B cells from 15 AA and 51 EA patients; CUT&Tag profiling of six histone marks (H3K4me1, H3K4me3, H3K27ac, H3K9me3, H3K27me3, H3K36me3) was done in 8 AA and 12 EA cases; RNA-seq was generated for all samples. Ancestry was genetically confirmed. Differential regions were linked to genes using ENCODE and Hi-C datasets. Results: ATAC-seq revealed 4,955 regions with increased and 3,000 with decreased accessibility in AA vs EA (fold change &gt;2, FDR ≤0.05). Regions with increased accessibility mapped to 2,313 genes; 599 were upregulated and enriched in TNF-α/NF-κB (p=1.40E-53) and apoptosis pathways (p=6.90E-11). Regions with decreased accessibility linked to 1,953 genes; 317 were downregulated, enriched in interferon-γ response (p=1.04E-03) and IL-6/JAK/STAT3 signaling (p=6.41E-03). Histone profiling showed ancestry-specific changes across all marks. For H3K27ac (active enhancer), 68 genes with a decreased signal in AA were downregulated and enriched in interferon-γ (p=1.55E-06) and IL-6/JAK/STAT3 (p=9.62E-05) pathways. Increased H3K27me3 (repressive histone modification) in AA affected 399 genes enriched in IL-6/JAK/STAT3 (p=8.13E-09) and interferon-γ (p=2.48E-05) pathways. These findings suggest coordinated regulation by active and repressive chromatin states. Conclusions: Despite limited sample size, this study suggests differences between AA and EA ancestries may exist in epigenetic signatures in CLL, implicating chromatin accessibility and histone modifications in pathways relevant to tumor biology. These signatures may also contribute to the differences in CLL incidence by ancestry. Future studies with more patients and functional validation experiments are needed to clarify the role of these epigenetic differences in CLL pathogenesis. Citation Format: Zhiquan Wang, Huihuang Yan, Mingma Sherpa, Daniel Bihnam, Cristine Allmer, Chantal McCabe, Daniel O’Brien, Dennis P. Robinson, James R. Cerhan, Neil E. Kay, Sameer A. Parikh, Esteban Braggio, Susan Slager. Ancestry-associated epigenetic differences in chronic lymphocytic leukemia [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 5064.