Citations

Abstract Introduction: The prostate cancer (PCa) tumor microenvironment (TME) is immunosuppressive and resistant to immune checkpoint blockade (ICB). Based on multi-omic single cell correlatives of response to neoadjuvant Fc-enhanced (FcE) αCTLA-4 in high-risk localized PCa (NCT04301414), we explored how modulating the balance between regulatory T cells (Tregs) and dendritic cells (DCs) in the PCa TME affects sensitivity to ICB. Methods: We leveraged three single cell transcriptomic atlases of PCa to assess how Tregs and DC frequencies are dynamically regulated during PCa progression. To investigate responses to Treg depletion (via FcE-αCTLA-4) alongside DC expansion (via Flt3L-Ig) and stimulation (via STING agonist ADU-S100) in PCa, we employed the castration-sensitive MycCaP PCa model and 45-parameter spectral flow cytometry. To investigate novel direct mechanisms of DC stimulation by FcE-αCTLA-4 via Fcγ receptor (FcγR) engagement, we optimized reductionist in vitro assays involving bone marrow-derived DCs (BMDCs) from wild-type (WT) mice or mice deficient in activating FcγRs (Fcer1g-/-) or inhibitory FcγRIIb (Fcgr2b-/-). To validate this effect in vivo we established a tumor antigen-specific T cell priming assay with both flow cytometry and ex vivo 2-photon live cell imaging readouts. Results: In three independent single cell transcriptomic PCa atlases, we find cDC2 frequencies are significantly decreased in advanced PCa while effector Tregs (TNFRSF9+) increase in proportion. Hypothesizing that excessive Treg function and DC insufficiency drive ICB resistance in PCa, we find in vivo DC expansion (Flt3L-Ig) prior to hormonal therapy, Treg depletion (FcE-αCTLA-4), and in situ DC stimulation (ADU-S100) drives robust control of established MycCaP tumors, with 87% of animals tumor-free 40-days post-treatment (27/31). Using 45-parameter spectral flow cytometry we find FcE-αCTLA-4 drives DC activation prior to Treg depletion in the TME, supporting a novel direct mechanism of DC modulation by FcE-αCTLA-4. In vitro, we find cell-associated FcE-αCTLA-4 is sufficient to drive BMDC maturation in an FcγR-dependent manner. In vivo, FcE-αCTLA-4 augments DC-mediated T cell priming in an FcγR-dependent manner. Ongoing experiments are investigating how FcE-αCTLA-4 shapes DC-T cell interactions via FcγR engagement and how DC/Treg axis modulation can be optimized to improve long-term curative response rates in the MycCaP model. Conclusions: DC insufficiency and effector Treg differentiation are hallmarks of advanced PCa. Enhancing DC number and function concomitant with Treg depletion can drive effective antitumor immunity in a pre-clinical PCa model. Direct DC modulation via FcγR engagement represents a novel mechanism of response to CTLA-4-targeted ICB. These findings will inform ongoing translation of FcE-αCTLA-4 agents and development of novel immunotherapy strategies for PCa. Citation Format: Jessica C. Hill, Kade R. Copple, Collin Jugler, Phuong Nguyen, Nilika Bhattacharya, Jessica N. Lancaster, Casey R. Ager. Rewiring the dendritic cell: Regulatory T cell axis sensitizes prostate cancer to immunotherapy [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 166.

Abstract Professional identity is defined as the attitudes, behaviors, values, and experiences by which individuals define themselves in a professional role and is influenced by socialization during training and in the workplace. As professional identity develops and is integrated with one's personal identities, it allows an individual to think, act, and feel like a member of their chosen profession and to develop a sense of meaning, confidence, and satisfaction in their work. Conflicts may arise due to perceived differences between one's professional identity and the collective identity of the profession, resulting in stress, burnout, and attrition, all of which can negatively impact patient care and the collective identity of the genetic counseling profession. Using Social Identity Theory (SIT) as a theoretical framework to develop the semi‐structured interview protocol, recorded interviews were conducted with 50 genetic counselors who were purposefully sampled to ensure diversity of personal demographics (gender, race/ethnicity, sexual orientation, disability, and caregiver status), as well as years, settings, and roles in genetic counseling practice. Transcripts were coded and subjected to codebook thematic analysis using NVivo. Genetic counselors described their professional identity in terms of who they are (characteristics and attributes), what they do (actions and skills), and what they have (training and knowledge). The majority of participants had a multidimensional perspective of what it means to be a genetic counselor, noting the transferability of their skills to a broad set of roles and settings, which supported their sense of professional identity, particularly for those who were no longer seeing patients. Yet many expressed tension with the collective identity of the profession. Expanded opportunities for genetic counselors to work in new settings and roles require review and revision of key professional documents to ensure they are reflective of the collective identity of the genetic counseling profession.

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

Objective: This study aimed to examine whether parent–child interaction therapy (PCIT), compared with other therapy modalities, was associated with differences in substance use and psychiatric outcomes in a cohort of children with attention-deficit/hyperactivity disorder (ADHD). Methods: This retrospective cohort study was conducted using medical record data from the Rochester Epidemiology Project (REP). The sample included 643 children aged ≤7 years who were diagnosed with ADHD and received either stimulant or nonstimulant medication, along with psychosocial therapy. Participants were categorized into two groups: those who documented exposure to PCIT versus other therapy modalities such as behavioral management, play therapy, cognitive behavioral therapy, parent management training, occupational therapy, speech therapy, parenting class, applied behavior analysis, and social skills training. Conditional logistic regression models were used to examine differences in baseline characteristics and outcomes between the two treatment groups. Results: Individuals in the PCIT group were more likely to have private insurance (66% vs. 57%; p = 0.016) and to fall into higher socioeconomic status quartiles ( p = 0.024) at baseline. PCIT recipients also had a higher prevalence of emotional and behavioral disturbances at baseline (40% vs. 25%; p < 0.001). The median age of the participants at follow-up was 19.6 years, indicating a median follow-up period of approximately 13 years from the initiation of treatment. At follow-up, the PCIT group demonstrated higher rates of problematic alcohol (24% vs. 17%; HR = 1.50, 95% CI: [1.02, 2.20]; p = 0.038) and cannabis use (25% vs. 18%; HR = 1.48, 95% CI: [1.03, 2.15]; p = 0.037). However, after controlling for covariates in the adjusted model, no statistically significant differences emerged between the groups across any substance use outcome. No significant differences were observed in other psychiatric diagnoses or mental health service utilization. Conclusions: Findings indicate that individuals who documented exposure to PCIT demonstrated elevated rates of alcohol and cannabis use in young adulthood, but had no other differences in psychiatric outcomes. While this aligns with prior literature reporting increased substance use risk in ADHD populations, our study cannot confirm this association relative to non-ADHD controls because such a comparison was not included. These associations likely reflect underlying differences in clinical severity and clinical comorbidities at baseline, rather than a direct effect of PCIT. Further investigation is warranted to determine the treatment effects based on baseline risk factors.

OBJECTIVE: Accurate assessment of skin and skin changes across diverse populations is critical for patient health. To promote the knowledge and skills nurses need in practice to identify skin changes, nurse educators must include content on assessment of diverse skin tones in nursing education programs. This study’s objective was to develop and pilot education modules about the assessment of diverse skin tones to be part of an undergraduate nursing course. METHODS: In this quality improvement project, modules highlighted the importance of skin assessment and appropriate techniques for assessing erythema, pallor, cyanosis, and jaundice on diverse skin tones. Undergraduate nursing students completed a questionnaire evaluating the modules and their learning experience. RESULTS: The majority of students (≥70%) agreed or highly agreed that the modules were interesting, informative, engaging, and increased their knowledge. Comments to open-ended questions supported their evaluation ratings. CONCLUSIONS: Undergraduate nursing students positively received education modules on assessing patients with diverse skin tones. Students perceived the modules as having the potential to enhance their learning and assessment skills to prevent and detect skin changes associated with pressure injury. The modules serve as an example of a strategy to integrate education content about diverse skin tones into nursing curricula.

TPS283 Background: Emerging evidence suggests that metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) can delay systemic therapy in oligometastatic castration-sensitive prostate cancer (omCSPC). However, the optimal timing of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) initiation in this setting remains undefined. While deferred ADT following MDT may preserve quality of life, early short-course ADT/ARPI may eradicate micrometastatic disease and extend progression-free survival. Extracellular vesicles (EVs) carrying PSMA-positive prostate cancer (PC) signals and circulating tumor DNA (ctDNA) may serve as real-time biomarkers of MRD and treatment response. Methods: DIVINE [NCT06378866] is an open-label, phase II, randomized trial enrolling men with omCSPC defined by 1–5 metastases (≥1 extrapelvic) on conventional imaging (CT/MRI and bone scan) and testosterone >100 ng/dL. PSMA PET may be obtained for correlative purposes but does not determine eligibility. Participants (N = 220) are randomized 1:1 to: Arm A (Early systemic): SBRT plus 6 months of ADT + ARPI. Arm B (Deferred systemic): SBRT alone with observation, reserving systemic therapy until radiographic progression not amenable to further SBRT (mrPD). SBRT is delivered per institutional standard; repeat SBRT is allowed until lesions become non-addressable. The primary endpoint, modified radiographic progression-free survival (mrPFS), is the time from randomization to death or radiographic progression not amenable to further MDT, defined by PCWG3 (bone) and modified RECIST 1.1 (soft tissue) criteria on conventional imaging. Soft-tissue progression requires ≥ 20% increase in measurable disease or a new lesion; bone progression requires ≥ 2 new confirmed lesions. Secondary endpoints include OS, biochemical PFS, time to local and distant progression, and grade 3–5 adverse events during systemic therapy. Exploratory endpoints evaluate EV and ctDNA kinetics as MRD markers, correlation of PSMA-positive EV burden with outcomes, and duration of response after short-course ADT/ARPI. Correlative analyses will longitudinally quantify PSMA-positive EVs and ctDNA at baseline, on treatment, and at progression to define MRD dynamics and resistance patterns. The trial uses Pocock–Simon dynamic allocation by EV strata and metastatic burden to ensure balance across arms. The trial is open and actively enrolling across all Mayo Clinic sites; as of October 2025, 35 of the planned 220 patients have been accrued. Clinical trial information: NCT06378866 .

Abstract Endoscopic sleeve gastroplasty (ESG) facilitates 13.6%–16.2% total body weight loss (TBWL) at 12 months, but falls short of that seen with surgical vertical sleeve gastrectomy, in part owing to the retention of the gastric fundus. In adults with obesity, gastric fundal mucosal ablation (GFMA) reduces fasting plasma ghrelin (FPG), hunger, cravings, and accommodation. Combined GFMA-ESG could improve TBWL. This study aimed to evaluate the effectiveness and safety of sequential GFMA followed by ESG in adults with obesity, building on previously published 6-month results of GFMA alone. This was a prospective, first-in-human, two-phase clinical trial. Ten participants underwent GFMA, followed by ESG at month 6, and were followed for 12 months post-ESG (18 months total). GFMA was performed using hybrid argon plasma coagulation to lift and ablate the entire gastric fundal mucosa. ESG was performed using standard full-thickness endoscopic suturing of the gastric body. The primary end point was TBWL; secondary end points were safety and changes in FPG, maximum tolerated volume (MTV), and validated appetite questionnaires. Mean TBWL was 22.5% (SD 8.3%) at month 18. Hunger-related behaviors and eating self-efficacy showed sustained improvements. FPG was decreased at month 6 and returned toward baseline by month 18, while MTV remained suppressed. No serious adverse events occurred. Sequential GFMA-ESG is safe and induces substantial weight loss, reduced MTV of ingested nutrients, and improved behavioral measures. This combination approach builds on prior traditional ESG and GFMA-only results and may represent a promising advancement of endoscopic therapeutic options for weight loss.

BACKGROUND: Pectus deformities are common chest wall abnormalities, with surgical correction recommended for severe cases. Female patients undergoing repair may have a history of breast implants or seek concurrent augmentation. This retrospective study examines clinical implications of pectus repair in patients with breast implants and provides recommendations. STUDY DESIGN: A retrospective review of female patients undergoing pectus repair at Mayo Clinic Arizona (January 1, 2010 to February 1, 2025) was conducted. Outcomes and complications were analyzed in patients with and without breast implants. RESULTS: In total, 456 female patients were included (447 excavatum, 7 arcuatum, and 2 carinatum; median age 32.7). Most patients (78.5%) underwent primary minimally invasive repairs (MIRPE); 6.6% underwent primary hybrid MIRPE, 5.5% underwent redo MIRPE, and 9.4% underwent primary redo open and complex reconstructions. In total, 104 patients (22.8%) had a history of breast implants, with 68 patients having breast implant-related procedures at the time of pectus surgery. At 12 months, the cumulative incidence of infection was significantly higher in patients with implants present at the time of pectus repair than in those without (8.8% vs 1.8%; log rank, p = 0.0015). A 4.9-fold increase in overall infection was seen in patients with indwelling or placed implants during pectus surgery. Deep infections were significantly more common in patients with implants (4.4%) than without (1.0%; p = 0.035). Similarly, superficial infections were more frequent in patients with implants (4.4%) than without (0.8%; p = 0.016). At 30 days, patients with implants had higher rates of infection (p = 0.032), pneumothorax (p = 0.008), and hematoma (p = 0.027), with no significant differences in other complications. CONCLUSIONS: Breast implants at the time of pectus repair were associated with increased risk of postoperative infection, pneumothorax, and hematoma. Removal of implants before pectus repair is recommended with delayed replacement, if desired.

Abstract Background: Clear cell renal cell carcinoma (ccRCC), metastatic castration-resistant prostate cancer (mCRPC), and glioblastoma (GBM) are highly treatment-refractory tumors characterized by elevated TGF-β1, a key suppressor of antitumor immunity and antigen presentation. Because CAR-T cells infiltrating these tumors experience persistent physiologic TGF-β exposure, assessing CAR-T functional resilience across increasing TGF-β concentrations is critical for determining therapeutic feasibility. Methylseleninic acid (MSA), a pharmacologic selenium compound, potently inhibits TGF-β1, PD-L1, and VEGF with minimal off-target toxicity. FN14, the TWEAK receptor and a metastasis driver, is selectively overexpressed in these malignancies, making it a high-specificity CAR target. Methods: We developed second-generation anti-FN14 CARs containing CD28 or 4-1BB costimulatory domains and a CD3ζ signaling motif, then lentivirally transduced into primary human CD4+ and CD8+ T cells. Cytotoxicity against FN14+ ccRCC, mCRPC, GBM lines and patient-derived cells was assessed using LDH release and xCELLigence assays. Effector function was evaluated through intracellular cytokine profiling, multiplex analysis, and phenotypic characterization by flow cytometry. CAR-T persistence in TGF-β-rich conditions was measured using CCK-8 proliferation assays, and Ki-67 and activation/exhaustion markers (PD-1, CXCR3) in the presence of 0-10 ng/mL TGF-β. MSA’s immunomodulatory and synergistic effects were tested at physiologically concentrations to measure impacts on CAR-T viability, metabolic activity, cytokine secretion, and tumor cell susceptibility. Results: Anti-FN14 CAR-T cells mediated rapid, antigen-specific lysis across all tumor types, achieving &gt;50% specific killing at a 1:1 E:T ratio. MSA (2.5-5 µM) reduced tumor PD-L1 and TGF-β expression by &gt;40% and enhanced CAR-T metabolic activity, IL-2, and IFN-γ secretion. CAR-T cells maintained comparable proliferation and activation in 0-5 ng/mL TGF-β, indicating that antigen-driven signaling counteracted low-to-moderate TGF-β-mediated suppression. Ex vivo CAR-T manufacturing with MSA (2.5 µM) improved cytotoxicity and persistence versus untreated CAR-T cells (p &lt; 0.01). MSA’s effects were dose- and schedule-dependent and remained within human-relevant exposure ranges without detectable toxicity. Conclusion: MSA enhances anti-FN14 CAR-T cytotoxicity, metabolic fitness, and sustained effector activity by suppressing tumor-derived TGF-β1 and PD-L1 and by directly improving CAR-T functional capacity. Consistent with this mechanism, physiological TGF-β levels (0-5 ng/mL) did not significantly impair CAR-T proliferation or activation, demonstrating intrinsic resilience of FN14 CAR-T cells in TGF-β-rich environments. As a clinically relevant TGF-β1 inhibitor and active metabolite of seleno-L-methionine, MSA represents a readily translatable strategy to reduce CAR-T exhaustion and enhance efficacy in TGF-β-rich solid tumors including ccRCC, mCRPC, and GBM. Citation Format: Obed B. Amissah, Casey Ager, Yousef Zakharia, Youcef M. Rustum, Gloria B. Kim. Anti-FN14 CAR-T cells overcome TGF-β-mediated suppression, and their synergy with methylseleninic acid enhances cytotoxicity and effector function in kidney, prostate, and brain tumors [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C010.