Citations

Abstract Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator Polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in wild-type cells. Here we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2+/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.

Through a Delphi process, all 33 panelists reached consensus on topics relating to MRI reporting of knee meniscus lesions, demonstrating that interdisciplinary and multi-institutional standardization is possible.

Abstract Purpose Bronchiectasis is a condition characterized by chronic cough, recurrent infections, and progressive airway damage that is rising in prevalence. While often idiopathic, a subset of patients have a genetic cause such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD), or alpha-1-antitrypsin deficiency (A1ATD). Genetic causes for bronchiectasis should be considered in patients with diffuse bronchiectasis involving ≥2 lobes, especially in those with early onset of symptoms, recurrent otitis media or chronic rhinosinusitis, infertility, organ laterality defects (e.g., situs inversus), exocrine pancreatic insufficiency or family history of bronchiectasis. Genetic testing may impact management decisions. Methods The Mayo Clinic Center for Individualized Medicine developed the Program for Rare and Undiagnosed Diseases (PRaUD) Genetic Testing and Counseling Unit (GTAC) provides abbreviated, point-of-care genetic counseling, and DNA sequencing-based testing. Patients with bronchiectasis evaluated by GTAC underwent exome or genome-based 52-gene panels which included PCD, CF, and A1ATD (SERPINA1)-associated genes. Sequencing panes results were reviewed and interpreted by a multidisciplinary team including genetic counselors, geneticists, and pulmonologists. Results From July 2022 to December 2025, 203 patients were identified; 163 patients completed testing (74% female, 93% white). A molecular diagnosis was confirmed in 10.4% (17/163) of cases, with known pathogenic variants identified in RSPH4A, SERPINA1 (A1ATD), and CFTR (CF). Variants of uncertain significance (VUS) were identified in 24% of patients. Notably, 11.6% (19/163) were identified as CF carriers, a rate significantly higher than the general European-ancestry population (∼4%). Clinical management was impacted for two patients, including the initiation of targeted CFTR modulator therapy in one patient with CF-related disorder (CFTRD) and one CFTR pathogenic variant heterozygote. Conclusions Genetic counselor-supported DNA sequencing for bronchiectasis led to an increased identification of genes that cause bronchiectasis. Interestingly, we found a high rate of CFTR heterozygote variant carriers in our clinic cohort, this aligns with the findings of other studies that CFTR variant carriers can have an increased frequency of bronchiectasis. The identification of pathogenic variants and VUS helps facilitate a diagnosis or potential genetic cause in a significant proportion of patients and highlights the need for further research in understanding the epidemiology of CF, PCD, and A1ATD-related variant genotypes in patients with bronchiectasis. Clinical Implications Comprehensive DNA sequencing, combined with genetic counseling and support from genetic counselors in partnership with pulmonologists can advance precision diagnostics and care for patients with bronchiectasis. This abstract is funded by: None

Abstract Rationale Glucagon-like peptide 1 (GLP-1) receptor agonists are novel antihyperglycemic drugs that have shown benefit in various disease states, namely in cardiovascular and renal disease. GLP-1 agonists in murine models of obstructive lung diseases have been shown to decrease airway inflammation and hyperresponsiveness. In humans, some observational studies show an association between GLP-1 agonist use and reduced exacerbations of chronic obstructive pulmonary disease (COPD). In a meta-analysis, GLP-1 agonist use decreased the risk of several respiratory disorders including bronchitis (3). Bronchiectasis is another chronic airway disease, characterized by abnormal airway dilation leading to impaired mucous clearance and increased risk of infection (4). Data on the association between GLP-1 agonist use and bronchiectasis is sparce. We, therefore, examined the effects of GLP-1 agonists on the mortality of patients with bronchiectasis in a large sample size. Methods In this retrospective case control study, we identified patients with bronchiectasis from a single-center database of patients at our institution. We identified patients with bronchiectasis who received a GLP-1 agonist and compared them to patients who never received a GLP-1 agonist. Data was displayed as median with interquartile range and a Kaplan-Meier curve was used for mortality analysis. Results We identified a total of 256,777 patients with bronchiectasis. Of these, 249911 patients with bronchiectasis had not received a GLP-1 agonist and 6866 patients had received a GLP-1 agonist. The median age for patients in the GLP-1 group was 63 vs. 64 for the control group. 54.5 % of patients in the GLP-1 group were female compared to 52.9% in the control. Patients who received a GLP-1 agonist had improved survival at 1 month (99.9% for the GLP-1 group vs. 98.7% for the control group), 5 months (98.9% for the GLP-1 group vs. 95.9% for the control group), 10 months (97.9% for the GLP-1 group vs. 93.5% for the control group), 30 months (91.9% for the GLP-1 group vs. 86.8% for the control group) and 60 months (81.8% for the GLP-1 group vs. 79.3% for the control group), p < 0.001, Hazard ratio 0.56 (95% CI 0.50 - 0.62). Conclusion Our study showed that GLP-1 agonists are associated with improved survival in patients with bronchiectasis. Several mechanisms may contribute to this effect, including weight loss and reduction of cardiovascular mortality. Further studies are needed to investigate GLP-1 agonists as a potential therapeutic option for bronchiectasis, and to elucidate the mechanisms behind this association. This abstract is funded by: none

This multicenter, single-arm, phase 1/2 study evaluated the safety and efficacy of CD19-directed allogeneic chimeric-antigen-receptor (CAR) immunotherapy CTX110 in adult patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). Patients received 1 or 2 treatment courses: standard lymphodepletion, followed by 1 CTX110 infusion at dose levels (DLs) 1-4 (3-60 × 107 CAR T-cells; dose escalation, N=32), or 2 infusions at DL4 on days 1 and 35 (cohort expansion, N=31). Primary endpoints in dose escalation and cohort expansion were incidence of dose-limiting toxicities and objective response rate, respectively. CTX110 was administered to 63 heavily pretreated patients: 59% primary refractory, 43% with ≥3 prior treatment lines. Among 57 patients whose first infusion was DL≥3, rates of objective and complete response (CR) were 65% and 39%, respectively. Among 22 patients achieving CR, 5 (23%) had ongoing CR at data cutoff, with 15-50 (median 34) months follow-up. The 2-infusion regimen appeared to prolong response duration compared to 1 infusion (hazard ratio 0.65). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 54% and 13% of treated patients, respectively, including 2 grade ≥3 cases each. The most common grade ≥3 adverse events were neutropenia (59%), and anemia and thrombocytopenia (35% each). Serious adverse events occurred in 32% of treated patients, including CRS (14%), ICANS (8%), and febrile neutropenia (6%). In this r/r NHL population, CTX110 was well-tolerated, resulting in clinically meaningful responses at DL≥3, with a second infusion demonstrating evidence of further clinical benefit. This trial (NCT04035434) was registered at www.clinicaltrials.gov.

ABSTRACT Background Street Medicine, where healthcare is provided in non‐traditional settings, provides care to people experiencing homelessness (PEH). Street medicine has been shown to improve patients' health and decrease Emergency Department visits, making it a cost effective way to provide medical care to PEH. Methods This paper is based on the SAEM25 didactic session as conducted in Philadelphia, where a panel of providers who are directly involved in street medicine clinics shared their experiences and perspectives on the various designs in practice. These topics included key logistical challenges and solutions, barriers to care and trust building, strategies for fostering sustainable partnerships with community organizations, and options for medical student or resident involvement. Results The design and unique approach of four different universities across the country was compared and contrasted by a panel of experts, all with experiences working directly with PEH. There are similarly identified barriers to providing care to PEH including location and transportation, financial and food insecurity, and trust between the community and the healthcare system. Conclusion There are multiple options that exist to provide a framework to create a clinic to support populations of PEH.

817 Background: Universal germline sequencing is increasingly utilized in practice, but existing evidence and guidelines are based on studies in predominantly white populations. This study aims to compare the prevalence of genetic alterations in white vs underrepresented minority (URM) populations and assess incremental findings discovered with universal testing beyond current guidelines. Methods: This prospective, multicenter study analyzed genetic alterations in white and URM cohorts with primary GI malignancies receiving care at Mayo Clinic cancer centers between April 2018 and April 2025. Patients underwent germline sequencing using a next-generation sequencing (NGS) platform targeting over 80 genes. We compared the distribution of results between white and URM populations. Concordance with NCCN testing guidelines and incremental findings were assessed. Results: A total of 1128 patients were studied, of which 758 were white and 370 were URM, (47.6% Hispanic, 22.7% Black, 13.8% Asian, 10.5% American Indian, 0.8% Pacific Islander, and 6.8% other). Pathogenic variants (PGV) were more common in the white population (16.1% vs 9.2% P < 0.001). Variants of uncertain significance (VUS) were more common in the URM population (53.2 vs 43.5%, P<0.001). A total of 156 patients were found to have a PGV. PGVs outside primary cancer genes were more common in white patients (57.4% vs. 32.4%; p=0.0241). Incremental findings from universal testing were higher in white patients (66.4% vs 35.3%; p=0.0011). Conclusions: This study reveals a significant difference in the prevalence of PGV and VUS between white and URM patients with primary GI malignancies. The higher rate of PGVs in white patients and VUS in URM patients highlights potential inequities in both detection and interpretation of genetic results. These findings emphasize the need for broader representation in genetic databases to ensure equitable access to precision oncology. Screening guidelines met by patients with PGV. White (N=122) URM (N=34) Total (N=156) p value Did they meet NCCN testing guidelines for their primary cancer? 0.0991 Yes 87 (71.3%) 29 (85.3%) 116 (74.4%) No 35 (28.7%) 5 (14.7%) 40 (25.6%) Was the PGV outside of the primary genes recommended for their primary cancer? 0.0241 Yes 70 (57.4%) 11 (32.4%) 81 (51.9%) No 47 (38.5%) 22 (64.7%) 69 (44.2%) Incremental Finding 0.0011 Yes 81 (66.4%) 12 (35.3%) 93 (59.6%) No 41 (33.6%) 22 (64.7%) 63 (40.4%)

Background: The use of spinal cord stimulation (SCS) for managing severe refractory chronic pain has expanded considerably due to positive statistical evidence regarding its use; however, the statistical robustness of the underlying randomized controlled trials (RCTs) requires further scrutiny. One such tool that can be used for this purpose is the fragility index, which quantifies how many individual outcome events must be altered for an outcome to lose statistical significance. Thus the index can be used quantitatively to assess the stability and robustness of an RCT’s conclusions, with higher values indicating increased trial stability. This study assesses the fragility of pain outcomes across RCTs investigating SCS for chronic pain to better understand the quality and robustness of evidence. Methods: A systematic search was conducted for RCTs assessing SCS for any chronic pain indication. The primary outcome was an evaluation of the trial-specific fragility index for the prespecified pain primary outcomes of RCTs. Secondary outcomes included an evaluation of fragility for (1) specified indications for SCS therapy, (2) reported pain outcomes appearing in three or more RCTs, (3) the presence/absence of a conflict of interest, and (4) comparisons of SCS to conservative management or different SCS waveform modalities. Results: A total of 30 RCTs were included. The median (interquartile range [IQR]) fragility index across the primary outcome of all trials was 5.45 (3.00 to 11.45). There was no statistical difference between the (1) types of outcomes (dichotomous vs. continuous; P = 0.710), (2) primary versus secondary pain outcomes ( P = 0.771), or (3) presence versus absence of trial conflict of interest ( P = 0.753). Indications with a median (IQR) fragility score greater than three included persistent spinal pain syndrome type 2 with a score of 8.00 (2.80 to 12.60), painful diabetic neuropathy with a score of 6.00 (3.00 to 11.80), complex regional pain syndrome with a score of 7.20 (4.62 to 81.50), mixed etiologies with a score of 9.00 (3.00 to 38.00), and other etiologies with a score of 3.00 (1.00 to 8.55). Conclusions: This study suggests that the majority of RCTs investigating primary pain outcomes after SCS therapy are robust with relatively high fragility scores. Reporting the fragility of outcomes in trials can provide a more comprehensive assessment of trial robustness and can further aid clinicians in interpreting trial results and making informed treatment decisions.

Abstract IDH-wildtype glioblastoma (GBM) is the most malignant primary adult brain tumor, with a five-year survival rate below 5%. Despite maximal treatment, including surgical resection, radiotherapy, and temozolomide (TMZ), recurrence is universal, driven by profound intratumoral heterogeneity, diffuse invasion, and therapy resistance. A hallmark of IDH-wildtype GBM is frequent alteration of epidermal growth factor receptor (EGFR), including amplification (50%), the EGFRvIII deletion variant (25%), and extracellular missense mutations such as G598V and A289V (10–15%). These missense mutations increase ligand affinity and receptor activity, yet their downstream signaling consequences and role in shaping the tumor phenotypes remain poorly defined. Recent pathway-based subclassifications identified four subtypes in IDH-wildtype GBM. Notably, neuronal (NEU) and glycolytic/plurimetabolic (GPM) subtypes predominate the invasive tumor margins. NEU programs are enriched in synaptic and neurodifferentiation signals, while GPM programs are associated with metabolic adaptation, angiogenesis, and immune evasion. Here, we show EGFR-G598V and EGFR-A289V mutations differentially regulate these invasive subtypes identities. Transcriptional analysis reveals EGFR G598V upregulates metabolic and inflammatory pathways consistent with the GPM phenotype, while EGFR A289V activates genes involved in neuronal differentiation and synaptic function, aligning with the NEU subtype. Phosphoproteomics and kinase-substrate analysis further uncovered distinct kinases to be functionally activated/inhibited in EGFR A289V-expressing cells and G598V cells. Mechanistic studies revealed EGFR A289V induces sustained EGFR phosphorylation at Y992, activating PLCγ2 via the SRC-family kinase LCK. This cascade drives calcium release, CAMK1 activation, and STAT5 phosphorylation, defining a novel EGFR A289V–LCK/PLCγ2/CAMK1/STAT5 axis. In addition, Y1068 phosphorylation is also constitutively active in EGFR A289V, resulting in increased BRAF activation. In contrast, EGFR G598V activates MAPK6 and CAMK2 inducing AKT2 activation, reinforcing GPM-associated signaling. These findings uncover mutation-specific signaling networks that drive subtype fate in invasive GBM and highlight unique pathway(s) as tractable targets for subtype-directed therapy in EGFR-mutant GBM.