Citations

Messenger RNA (mRNA) therapeutics have transformed vaccination and protein replacement strategies, yet efforts to improve their performance have focused largely on sequence engineering, nucleotide modification, and delivery vehicles. Here we show that mRNA function can be controlled by rational design of higher-order RNA architectures. We develop self-assembling mRNA origami (mRNA-OG), a class of unimolecular RNA nanostructures that encode protein-coding sequences within higher-order, programmable, and compact nucleic acid architectures. Using computational design and experimental validation, we demonstrate that mRNA-OG folds into well-defined nanostructures while remaining translationally competent in mammalian cells. Although folded mRNA-OG recruits ribosomes comparably to unfolded constructs, it produces lower protein output, indicating that RNA architecture can directly influence translational efficiency. The compact geometry of mRNA-OG also enhances encapsulation by cationic lipid delivery systems, suggesting a structural route to improved cargo packaging. Beyond its effects on translation, mRNA architecture modulates innate immune recognition. In primary human dendritic cells, folded and unfolded mRNA-OG elicit distinct cytokine programs and differential activation of stress-response pathways, including a modest induction of the integrated stress response that is not fully explained by canonical PKR signaling. Our results establish programmable structure as a new design parameter for mRNA therapeutics that can affect its functionality, delivery properties, and immune sensing.

Abstract Global incidence and mortality rates for endometrial and cervical cancers have been steadily rising, while these rates for ovarian cancer have decreased. Although these cancers represent unique diseases and challenges, overlapping biology and responses to targeted and immunotherapies create opportunities to advance research through shared knowledge and resources. In 2025, investigators funded by National Cancer Institute (NCI) Specialized Programs of Research Excellence (SPORE) and other NCI-supported grants convened a hybrid meeting to identify challenges and knowledge gaps in translational research, highlight advances, define shareable resources and technologies, and foster collaboration among the Gynecologic Cancer SPORE sites, patient advocates, and NCI staff. Special sessions were arranged for presentations by Patient Advocates, Early-stage Investigators, Investigators Transitioning to Gynecologic Cancer Research. Meeting-wide workshops on Sharing Resources and Reducing Time to Activation of Clinical Trials and networking events were included. Collectively, the presentations converged on three overarching themes: (i) interception and early disease biology, (ii) development of innovative targeted and immune-based therapies, (iii) critical role of shared resources and collaborative infrastructure in accelerating translational progress. The unifying theme across disease sites was molecular advances to improve early detection/prevention and to drive therapeutic advancements. Novel findings discussed included: candidate precursor cells and mechanisms of high grade serous ovarian cancer development; therapeutic vaccines and their delivery methods for cervical dysplasia; identification of immune-targetable ovarian cancer antigens; various novel molecularly targeted drugs and immune-based agents for endometrial and ovarian cancers; and approaches to bypass drug resistance. Workshops delineated actionable strategies to further advance gynecologic cancer translational research.

ABSTRACT Purpose This study assesses the association between colorectal cancer (CRC) screening and a validated, housing-based measure of individual-level socioeconomic status (SES, called HOUSES hereafter) within rural communities and determines whether HOUSES-integrated geospatial analysis can be used to tailor interventions. Methods We used CRC screening data from a subset of Mayo Clinic Midwest patients living in cities without ready access to routine care in the Mayo Clinic Health System in 2019 to represent rural communities. At the individual level, we assessed the association between CRC screening rates and the HOUSES index, adjusting for age, sex, race/ethnicity, comorbidity, distance from home address to clinic, and area deprivation index, using a multilevel mixed-effects logistic regression model. Additionally, we conducted geospatial analysis to examine the correlation between hotspots of 1) lower CRC screening rates and 2) lower SES of the subject population (HOUSES quartile 1). Findings Among 34,489 individuals (median age 64.0 years, 52.4% female), those with the lowest SES (HOUSES Q1) had 37% lower odds of being CRC screening adherent than those with the highest SES (HOUSES Q4) (adj. OR [95% CI]: 0.63 [0.58-0.69]). In the 14 identified HOUSES Q1 hotspots, there was a significant correlation in counts of HOUSES Q1 and low CRC screening (correlation coefficient=0.81). Conclusion Lower SES was significantly associated with lower CRC screening among rural populations. HOUSES-enabled geospatial analysis identified geographic hotspots with lower CRC screening rates for targeted interventions to address disparities in CRC screening in rural communities. HOUSES may be a useful digital tool for cancer preventive care and research.

Background Alzheimer's disease (AD) and related dementias are leading causes of death worldwide. While socioeconomic status (SES) is a critical determinant, its impact on mortality after diagnosis remains understudied. Objective To investigate the roles of neighborhood-level and individual-level SES in predicting mortality risk among older adults with incident dementia. Methods We analyzed data from 924 participants with incident dementia from the Mayo Clinic Study of Aging (N = 6909), a cohort with clinical follow-up visits every 15 months. We assessed mortality risk using Cox's time-varying survival regression, adjusting for time-fixed and time-varying covariates. Primary predictors were neighborhood-level SES (Area Deprivation Index [ADI]) and individual-level SES (housing-based SES index [HOUSES], education, and occupation). We also applied a random survival forest model to assess the predictive contribution of SES indicators and identify influential predictors. Results 857 participants (92.7%) died, with a median time from dementia diagnosis to death of 29 months (IQR: 12–54). Lower SES measured by HOUSES was associated with increased mortality risk (HR 1.28, 95% CI 1.07–1.52). Conversely, ADI, education, and occupation were not associated with mortality. Male sex, older age, congestive heart failure and diabetes were associated with higher mortality risk. In predictive analysis, HOUSES ranked among the top 10 contributors to mortality risk. Conclusions Among older adults with dementia, lower HOUSES was associated with higher mortality risk beyond neighborhood-level deprivation, education, and occupation. Integrating this housing-based individual-level SES measure into dementia care planning may help identify patients with greater socioeconomic vulnerability and inform mortality risk stratification.

PURPOSE Detection of bone marrow disease has been a major component of rhabdomyosarcoma (RMS) staging with bilateral bone marrow aspirates/biopsies (BMAB) from the iliac crests considered the diagnostic gold standard. This study's goal was to determine if 2- 18 F-labeled fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) or PET/magnetic resonance imaging (MRI) may replace BMAB in RMS staging. METHODS Patients were recruited in Europe and North America. Medical records, FDG PET/CT or FDG PET/MRI (PET), and BMAB reports were collected retrospectively. Images were re-reviewed by nuclear medicine physicians at the patients' home institutions if PET reports indicated increased FDG uptake at bone/bone marrow sites or if tumor cells were detected in bone marrow samples. RESULTS PET imaging and BMAB were performed before chemotherapy and tumor resection in 301 patients with FDG-avid RMS. Bone marrow metastases were detected by PET and BMAB in 54, by PET only in 24, and by BMAB only in one of 301 patients with FDG-avid primary tumors. Absence of bone marrow metastases was confirmed by PET and BMAB in 222 of 301 patients. These observations translated into 98% sensitivity and 90% specificity for PET in detecting bone marrow metastases when BMAB was considered as gold standard. FDG-avid marrow disease was patchy (1-5 foci) in one third of cases. Patients with marrow disease indicated by PET and BMAB had more FDG-avid bone marrow foci, more metastatic sites, and lower survival than those with marrow disease indicated by PET only, suggesting more advanced disease stages. CONCLUSION Bone marrow sampling may be omitted in patients without evidence of FDG-avid bone marrow disease by PET. If there are FDG-avid bone marrow lesions, further investigation by MRI and/or biopsy should be considered.

Background: Several breast cancer (BC) risk prediction models have been developed to provide personal risk assessments. Though individually validated, their performance has not been systematically evaluated across a wide range of populations or ages. Methods: We harmonized individual-level baseline questionnaire data and incident BC diagnoses from 21 cohorts from North America, Europe, and Australia participating in the Breast Cancer Risk Prediction Project. Five-year absolute risk of invasive BC was estimated for five established risk prediction models using classical risk factors only. Discrimination was evaluated by area under the curve (AUC). Calibration was assessed using average and risk-decile specific expected to observed (E/O) ratios. Performance metrics were meta-analyzed across cohorts and models. Metaregression tested associations between cohort characteristics and performance metrics. Results: This analysis included 1,595,977 women aged 20-75 years, enrolled in studies between 1976-2015, with 19,062 (1.2%) invasive BC cases ascertained within 5 years from exposure assessment. Age-adjusted AUCs were similar across models and cohorts (pooled AUCs by model: 0.57-0.58), while E/O ratios varied substantially (pooled E/O ratios by model: 0.83-1.25). Overestimation was common among predicted high-risk individuals (>3%). No appreciable differences in model performance by cohort age, birth year, race, and variable missingness emerged. Calibration improved after assigning race-specific incidence rates. Conclusion: Existing BC risk prediction models provided similar risk discrimination across multiple cohorts, although there was overestimation of risk for high-risk individuals. Performance variation across cohorts was not driven by specific characteristics, which supports development of a unified risk model for diverse populations that leverages appropriate incidence rates.

Primary mediastinal B-cell lymphoma (PMBCL) is a rare form of large B-cell lymphoma (LBCL) with around 90% of patients cured with frontline treatment. For relapsed or refractory (R/R) disease, the optimal treatment is unclear. CD19 chimeric antigen receptor-T cell (CAR-T) has been established as the preferred second line (2L) treatment for primary refractory or early relapsing LBCL based on the overall survival benefits observed in the landmark phase III trials. However, PMBCL patients were underrepresented on these pivotal studies. This study evaluated outcomes of 252 patients treated with 2L therapies for R/R PMBCL at 14 US institutions between 2001 and 2025. Platinum-based salvage with intent to proceed to high dose therapy and autologous stem cell transplant (HDT/ASCT) (platinum cohort) and CD19 CAR-T (CAR-T cohort) were given as 2L therapy in the real-world setting in 157 and 26 patients, respectively. Overall response rate (ORR), complete response (CR) rate and median progression-free survival (PFS) were significantly higher in the CAR-T cohort compared with the platinum cohort (ORR: 91.3% vs 44.2%, p <0.001; CR 65.2% vs 14.7%, p<0.001; median PFS not reached vs 3.5 months, hazard ratio (HR) 0.28, 95% CI 0.15-0.54, p=0.001). No significant difference was observed in overall survival. This study demonstrated superior response rate and PFS of CD19 CAR-T over platinum-based salvage with intent to proceed to HDT/ASCT as 2L treatment for R/R PMBCL.

Importance Many patients are diagnosed with atypical lesions or lobular carcinoma in situ (LCIS); however, evidence- and consensus-based guidelines for the management of many of these lesions are limited. Observations The American Society of Breast Surgeons, in collaboration with the Society of Breast Imaging and College of American Pathology, assembled a steering group to create guidelines for the management of atypical lesions and LCIS, inclusive of flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), classic LCIS (C-LCIS), and the variant LCIS forms pleomorphic LCIS (P-LCIS) and florid LCIS (F-LCIS). The natural history of ADH, ALH, and C-LCIS suggests that these lesions are associated with an elevated future breast cancer risk; therefore, patients diagnosed with these lesions should be recommended to undergo comprehensive risk assessment and counseling about breast cancer risk-reducing strategies. The magnitude of future breast cancer risk associated with P-LCIS and F-LCIS remains uncertain, yet if these lesions are determined to be hormone receptor positive, risk-reducing medications should be considered. There is no evidence that FEA is associated with an elevated future breast cancer risk. A second pathology review confirmation is recommended for ADH, should be considered for FEA, and is not necessary for ALH or LCIS. Currently available evidence supports the need to diagnostically excise most ADH, P-LCIS, and F-LCIS cases identified on core biopsy, although some ADH cases fulfilling strict criteria and multidisciplinary consensus can be observed. P-LCIS and F-LCIS require a negative margin, but ADH does not. ALH and C-LCIS can be safely observed if the core biopsy diagnosis is concordant with imaging features (ie, radiographic-pathologic concordance is established). Provided radiologic-pathologic concordance is confirmed, diagnostic excision is generally not indicated after a diagnosis of FEA alone. Conclusions and Relevance These guidelines provide evidence-informed, consensus-based recommendations for the management of atypical lesions of the breast, including ADH, ALH, FEA, C-LCIS, P-LCIS, and F-LCIS. Practicing clinicians who treat patients with atypical breast lesions or LCIS should consider integrating these guidelines into clinical management.