Citations

OBJECTIVE Genetic variation in the glucagon-like peptide 1 receptor (GLP1R) has been implicated in type 2 diabetes (T2D) risk and treatment response. We investigated whether GLP1R R131Q, which was previously reported as a T2D-protective variant in genome-wide association studies, alters receptor signaling, β-cell function, and response to glucagon-like peptide 1 receptor agonists (GLP-1RAs). RESEARCH DESIGN AND METHODS Trajectory of β-cell function was evaluated in a 20-year community-based prospective cohort in Korea (n = 6,373), where participants underwent biennial 2-h 75-g oral glucose tolerance tests, and disposition index was used as surrogate marker. Pharmacogenetic response to GLP-1RAs was assessed in a hospital-based T2D cohort in Korea (n = 177). Hyperglycemic clamp studies (n = 17), human islet experiments (n = 21), and in vitro assays were conducted to characterize GLP1R R131Q effects on receptor signaling and islet function. RESULTS GLP1R R131Q was associated with slower decline in disposition index in individuals without T2D, with reductions from baseline of 30% in homozygous carriers, 35% in heterozygotes, and 37% in wild-type individuals. In people with T2D, each allele conferred an additional 0.53% or 5.8 mmol/mol reduction in HbA1c after 6 months of GLP-1RA treatment (P = 5.8 × 10−4). Hyperglycemic clamp and human islet experiments demonstrated allele-dependent enhancement of GLP-1RA–stimulated insulin secretion (P = 0.050 and P = 0.037, respectively). In vitro, GLP1R R131Q increased GLP-1RA–stimulated cAMP production with directional observations consistent with pathway bias. CONCLUSIONS GLP1R R131Q is a gain-of-function variant associated with preservation of β-cell function and enhanced glycemic response to GLP-1RA treatment, supporting further investigation as a candidate pharmacogenetic marker for precision diabetes care.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Background & Objectives Cholangiocarcinoma (CCA) is a highly aggressive malignancy arising from the bile duct epithelium. Despite advancements in diagnostic techniques, the diagnosis of cholangiocarcinoma (CCA) remains challenging. Currently, CA19-9 is the best available blood-based marker for detection of CCA, which has a sensitivity of 50-60% and a specificity of 80%. Moreover, individuals who are Lewis-antigen-negative (∼20% in some populations) have undetectable CA 19–9 levels resulting in false negative diagnoses. Therefore, there is a critical need for developing novel blood-based diagnostic approach for improving the sensitivity of diagnosis of CCA to improve clinical outcomes. Glycosylation, one of the most prevalent post-translational modifications, plays a crucial role in regulating biological functions such as cell-cell communication, protein folding and receptor signaling and is frequently dysregulated in cancer. Cell surface proteins, including glycoproteins, are overexpressed in CCA are likely to be shed into the blood and we investigated development of mass spectrometry-based methods to measure changes in glycosylation in patients with CCA. Methods Mass spectrometry data were acquired in parallel reaction monitoring mode using Orbitrap Eclipse Tribrid mass spectrometers. In addition, we tested the use of heavy glycopeptides for absolute quantitation of each glycopeptide. Mass spectrometry data were analyzed using Skyline to estimate glycopeptide abundance. Results First, we performed tandem mass tag-based quantitative proteomics and glycoproteomics of tumor tissues and serum collected from CCA patients using high-resolution mass spectrometry. From these experiments, a number of glycopeptides were found to be increased in abundance in CCA patients. We subsequently developed a targeted mass spectrometry–based assay to monitor four candidate glycopeptides derived from polymeric immunoglobulin receptor and aminopeptidase N to validate their performance in a large patient cohort from 269 patients with CCA and 100 healthy individuals. Conclusion We anticipate that this finding will lay the foundation for novel diagnostics that could benefit patients with this aggressive malignancy.

Abstract Background Point-of-care testing (POCT) has expanded rapidly across healthcare systems, increasing both program scale and operational complexity. However, quantitative benchmarking data describing how POCT programs are structured and supported across institutions remain limited. Methods We conducted a cross-sectional survey to characterize POCT program support, including program scope, staffing, operational practices, governance, and challenges. The survey was distributed electronically through professional networks, and 93 institutional responses were analyzed. Descriptive analyses were performed, and derived metrics, including sites per point-of-care testing coordinator (POCC), were used to evaluate the relationship between program scale and staffing. Results POCT programs demonstrated substantial variability in scale, with wide ranges in the number of testing sites and operator populations. Adoption spanned multiple test categories, and many institutions reported use of multiple platforms for the same assays. Training, competency assessment, and quality management activities were primarily supported by laboratory staff and POCCs, with documentation frequently partially electronic. Median POCC staffing increased with program size; however, sites per POCC also increased significantly across program scale tiers (Kruskal–Wallis P < 0.001). Governance structures and operational responsibilities varied across institutions, and common challenges included staffing limitations, training and compliance burden, multisite coordination, and IT/connectivity constraints. Conclusions POCT programs are expanding in scale and complexity, but workforce capacity and governance structures have not scaled proportionally. This mismatch creates a cumulative and multiplicative operational burden. These findings provide benchmarking data to inform scalable staffing models, governance strategies, and infrastructure development for sustainable POCT program management.

TPS11592 Background: Epithelioid hemangioendothelioma (EHE) is an ultra-rare vascular sarcoma with about 120 cases diagnosed in the US per year. Although it is commonly considered an indolent disease, in its aggressive form clinical outcomes are poor. Molecularly, EHE is characterized by the presence of oncogenic fusions with HIPPO pathway effectors TAZ or YAP; TAZ-CAMTA1 or YAP-TFE3. YAP/TAZ are modulators of mTORC1 in preclinical models, suggesting that mTOR inhibition may be an effective treatment mechanism for EHE. Nab-sirolimus is albumin bound sirolimus, which achieves higher intratumoral accumulation compared to oral sirolimus and has demonstrated increased antitumor activity in preclinical cancer models compared to the oral mTOR inhibitors sirolimus and everolimus. This is an open label, multi-center, single arm, phase II clinical trial with a two-stage design, testing nab-sirolimus for progressing or symptomatic EHE. The primary objective is to determine ORR of nab-sirolimus in patients with EHE who require systemic treatment. We hypothesize that nab-sirolimus will have significant clinical efficacy for EHE as measured by the primary endpoint of objective response rate, as well as by secondary outcomes including progression free survival benefit over historical controls and by improvement in patient reported outcomes (PROs). If positive, this trial could lead to a new standard of care for treating EHE. Methods: This is a single arm, multi-center, phase 2 study with a two-stage design. Key inclusion criteria include histologically or cytologically confirmed EHE that is either progressing or clinically symptomatic, not a candidate for curative intent surgery, and requires systemic therapy in the opinion of the investigator, radiographically evaluable disease by RECIST v1.1, age ≥18 years, ECOG performance status ≤ 2, and adequate end organ function. With a Simon two-stage optimal design with one sided alpha 0.10, power 90%, assuming a historical control ORR 5% to detect an ORR of 20% (alternative hypothesis), 12 patients will be included in the first stage. If there is ≥ 1 response, an additional 25 patients will be enrolled to a total of 37 patients. ≥ 4 responses are needed for a significant result. The total planned accrual is 41 patients to account for unevaluable patients who may be enrolled, 10% above the required evaluable patients. Planned post hoc subgroup analyses will include outcomes by fusion type and presence of serosal effusions at the time of study enrollment. The trial is registered at clinicaltrials.gov NCT07104331. Clinical trial information: NCT07104331 .

11502 Background: To report results from the open-label alveolar soft part sarcoma (ASPS) cohort of the phase III APROMISS trial (NCT03016819) evaluating Catequentinib hydrochloride (AL3818), an oral multitargeted receptor tyrosine kinase inhibitor, in adults with advanced or metastatic ASPS. Methods: Adult patients with pathologic and molecularly confirmed advanced ASPS, either treatment-naive or previously treated (excluding cediranib), were enrolled in the open-label, non-randomized ASPS cohort of the phase III APROMISS trial conducted across the United States, Asia, and Europe. Catequentinib hydrochloride was administered orally at 12 mg once daily in 21-day cycles (14 days on/7 days off) until disease progression, toxicity, or death. The primary endpoint was objective response rate (ORR) assessed per RECIST by Blinded Independent Central Review (BICR) (predefined threshold: 31%). Secondary endpoints included duration of response (DOR) with a predefined target of =/>6 months, progression free survival (PFS) and overall survival (OS). Results: From July 2017 to August 2022, a total of 56 patients entered the trial; 56 patients were evaluable for the primary endpoint. Median (m-) age was 29.5 years (range: 18 – 66), with 24 female and 32 male. Best overall response included 1/56 complete response (1.8%), 14/56 partial responses (25.0%), 36/56 stable disease (64.3%), and 3/56 (5.4%) progressive disease. RECIST ORR by BICR was 26.8% (95% CI, 15.8–40.3); m-DOR was 22.57 months (95%CI: 10.38-NE). The study data was collected close to 8 years for all patients. mPFS was 18.33 months (95% CI, 14.19–23.13), with 6- and 12-month progression-free rates of 88.77% (95% CI, 76.68–94.79) and 65.54% (95% CI, 50.42–77.06), respectively. mOS was 59.27 months (95% CI, 44.09–NE), with 6- and 12-month overall survival rates of 94.64% (95% CI, 84.30–98.24) and 90.81% (95% CI, 79.30–96.08), respectively. Overall, 27/56 (48.2%) patients experienced grade ≥3 treatment-related adverse events, most commonly diarrhea (50.0%), hypertension (44.6%), fatigue (37.5%), nausea (35.7%), and palmar-plantar erythrodysesthesia syndrome (30.4%); one patient (1.8%) had a grade 5 event (respiratory failure). Conclusions: Catequentinib hydrochloride demonstrated meaningful antitumor activity and durable responses in adults with advanced ASPS. Despite the ORR of 26.8% slightly below the predefined 31% threshold, disease control was prolonged, with a m-DOR exceeding 22 months. Favorable PFS and OS outcomes, together with a manageable safety profile, support its clinical benefit in this ultra-rare sarcoma. Clinical trial information: NCT03016819 .

Elevated intratumoral interstitial fluid pressure (IFP) can negatively impact the efficacy of neoadjuvant chemotherapy (NAC) of breast cancer. This study aims to predict breast cancer pathological complete response (pCR) to NAC based on IFP measures by 3-D subharmonic-aided pressure estimation (SHAPE). SHAPE uses the inverse linear relationship between hydrostatic pressure and subharmonic signal magnitude from intravascular ultrasound contrast agents. Thirty-eight breast cancer patients undergoing NAC from three clinical sites were enrolled for this study. SHAPE data were collected for each subject at 0%, 10%, and 30% of NAC completion using a Logiq E9 system (GE HeathCare) equipped with an RSP6-16D probe. The contrast agent used was Definity (Lantheus Medical Imaging). The subharmonic signal gradients between tumor and adjacent normal tissue were calculated and compared with patient pathological response outcome using t-test and receiver operating characteristic (ROC) curve analysis. Pressure gradients between pCR (15 patients) and non-pCR (23 patients) groups were significantly different at 0 (p = 0.02), 10 (p = 0.03), and 30% (p = 0.0003) completion of NAC. Area under the curve values of 0.69, 0.77, and 0.86 were achieved at 0%, 10%, and 30% of NAC completion, respectively. Overall, SHAPE pressure gradients may aid prediction of NAC pathological response in breast cancer patients.

Background: The timing of coronary artery bypass grafting (CABG) in patients with non-ST-elevation myocardial infarction (NSTEMI) may critically impact clinical outcomes, yet the ideal surgical window remains unclear. We aimed to evaluate the association between time-to-CABG and in-hospital outcomes among NSTEMI admissions undergoing CABG. Methods: This retrospective cohort study utilized the US National Inpatient Sample database from 2017 to 2021 to evaluate the association between time-to-CABG and key in-hospital outcomes, including mortality, cardiac arrest, cardiogenic shock, ischemic stroke, acute kidney injury, and blood transfusion rates, while assessing length of stay (LOS) and hospital charges exclusively among survivors. Adult admissions with principal diagnosis of NSTEMI who underwent CABG without prior interhospital transfer were grouped by the calendar day of CABG from admission (0, 1, 2, 3, 4, 5, 6, and ≥7). Multivariate regression models were used to assess the outcomes across these eight groups. Results: Of 142,200 included admissions, same-day CABG (hospital day 0) was associated with the highest rates of in-hospital mortality, cardiac arrest, cardiogenic shock, and ischemic stroke. The adjusted odds of mortality, cardiac arrest, and cardiogenic shock were lower among admissions undergoing CABG between days 2 and 5. Likewise, the adjusted odds of ischemic stroke were lowest when CABG occurred on days 2 to 4. The odds of AKI increased when CABG was delayed beyond day 6, whereas blood transfusion rates showed no statistically significant association with time-to-CABG. Among survivors, LOS and hospital charges progressively increased with delayed CABGs. Conclusions: Among NSTEMI admissions undergoing CABG, CABG performed on hospital days 2 to 4 was associated with lower adjusted odds of several adverse in-hospital outcomes compared with same-day CABG. Further prospective studies are needed to validate these results and guide clinical decision-making.

Abstract Scientific foundation models learn high-dimensional representations from diverse data modalities, yet what they encode and how to extract that knowledge remain open questions. Here we show that probing the internal representations of Evo 2, a 7-billion-parameter genomic foundation model, enables accurate and interpretable genetic variant effect prediction. We introduce a covariance-based probe that captures second-order structure from Evo 2 sequence embeddings to predict variant pathogenicity across variant types and functional consequences, matching or exceeding specialized predictors within their domains. To ground these predictions in known biological mechanisms, we train a complementary panel of probes on existing annotations to detect which genomic properties are disrupted by a variant. This categorized evidence is then integrated with each variant’s genomic context through a language model to generate variant-specific mechanistic hypotheses. Our pathogenicity predictions correlate with experimental measures of variant function, clinical penetrance, and biobank disease associations while the mechanistic hypotheses are consistent with expert reviews, known mechanism classes, and downstream molecular readouts. We release pathogenicity scores, disruption profiles, and contextualized interpretations for 4.2 million variants from the ClinVar database as an open resource through the Evo Variant Effect Explorer (EVEE). More broadly, this structured probing approach offers a general framework for interrogating foundation models across scientific disciplines and grounding their outputs in existing domain concepts.