Citations

Abstract Chronic widespread pain (CWP) remains challenging due to its heterogeneous causes and complex mechanisms. A total of 2920 plasma proteins are analyzed from 29,254 UK Biobank participants. A total of 256 proteins are identified as cross‐sectionally correlated with CWP. A simple (top 10 proteins) and comprehensive (all significant proteins) proteomic‐based score (ProtS) is created for CWP diagnosis, both outperforming and improving the existing clinical score (area under the curve, AUC: 0.801, 0.723, and 0.791 alone, and 0.856 and 0.880 in combination). In addition, the protein score predicted 13‐years risk of pain‐related traits over the body, including pain onset, progression, and intensity; Moreover, it has stronger associations with nociplastic pain and fibromyalgia compared to nociceptive and neuropathic pain, implying a unique protein signature of different pain mechanisms. Finally, among 434 candidate proteins prioritized in the observational analysis, 18 are corroborated with causal relevance by Mendelian randomization, and importantly, four (CA14, DPEP1, LGALS3, and TNF) showed potential as novel drug targets repurposed for treating CWP.

Objectives Evaluate the value of ultrasound specialist assessment of ovarian masses over 50 mm with sonograms interpreted as possible hemorrhagic ovarian cysts (HOC). Methods Retrospective review of consecutive endovaginal pelvic US reports of premenopausal women at one organization identified adnexal masses over 50 mm maximum diameter designated as possibly being HOC (large HOC). Four ultrasound specialists reviewed studies, scoring two assessments as true or false: 1) US features are most consistent with either an ovarian hemorrhagic cyst (HOC) or endometrioma; 2) If assessment 1 was true, the mass meets O‐RADS criteria of classic HOC except for size. Results A total of 457 of 51,305 women (0.9%) had reports indicating possible large HOC. For 366 patients with established outcomes, 225 (61.5%) had a large HOC (87.1% ≤ 70 mm). Assessment 1 was true for 318 patients; outcomes showed 224 (70.4%) HOC, 89 (28.0%) endometriomas, 4 (1.3%) TOAs, and 1 (0.3%) cystadenoma. Assessment 1 was false for 48 patients; outcomes showed 1 (2.1%) HOC, 1 (2.1%) endometrioma, 6 (12.5%) other non‐neoplastic cysts, 33 (68.8%) benign neoplasms, 5 (10.4%) borderline tumors, and 2 (4.2%) high‐grade malignancies. The decrease in neoplasms and malignancies with true assessment 1 was significant ( p < .001). Assessment 2 was true for 190 patients (180 [94.7%] HOC, 9 [4.7%] endometrioma, 1 [0.5%] cystadenoma), false for 128 patients (44 [34.4%] HOC, 80 [62.5%] endometrioma, and 4 [3.1%] TOA) ( p < .001), and not applicable for 48 patients. Conclusions Ultrasound specialist review of adnexal masses designated as a possible large HOC adds value since over 10% are neoplasms (nearly 2% malignant). Ultrasound specialist assessment can expedite additional imaging or intervention when necessary and obviate follow‐up when HOC features are typical.

Abstract With the rapid advancements in large language model technology and the emergence of bioinformatics‐specific language models (BioLMs), there is a growing need for a comprehensive analysis of the current landscape, computational characteristics, and diverse applications. This survey aims to address this need by providing a thorough review of BioLMs, focusing on their evolution, classification, and distinguishing features, alongside a detailed examination of training methodologies, datasets, and evaluation frameworks. We explore the wide‐ranging applications of BioLMs in critical areas such as disease diagnosis, drug discovery, and vaccine development, highlighting their impact and transformative potential in bioinformatics. We identify key challenges and limitations inherent in BioLMs, including data privacy and security concerns, interpretability issues, biases in training data and model outputs, and domain adaptation complexities. Finally, we highlight emerging trends and future directions, offering valuable insights to guide researchers and clinicians toward advancing BioLMs for increasingly sophisticated biological and clinical applications.

Abstract BACKGROUND Intraductal papillary mucinous neoplasm (IPMN) is one of the two most common precursor lesions leading to the development of pancreatic ductal adenocarcinoma (PDA). IPMNs comprise a heterogeneous group of tumors with a wide range of grades and histotypes, and the emergence of single-cell RNA sequencing (RNA-seq) and multiplex digital spatial profiling have characterized unique cell populations, including dysplastic epithelial and immune cells, within the heterogeneous tumor microenvironment that carry signature gene expressions, which could be used as markers for disease progression. However, it is not clear on the heterogeneity of the epithelial and immune response of the evolution during progression of IPMN to PDA. OBJECTIVE Combining nuclear GSK-3β with oncogenic KRas mice (referred to as KNGC – KRas, nuclear GSK-3β, Cre) resulted in the development of IPMN. We have found that 4-week-old KNGC mice show progressive desmoplasia and ductal lesion development with increased M2-like macrophage infiltration. Interestingly, CX3CL1 (fractalkine), a chemokine involved in the recruitment of CX3CR1-expressing monocytes and M2-like macrophage conversion in various disease models is expressed by IPMN progenitor ductal cells. We aim to investigate expression and contribution of CX3CL1-CX3CL1 axis in the development and progression of IPMN. METHODS We utilized a newly generated CX3CL1-mCherry and well-established CX3CR1-GFP knockin/knockout mouse for crossbreeding with KNGC and KGC (KRas, GNas, Cre) for lineage tracing and function analysis by immunofluorescent staining, flow cytometry and CyTOF. RESULTS Both KNGC- and KGC-3LmCherry/+ mice harbor a large population of CX3CL1-mCherry/EPCAM+ epithelial cells as compared to 3LmCherry/+ and wildtype (WT) control mice. In KNGC and KGC mice, we show that there was a unique population of macrophages (CD45+ CD11b+ Ly6G- F4/80+ Ly6c- ) with significantly higher expression of CX3CR1 (CX3CR1Hi) that was not seen in WT mice. Significantly, Knockout of CX3CR1 in KNGC-3RGFP/GFP animals had a paucity of M2-like macrophages, reduced T regulatory cells (Tregs), substantially reduced desmoplasia and impaired development of IPMN. CONCLUSIONS The study provides important knowledge regarding the role of CX3CL1-CX3CR1 axis in recruitment and generation of M2-like macrophages, and their impact on the initiation of the immune/stroma microenvironment facilitating IPMN development. Further investigations using these models have the potential to identify new biomarkers for risk stratification and therapeutic intervention. Citation Format: Li Ding, Kaely Roeck, Easton Maeder, Cheng Zhang, Taylor Weiskittel, Esther Rodman, Mark Maynes, Bibo Zhu, Aaron Johnson, Jie Sun, Li Hu, Daniel Billadeau. Uncoupling CX3CL1-CX3CR1 Axis in IPMN Development Through Transgenic Mouse Models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A064.

Background The eccentric stenosis morphology in patients with intracranial atherosclerotic stenosis (ICAS) has a critical impact on the efficacy of endovascular treatment. This study aimed to establish a rabbit model of eccentric carotid atherosclerotic stenosis that mimics the pathophysiological and morphological characteristics of eccentric plaques in humans. Methods Rabbits received localized cryoinjury of the right carotid artery after 2 weeks of a high fat, high cholesterol diet, followed by an additional 8 weeks on the same diet. On the experimental endpoint, comprehensive analyses of the model’s pathological changes were conducted using serum lipid analysis, DSA, optical coherence tomography (OCT), histopathological analysis, and immunohistochemistry. Results The high fat, high cholesterol diet significantly elevated serum lipid levels in rabbits. Hematoxylin and eosin staining results at 24 hours postoperatively revealed focal intimal damage induced by 5 s of cryoinjury. After localized cryoinjury and high fat, high cholesterol diet feeding, DSA results demonstrated significant carotid stenosis, with a stenosis degree of 47±5% and a length of approximately 9 mm. OCT images revealed eccentric fibrous plaque formation at the stenotic site. Morphological analysis of the plaque samples demonstrated a plaque eccentricity index of 0.66±0.05 and a plaque burden of 60.68±7.41%. Histopathological analysis showed that atherosclerotic lesions developed in all rabbits of the model group. Among them, three rabbits had intermediate lesions, one rabbit had atheroma, and eight rabbits had fibroatheroma. Conclusions This study successfully established a rabbit model of eccentric carotid atherosclerotic stenosis, providing a novel experimental platform for transformation research of neurointerventional devices.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Key Points ift140 -deficient zebrafish exhibited phenotypes observed in mammals, including skeletal defects and kidney cysts. Beyond ciliogenesis, ift140 also regulated cell polarity and intracellular microtubule stability, potentially contributing to cystogenesis. Microhomology-mediated end joining–induced mosaic ift140 crispants enabled evaluation of cystogenesis in adult fish and F0-based screening for modifiers of kidney cysts. Background Genetic modifiers are believed to play an important role in the onset and severity of polycystic kidney disease, but identifying these modifiers has been challenging due to the lack of effective methodologies. Methods We generated zebrafish mutants of IFT140 , a skeletal ciliopathy gene and newly identified autosomal dominant polycystic kidney disease gene, to examine skeletal development and kidney cyst formation in larval and juvenile mutants. In addition, we used ift140 crispants, generated through efficient microhomology-mediated end joining–based genome editing, to compare phenotypes with mutants and conduct a pilot genetic modifier screen. Results ift140 mutants developed kidney cysts and bone defects similar to those seen in mammalian models. ift140 crispants recapitulated mutant phenotypes while bypassing the early lethality of the mutants, enabling the analysis of kidney cyst formation in adult fish. In addition to cilia defects, we identified nonciliary phenotypes, including disrupted cell polarity and aberrant cytoplasmic microtubule stabilization in kidney epithelial cells, as potential contributors to ift140 -associated cystogenesis. The ability to detect ift140 -associated kidney cysts with ease allowed us to develop an F0-based genetic screen to identify potential protective modifiers. A pilot screen of 16 genes previously implicated in dysregulated signaling pathways in autosomal dominant polycystic kidney disease revealed both known and novel modifiers, including mtor and ulk1a . We further found that inhibition of mtor and ulk1a reversed both cilia-related and non–cilia-related abnormalities in the kidney. Conclusions By establishing a zebrafish model of ift140 -associated cystic kidney disease, we recapitulated ift140 ’s ciliary role and uncovered a nonciliary function in kidney cystogenesis. Importantly, we demonstrated the feasibility of using ift140 mosaic crispants to evaluate cystogenesis in adult fish and to perform F0-based screening for identifying genetic modifiers of kidney cysts.

Abstract Bispecific T-cell engagers (TCEs) targeting B-cell maturation antigen (BCMA) and CD3, induce deep hematologic responses in ∼60% of heavily pretreated patients with multiple myeloma (MM). We and others found that high tumor burden leads to resistance to TCE and novel strategies are urgently needed to improve responses in this setting. Ikaros degraders, including immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs), represent logical partners for TCEs due to their direct anti-MM effects and additional immune-stimulatory activity; however, it is unclear how to optimally combine them with TCEs. Taking advantage of the immunocompetent IMiD-sensitive Vk∗MYChCRBN murine model of MM, we optimized strategies to overcome primary resistance to BCMA-TCEs and achieve sustained remission, while maintaining a manageable safety profile. The addition of anti–programmed cell death protein 1 (PD1) and pomalidomide reduced the T-cell exhaustion that occurs in response to TCEs in high tumor burden settings. This allowed for a higher degree of T-cell activation and significant improvement in response rates but also increased risk of lethal cytokine release syndrome (CRS). To moderate the response and prevent CRS, we evaluated Ikaros degraders and dexamethasone (DEX) with step-up–dosed TCEs. Pretreatment with iberdomide and DEX reshaped the bone marrow T-cell compartment, promoted infiltration of naïve T cells, and generated 100% response rates and the longest survival in subjects with high tumor burden. This was accompanied by more favorable T-cell profiling, with limited expansion of regulatory T cells and exhaustion. Overall, administering a TCE after DEX and iberdomide treatments provided deeper and more durable responses with a reduced risk of CRS.