Citations

Abstract Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects about 32% of adults worldwide and is projected to increase in many parts of the world. Liver cancer is a recognized complication of end-stage MASLD. An estimated 20% of patients with MASLD will progress to cirrhosis, a premalignant state in liver cancer evolution. Because MASLD is usually asymptomatic, its progression to cirrhosis can be difficult to detect early for timely intervention. There are currently no known biological markers for predicting cirrhosis risk in patients with MASLD, making it challenging to identify patients at risk of disease progression. The aim of this study was to identify plasma protein biomarkers that can predict future cirrhosis development in patients with MASLD. Methods: We performed a nested case-control study among patients with MASLD at baseline who later progressed to cirrhosis and control patients with MASLD at baseline who never progressed to cirrhosis, matched on age at MASLD diagnosis (± 1-year), sex, race, year of blood sample collection, and length of follow-up (± 1-year). An aptamer-based array (SOMAscan™) platform was used to measure over 7000 proteins in baseline plasma samples obtained from the participants. The study sample was split 70/30 for training and validation analyses. We identified plasma protein biomarkers significantly differentially expressed in the training sample, adjusting for multiple testing with Bonferroni-corrected p-values. The significant set of proteins from the training set was used for prediction modeling in the validation sample, computing prediction metrics (area under the curve [AUC], sensitivity, specificity, and accuracy). Results: A total of 64 MASLD to cirrhosis cases matched to 64 MASLD controls were included in the analysis. Six protein biomarkers (PTPRU, ATL2, MFAP4, C7, CSTN2, and COLEC11) were overexpressed in cases, compared to controls, in the training data. Prediction modeling of the six-protein biomarker panel in the validation sample yielded an AUC = 0.85, sensitivity = 0.72, specificity = 0.78, and accuracy = 0.75. Conclusions: We have identified a panel of six plasma protein biomarkers that predict risk of cirrhosis development in patients with MASLD. These proteins could serve as candidates for future mechanistic studies on MASLD progression to advanced liver disease. If validated in larger studies and with assays suitable for clinical laboratory testing (e.g., ELISA), these protein biomarkers could be useful clinically for cirrhosis risk prediction in MASLD patients, and hence those at risk of liver cancer, enabling timely surveillance or interventions to prevent disease progression. Citation Format: Pasang Sherpa, Sebastian M. Armasu, Jacob A. Frank, Irene K. Yan, Kirk J. Wangensteen, Tushar Patel, Samuel O. Antwi. Predicting cirrhosis risk in patients with metabolic dysfunction-associated steatotic liver disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2335.

Introduction: Despite being healthier than the general population on arrival, immigrants to the US often face systemic barriers to healthy lifestyle behaviors and increased risk of cardiovascular disease (CVD). Self-efficacy has been associated with healthy diet and physical activity behaviors, but associations and construct validity have not been well studied in large samples of immigrant populations. Hypothesis: Self-efficacy for a healthy diet and physical activity will be associated with better dietary quality and intake and more physical activity, respectively. We also assessed the construct validity of measurement scales in this population. Methods: Set in southeast Minnesota and embedded with the Rochester Healthy Community Partnership, a 20-year community-based participatory research partnership, the Healthy Immigrant Community study enrolled Hispanic/Latinx and Somali immigrants into a randomized intervention to reduce obesity and CVD risks. Baseline assessments included biometric measures and self-reports of dietary intake, physical activity, and quality of life in English, Spanish, or Somali. Two self-efficacy items (“How confident are you that you can eat a healthy diet?”; “How confident are you that you can participate in regular exercise or physical activity?”) were rated as a percentage interval (0%=not at all confident; 25%; 50%=somewhat confident; 75%; 100%=very confident). Results: In total, 451 participants, 268 (59%) Hispanic/Latinx and 183 (41%) Somali, completed baseline assessments for this analysis. The mean age was 45 years (range=18-87), 59% were female, and 37% lacked health insurance over ≤12 months. Participants reporting more confidence to eat a healthy diet were more likely to eat fruits and vegetables as snacks ( p =<0.001), and less likely to drink fruit drinks or sports drinks ( p =0.02) or regular soda ( p =<0.001). Those reporting more confidence to be physically active were also reported higher levels of physical activity ( p =0.001). Validated self-efficacy scales had a wide distribution of scores, suggesting that the measures can be appropriately used among these immigrant communities. Conclusion: Higher self-efficacy for a healthy diet and physical activity were significantly associated with healthier eating and physical activity behaviors. Lifestyle interventions to reduce CVD risk may benefit from incorporating culturally tailored strategies to enhance self-confidence and support health equity in immigrant communities.

Abstract Purpose Ultra‐low field MRI scanners have the potential to improve health care delivery, both through improved access in areas where there are few MRI scanners and allowing more frequent monitoring of disease progression and treatment response. This may be particularly true in white matter disorders, including leukodystrophies and multiple sclerosis, in which frequent myelin‐sensitive imaging, such as magnetization transfer (MT) imaging, might improve clinical care and patient outcomes. Methods We implemented an on‐resonance approach to MT imaging on a commercial point‐of‐care 64 mT scanner using a non‐balanced steady‐state free precession sequence. Phantom and in vivo experiments were used to evaluate and optimize the sequence sensitivity and reproducibility, and to demonstrate in vivo performance and inter‐site reproducibility. Results From phantom experiments, T 1 and T 2 effects were determined to have a negligible effect on the differential MT weighting. MT ratio (MTR) values in white matter were 23.1 ± 1.0% from 10 healthy volunteers, with an average reproducibility coefficient of variation of 1.04%. Normal‐appearing white matter MTR values in a multiple sclerosis participant (21.5 ± 6.2%) were lower, but with a similar spread of values, compared to an age‐matched healthy volunteer (23.3 ± 6.2%). Conclusion An on‐resonance MT imaging approach was developed at 64 mT that can be performed in as little as 4 min. A semi‐quantitative myelin‐sensitive imaging biomarker at this field strength is available for assessing both myelination and demyelination.

Aim Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may guide development of future therapies. Methods Participants ( n = 354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium. Dementia stage was defined as early (CDR® plus NACC FTLD ≤1) or advanced (CDR® plus NACC FTLD ≥1). Baseline and annual follow‐up visit data were analyzed to compare NPS across stages of bvFTD. Psychiatric states were captured using the Neuropsychiatric Inventory‐Questionnaire and Clinician Judgment of Symptoms. Polychoric cluster analysis was used to describe NPS clusters. Results NPS were highly prevalent (≥90%) in early and late bvFTD. Four NPS clusters were identified based on magnitude of factor loadings: affective, disinhibited, compulsive, and psychosis. Neuropsychiatric symptoms fluctuated across visits. In the affective cluster, depression showed the least visit‐to‐visit stability. In the disinhibited cluster, elation showed the least stability. Symptoms in the psychosis and compulsive clusters (hallucinations, delusions, obsessions/compulsions, and hyperorality) were largely stable, persisting from visit‐to‐visit in more than 50% of cases. Symptoms in the affective and disinhibited cluster were associated with the highest caregiver burden, while symptoms in the obsessive cluster were associated with the most functional impairment. Conclusion NPS in bvFTD are frequent and cluster into four discrete groups. The fluctuating nature of some NPS in bvFTD suggests that they may not be reliable markers of disease progression or stage.

Abstract The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

ABSTRACTIntroductionStudies demonstrate an overlap of constipation with gastroparesis and functional dyspepsia, but the impact of treatments that target constipation on improving upper gastrointestinal (UGI) symptoms is unexplored. We quantified the effects of constipation medication therapies on UGI and constipation symptom severity in subjects presenting with symptoms of gastroparesis.MethodsFifty‐six subjects with symptoms of gastroparesis underwent concurrent wireless motility capsule and gastric emptying scintigraphy and were recommended to receive either a new medication therapy for constipation or a change in constipation therapy based on investigator interpretation of test results. Gastroparesis Cardinal Symptom Index (GCSI), upper abdominal pain, and constipation scores were compared between baseline and 6 months. Data were compared between delayed or non‐delayed gastric emptying and the presence or absence of slow colonic transit.Key ResultsSubjects with slow colonic transit had improvements in GCSI (p = 0.007) and constipation scores (p = 0.004) after treatment with a new or changed constipation medication, with the delayed emptying subgroup driving GCSI improvements (p = 0.004). Reductions in nausea/vomiting (p = 0.02) and early satiety/fullness subscores (p = 0.002) with trends to improved bloating/distention subscores (p = 0.06) were observed in this subgroup, but upper abdominal pain was unchanged. Subjects with normal colonic transit showed no improvement in GCSI scores regardless of gastric emptying status (p > 0.05).Conclusions and InferencesIdentifying and treating delayed colonic transit in gastroparetic (delayed gastric emptying) subjects improves global UGI symptoms as well as selected individual symptoms. Evaluation of whole gut motility as well as recognizing and managing extragastric delay may promote improved outcomes in these patients.Trial RegistrationClinicalTrials.gov: NCT02022826

Abstract Background and Aims Inflammatory bowel disease (IBD) is associated with altered mucus and increased intestinal permeability (IP). Prior reports on permeability in IBD typically used lactulose-to-mannitol ratio (LMR). Food contamination with 12C-mannitol is a significant potential confounder in IP assessment. We aimed to compare small intestinal (SI) and colonic (COL) permeability in IBD, both active (ACT) and in remission (REM), to normal healthy volunteers (NHV). Methods Inflammatory bowel disease activity was based on Simple Endoscopic Score for Crohn’s Disease (SES-CD) and Mayo endoscopy score for ulcerative colitis (UC). We performed 24-hour IP test using 100 mg 13C-mannitol and 1000 mg lactulose with urine collected during 0-2, 2-8, and 8-24 hours. The primary endpoint was mg excretion of 13C-mannitol and lactulose during 2-24 hours reflecting SI and COL permeability. Results Among 17 CD patients, 7 were ACT (SES-CD &gt;6), and 10 REM (SES-CD 0-2). Among 20 UC patients, 10 had ACT (Mayo score 2-3), and 10 REM (Mayo score 0-1). Urinary excretions over 2-24 hours were higher for IBD than NHV: 13C-mannitol (13.8 [IQR 8.8, 18.7] NHV; 18.4 [15.6, 29.9] REM; 19.7 [13.8, 23.6] ACT, P = .003) and lactulose (1.8 [1.3, 3.1] NHV; 3.6 [2.0, 5.0] REM; 3.5 [2.0, 6.6] ACT, P = .006). There was no difference between ACT and REM for any timed urine collection. LMR at 2-24 hours (or 2-8 and 8-24 hours) were not statistically significant between the 3 groups (0.014 [0.010, 0.021] NHV; 0.016 [0.010, 0.023] REM; 0.016 [0.012, 0.038] ACT, P = .237). Conclusions Intestinal permeability is increased in IBD using validated in vivo assay relative to NHV; increased IP in IBD persists during remission.