Citations

Abstract Background/Aims Sleep disturbance is a defining feature of fibromyalgia (FM), contributing to pain, fatigue, cognitive dysfunction, and reduced quality of life. Effective management options remain limited. Cognitive behavioural therapy for insomnia (CBT-I) is effective in primary insomnia, but evidence in FM is sparse and access to face-to-face therapy is limited. Digital CBT-I (dCBT-I) offers a scalable, self-directed solution that may overcome these barriers. We conducted the first randomised controlled trial of dCBT-I in FM to evaluate its impact on quality of life and associated symptoms. Methods This single-blind randomised controlled trial evaluated Sleepio, a validated dCBT-I programme of six self-directed 20-minute sessions delivered over 12 weeks. Participants with a clinical diagnosis of FM, self-reported sleep disturbance, and cognitive complaints were recruited in Oxford, UK. After baseline assessment, participants were randomized to dCBT-I or a control group. All participants also received standardised sleep hygiene advice. The primary outcome was disease-specific quality of life measured by the revised Fibromyalgia Impact Questionnaire (FIQR). Secondary outcomes included insomnia severity (Insomnia Severity Index), actigraphy-derived sleep parameters, pain (SF36 Bodily Pain Scale), cognitive complaints (British Columbia Cognitive Complaints Inventory), sustained attention, and fear of movement (Tampa Scale of Kinesiophobia). Outcomes were collected online at baseline, 3 months, and 6 months. Analyses followed the intention-to-treat principle using constrained longitudinal data analysis. Ethical approval was obtained from South Central - Oxford B Research Ethics Committee (19/SC/0168). The study was pre-registered with clinicaltrials.gov (NCT05962138). Results Of 514 individuals contacted, 241 were screened, 132 were eligible, and 80 were randomised (42 dCBT-I, 38 control). The mean age was 46.6 (SD 14.5) years; 93.8% were female. Retention was high: 97.5% of participants provided outcomes at 3 months, and 83.8% at 6 months. In the dCBT-I group, 90.5% initiated the programme, and 54.8% reached the core session on sleep restriction therapy. At 3 months, there was no significant difference between groups in FIQR (mean difference −2.79; p = 0.3). At 6 months, however, dCBT-I participants demonstrated greater improvement in FIQR compared with controls (mean difference −5.45; 95% CI − 10.5 to − 0.4; p = 0.035), corresponding to a small-to-moderate effect size (Cohen’s d = −0.31). No significant between-group differences were observed for secondary outcomes. Conclusion In adults with FM, dCBT-I produced a sustained, clinically meaningful improvement in disease-related quality of life at 6 months compared with a sleep hygiene control. Although benefits were not observed across secondary outcomes, this trial provides the first controlled evidence that dCBT-I can address an important unmet need in FM. Digital behavioural therapies represent scalable, accessible, non-pharmacological interventions with potential for rapid integration into clinical care. Disclosure E. Kelleher: Grants/research support; National Institute for Health Research (NIHR) Pfizer Doctoral Fellowship (NIHR301808). A.J. Wall: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA. V. Wanigasekera: None. R. Sharman: None. S. Kyle: None. I. Tracey: None. B. Seymour: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA. A. Irani: Grants/research support; Grant is funded by UKRI and Versus Arthritis as part of the UKRI Strategic Priorities Fund (SPF) Advanced Pain Discovery Platform (APDP), a co-funded initiative by UKRI (MRC, BBSRC, ESRC), VA.

Background: Hepatocellular carcinoma (HCC) has a poor long-term prognosis due to high recurrence and cirrhosis-related mortality, even after potentially curative treatments such as liver transplantation (LT), surgical resection, or ablation. This study aimed to identify factors associated with ≥10-year survival in HCC patients. Methods: A retrospective cohort study was conducted among HCC patients diagnosed between 2004 and 2022 using the National Cancer Database. Multivariable Cox regression was used to identify predictors of overall survival, and logistic regression was used to identify predictors of ≥10-year survival. Results: Among 249,600 HCC patients, 177,585 (71.2%) died within 5 years, 8613 (3.5%) died at 5–10 years, 54,988 (22.0%) were alive with <10 years of follow-up, and 8219 (3.3%) survived ≥10 years. LT, resection, and ablation were performed in 6.6%, 9.3%, and 11% of patients, respectively. Compared with ablation as the reference group, LT [adjusted odds ratio (aOR) 11.96, 95% confidence interval (CI): 11.27–13.29] and resection (aOR: 2.83, 95% CI: 2.57–3.08) increased the odds of ≥10-year survival, while non-curative treatments reduced the odds compared with ablation (aOR: 0.50, 95% CI: 0.47–0.55). Cox regression results were consistent with the logistic model, confirming the association. Decision tree analysis confirmed LT as the dominant determinant of long-term survival. Black individuals were associated with lower odds of ≥10-year survival (aOR: 0.88, 95% CI: 0.820–0.96) and decreased likelihood of receiving LT (aOR: 0.73, 95% CI: 0.55–0.96). Conclusions: LT offers the best chance of ≥10-year survival in HCC. Ensuring equitable access is essential, especially for Black patients who have lower transplant rates and worse outcomes.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Abstract Background Immigrants to the United States often face challenges from limited healthcare access and less healthy environments which contribute to rising obesity and cardiovascular risk. Purpose To assess the feasibility and effectiveness of a community-based social network intervention for cardiovascular risk reduction among Hispanic and Somali adults. Methods A social network-informed, community-based participatory research-derived health promotion intervention was delivered by Hispanic and Somali lay health promoters (HPs) to members of their social networks over 1 year (12 biweekly sessions in months 0-6; 12 biweekly check-ins in months 7-12). Using a closed-cohort stepped wedge cluster randomized design, social networks were randomly assigned to receive the intervention immediately or after a delay of 1 year. Measurements at baseline, 6 months, and 12 months were derived from 6 of the American Heart Association’s “Life’s Simple 7”: BMI, blood pressure, fasting glucose, cholesterol, physical activity and dietary quality (range 0-12, with higher values indicating lower cardiovascular risk). Waist circumference and proportion of participants who achieved &gt;5% body weight loss were also assessed. Results Four hundred seventy-five participants were enrolled among 51 HPs (29 Hispanic; 22 Somali). There was a statistically significant improvement in cardiovascular risk in the intervention group (n = 246) compared with controls (n = 229) at 6 months (0.4 [1.8] vs. −0.1 [1.7]; P = .03) that was not sustained at 12 months (0.5 [1.9] vs. 0.3 [1.8]; P = .38). There was a statistically significant higher proportion of participants who lost &gt;5% of body weight in the intervention group compared with controls at 12 months (37% [15] vs. 18% [7.9]; P = .02). Reductions in weight and waist circumference in the intervention group compared with controls did not achieve statistical significance. Conclusion A social network intervention, delivered by lay HPs was feasible and resulted in a modest improvement of cardiovascular risk and clinically significant weight loss. Clinical Trial Identification Number NCT05136339.

Abstract INTRODUCTION: Cholangiocarcinoma (CCA) is a deadly cancer of the hepatic bile duct epithelial cells. Loss-of-function mutations of epigenetic regulator ubiquitin C-terminal hydrolase deubiquitinase BRCA1-associated protein 1 (BAP1) occur in 26-32% of human CCA and are associated with worse prognosis and resistance to cytotoxic therapy. The goal of this study is to identify how BAP1 loss promotes cell death evasion through metabolic rewiring. MATERIALS & METHODS: Isogenic wild-type and BAP1-deficient human and murine CCA cell lines were generated with shRNA/siRNA or CRISPR/Cas9 and were used to assess ferroptosis sensitivity by treatment with ferroptosis inducers. In vitro, ferroptosis was assessed by phospholipid peroxidation (C-11BODIPY), mitochondrial phospholipid peroxidation (MitoPeDPP, MitoCLox), iron oeverload (MitoFerro green) and cell death (CellTiter-Glo). Phospholipidomics and proteomics were performed in isogenic cells by LC-MS/MS. Isogenic liver orthotopic CCA murine models were used for in vivo pre-clinical studies. RESULTS: Our findings indicate that BAP1 loss confers CCA ferroptosis resistance. BAP1 loss protects CCA against mitochondrial iron overload, ROS accumulation, and phospholipid peroxidation. Strikingly, BAP1 loss protects from mitochondrial phospholipid peroxidation and cardiolipin oxidation. Unbiased phospholipidomic profiling revealed that BAP1 loss remodels membrane phospholipid composition, enriching for ferroptosis-blocking monounsaturated phospholipids (MUFA-PLs) at the expense of ferroptosis-inducing polyunsaturated (PUFA-PLs). We found that BAP1 loss upregulates TLCD1, a phosphatidylethanolamine acyltransferase that incorporates MUFAs into membrane phospholipids, thereby stabilizing membranes against peroxidation. TLCD1 knockdown in BAP1-deficient CCA cells, restored ferroptosis sensitivity Notably, TLCD1 is significantly upregulated in human BAP1-mutant CCA as compared to WT tumors. We identified TLCD1 in the endoplasmic reticulum, Golgi and by mitochondrial outer membrane. In syngeneic liver orthotopic CCA murine models, engineered EpCAM-aptamer-coated lactosomes carrying GPX4 siRNA selectively targeted CCA cells, inducing ferroptosis and robustly suppressing tumor growth without systemic toxicity. Lastly, BAP1-mutant patient-derived xenografts (PDXs) and organoids were resistant to ferroptosis inducers, as compared to WT controls. CONCLUSIONS: Our findings reveal that BAP1 loss rewires mitochondrial phospholipid metabolism thus conferring CCA resistance to ferroptosis, identifying TLCD1 as a targetable metabolic vulnerability in BAP1-mutant CCA. Citation Format: Yu Zhao, Peyton Classon, Danielle Marie Carlson, Jayla Millender, Irene K. Yan, Sumera Ilyas, Rory L. Smoot, Gregory J. Gores, TUSHAR PATEL, Davide Povero. BAP1 loss confers ferroptosis resistance to cholangiocarcinoma via TLCD1-mediated membrane phospholipid remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2433.

Abstract Background: Cholangiocarcinoma (CCA) is a highly lethal epithelial cell malignancy of the hepatic biliary tract. Efficacy of current standard-of-care therapy is limited. Ferroptosis, an iron-catalyzed, caspase-independent cell death driven by phospholipid peroxidation, has emerged as a novel therapeutic target. Our goal is to develop a tumor-selective therapeutic approach targeting ferroptosis in CCA using siRNA-based nanotherapeutics. Materials & Methods: Milk-derived nanovesicles (lactosomes) coated with EpCAM aptamer and packaged with siRNA against Glutathione Peroxidase 4 (siGPX4-lactosomes) and Ferroptosis Suppressor Protein 1 (siFSP1-lactosomes), were used to induce ferroptosis in murine CCA cells (FAC) and in syngeneic liver orthotopic CCA-bearing mice. In vitro, lactosome uptake and efficacy were assessed by fluorescence-based, cell-viability and molecular biology assays. In vivo, target engagement, tissue distribution, safety and efficacy were assessed. Results: EpCAM (epithelial cell adhesion molecule expressed on CCA cells)-coated lactosomes showed robust uptake by FAC cells in a EpCAM-dependent manner. EpCAM knockdown via siRNA reduced lactosome uptake, confirming aptamer selectivity. Dose-dependent siGPX4/siFSP1-lactosome treatment led to GPX4/FSP1 knockdown and induced ferroptotic cell death in up to 60% of FAC cells after 72 hours (p&lt;0.001 vs. siNC). In CCA-bearing mice, intravenous administration of siRNA lactosomes was well-tolerated with no liver or systemic toxicity observed and demonstrated robust tumor distribution compared to non-tumorous tissues. Efficacy studies demonstrated that siGPX4/siFSP1-lactosomes significantly reduced intratumor Gpx4 and FSP1 mRNA expression by 40-60% and induced significant upregulation of ferroptosis markers Ptgs2 and Acsl4 (p&lt;0.01 vs. siNC). Ferroptosis in siRNA-lactosome treated tumors was confirmed by immunohistochemistry for phospholipid peroxidation markers oxPAPC and 4-HNE. Additionally, proliferation marker Ki67 was significantly downregulated in siGPX4/siFSP1-lactosome treated tumors (p&lt;0.05 vs. siNC), indicating ferroptosis-mediated tumor suppression. Importantly, siGPX4/siFSP1-lactosomes reduced tumor burden and expression of CCA markers CK19/7 in treated mice, as compared to control mice. Conclusions: siRNA-based nanotherapeutics targeting CCA can effectively and safely induce ferroptosis in vitro and in vivo, representing a potential therapeutic strategy for CCA treatment. Citation Format: Peyton Classon, Danielle Marie Carlson, Jayla Millender, Irene Yan, Sumera Ilyas, Rory L. Smoot, TUSHAR PATEL, Gregory J. Gores, Davide Povero. Targeting cholangiocarcinoma with ferroptosis-inducing siRNA-based nanotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5664.

Due to systemic barriers, policymakers in the United States may be unaware of immigrants’ health-related priorities. In response, Rochester Healthy Community Partnership, a 22-year community-engaged partnership, collaborated with 14 Hispanic/Latino and Somali immigrant health promoters in fall 2023 using Photovoice to document their health-related assets and needs. After taking photos, the health promoters reflected, discussed the issues revealed in their images, and developed policy recommendations. Guided by Public Health Critical Race Praxis, we used thematic analysis to analyze health promoters’ reflections. Three themes emerged: healthy choices, inclusion of people and cultural celebrations, and access to opportunity. Health promoters want to expand healthy choices in Southeast Minnesota by growing community garden programming, protecting the environment, making healthy options accessible, and opening an affordable gym. They highlighted the importance of integrating culture and community into youth education, access to culturally appropriate foods, and the need to address Islamophobia. Health promoters wanted increased access to job opportunities, affordable housing, and health care. They saw these opportunities as vehicles for self-improvement but emphasized time management as essential in the United States. Ensuring that immigrants have a meaningful voice in shaping policies that affect health is critical. Policymakers can leverage these findings by demonstrating responsiveness to community-identified priorities and acting on health promoters’ policy recommendations. We encourage future Photovoice researchers to apply explicitly anti-racist frameworks, such as Public Health Critical Race Praxis, to document and challenge systemic oppression.

Abstract Despite effective control of inflammation in rheumatoid arthritis (RA), persistent and severe pain remains a challenge. Dysregulated pain processing in the central nervous system may underlie this disconnect. The PainDETECT questionnaire, originally developed to identify neuropathic pain, may capture features of central sensitization. We hypothesized that neuropathic-like pain at diagnosis predicts worse pain prognosis in early RA, independent of baseline pain severity and inflammation. We also explored brain activation patterns using neuroimaging. In this prospective cohort study, adults with newly diagnosed RA completed the PainDETECT questionnaire at baseline. Bodily pain was measured using the SF-36 Bodily Pain Subscale at baseline, 3, 6, and 12 months. C-reactive protein (CRP) was monitored. Linear mixed-effects models examined associations between PainDETECT, as a continuous measure, and bodily pain and CRP over time, adjusting for baseline outcome values. A neuroimaging substudy (n = 27) used task-based functional MRI to assess brain responses to evoked pressure pain. Among 158 participants (mean age 58.4 years; 35% male), 24.7% had likely neuropathic-like pain (PainDETECT ≥19) at baseline. Higher baseline PainDETECT scores were associated with worse bodily pain throughout follow-up in fully adjusted models (β = −0.43; 95% CI: −0.84 to −0.02; P = 0.043), independent of socio-demographics and comorbidities. No association was found between PainDETECT and CRP. On neuroimaging, higher PainDETECT scores correlated with increased activation in the left insula, dorsal anterior cingulate cortex, and left amygdala during evoked wrist pain. Neuropathic-like pain at diagnosis predicts a worse pain prognosis in early RA, independently of inflammation. Early identification may support more targeted and effective pain management.

The results underscore a multifaceted interaction among cardiopulmonary hemodynamics, right heart pressures, ventilatory response, and autonomic regulation. In particular, altered RV-PA coupling correlated with heightened sympathetic drive, indicating that cardiopulmonary efficiency and hemodynamics may influence central autonomic outputs. This suggests that mechanical stress or overload in the right heart could modulate sympathovagal balance, thereby contributing to altered autonomic responses during exercise in patients with cardiopulmonary disorders.

Abstract Objective Advanced adrenocortical carcinoma (ACC) is treated with mitotane alone or combined with cytotoxic chemotherapy, yet outcomes remain poor and prognostic models in this setting are lacking. This study aimed to evaluate the prognostic value of clinical parameters in a large cohort of patients with advanced ACC undergoing systemic therapy. Methods Multicenter, international cohort study investigating 418 patients with advanced ACC (61.5% = women, median age = 52 years) from 11 centers. Patients received mitotane monotherapy (n = 161), etoposide + doxorubicin + cisplatin ± mitotane (n = 178), or second-line regimens (gemcitabine + capecitabine ± mitotane or temozolomide + mitotane, n = 79). Variables included age, cortisol excess, performance status (ECOG-PS), tumor burden, and neutrophil-to-lymphocyte ratio (NLR) at start of therapy. Outcomes were overall survival (OS), time to progression (TTP), and best objective response. Results Tumor burden, cortisol excess, ECOG-PS, and NLR ≥5 independently predicted shorter OS (hazard ratio [HR] 1.55-2.68). We developed an integrated ENSAT Risk Score for Advanced ACC combining these variables: tumor burden (0-2), cortisol excess (0/1), ECOG-PS (0-2), and NLR (0/1). A score &gt;2 (poor-risk) was significantly associated with worse OS and TTP across all treatment groups (HRs for OS: 3.05-3.96; TTP: 2.53-3.08). It also predicted poorer response to mitotane (P &lt; .01) and second-line therapies (P = .04). Conclusions The ENSAT Risk Score for Advanced ACC is a practical, prognostic tool for patients with advanced ACC receiving systemic therapy. Based on accessible clinical and biochemical markers, it can support treatment decisions and facilitate informed discussions in routine care.