Citations

Abstract Description Hypertensive disorders of pregnancy (HDP) include preeclampsia (PE) and gestational hypertension (gHTN), both suspected to be immune-driven pathologies. Our data shows that both PE and gHTN involve systemic immune cell activation and increased proinflammatory cytokines however it is unclear how these immune profiles play a role in the pathogenesis of disease. We hypothesize that pregnancies complicated with HDP have dysregulated immune profiles, including hyperactive T cells which are activating the vascular endothelium. We have investigated the circulating immune profiles of patients with normotensive (NT), PE or gHTN pregnancies at the RNA, protein and cellular levels, which show significant alterations in T cells, among others. We have seen increased levels of IL-6, CXCL9 and CXCL10 in the plasma of HDP patients vs NT, suggesting the polarization and recruitment of T cells. Using cytometry by time of flight (CyTOF), we have seen changes in expression of CD11a and CXCR3 on CD4+, CD8+ and yd T cells in HDP compared to NT. Single cell RNA sequencing of CD4+ and CD8+ T cells from PE vs NT shows increased expression of genes related to pathways such as allograft rejection, angiogenesis and cytokine signaling. Our in vitro co-culture experiments examine the ability of immune cells, specifically T cells, to activate endothelial cells. These studies will address the functional contribution of T cells to endothelial activation, which is a hallmark of the hypertension seen in HDP. Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)

Peritoneal metastasis (PM) is a common and lethal complication of gastric cancer (GC), occurring in approximately 50% of patients with advanced disease. It is characterized by a highly immunosuppressive microenvironment and limited response to current systemic therapies, resulting in a median survival of only 3–6 months. The objective of this review was to explore the critical role of resident macrophages within the peritoneal immune microenvironment in the development and progression of GC PM and to discuss their potential as therapeutic targets. Peritoneal resident macrophages (PRMs), particularly the GATA6⁺ large peritoneal macrophages (LPMs), are hijacked by GC cells through metabolic reprogramming, transcriptional regulation, and paracrine signaling. These macrophages adopt a protumor M2-like phenotype, promote immunosuppression through T-cell exclusion and Treg recruitment, facilitate cancer cell adhesion and spheroid formation, and contribute to chemotherapy resistance. Emerging therapeutic strategies, including cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), nanoparticle-mediated macrophage repolarization, CSF-1 R/CCR2 axis inhibition, and chimeric antigen receptor macrophages (CAR-M), show promise in targeting these cells to restore antitumor immunity. In conclusion, resident macrophages are pivotal in shaping the immunosuppressive landscape of GC PM. Targeting these cells represents a promising avenue for novel combination therapies aimed at improving outcomes for patients with GC PM.

Background: People living with chronic heart conditions often experience poor quality of life (QoL) and reduced well-being; however, the intervention preferences to promote well-being among these individuals are not well known. Purpose: The purpose of this study was to describe QoL and preferences for wellbeing interventions in people with chronic heart conditions and to describe differences by heart condition diagnosis. Method: We conducted a cross-sectional study and recruited participants from a national online support group for people with heart conditions from April 29 to June 3, 2025. We measured QoL (WHO-QOL 28-item) and priorities for interventions via an investigator-developed questionnaire. Descriptive and bivariate analyses were conducted by heart condition. Results: In our preliminary findings among 107 participants [mean age=65.7 years (SD=12.5)], female (53%), White (82%), 67% ≥ 2 heart conditions] most reported being diagnosed with arrhythmias (36%), congenital heart disease (35%), and heart failure (34%), and the fewest reported cardiomyopathy (22%). Participants reported their physical health QoL as the lowest (M = 56.8±12.6), followed by psychological health (M = 62.5±13.1), and social relationships (M = 65.7±19.0). Most participants preferred non-pharmacological wellness interventions (79%) over pharmacological (23%). The highest interest in interventions was for nutrition/weight (80%), exercise (78%), relaxation (78%), mind-body (yoga or tai-chi) (72%), and meditation/mindfulness (69%). Most preferred delivery in-person (64%) or self-guided app/Website (60%). WHO-QOL ratings of Very Satisfied/Satisfied for Health Satisfaction were compared by heart condition (with and without) and were lower for two conditions: cardiomyopathy, (35% vs 63% p=0.015) and arrhythmias (44% vs 65%, p = 0.033). Participants with arrhythmias prioritized social support interventions (74% vs 48%, p = 0.010), while those with cardiomyopathy preferred interventions for depression (70% vs 43%, p = 0.025) (Table 1). Conclusion: We found that people were highly interested in behavioral interventions to promote their well-being. However, preferences for wellness interventions differed by diagnosis. Findings can guide interventions tailored based on condition.

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs. A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements. Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Abstract Introduction: Despite treatment advances, ovarian cancer (OC) remains the deadliest gynecological cancer, with a ∼70% mortality rate. OCs initially respond to platinum chemotherapy but often develop resistance. While PARP inhibitors improve relapse-free survival in responsive cases, they do not extend overall survival. This underscores the need for effective combination therapies beyond BRCA status. The lysosomal protein cathepsin L (CTSL) can traffic to the nucleus, where it can regulate DNA repair and serve as a chromatin modifier. We found that nucleoside analog clofarabine (CLF) induces CTSL nuclear trafficking in OC cells. Here we tested the hypothesis that accumulation nuclear CTSL (nCTSL) is a biomarker of sensitivity to DNA damaging therapy in OCs for improved therapeutic options. Methods: To determine the role of CLF induced nuclear CTSL in DNA damage and its synergy with PARP and CRM1 inhibitors in PARP inhibitor–sensitive and –resistant ovarian cancer (OC) cell lines, ex vivo cultures of ascites-derived patient OC cells (OVA-3D spheroids), primary ovarian tumors, and patient-derived xenograft (PDX) models and validated by colony formation assays. Nuclear CTSL localization was determined in subcellular fractionated lysates by western blots and immunofluorescence cytometry (IFC). Tumor regression was determined in vivo using ex vivo cultures of PDX derived cells. Results: In ovarian cancer (OC) cell lines, CLF monotherapy induced nuclear CTSL (nCTSL) in a subset of models classified as CLF-responsive (CLF-r), sensitizing them to the PARP inhibitors olaparib and rucaparib. In CLF-non-responsive (CLF-nr) models, nCTSL induction and therapeutic synergy were observed only with the CLF+olaparib combination. Synergy was detected in 47% of CLF-r and 24% of CLF-nr patient-derived ascites samples (OVA). Mechanistically, CLF induced nuclear import of CTSL via KPNB1 in CLF-r cells, while this import was triggered by the CLF+olaparib combination in CLF-nr cells. CLF also downregulated the nuclear export protein CRM1 (XPO1) in both groups. Knockdown of CTSL in either CLF-r or CLF-nr cells abrogated sensitivity to the combination. Notably, in 29% of OVA samples classified as CLF-resistant (CLF-Res), CLF failed to suppress CRM1 expression. In these cases, CRM1 inhibition with KPT8602 restored CLF+PARP inhibitor synergy. In vivo, CLF-r and CLF-nr PDX models treated with the combination exhibited increased DNA damage, reduced tumor burden, and extended survival. Conclusion: These findings identify nuclear CTSL (nCTSL) induction as a potential biomarker of response to DNA-damaging therapies. The combination of CLF and olaparib represents a promising strategy to overcome drug resistance in ovarian cancer by promoting CTSL nuclear localization and enhancing DNA damage. Citation Format: Prabhu Thirusangu, Ling Jin, Upasana Ray, Anya Zhao, Julie Staub, Xinyan Wu, Xiaonan Hou, Jamison L. VanBlaricom, Syed Mohamed Musheer Aalam, Sun-Hee Lee, Ann Oberg, Nagarajan Kannan, John Weroha, Jeremy Chien, Scott H. Kaufmann, Jamie N. Bakkum-Gamez, Viji Shridhar. Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A050.

Abstract Frailty is highly prevalent in cardiovascular disease and associates with poor clinical outcomes. Several cardiovascular conditions benefit from invasive interventions, but the impact of these procedures in frail patients remains unclear. We thus performed a systematic review and meta-analysis to summarize evidence and quantify the pooled effect of clinical outcomes of invasive cardiovascular interventions among frail vs. non-frail patients. Systematic search of two electronic databases from January 2015 to April 2025 was performed including all randomized controlled trials (RCTs) and prospective cohort studies examining outcomes of invasive cardiovascular interventions stratified by frailty. Outcomes included all-cause mortality, hospitalizations, and other adverse outcomes. Risk ratios (RRs) and their 95% confidence intervals (CI) were assessed using random-effects models. Thirty-one studies (10 RCTs, 21 prospective, 3 retrospective studies) with a total of 27 534 participants were included. Compared with non-frail patients, frail patients after cardiovascular procedures were at higher risks of all-cause mortality (RR 3.14, 95% CI: 2.29-4.30), and hospitalizations (RR 1.88, 95% CI: 1.29-2.73). Frail patients undergoing transcatheter aortic-valve implantation and percutaneous mitral-valve interventions did not have significant increased mortality risks compared with non-frail patients (P > 0.05). Pre-frailty predicted lower mortality risks amongst patients undergoing transcatheter vs. surgical aortic valve replacement (HR 0.78, 95% CI: 0.67-0.92). Frail patients with non-ST elevation myocardial infarction derived similar mortality benefits from an invasive vs. conservative approach (HR 1.13, 95% CI: 0.64-2.01). In conclusion, frailty prognosticates adverse outcomes following invasive cardiovascular interventions and influences treatment efficacy, highlighting its significance in treatment selection

Abstract Post-translational modifications (PTM) of tau are implicated in Alzheimer disease (AD) progression and are established biomarkers in cerebrospinal fluid and plasma; however, the labor-intensive nature of conventional proteomics limits their investigation in histology-specific contexts. We describe the findings of an artificial intelligence-guided laser capture microdissection (LCM) pipeline for harvesting neurofibrillary tangles (NFTs) by maturation level into pretangles (pre-NFTs), mature tangles (iNFTs), and ghost tangles (eNFTs) using 38 cases obtained from 2 independent biobanks. We evaluated the performance characteristics of proprietary machine learning algorithms for the subclassification of these NFT categories in anti-pTau217-stained whole slide images of entorhinal cortex, hippocampus, frontal, and parietal cortex sections. Overall precision/recall/F1 scores were highest for Classifier A (0.6/0.46/0.5). The best performing algorithm was used to guide LCM capture and inform NFT enrichment. Targeted proteomics on tau signature peptides (pTau181, pTau217, and TauMTBR) was performed on approximately 1250 NFT collections. The results demonstrated that their abundance increased from pretangles to mature tangles (∼2-11-fold increase), and that this was followed by a sharp reduction in ghost tangles (∼3-116-fold decrease), with pTau217 showing the most drastic change. Pathologist-trained NFT classifiers represent an objective albeit imperfect means to enrich specific morphologic forms permitting coupled LCM-MS (mass spectrometry) to investigate AD-associated PTM.

Abstract Background The incidence, epidemiology, and clinical characteristics of enterococcal bloodstream infection (BSI) have not previously been studied on a population-based level in the United States. Methods We utilized the Expanded Rochester Epidemiology Project medical records linkage system to conduct a contemporary 5-year, retrospective, population-based study of monomicrobial enterococcal (ME) BSI among adult residents of 8 counties in southeast Minnesota from January 1, 2018 to December 31, 2022. Results A total of 109 cases of ME-BSI were identified. The overall age- and sex-adjusted incidence rate was 6.7 per 100 000 person-years (95% confidence interval, 5.4–7.9). Multivariable analysis revealed that male sex (P < .001) and older age (P < .001) were each independently associated with increased incidence, whereas no temporal association was demonstrated (year effect, P = .475). The median age of incident cases was 76.8 years (interquartile range, 65.0–83.3). Urinary tract source was the most common presumed source (42.2%), and Enterococcus faecalis was the predominant (83.5%) pathogen. Overall, 14.4% of patients met modified Duke criteria for definite infective endocarditis. Cumulative mortality was 28.4% at 12 weeks and 43.1% at 1 year. Conclusions In this population-based study, ME-BSI was significantly associated with older age and male sex. There was a high rate of mortality at 12 weeks and 1 year, with ∼1 out of 7 cases complicated by definite infective endocarditis. These findings underscore the importance of ongoing investigation of this syndrome.

ABSTRACTBackgroundEsophageal‐pericardial fistula (EPF) is rare with an incidence of 0.016%–0.04%. With novel procedures involving intracardiac or esophageal instrumentation in the last few decades, including atrial fibrillation (AF) ablation, further understanding of this unique entity is warranted. In this systematic review, we summarize the etiology, diagnostic features, management, and outcomes of EPF.MethodsA librarian conducted a systematic literature review of case reports/series describing adults diagnosed with EPF through 7 major databases/registries from inception to 7/30/2024.ResultsOne hundred twenty patients from 115 papers met the inclusion criteria. Median age(IQR) was 57(44–67) years, with a male predominance (73.7%). The primary etiology of EPF shifted from benign esophageal diseases before 2000 to AF ablation on/after 2000. Median time(IQR) from AF ablation to EPF presentation/diagnosis was 17(13–23) days. Chest pain (70.8%) and pneumopericardium (90.0%) were, respectively, the most common presenting symptom and pericardial finding. Water‐soluble contrast esophagram (WSCE) had the highest diagnostic sensitivity (82.8%). Management included surgery (47.5%), stent placement (22.5%), combined surgery/stenting (19.2%), and conservative (10.8%). Overall mortality was 37.5%; median(IQR) time to death was 20(9–41) days. EPF from malignancy had poorer survival than those from benign esophageal causes (HR 2.65 [1.36–5.17]; p = 0.004) and cardiac ablation (HR 5.74 [2.41–13.65]; p < 0.0001). Patients who received any intervention (HR 0.28 [0.13‐0.57]; p = 0.0005) or had confirmed EPF resolution (HR 0.27 [0.12–0.59]; p = 0.0009) demonstrated better survival. There was no difference in survival between surgery and stenting alone (p = 0.91).ConclusionsAF ablation is now the leading etiology of EPF. Given its high mortality, a high degree of clinical suspicion is essential in those presenting with key signs/symptoms following AF ablation to enable urgent diagnosis and multi‐disciplinary management. WSCE may be the diagnostic modality to perform, given its high sensitivity. Future studies are warranted to investigate whether stenting should be the primary management given possible non‐inferiority to surgery.

Key Points In individuals undergoing bariatric surgery, the magnitude of decline in GFR postbariatric surgery is directly associated with presurgery GFR. Reductions in GFR postsurgery were only weakly correlated with weight loss. In obese individuals, GFR-estimating equations performed best when deindexed and when applied in people with reduced kidney function. Background Important questions remain about how bariatric ( i.e ., weight loss) surgery affects measured GFR (mGFR) and eGFR as well as what factors influence change in mGFR postsurgery. Methods Data were pooled from all seven available studies (dates: 2004–2018) measuring GFR prebariatric and postbariatric surgery using gold standard methods. Change in postsurgery mGFR, factors that could influence change in mGFR, and effects on five GFR-estimating equations were analyzed using standard statistical methods. Results The cohort included 105 individuals from the United States and Europe. Sixty-eight percent were female, 97% were White, the mean age was 50 years (range, 24–70), and the mean body mass index was 46±8 kg/m 2 . The mean presurgery mGFR of 107 ml/min (range, 31–215) fell to 92 ml/min (−14%; 95% confidence interval, −21 to −10) postsurgery, with a strong linear relationship existing between presurgery mGFR and % change in GFR ( r =−0.51; −0.64 to −0.35). Individuals with presurgery mGFR ≥90, 60 to <90, and<60 ml/min had −25 (−32 to −19), 1 (−11 to 13), and 7 (0 to 14) ml/min mean postoperative changes in mGFR. Change in weight was significantly correlated with change in mGFR ( r =0.22; 0.03 to 0.40). After adjusting for sex, changes in mGFR postsurgery were associated with higher presurgical age (−0.6 ml/min per year; −1.1 to −0.2), mGFR (−0.5 ml/min per 1 ml/min; −0.6 to −0.4), and change in systolic BP (−0.3 ml/min per 1 mm Hg; −0.6 to 0.0). All GFR-estimating equations significantly underestimated postsurgical GFR reductions in people with preserved kidney function and had improved bias, precision, and accuracy when deindexed and applied to individuals with mGFR <90 ml/min. Conclusions In individuals with obesity undergoing bariatric surgery, the magnitude of postsurgical decline in mGFR was directly associated with presurgery GFR and weakly correlated with weight loss. In addition, GFR-estimating equations' performance improved when deindexed and used in people with reduced kidney function, with the combined creatinine/cystatin C equations having the best overall performance.