Citations

AbstractSurvivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer ‐ metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population‐based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow‐up time of 12 years (incidence: 2.0 per 1000 person‐years). CRC cases with a synchronous CRC were 3.4‐fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89–5.98) than those without a synchronous tumour. CRC cases with MMR‐deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11–2.64) compared to those with MMR‐proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06–0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR‐deficient.

CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer’s disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management.

Introduction: Abdominal aortic aneurysms (AAA) are common among individuals over age 65 with a prevalence of 9%. Most AAAs are small and require surveillance imaging to monitor size and growth rates. Tools capable of predicting growth rates would be clinically useful. Hypothesis: We investigated how computational hemodynamics derived from CT angiography (CTA) differentiated slow and rapid-growing AAAs. Methods: Using readily available computing power in the clinical workflow, 3D models were generated for 25 subjects with AAA from available 3D CTA data. AAA growth rates were categorized as slow ( less than 5 mm/year) or rapid (greater than 5 mm/year) based on serial imaging. A geometrical analysis was performed using 7 indices (Volume, Surface Area, Length, Max/Min radius, Expansion Ratio [Mean radius/vessel radius], Proximal vessel area, Voronoi diagram-based metrics) for each AAA. Computational hemodynamics were performed using commercial software (ANSYS-Fluent). Computational hemodynamics were completed for all cases (see Fig. 1). In-house software assessed wall shear stress-(WSS) and vortex-based hemodynamics. Support vector machine (SVM) was run with cross-validation (50 iterations) to assess predictive strength using these 16 parameters. Results: Among 25 AAAs studied, 7 were rapid and 18 were slow-growing. The combination of proximal vessel area, spatiotemporally averaged WSS, and spatially averaged OSI provided the best accuracy for growth differentiation. The area under receiving operating curve (AUROC) and total accuracy are 0.770 and 0.765, respectively, with 48% and 86% of rapid and slow-growing AAAs correctly identified, respectively. Conclusions: Computational hemodynamics appears feasible with reasonable growth rate prediction. With optimization, this tool may enable resource utilization refinement for imaging surveillance strategies by distinguishing rapid from slow-growing AAAs.

The mammalian heart loses its regenerative potential within a week after birth. Although under certain circumstances adult cardiomyocytes can re-enter the cell cycle, initiate DNA synthesis and progress towards mitosis, however, they do not complete a conventional mitosis cycle and proceed towards endomitosis resulting in polyploidy. This suggests that high-energy dependent steps in cell cycle and myofibrillar disassembly are malfunctioning in adult cardiomyocytes. It is known that nucleotide-based energetic signaling and metabolic environment are critical for initiation of tissue regeneration after injury. The regulatory mechanisms and energetic-metabolic signaling circuits that govern cardiomyocyte cell cycle withdrawal and binucleation are poorly understood. Using mouse neonatal (2 and 10 days) hearts, with high and low regenerative capacity, respectively, we have determined metabolomic profiles and dynamics of phosphotransfer circuits and AMP-signaling using 18O-phosphoryl labeling mass-spectrometric and 18O-assisted 31P NMR techniques. The results demonstrate that loss of heart regenerative capacity 10 days after birth is associated with marked changes in heart metabolome and adenylate kinase (AK)-catalyzed phosphotransfer flux. Among most altered metabolites were putrescine and myo-inositol, involved in tissue regeneration, Krebs cycle and amino acid metabolites, creatinine, glucose-6-phosphate and lactate indicating rearrangements in energy and substrate metabolic systems. AK flux was the only phosphotransfer flux significantly upregulated in hearts at 10 days of age along with increased in mitochondrial and glycolytic capacities and mitochondrial AK2 expression. Increased AK2 expression was associated with augmented AMP phosphorylation, measured by generation of β-ATP[18O], and reduction of AMPK activity. Thus, increased channeling of AMP into mitochondria and reduction of AK-AMP-AMPK signaling axis could contribute to the withdrawal from completion of cell cycle in terminally differentiated adult cardiomyocytes. The uncovered metabolic signaling mechanism opens new avenues for targeted regulation of heart regenerative potential critical for repair of injured hearts.

Introduction: Cardiac remodeling in heart failure (HF) is associated with conduction abnormalities and dyssynchrony which results in poorly coordinated contractions precipitating metabolic heterogeneity and energetic inefficiency. Cardiac resynchronization therapy (CRT) improves HF symptoms, ventricular function and overall survival. The aim of this study was to determine the changes in metabolomic profiles and substrate utilization after CRT. Methods: 18 patients with advanced HF and 7 healthy controls were included in this study. Blood samples were collected from peripheral vein, femoral artery (FA) and coronary sinus (CS) before and 10-min after CRT. Metabolomic profiling of plasma samples were performed using GC/MS and 1 H NMR spectroscopy. Partial Least Squares Discriminant Analysis (PLS-DA) score plots and regression coefficients were used to examine metabolomic profiles. Results: HF patients have altered plasma metabolomic profile (Fig. A) with distinct panel of metabolites including free fatty acids (FFA), glycerol, 2-hydroxybutyrate, glycine, succinate and uric acid important in group classification compared to controls. Increased release of fumarate and glycerol-3-phosphate from myocardium in HF indicate mitochondrial and substrate shuttle dysfunction. Immediately after CRT, transcardiac metabolomic profile of plasma from CS shifted to a different state with increased myocardial uptake and metabolism of FFA and decreased release of creatinine indicating improved energetic conditions (Fig. B). Conclusion: Metabolomic profiling indicates that CRT improves myocardial substrate metabolism and utilization in patients with advanced HF.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases (NOS), and is degraded primarily by dimethylarginine dimethylaminohydrolase-1 (DDAH1). While ADMA is elevated in patients with fibrocalcific aortic valve stenosis (FCAVD), is it unknown whether tissue levels of DDAH1 are altered in FCAVD, and whether systemic elevations in ADMA levels accelerate initiation and/or progression of FCAVD. In the present study, we measured expression of DDAH1 in normal and stenotic human aortic valves, and tested the hypothesis that increases in ADMA worsen hypertension and endothelial dysfunction and accelerate the initiation and progression of FCAVD in hypercholesterolemic mice. In tissue from humans with FCAVD, expression of DDAH1 was significantly increased compared to normal valve tissue (normal = 1.0 ± 0.1, FCAVD = 1.3 ± 0.1, ⋔⋔Ct method; p < 0.05). To experimentally alter DDAH1 levels, we used low density lipoprotein receptor-deficient, apolipoprotein B100-only (LA) mice that were either wild-type (D +/+ ) or heterozygous (D +/- ) for DDAH1. Blood pressure (tail cuff), aortic endothelial function (isolated organ bath), and aortic valve function (echocardiography), were measured at 3 and 6 month time points in these mice. Compared to LA-D +/+ mice, systolic arterial pressure was significantly increased in LA-D +/- mice at both 3 month (121±4 mmHg and 144±4 mmHg) and 6 months (138±6 mmHg and 148±4 mmHg). Aortic endothelial function progressively declined with prolonged hypercholesterolemia, but maximum relaxation to acetylcholine did not differ between LA-D +/+ and LA-D +/- mice at 3 or 6 months. While aortic valve function was similar between LA-D +/+ and LA-D +/- mice at 3 months (peak transvalvular velocity: 1.98±0.07 m/sec versus 1.94±0.06 m/s, respectively), aortic valve function was significantly worse in LA-D +/- (2.41±0.11 m/sec) compared to LA-D +/+ mice (2.20±0.09 m/sec) at 6 months (p < 0.05). In conclusion, our data support a working model in which increases in valvular DDAH1 levels protect against progression of FCAVD. Importantly, loss of DDAH1 in mice does not alter aortic valve function during early stages of FCAVD, but accelerates progression of FCAVD independently of changes in endothelial function.

Background: We have found that the vascular large conductance Ca 2+ -activated K + channels (BK) are targeted to caveolae. The goal of this study is to determine the role of caveolae in BK regulation by angiotensin II (AII) in normal and diabetic rats. Results: In coronary arterial smooth muscle cells (CASMC) from control rats, AII (2 μ M) inhibited BK by 40.5% from 227±26 pA/pF to 135±14 pA/pF (HP −60 mV, TP 150 mV, n=7, p<0.05). However, AII had no effects on BK in CASMC transfected with caveolin-1 siRNA (vs 50% inhibition in cells transfected with control siRNA) or in cells from Cav1−/− mice, suggesting the AII effects are caveolae-dependent. Density gradient analysis of rat vessel homogenates showed that caveolin-1, BK, Gq, cSrc, and NOX-1 all reside in the caveolae-rich fraction, where AT 1 R was absent unless the animal was pre-treated with AII, suggesting receptor translocation upon agonist activation. However, CASMC from streptozotocin-induced diabetic rats showed significant reduction in BK (61.5±10.6 pA/pF) with no response to AII (61.2±15.7 pA/pF, n=8). Vascular BK, caveolin-1, AT 1 R, cSrc, and NOX-1 expression in caveolae were all upregulated by 1.6- to 3.1-fold in diabetes. Density gradient analysis of diabetic vessels showed the presence of AT 1 R in the caveolae-rich fraction without AII pretreatment, suggesting that the AT 1 R signaling pathway might be constitutively active in diabetes. This was accompanied by a 2-fold increase in BK tyrosine phosphorylation and BK tyrosine nitration. The AII effects on BK function in diabetic CASMC were abolished by pretreatment (1 hr) with PKC inhibitor or by LavA (cSrc inhibitor) and can be mimicked by incubation (2 hr) of control CASMC with peroxynitrite. Conclusion: AT 1 R-BK-enzyme complex in the caveolae microdomain is critical in vascular BK regulation. Enhanced AII-signaling facilitates BK post-translational modification, resulting in BK dysfunction in diabetes.

AbstractObjectiveTo elucidate the relationship between USP19 and O(6)‐methylguanine‐DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with chemotherapy resistance.MethodsScreening the deubiquitinase pannel and identifying the deubiquitinase directly interacts with and deubiquitination MGMT. Deubiquitination assay to confirm USP19 deubiquitinates MGMT. The colony formation and tumor growth study in xenograft assess USP19 affects the GBM sensitive to TMZ was performed by T98G, LN18, U251, and U87 cell lines. Immunohistochemistry staining and survival analysis were performed to explore how USP19 is correlated to MGMT in GBM clinical management.ResultsUSP19 removes the ubiquitination of MGMT to facilitate the DNA methylation damage repair. Depletion of USP19 results in the glioblastoma cell sensitivity to temozolomide, which can be rescued by overexpressing MGMT. USP19 is overexpressed in glioblastoma patient samples, which positively correlates with the level of MGMT protein and poor prognosis in these patients.ConclusionThe regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients’ temozolomide chemotherapy response.

Abstract Introduction Inflammatory Bowel Disease (IBD) is a chronic, immune-mediated condition, encompassing Crohn's disease (CD) and ulcerative colitis (UC). Up to 80% of individuals with IBD report poor sleep quality. However, there is limited information on factors that predict sleep characteristics in this population. This study aims to explore the associations between demographic, clinical, and psychological factors with sleep characteristics in adults with IBD. Methods We conducted a retrospective analysis of two IBD sleep studies. Participants aged 18-64 years old with a diagnosis of IBD were recruited from two academic medical centers and completed Patient-Reported Outcomes Measure Information System (PROMIS) depression and anxiety questionnaires and wore a wrist actigraph for 10 days continuously. We employed Independent T-Tests and Pearson’s correlation to assess the association of biologic treatment, IBD type, sex, depression, and anxiety on sleep efficiency (SE), total sleep time (TST), and sleep onset latency (SOL). Results We included 58 participants with a mean age of 35.6 years (SD=12.1). 60.3% were female, and 60.3% were diagnosed with CD. The mean depression score was 51.3 (SD = 10.2) and the anxiety score was 52.2 (SD = 15.5). The mean SOL was 19.3 minutes (SD = 15.5), TST was 413.3 minutes (SD = 53.2), and SE was 83.5% (SD = 5.7). TST was significantly longer in females compared to males (427.4 vs. 391.9 minutes , p&lt; 0.05). SE was significantly higher among females compared to males (85.1% vs. 81.0%, p&lt; 0.001) and among individuals with Crohn's disease compared to Ulcerative colitis ((85.1% vs. 81.0%, p&lt; 0.01). SOL was longer among individuals with Ulcerative colitis compared to Crohn's disease (15.6 vs.25.0minutes , p&lt; 0.05). Depression and anxiety scores were not significantly correlated with any sleep characteristic. Conclusion Sleep continuity was poor in people with IBD. Given that we found sex and IBD type impacted sleep continuity, these factors should be considered in future precision sleep health interventions for this population. Support (if any) This study was funded by the University of Washington School of Nursing, NINR (K23 NR020044) (Kendra Kamp, and the American Nurses Foundation (Samantha Conley).

Abstract Background Error analysis plays a crucial role in clinical concept extraction, a fundamental subtask within clinical natural language processing (NLP). The process typically involves a manual review of error types, such as contextual and linguistic factors contributing to their occurrence, and the identification of underlying causes to refine the NLP model and improve its performance. Conducting error analysis can be complex, requiring a combination of NLP expertise and domain-specific knowledge. Due to the high heterogeneity of electronic health record (EHR) settings across different institutions, challenges may arise when attempting to standardize and reproduce the error analysis process. Objectives This study aims to facilitate a collaborative effort to establish common definitions and taxonomies for capturing diverse error types, fostering community consensus on error analysis for clinical concept extraction tasks. Materials and Methods We iteratively developed and evaluated an error taxonomy based on existing literature, standards, real-world data, multisite case evaluations, and community feedback. The finalized taxonomy was released in both .dtd and .owl formats at the Open Health Natural Language Processing Consortium. The taxonomy is compatible with several different open-source annotation tools, including MAE, Brat, and MedTator. Results The resulting error taxonomy comprises 43 distinct error classes, organized into 6 error dimensions and 4 properties, including model type (symbolic and statistical machine learning), evaluation subject (model and human), evaluation level (patient, document, sentence, and concept), and annotation examples. Internal and external evaluations revealed strong variations in error types across methodological approaches, tasks, and EHR settings. Key points emerged from community feedback, including the need to enhancing clarity, generalizability, and usability of the taxonomy, along with dissemination strategies. Conclusion The proposed taxonomy can facilitate the acceleration and standardization of the error analysis process in multi-site settings, thus improving the provenance, interpretability, and portability of NLP models. Future researchers could explore the potential direction of developing automated or semi-automated methods to assist in the classification and standardization of error analysis.