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Background: Early diagnosis and treatment of Crohn's Disease are associated with decreased risk of surgery and complications. However, diagnostic delay is frequently seen in clinical practice. To better understand Crohn's Disease risk factors and disease indicators, we identified, described, and predicted incident Crohn's Disease patients based on the Electronic Health Record data of the Mount Sinai Health System., Methods: We developed two phenotyping algorithms based on structured Electronic Health Record data (i.e., coded diagnosis, medication prescription, and healthcare utilization), and a more simple and advanced approach of information extraction from clinical notes, including data between 2011 and 2023. We conducted an ablation study for the classification task using different models, prediction time points, data inputs, text encoding methods, and case-control matching variables., Results: We identified 247 incident Crohn's Disease cases and 1221 matched controls and validated our cohorts through manual chart review. A second control cohort (n = 1235) was created without matching on race. Gastrointestinal symptoms were significantly overrepresented in cases at least 180 days before the first coded Crohn's Disease diagnosis. Adding text-based features to the clinical prediction models increased their overall performances. However, adding race as a matching variable had more effects on the model performance than the choice of modeling algorithm or input data, with an area under the receiver operating characteristic difference of 0.09 between the best-performing models., Conclusion: We demonstrate the feasibility of identifying newly diagnosed Crohn's Disease patients within a United States health system using Electronic Health Records. For the predictive modeling task, cases and controls were distinguished only with modest performance, even though various state-of-the-art methods were applied based on features from structured and unstructured data. Our findings suggest the benefit of adding information from clinical notes in a supervised or unsupervised manner for cohort creation and predictive modeling., Competing Interests: Declaration of competing interest RCU has served as a consultant and/or advisory board member for AbbVie, Bristol Myers Squibb, Celltrion, Inotrem, Lilly, Janssen, Pfizer, Roivant, Takeda. BYR has served as a consultant and/or holds intellectual property rights commercialized by Seqstant, Biontech, Genentech (Roche). The remaining authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The impact of pregnancy on the development of pouchitis in women who have undergone total proctocolectomy with ileal pouch anal anastomosis for ulcerative colitis is poorly understood., Methods: This was a retrospective study of women with ulcerative colitis who underwent total proctocolectomy with ileal pouch anal anastomosis and subsequently became pregnant at Mount Sinai Hospital. The primary outcome was acute pouchitis during pregnancy or the postpartum period defined as symptoms of increased stool frequency and urgency treated with antibiotics., Results: A total of 44 women with 63 pregnancies and complete data were identified. Acute pouchitis occurred in 14 pregnancies (22.2%) in 12 women and in the postpartum period of 10 pregnancies (15.9%) in 9 women. Acute pouchitis occurred more frequently in women with a history of acute pouchitis immediately before, during, or after pregnancy., Discussion: Acute pouchitis was common during pregnancy and the postpartum period, likely due to microbial shifts. Although not statistically significant, these results provide insight into the impact of pregnancy on the risk of pouchitis and establish the framework for preconception counseling that focuses on prevention and management of pouchitis during pregnancy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background& Aims: Tumor necrosis factor (TNF) antagonists often are used as first-line medications to treat moderate to severe inflammatory bowel disease (IBD), but many patients do not achieve or maintain response. Our aim was to compare the effectiveness of second-line treatments (ustekinumab, vedolizumab, or a second TNF antagonist) after TNF antagonist exposure in patients with Crohn's disease (CD) and ulcerative colitis (UC) from 2 electronic health records-based cohorts., Methods: We identified patients with prior TNF antagonist exposure who switched to a different biologic in the Mount Sinai Health System (MSHS) electronic health records (CD, n = 527; UC, n = 165) and the Study of a Prospective Adult Research Cohort (SPARC) from the Inflammatory Bowel Disease Plexus Program of the Crohn's & Colitis Foundation (CD, n = 412; UC, n = 129). Treatment failure was defined as the composite of any IBD-related surgery, IBD-related hospitalization, new prescription of oral/intravenous corticosteroids, or need to switch to a third biologic agent. Time-to-event analysis was conducted with inverse probability of treatment-weighted data., Results: Overall, treatment failure occurred in 85% of MSHS and 72% of SPARC CD patients. In SPARC, the likelihood of treatment failure was significantly lower with ustekinumab compared with vedolizumab as second-line treatment (adjusted hazard ratio, 0.66; 95% CI, 0.54-0.82; P < .001), a trend confirmed in MSHS (adjusted hazard ratio, 0.89; 95% CI, 0.77-1.04; P = .15). In both cohorts, the superiority of ustekinumab compared with vedolizumab was shown when considering treatment failure as prescription of steroids or a third biologic agent. In UC, no differences between second-line treatment groups were identified., Conclusions: In 2 independent real-world cohort settings, second-line therapy in CD with ustekinumab after TNF antagonist treatment failure was associated with a lower likelihood of treatment failure than second-line vedolizumab., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Due to the increasing application of genome analysis and interpretation in medical disciplines, professionals require adequate education. Here, we present the implementation of personal genotyping as an educational tool in two genomics courses targeting Digital Health students at the Hasso Plattner Institute (HPI) and medical students at the Technical University of Munich (TUM)., Methods: We compared and evaluated the courses and the students' perceptions on the course setup using questionnaires., Results: During the course, students changed their attitudes towards genotyping (HPI: 79% [15 of 19], TUM: 47% [25 of 53]). Predominantly, students became more critical of personal genotyping (HPI: 73% [11 of 15], TUM: 72% [18 of 25]) and most students stated that genetic analyses should not be allowed without genetic counseling (HPI: 79% [15 of 19], TUM: 70% [37 of 53]). Students found the personal genotyping component useful (HPI: 89% [17 of 19], TUM: 92% [49 of 53]) and recommended its inclusion in future courses (HPI: 95% [18 of 19], TUM: 98% [52 of 53])., Conclusion: Students perceived the personal genotyping component as valuable in the described genomics courses. The implementation described here can serve as an example for future courses in Europe., (© 2023. The Author(s).)

Background: MicroRNAs (miRNAs) and isomiRs play important roles in tumorigenesis as essential regulators of gene expression. 5'isomiRs exhibit a shifted seed sequence compared to the canonical miRNA, resulting in different target spectra and thereby extending the phenotypic impact of the respective common pre-miRNA. However, for most miRNAs, expression and function of 5'isomiRs have not been studied in detail yet. Therefore, this study aims to investigate the functions of miRNAs and their 5'isomiRs., Methods: The expression of 5'isomiRs was assessed in The Cancer Genome Atlas (TCGA) breast cancer patient dataset. Phenotypic effects of miR-183 overexpression in triple-negative breast cancer (TNBC) cell lines were investigated in vitro and in vivo by quantifying migration, proliferation, tumor growth and metastasis. Direct targeting of E2F1 by miR-183-5p|+2 was validated with a 3'UTR luciferase assay and linked to the phenotypes of isomiR overexpression., Results: TCGA breast cancer patient data indicated that three variants of miR-183-5p are highly expressed and upregulated, namely miR-183-5p|0, miR-183-5p|+1 and miR-183-5p|+2. However, TNBC cell lines displayed reduced proliferation and invasion upon overexpression of pre-miR-183. While invasion was reduced individually by all three isomiRs, proliferation and cell cycle progression were specifically inhibited by overexpression of miR-183-5p|+2. Proteomic analysis revealed reduced expression of E2F target genes upon overexpression of this isomiR, which could be attributed to direct targeting of E2F1, specifically by miR-183-5p|+2. Knockdown of E2F1 partially phenocopied the effect of miR-183-5p|+2 overexpression on cell proliferation and cell cycle. Gene set enrichment analysis of TCGA and METABRIC patient data indicated that the activity of E2F strongly correlated with the expression of miR-183-5p, suggesting transcriptional regulation of the miRNA by a factor of the E2F family. Indeed, in vitro, expression of miR-183-5p was regulated by E2F1. Hence, miR-183-5p|+2 directly targeting E2F1 appears to be part of a negative feedback loop potentially fine-tuning its activity., Conclusions: This study demonstrates that 5'isomiRs originating from the same arm of the same pre-miRNA (i.e. pre-miR-183-5p) may exhibit different functions and thereby collectively contribute to the same phenotype. Here, one of three isomiRs was shown to counteract expression of the pre-miRNA by negatively regulating a transcriptional activator (i.e. E2F1). We speculate that this might be part of a regulatory mechanism to prevent uncontrolled cell proliferation, which is disabled during cancer progression., (© 2022. The Author(s).)

Background: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC). Treatment options for TNBC patients are limited and further insights into disease aetiology are needed to develop better therapeutic approaches. microRNAs' ability to regulate multiple targets could hold a promising discovery approach to pathways relevant for TNBC aggressiveness. Thus, we address the role of miRNAs in controlling three signalling pathways relevant to the biology of TNBC, and their downstream phenotypes., Methods: To identify miRNAs regulating WNT/β-catenin, c-Met, and integrin signalling pathways, we performed a high-throughput targeted proteomic approach, investigating the effect of 800 miRNAs on the expression of 62 proteins in the MDA-MB-231 TNBC cell line. We then developed a novel network analysis, Pathway Coregulatory (PC) score, to detect miRNAs regulating these three pathways. Using in vitro assays for cell growth, migration, apoptosis, and stem-cell content, we validated the function of candidate miRNAs. Bioinformatic analyses using BC patients' datasets were employed to assess expression of miRNAs as well as their pathological relevance in TNBC patients., Results: We identified six candidate miRNAs coordinately regulating the three signalling pathways. Quantifying cell growth of three TNBC cell lines upon miRNA gain-of-function experiments, we characterised miR-193b as a strong and consistent repressor of proliferation. Importantly, the effects of miR-193b were stronger than chemical inhibition of the individual pathways. We further demonstrated that miR-193b induced apoptosis, repressed migration, and regulated stem-cell markers in MDA-MB-231 cells. Furthermore, miR-193b expression was the lowest in patients classified as TNBC or Basal compared to other subtypes. Gene Set Enrichment Analysis showed that miR-193b expression was significantly associated with reduced activity of WNT/β-catenin and c-Met signalling pathways in TNBC patients., Conclusions: Integrating miRNA-mediated effects and protein functions on networks, we show that miRNAs predominantly act in a coordinated fashion to activate or repress connected signalling pathways responsible for metastatic traits in TNBC. We further demonstrate that our top candidate, miR-193b, regulates these phenotypes to an extent stronger than individual pathway inhibition, thus emphasizing that its effect on TNBC aggressiveness is mediated by the coordinated repression of these functionally interconnected pathways., (© 2021. The Author(s).)

MicroRNAs (miRNAs) are small non-coding RNAs with diverse functions in post-transcriptional regulation of gene expression. Sequence and length variants of miRNAs are called isomiRs and can exert different functions compared to their canonical counterparts. The Cancer Genome Atlas (TCGA) provides isomiR-level expression data for patients of various cancer entities collected in a multi-center approach over several years. However, the impact of batch effects within individual cohorts has not been systematically investigated and corrected for before. Therefore, the aim of this study was to identify relevant cohort-specific batch variables and generate batch-corrected isomiR expression data for 16 TCGA cohorts. The main batch variables included sequencing platform, plate, sample purity and sequencing depth. Platform bias was related to certain length and sequence features of individual recurrently affected isomiRs. Furthermore, significant downregulation of reported tumor suppressive isomiRs in lung tumor tissue compared to normal samples was only observed after batch correction, highlighting the importance of working with corrected data. Batch-corrected datasets for all cohorts including quality control are provided as supplement. In summary, this study reveals that batch effects present in the TCGA dataset might mask biologically relevant effects and provides a valuable resource for research on isomiRs in cancer (accessible through GEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE164767)., (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.)

Dendrite arbor growth, or dendritogenesis, is choreographed by a diverse set of cues, including the NMDA receptor (NMDAR) subunits NR2A and NR2B. While NR1NR2B receptors are predominantly expressed in immature neurons and promote plasticity, NR1NR2A receptors are mainly expressed in mature neurons and induce circuit stability. How the different subunits regulate these processes is unclear, but this is likely related to the presence of their distinct C-terminal sequences that couple different signaling proteins. Calcium-calmodulin-dependent protein kinase II (CaMKII) is an interesting candidate as this protein can be activated by calcium influx through NMDARs. CaMKII triggers a series of biochemical signaling cascades, involving the phosphorylation of diverse targets. Among them, the activation of cAMP response element-binding protein (CREB-P) pathway triggers a plasticity-specific transcriptional program through unknown epigenetic mechanisms. Here, we found that dendritogenesis in hippocampal neurons is impaired by several well-characterized constructs (i.e., NR2B-RS/QD) and peptides (i.e., tatCN21) that specifically interfere with the recruitment and interaction of CaMKII with the NR2B C-terminal domain. Interestingly, we found that transduction of NR2AΔIN, a mutant NR2A construct with increased interaction to CaMKII, reactivates dendritogenesis in mature hippocampal neurons in vitro and in vivo. To gain insights into the signaling and epigenetic mechanisms underlying NMDAR-mediated dendritogenesis, we used immunofluorescence staining to detect CREB-P and acetylated lysine 27 of histone H3 (H3K27ac), an activation-associated histone tail mark. In contrast to control mature neurons, our data shows that activation of the NMDAR/CaMKII/ERK-P/CREB-P signaling axis in neurons expressing NR2AΔIN is not correlated with increased nuclear H3K27ac levels., (© 2017 Wiley Periodicals, Inc.)