Citations

Abstract Objectives To develop and validate a standards-based phenotyping tool to author electronic health record (EHR)-based phenotype definitions and demonstrate execution of the definitions against heterogeneous clinical research data platforms. Materials and Methods We developed an open-source, standards-compliant phenotyping tool known as the PhEMA Workbench that enables a phenotype representation using the Fast Healthcare Interoperability Resources (FHIR) and Clinical Quality Language (CQL) standards. We then demonstrated how this tool can be used to conduct EHR-based phenotyping, including phenotype authoring, execution, and validation. We validated the performance of the tool by executing a thrombotic event phenotype definition at 3 sites, Mayo Clinic (MC), Northwestern Medicine (NM), and Weill Cornell Medicine (WCM), and used manual review to determine precision and recall. Results An initial version of the PhEMA Workbench has been released, which supports phenotype authoring, execution, and publishing to a shared phenotype definition repository. The resulting thrombotic event phenotype definition consisted of 11 CQL statements, and 24 value sets containing a total of 834 codes. Technical validation showed satisfactory performance (both NM and MC had 100% precision and recall and WCM had a precision of 95% and a recall of 84%). Conclusions We demonstrate that the PhEMA Workbench can facilitate EHR-driven phenotype definition, execution, and phenotype sharing in heterogeneous clinical research data environments. A phenotype definition that integrates with existing standards-compliant systems, and the use of a formal representation facilitates automation and can decrease potential for human error.

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status. This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of patients with PDAC and MSI-H identified on Guardant360 from October 2018 to April 2021 was performed; clinical outcomes were submitted by treating providers. From 52 patients with PDAC +MSI-H, outcomes were available for 10 (19%) with a median age of 68 years (range: 56–82 years); the majority were male (80%) and had metastatic disease (80%). Nine of 10 patients were treated with ICI. Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab. The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9). The median progression-free survival and overall survival were not reached in this cohort. The median duration of treatment with ICI was 8 months (range: 1–24), and six out of seven responders continued to show response at the time of data cut-off after a median follow-up of 21 months (range: 11–33). Tissue-based MSI results were concordant with plasma-based G360 results in five of six patients (83%) who had tissue-based test results available, with G360 identifying one more patient with MSI-H than tissue testing. These results suggest that detecting MSI-H by a well-validated liquid biopsy test could predict a robust response to ICI in patients with PDAC. The use of liquid biopsy may expand the identification of PDAC patients with MSI-H tumors and enable treatment with ICI resulting in improved outcomes.

Abstract Background: Stem cell senescence and depletion are major causes of organismal aging and aging-related diseases. The NAD–SIRT1–PARP1 axis has garnered remarkable interest owing to its significant role in regulating stem cell senescence and organismal aging. Event though our recent study showes that PBX1 overexpression attenuates hair follicle-derived mesenchymal stem cell (HF-MSC) senescence and apoptosis by regulating ROS-mediated DNA damage via downregulation of PARP1 expression, suggesting PARP1 downregulation is a common manifestation of the roles of both PBX1 and SIRT1 in the attenuation of HF-MSC senescence, and implying a potential link between PBX1 and SIRT1 via PARP1. Methods: HF-MSCs overexpressing PBX1, overexpressing both PBX1 and PARP1, downregulating SIRT1, and overexpressing PBX1 and downregulating SIRT1 were generated, and biomarkers related to cell senescence, apoptosis, DNA damage, and repair were detected at the cellular and protein levels. Results: (1) PBX1 overexpression alleviated HF-MSC senescence and apoptosis accompanied by upregulation of SIRT1 expression, downregulation of PARP1 expression, and increased intracellular NAD and ATP levels. (2) SIRT1 knockdown or PARP1 overexpression enhanced cellular senescence and apoptosis, accompanied by increased ROS accumulation and DNA damage aggravation and decreased intracellular NAD and ATP levels. (3) PBX1 overexpression rescued HF-MSC senescence and apoptosis induced by SIRT1 knockdown or PARP1 overexpression. (4) Dual luciferase reporter showed PBX1 enhanced SIRT1 expression by activating SIRT1 promoter. Conclusions: Our results reveal that a positive interaction feedback loop exists between PBX1 and SIRT1, that PBX1 is the upstream of SIRT1. To the best of our knowledge we are the first to report that there is a PBX1-SIRT1-PARP1 axis and this axis plays a critical role in alleviation of HF-MSC senescence and apoptosis. The results provide a new perspective on the mechanism of stem cell senescence and age-related disease prevention and treatment.

Abstract Introduction: Paclitaxel induced peripheral neuropathy (TIPN) is one of the most important survivorship issues of cancer patients with the potential to substantially impact quality of life. TIPN can lead to dose reductions, early cessation, and has the potential to compromise treatment efficacy. We previously reported both rare (SBF2) and common germline (FCAMR) predictors for TIPN in patients of African descent through whole-exome sequencing (WES) and a genome-wide association study (GWAS), respectively, in the adjuvant, randomized phase III breast cancer trial, E5103. These predictors are now being evaluated in the prospective ECOG-ACRIN trial EAZ171 (NCT04001829). We have also previously reported our evaluation of common germline variants for patients of European descent through GWAS in E5103 with validation in another adjuvant breast cancer trial, E1199. Herein, we evaluated for rare variants that were associated with risk of TIPN in patients of European ancestry from WES in E5103. Methods: Gene-based rare variant analyses using SKAT were performed to compare select cases of severe TIPN (n=172) and controls without any evidence of TIPN (n=170) derived from E5103. Cases were defined as those with at least grade 3 TIPN and controls were optimally. matched by demographic and risk factors and had no reported evidence for TIPN of any grade. Germline WES was conducted using Ion Proton™ Sequencers from Life Technologies with an average >100X coverage of the exome. Rare variants with a minor allele frequency <3% predicted to be deleterious by protein prediction programs were retained for the analysis. 7,278 genes passed quality control and were included in the analysis, setting the threshold for significance at a p-value < 6.87 ×10-6 after Bonferroni correction. Results: Cytochrome P450 oxidoreductase (POR) was significantly associated with an increased risk of grade 3+ TIPN (p =1.82 ×10-6). Six variants predicted to be deleterious in POR were identified in the study population. Paclitaxel is predominately metabolized by cytochrome P450 (CYP) 2C8 and 3A4. A functional cytochrome P450 oxidoreductase is required for the catalytic activities of all 57 CYP family members to metabolize drugs, xenobiotics, and steroid hormones. Conclusion: Rare variants in cytochrome P450 oxidoreductase predicted an increased risk of severe TIPN in patients receiving paclitaxel. These rare variants in POR may modulate the catalytic activities of P450 enzymes that are responsible for paclitaxel metabolism and have a striking biological rationale as contributors to TIPN. Work is ongoing to validate these findings mechanistically and to identify strategies to nullify the impact of these deleterious variants. Citation Format: Fei Shen, Guanglong Jiang, Laura Gardner, Gloria Xue, Santosh Philips, Reynold Ly, Osei Wilberforce, Xi Wu, Erica Cantor, Chau Dang, Donald Northfelt, Todd Skaar, Kathy D. Miller, George Sledge, Bryan P Schneider. Cytochrome P450 reductase gene, POR, associated with paclitaxel induced peripheral neuropathy in patients of European ancestry from the adjuvant breast cancer trial, ECOG-ACRIN E5103 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-02.

AbstractIntroductionMultiple positron emission tomography (PET) tracers are available for amyloid imaging, posing a significant challenge to consensus interpretation and quantitative analysis. We accordingly developed and validated a deep learning model as a harmonization strategy.MethodA Residual Inception Encoder‐Decoder Neural Network was developed to harmonize images between amyloid PET image pairs made with Pittsburgh Compound‐B and florbetapir tracers. The model was trained using a dataset with 92 subjects with 10‐fold cross validation and its generalizability was further examined using an independent external dataset of 46 subjects.ResultsSignificantly stronger between‐tracer correlations (P < .001) were observed after harmonization for both global amyloid burden indices and voxel‐wise measurements in the training cohort and the external testing cohort.DiscussionWe proposed and validated a novel encoder‐decoder based deep model to harmonize amyloid PET imaging data from different tracers. Further investigation is ongoing to improve the model and apply to additional tracers.

Surgical sealing and repair of injured and resected gastrointestinal (GI) organs are critical requirements for successful treatment and tissue healing. Despite being the standard of care, hand-sewn closure of GI defects using sutures faces limitations and challenges. In this work, we introduce an off-the-shelf bioadhesive GI patch capable of atraumatic, rapid, robust, and sutureless repair of GI defects. The GI patch integrates a nonadhesive top layer and a dry, bioadhesive bottom layer, resulting in a thin, flexible, transparent, and ready-to-use patch with tissue-matching mechanical properties. The rapid, robust, and sutureless sealing capability of the GI patch is systematically characterized using ex vivo porcine GI organ models. In vitro and in vivo rat models are used to evaluate the biocompatibility and degradability of the GI patch in comparison to commercially available tissue adhesives (Coseal and Histoacryl). To validate the GI patch’s efficacy, we demonstrate successful sutureless in vivo sealing and healing of GI defects in rat colon, stomach, and small intestine as well as in porcine colon injury models. The proposed GI patch provides a promising alternative to suture for repair of GI defects and offers potential clinical opportunities for the repair of other organs.

Abstract Family involvement in end-of-life (EOL) care is critical to ensure older adults’ health and quality of life. Older adults’ self-efficacy in discussing EOL care plans with family members can facilitate family involvement in EOL care planning. Research shows that family relationships are associated with self-efficacy in discussing EOL care with family members among older Chinese Americans. However, the roles of family conflict and acculturation remain unknown. This study examines the association between family conflict and self-efficacy in discussing EOL care with family members and whether such an association differs by acculturation levels among older Chinese Americans. Data were collected from 207 Chinese Americans aged 65-102 in two metropolitan areas in 2017. Ordinary least squares regression was conducted to examine the association between family conflict, acculturation, and self-efficacy in discussing EOL care with family. Family conflict was negatively associated with older adults’ self-efficacy in discussing EOL care with family. More specifically, the negative association between family conflict and self-efficacy in discussing EOL care with family members was more pronounced for those with higher levels of acculturation. Findings highlighted differential effects of family conflict on self-efficacy of EOL care plan discussion for older adults with different acculturation levels. Those with higher acculturation may be more independent in their EOL care planning and aware of the possible negative effects of family conflict in their EOL care planning discussions. Acculturation needs to be considered by geriatric health providers to develop family-centered interventions in improving end-of-life care planning for this population.

R47H- TREM2 mutation enhances AKT signaling in human AD microglia and mediates proinflammatory and synaptic toxicity in a tauopathy mouse model.