In an in-situ approach towards tissue engineered cardiovascular replacement grafts, cell-free scaffolds are implanted that engage in endogenous tissue formation. Bioactive molecules can be incorporated into such grafts to facilitate cellular recruitment. Stromal cell derived factor 1α (SDF1α) is a powerful chemoattractant of lymphocytes, monocytes and progenitor cells and plays an important role in cellular signaling and tissue repair. Short SDF1α-peptides derived from its receptor-activating domain are capable of activating the SDF1α-specific receptor CXCR4. Here, we show that SDF1α-derived peptides can be chemically modified with a supramolecular four-fold hydrogen bonding ureido-pyrimidinone (UPy) moiety, that allows for the convenient incorporation of the UPy-SDF1α-derived peptides into a UPy-modified polymer scaffold. We hypothesized that a UPy-modified material bioactivated with these UPy-SDF1α-derived peptides can retain and stimulate circulating cells in an anti-inflammatory, pro-tissue formation signaling environment. First, the early recruitment of human peripheral blood mononuclear cells to the scaffolds was analyzed in vitro in a custom-made mesofluidic device applying physiological pulsatile fluid flow. Preferential adhesion of lymphocytes with reduced expression of inflammatory factors TNFα, MCP1 and lymphocyte activation marker CD25 was found in the bioactivated scaffolds, indicating a reduction in inflammatory signaling. As a proof of concept, in-vivo implantation of the bioactivated scaffolds as rat abdominal aorta interposition grafts showed increased cellularity by CD68+ cells after 7 days. These results indicate that a completely synthetic, cell-free biomaterial can attract and stimulate specific leukocyte populations through supramolecular incorporation of short bioactive SDF1α derived peptides.
Drug-induced liver injury (DILI) presents a significant challenge to drug development and regulatory science. The FDA’s Liver Toxicity Knowledge Base (LTKB) evaluated >1000 drugs for their likelihood of causing DILI in humans, of which >700 drugs were classified into three categories (most-DILI, less-DILI, and no-DILI). Based on this dataset, we developed and compared 2-class and 3-class DILI prediction models using the machine learning algorithm of Decision Forest (DF) with Mold2 structural descriptors. The models were evaluated through 1000 iterations of 5-fold cross-validations, 1000 bootstrapping validations and 1000 permutation tests (that assessed the chance correlation). Furthermore, prediction confidence analysis was conducted, which provides an additional parameter for proper interpretation of prediction results. We revealed that the 3-class model not only had a higher resolution to estimate DILI risk but also showed an improved capability to differentiate most-DILI drugs from no-DILI drugs in comparison with the 2-class DILI model. We demonstrated the utility of the models for drug ingredients with warnings very recently issued by the FDA. Moreover, we identified informative molecular features important for assessing DILI risk. Our results suggested that the 3-class model presents a better option than the binary model (which most publications are focused on) for drug safety evaluation.
Drug-induced liver injury (DILI) is the most frequently reported single cause of safety-related withdrawal of marketed drugs. It is essential to identify drugs with DILI potential at the early stages of drug development. In this study, we describe a deep learning-powered DILI (DeepDILI) prediction model created by combining model-level representation generated by conventional machine learning (ML) algorithms with a deep learning framework based on Mold2 descriptors. We conducted a comprehensive evaluation of the proposed DeepDILI model performance by posing several critical questions: (1) Could the DILI potential of newly approved drugs be predicted by accumulated knowledge of early approved ones? (2) is model-level representation more informative than molecule-based representation for DILI prediction? and (3) could improved model explainability be established? For question 1, we developed the DeepDILI model using drugs approved before 1997 to predict the DILI potential of those approved thereafter. As a result, the DeepDILI model outperformed the five conventional ML algorithms and two state-of-the-art ensemble methods with a Matthews correlation coefficient (MCC) value of 0.331. For question 2, we demonstrated that the DeepDILI model's performance was significantly improved (i.e., a MCC improvement of 25.86% in test set) compared with deep neural networks based on molecule-based representation. For question 3, we found 21 chemical descriptors that were enriched, suggesting a strong association with DILI outcome. Furthermore, we found that the DeepDILI model has more discrimination power to identify the DILI potential of drugs belonging to the World Health Organization therapeutic category of 'alimentary tract and metabolism'. Moreover, the DeepDILI model based on Mold2 descriptors outperformed the ones with Mol2vec and MACCS descriptors. Finally, the DeepDILI model was applied to the recent real-world problem of predicting any DILI concern for potential COVID-19 treatments from repositioning drug candidates. Altogether, this developed DeepDILI model could serve as a promising tool for screening for DILI risk of compounds in the preclinical setting, and the DeepDILI model is publicly available through https://github.com/TingLi2016/ DeepDILI.
Studies on gene expression in response to therapy have led to the discovery of pharmacogenomics biomarkers and advances in precision medicine. Whole transcriptome sequencing (RNA-seq) is an emerging tool for profiling gene expression and has received wide adoption in the biomedical research community. However, its value in regulatory decision making requires rigorous assessment and consensus between various stakeholders, including the research community, regulatory agencies, and industry. The FDA-led SEquencing Quality Control (SEQC) consortium has made considerable progress in this direction, and is the subject of this review. Specifically, three RNA-seq platforms (Illumina HiSeq, Life Technologies SOLiD, and Roche 454) were extensively evaluated at multiple sites to assess cross-site and cross-platform reproducibility. The results demonstrated that relative gene expression measurements were consistently comparable across labs and platforms, but not so for the measurement of absolute expression levels. As part of the quality evaluation several studies were included to evaluate the utility of RNA-seq in clinical settings and safety assessment. The neuroblastoma study profiled tumor samples from 498 pediatric neuroblastoma patients by both microarray and RNA-seq. RNA-seq offers more utilities than microarray in determining the transcriptomic characteristics of cancer. However, RNA-seq and microarray-based models were comparable in clinical endpoint prediction, even when including additional features unique to RNA-seq beyond gene expression. The toxicogenomics study compared microarray and RNA-seq profiles of the liver samples from rats exposed to 27 different chemicals representing multiple toxicity modes of action. Cross-platform concordance was dependent on chemical treatment and transcript abundance. Though both RNA-seq and microarray are suitable for developing gene expression based predictive models with comparable prediction performance, RNA-seq offers advantages over microarray in profiling genes with low expression. The rat BodyMap study provided a comprehensive rat transcriptomic body map by performing RNA-Seq on 320 samples from 11 organs in either sex of juvenile, adolescent, adult and aged Fischer 344 rats. Lastly, the transferability study demonstrated that signature genes of predictive models are reciprocally transferable between microarray and RNA-seq data for model development using a comprehensive approach with two large clinical data sets. This result suggests continued usefulness of legacy microarray data in the coming RNA-seq era. In conclusion, the SEQC project enhances our understanding of RNA-seq and provides valuable guidelines for RNA-seq based clinical application and safety evaluation to advance precision medicine.
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