Brain informatics is a novel interdisciplinary area that focuses on scientifically studying the mechanisms of human brain information processing by integrating experimental cognitive neuroscience with advanced Web intelligence-centered information technologies. Web intelligence, which aims to understand the computational, cognitive, physical, and social foundations of the future Web, has attracted increasing attention to facilitate the study of brain informatics to promote human health. A large number of articles created in the recent few years are proof of the investment in Web intelligence-assisted human health. This study systematically reviews academic studies regarding article trends, top journals, subjects, countries/regions, and institutions, study design, artificial intelligence technologies, clinical tasks, and performance evaluation. Results indicate that literature is especially welcomed in subjects such as medical informatics and health care sciences and service. There are several promising topics, for example, random forests, support vector machines, and conventional neural networks for disease detection and diagnosis, semantic Web, ontology mining, and topic modeling for clinical or biomedical text mining, artificial neural networks and logistic regression for prediction, and convolutional neural networks and support vector machines for monitoring and classification. Additionally, future research should focus on algorithm innovations, additional information use, functionality improvement, model and system generalization, scalability, evaluation, and automation, data acquirement and quality improvement, and allowing interaction. The findings of this study help better understand what and how Web intelligence can be applied to promote healthcare procedures and clinical outcomes. This provides important insights into the effective use of Web intelligence to support informatics-enabled brain studies. 

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Machine and cognitive intelligence for human health: systematic review

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Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predicted repurposable drugs, topoisomerase II inhibitors (doxorubicin, teniposide, idarubicin, mitoxantrone, and epirubicin) presented a high potential to reverse rectal cancer gene expression signatures. We showed that these drugs effectively reduced the growth of colorectal cancer cell lines closely representing rectal cancer signatures. We also found a clear correlation between topoisomerase 2A (TOP2A) gene copy number or expression levels with the sensitivity to topoisomerase II inhibitors. Furthermore, CRISPR-Cas9 and shRNA screenings confirmed that loss-of-function of the TOP2A has the highest efficacy in reducing cellular proliferation. Finally, we observed significant TOP2A copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate TOP2A status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients.

Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer

The global efforts in the past year have led to the discovery of nearly 200 drug repurposing candidates for COVID-19. Gaining more insights into their mechanisms of action could facilitate a better understanding of infection and the development of therapeutics. Leveraging large-scale drug-induced gene expression profiles, we found 36% of the active compounds regulate genes related to cholesterol homeostasis and microtubule cytoskeleton organization. Following bioinformatics analyses revealed that the expression of these genes is associated with COVID-19 patient severity and has predictive power on anti-SARS-CoV-2 efficacy in vitro. Monensin, a top new compound that regulates these genes, was further confirmed as an inhibitor of SARS-CoV-2 replication in Vero-E6 cells. Interestingly, drugs co-targeting cholesterol homeostasis and microtubule cytoskeleton organization processes more likely present a synergistic effect with antivirals. Therefore, potential therapeutics could be centered around combinations of targeting these processes and viral proteins.

Published anti-SARS-CoV-2 in vitro hits share common mechanisms of action that synergize with antivirals.

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Convolutional Neural Network Approach to Predict Tumor Samples Using Gene Expression Data

As the field of precision medicine progresses, treatments for patients with cancer are starting to be tailored to their molecular as well as their clinical features. The emerging cancer subtypes defined by these molecular features require that dedicated resources be used to assist the discovery of drug candidates for preclinical evaluation. Voluminous gene expression profiles of patients with cancer have been accumulated in public databases, enabling the creation of cancer-specific expression signatures. Meanwhile, large-scale gene expression profiles of cellular responses to chemical compounds have also recently became available. By matching the cancer-specific expression signature to compound-induced gene expression profiles from large drug libraries, researchers can prioritize small molecules that present high potency to reverse expression of signature genes for further experimental testing of their efficacy. This approach has proven to be an efficient and cost-effective way to identify efficacious drug candidates. However, the success of this approach requires multiscale procedures, imposing considerable challenges to many labs. To address this, we developed Open Cancer TherApeutic Discovery (OCTAD; http://octad.org
 ): an open workspace for virtually screening compounds targeting precise groups of patients with cancer using gene expression features. Its database includes 19,127 patient tissue samples covering more than 50 cancer types and expression profiles for 12,442 distinct compounds. The program is used to perform deep-learning-based reference tissue selection, disease gene expression signature creation, drug reversal potency scoring and in silico validation. OCTAD is available as a web portal and a standalone R package to allow experimental and computational scientists to easily navigate the tool. OCTAD is a software pipeline for finding drugs that alter gene expression in such a way that they are likely to reverse the expression pattern of the disease. This protocol describes how to use both the web portal and the desktop version of OCTAD.

Anita Wen

Papers

OCTAD: an open workspace for virtually screening therapeutics targeting precise cancer patient groups using gene expression features.