Design, synthesis and biological evaluation of novel quinazoline derivatives as immune checkpoint inhibitors.

In this work, we report 14 novel quinazoline derivatives as immune checkpoint inhibitors, IDO1 and PD-L1. The antitumor screening of synthesized compounds on ovarian cancer cells indicated that compound V-d and V-l showed the most activity with IC50 values of about 5 µM. Intriguingly, compound V-d emerges as a stand out, triggering cell death through caspase-dependent and caspase-independent manners. More importantly, V-d presents its ability to hinder tumor sphere formation and re-sensitized cisplatin-resistant A2780 cells to cisplatin treatment. These findings suggest that compound V-d emerges as a promising lead candidate for the future development of immuno anticancer agents.

Investigation of target sequencing of SARS-CoV-2 and immunogenic GWAS profiling in host cells of COVID-19 in Vietnam.

BACKGROUND: A global pandemic has been declared for coronavirus disease 2019 (COVID-19), which has serious impacts on human health and healthcare systems in the affected areas, including Vietnam. None of the previous studies have a framework to provide summary statistics of the virus variants and assess the severity associated with virus proteins and host cells in COVID-19 patients in Vietnam. METHOD: In this paper, we comprehensively investigated SARS-CoV-2 variants and immune responses in COVID-19 patients. We provided summary statistics of target sequences of SARS-CoV-2 in Vietnam and other countries for data scientists to use in downstream analysis for therapeutic targets. For host cells, we proposed a predictive model of the severity of COVID-19 based on public datasets of hospitalization status in Vietnam, incorporating a polygenic risk score. This score uses immunogenic SNP biomarkers as indicators of COVID-19 severity. RESULT: We identified that the Delta variant of SARS-CoV-2 is most prevalent in southern areas of Vietnam and it is different from other areas in the world using various data sources. Our predictive models of COVID-19 severity had high accuracy (Random Forest AUC = 0.81, Elastic Net AUC = 0.7, and SVM AUC = 0.69) and showed that the use of polygenic risk scores increased the models' predictive capabilities. CONCLUSION: We provided a comprehensive analysis for COVID-19 severity in Vietnam. This investigation is not only helpful for COVID-19 treatment in therapeutic target studies, but also could influence further research on the disease progression and personalized clinical outcomes.

BRCA1/2 Mutations in Vietnamese Patients with Hereditary Breast and Ovarian Cancer Syndrome.

(1) Background: Individuals with BRCA1/2 gene mutations are at increased risk of breast and ovarian cancer. The prevalence of BRCA1/2 mutations varies by race and ethnicity, and the prevalence and the risks associated with most BRCA1/2 mutations has not been unknown in the Vietnamese population. We herein screen the entire BRCA1 and BRCA2 genes for breast and ovarian cancer patients with a family history of breast cancer and ovarian cancer, thereby, suggesting a risk score associated with carrier status and history for aiding personalized treatment; (2) Methods: Between December 2017 and December 2019, Vietnamese patients who had a pathological diagnosis of breast and epithelial ovarian cancer were followed up, prospectively, after treatment from two large institutions in Vietnam. Blood samples from 33 Vietnamese patients with hereditary breast and ovarian cancers (HBOC) syndrome were collected and analyzed using Next Generation Sequencing; (3) Results: Eleven types of mutations in both BRCA1 (in nine patients) and BRCA2 (in three patients) were detected, two of which (BRCA1:p.Tyr1666Ter and BRCA2:p.Ser1341Ter) have not been previously documented in the literature. Seven out of 19 patient's relatives had BRCA1/2 gene mutations. All selected patients were counselled about the likelihood of cancer rising and prophylactic screening and procedures. The study established a risk score associated with the cohorts based on carrier status and family history; (4) Conclusions: Our findings suggested the implications for the planning of a screening programme for BRCA1 and BRCA2 genes testing in breast and ovarian cancer patients and genetic screening in their relatives. BRCA1/2 mutation carriers without cancer should have early and regular cancer screening, and prophylactic measures. This study could be beneficial for a diverse group in a large population-specific cohort, related to HBOC Syndrome.

A framework using topological pathways for deeper analysis of transcriptome data.

BACKGROUND: Pathway analysis is one of the later stage data analysis steps essential in interpreting high-throughput gene expression data. We propose a set of algorithms which given gene expression data can recognize which portion of sub-pathways are actively utilized in the biological system being studied. The degree of activation is measured by conditional probability of the input expression data based on the Bayesian Network model constructed from the topological pathway. RESULTS: We demonstrate the effectiveness of our pathway analysis method by conducting two case studies. The first one applies our method to a well-studied temporal microarray data set for the cell cycle using the KEGG Cell Cycle pathway. Our method closely reproduces the biological claims associated with the data sets, but unlike the original work ours can produce how pathway routes interact with each other above and beyond merely identifying which pathway routes are involved in the process. The second study applies the method to the p53 mutation microarray data to perform a comparative study. CONCLUSIONS: We show that our method achieves comparable performance against all other pathway analysis systems included in this study in identifying p53 altered pathways. Our method could pave a new way of carrying out next generation pathway analysis.

BioTarget: A Computational Framework Identifying Cancer Type Specific Transcriptional Targets of Immune Response Pathways.

Transcriptome data can provide information on signaling pathways active in cancers, but new computational tools are needed to more accurately quantify pathway activity and identify tissue-specific pathway features. We developed a computational method called "BioTarget" that incorporates ChIP-seq data into cellular pathway analysis. This tool relates the expression of transcription factor TF target genes (based on ChIP-seq data) with the status of upstream signaling components for an accurate quantification of pathway activity. This analysis also reveals TF targets expressed in specific contexts/tissues. We applied BioTarget to assess the activity of TBX21 and GATA3 pathways in cancers. TBX21 and GATA3 are TF regulators that control the differentiation of T cells into Th1 and Th2 helper cells that mediate cell-based and humoral immune responses, respectively. Since tumor immune responses can impact cancer progression, the significance of our pathway scores should be revealed by effective patient stratification. We found that low Th1/Th2 activity ratios were associated with a significantly poorer survival of stomach and breast cancer patients, whereas an unbalanced Th1/Th2 response was correlated with poorer survival of colon cancer patients. Lung adenocarcinoma and lung squamous cell carcinoma patients had the lowest survival rates when both Th1 and Th2 responses were high. Our method also identified context-specific target genes for TBX21 and GATA3. Applying the BioTarget tool to BCL6, a TF associated with germinal center lymphocytes, we observed that patients with an active BCL6 pathway had significantly improved survival for breast, colon, and stomach cancer. Our findings support the effectiveness of the BioTarget tool for transcriptome analysis and point to interesting associations between some immune-response pathways and cancer progression.

A route-based pathway analysis framework integrating mutation information and gene expression data.

We propose a new way of analyzing biological pathways in which the analysis combines both transcriptome data and mutation information and uses the outcome to identify "routes" of aberrant pathways potentially responsible for the etiology of disease. Each pathway route is encoded as a Bayesian Network which is initialized with a sequence of conditional probabilities which are designed to encode directionality of regulatory relationships encoded in the pathways, i.e. activation and inhibition relationships. First, we demonstrate the effectiveness of our model through simulation in which the model was able to easily separate Test samples from Control samples using fictitiously perturbed pathway routes. Second, we apply our model to analyze the Breast Cancer data set, available from TCGA, against many cancer pathways available from KEGG and rank the significance of identified pathways. The outcome is consistent with what have already been reported in the literature. Third, survival analysis has been carried out on the same data set by using pathway routes as features. Overall, we envision that our model of using pathway routes for analysis can further refine the conventional ways of subtyping cancer patients as it can discover additional characteristics specific to individual's tumor.