Multivariate competing endogenous RNA network characterization for cancer MicroRNA biomarker discovery: a novel bioinformatics model with application to prostate cancer metastasis

Background MicroRNAs (miRNAs) are post-transcriptional regulators with the potential as biomarkers for cancer management. Data-driven competing endogenous RNA (ceRNA) network modeling is an effective way to decipher the complex interplay between miRNAs and spongers. However, no general rules are discovered for ceRNA network-based biomarker prioritization. Methods and Results In this study, a novel bioinformatics model was developed by integrating gene expression with multivariate miRNA-target data for ceRNA network-based biomarker discovery. Compared with traditional methods, the structural vulnerability in human lncRNA-miRNA-mRNA network was comprehensively analyzed, and the single-line regulatory or competing mode among miRNAs, lncRNAs and mRNAs was characterized and quantified as statistical evidence for miRNA biomarker identification. The application of this model to prostate cancer (PCa) metastasis identified a total of 12 miRNAs as putative biomarkers from metastatic PCa-specific lncRNA-miRNA-mRNA network and nine of them have been previously reported as biomarkers for PCa metastasis. The receiver operating characteristic curve and cell line qRT-PCR experiments demonstrated the power of miR-26b-5p, miR-130a-3p, and miR-363-3p as novel candidates for predicting PCa metastasis. Moreover, PCa-associated pathways such as prostate cancer signaling, ERK/MAPK signaling, and TGF-β signaling were significantly enriched by targets of identified miRNAs, indicating the underlying mechanisms of miRNAs in PCa carcinogenesis. Conclusions A novel ceRNA-based bioinformatics model was proposed and applied to screen candidate miRNA biomarkers for PCa metastasis. Functional validations using human samples and clinical data will be performed for future translational studies on the identified miRNAs.

AI in spotting high-risk characteristics of medical imaging and molecular pathology

Medical imaging provides a comprehensive perspective and rich information for disease diagnosis. Combined with artificial intelligence technology, medical imaging can be further mined for detailed pathological information. Many studies have shown that the macroscopic imaging characteristics of tumors are closely related to microscopic gene, protein and molecular changes. In order to explore the function of artificial intelligence algorithms in in-depth analysis of medical imaging information, this paper reviews the articles published in recent years from three perspectives: medical imaging analysis method, clinical applications and the development of medical imaging in the direction of pathological molecular prediction. We believe that AI-aided medical imaging analysis will be extensively contributing to precise and efficient clinical decision.

Immunotherapy in non-small cell lung cancer: rationale, recent advances and future perspectives

ABSTRACT Lung cancer, with non-small cell lung cancer (NSCLC) being the major type, is the second most common malignancy and the leading cause of cancer-related death globally. Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has been one of the greatest advances in recent years for the treatment of solid tumors including NSCLC. However, not all NSCLC patients experience an effective response to immunotherapy with the established selection criteria of programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB). Furthermore, a considerable proportion of patients experience unconventional responses, including pseudoprogression or hyperprogressive disease (HPD), immune-related toxicities, and primary or acquired resistance during the immunotherapy process. To better understand the immune response in NSCLC and provide reference for clinical decision-making, we herein review the rationale and recent advances in using immunotherapy to treat NSCLC. Moreover, we discuss the current challenges and future strategies of this approach to improve its efficacy and safety in treating NSCLC.

Dichotomous roles of neutrophils in modulating pathogenic and repair processes of inflammatory bowel diseases

Neutrophils are considered as complex innate immune cells and play a critical role in maintaining intestinal mucosal homeostasis. They exert robust pro-inflammatory effects and recruit other immune cells in the acute phase of pathogen infection and intestinal inflammation, but paradoxically, they also limit exogenous microbial invasion and facilitate mucosal restoration. Hyperactivation or dysfunction of neutrophils results in abnormal immune responses, leading to multiple autoimmune and inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases (IBD). As a refractory intestinal inflammatory disease, the pathogenesis and progression of IBD are associated with complicated immune response processes in which neutrophils are profoundly involved. However, the consensus on potential roles of neutrophils in modulating pathogenic and repair processes of IBD remains not fully understood. Accumulated infiltrating neutrophils cross the epithelial barrier and contribute to microbial dysbiosis, aggravated intestinal architectural damage, compromised resolution of intestinal inflammation and increased risk of thrombosis during IBD. Paradoxically, activated neutrophils are also associated with effective elimination of invaded microbiota, promoted angiogenesis and tissue restoration of gut mucosa in IBD. Here, we discuss the beneficial and detrimental roles of neutrophils in the onset and resolution of intestinal mucosal inflammation and provide a precise overview of neutrophil functions in the pathogenesis of IBD.

COVID-19 Delta Variants – Current Status and Implications as of August 2021

The SARS-CoV-2 Delta variant has evolved as the dominant strain of the current pandemic. Studies have shown that this variant has increased infectivity/viral load, and reduced neutralization by the host antibodies from convalescent patients/vaccinees. Clinically, Delta variant infection have been observed/documented in convalescent patients/vaccinees, although with less incidence of severe diseases, but can serve as reservoir to spread the infection to the unvaccinated. The current understanding (as of August 18, 2021) on the virologic aspect (including the amino acid substitutions), clinical implications, and the public health implications will be discussed in this review, and recommendations to health authorities will be provided.

Inhibitive activity of medicinal mushroom Ganoderma lucidum on colorectal cancer by attenuating inflammation

The medicinal mushroom Ganoderma lucidum (GL, Reishi or Lingzhi) exhibits inhibitive effect on cancers. However, the underline mechanism of the antitumor activity of GL is still not fully understood. In this study, we characterized the gene networks regulated by a commercial product of GL containing mixture of spore and fruiting body, namely “GLSF”, in colorectal carcinoma. We found that, in vitro co-administration of GLSF extract at non-toxic concentrations significantly potentiated growth inhibition and apoptosis induced by paclitaxel in CT26 and HCT-15 cells. GLSF inhibited NF-κB promoter activity in HEK-293 cells but did not affect the function of P-glycoprotein in K562/DOX cells. Furthermore, we found that when mice were fed with a modified diet containing GLSF for one month prior to the CT26 tumor cell inoculation, GLSF alone or combined with Nab-paclitaxel markedly suppressed tumor growth and induced apoptosis. RNA-seq analysis of tumor tissues derived from GLSF-treated mice identified 53 differentially expressed genes compared to normal tissues. Many of GLSF-downregulated genes were involved in NF-κB-regulated inflammation pathways, such as IL-1β, IL-11 and Cox-2. Pathway enrichment analysis suggested several inflammatory pathways involving leukocyte migration and adhesion were most affected by the treatment. Upstream analysis predicted activation of multiple tumor suppressors such as α-catenin and TP53 and inhibition of critical inflammatory mediators. “Cancer” was the major significantly inhibited biological effect due to GLSF treatment. These results demonstrate that GLSF can improve the therapeutic outcome for colorectal cancer through a mechanism involving suppressing NF-κB-regulated inflammation and carcinogenesis.

Repurposable Drugs for SARS-CoV-2 and Influenza Sepsis with scRNA-Seq Data Targeting Post-Transcription Modifications

Coronavirus disease 2019 (COVID-19) has been impacting almost every part of human life worldwide, posing a massive threat to human health. Due to the lack of time for new drug discovery and the urgent need for rapid disease control, drug repurposing presents a quick and effective alternative to finding therapeutics to reduce mortality. To identify potentially repurposable drugs, we employed a systematic approach to mine candidates from U.S. FDA-approved drugs and preclinical small-molecule compounds by integrating the gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from mild and severe COVID-19 patients (GEO: GSE145926, public data available and accessed on April 22, 2020). We identified 281 FDA-approved drugs that have the potential to be effective against SARS-CoV-2 infection, 16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19. We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a, two chemical inhibitors of glycosylation (a post-translational modification) on the replication of the single-stranded ribonucleic acid (ssRNA) virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators (IFNs and ISGs). In conclusion, we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach, which may have the potential for treating these viral infections and their complications (sepsis).

CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model

Somatic gene therapy remains technically challenging, especially in the central nervous system (CNS). Efficiency of gene delivery, efficacy in recipient cells, and proportion of cells required for overall benefit are the key points needed to be considered in any therapeutic approach. Recent efforts have demonstrated the efficacy of RNA-guided nucleases such as CRISPR/Cas9 in correcting point mutations or removing dominant mutations. Here we used viral delivered Cas9 plasmid and two guide RNAs to remove a recessive insertional mutation, vibrator (vb), in the mouse brain. vb mice express ∼20% of normal levels of phosphatidylinositol transfer α (Pitpna) RNA and protein due to an endogenous retrovirus inserted in intron 4, resulting in early-onset tremor, degeneration of brainstem and spinal cord neurons, and juvenile death. The in situ CRISPR/Cas9 viral treatment effectively delayed neurodegeneration, attenuated tremor, and bypassed juvenile death. Our studies demonstrate the potential of CRISPR/Cas9-mediated gene therapy for insertional mutations in the postnatal brain.

CXCL13 expression in mouse 4T1 breast cancer microenvironment elicits anti-tumor immune response by regulating immune cell infiltration

Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide. Previous studies have reported contradictory performance of chemokine CXC motif ligand 13 (CXCL13) in breast cancer. In this study, TCGA database analysis revealed that CXCL13 was overexpressed in various human cancers including breast carcinoma, and associated with good clinical prognosis in breast cancer. Flow cytometry detection also found up-regulated intracellular CXCL13 expression in human breast cancer cell lines. To explore the possible role of CXCL13 in breast cancer microenvironment, mouse triple negative breast cancer (TNBC) was lentivirally transfected to stably overexpress mouse CXCL13 (4T1-CXCL13). Both parental 4T1 and 4T1-CXCL13 strains showed no in vitro and in vivo endogenous cell surface CXCR5 expression. In immune-competent BALB/c mice, the in vivo tumor growth of 4T1-CXCL13 was significantly inhibited and even completely eradicated, accompanied with increased infiltrations of CD4+, CD8 + T lymphocytes and CD11b + CD11c + DCs. Further investigations showed that CXCL13 expression in 4T1 tumor microenvironment elicited long-term anti-tumor immune memory, and rejection of distal parental tumor. The anti-tumor activity of CXCL13 was remarkedly impaired in BALB/cA-nu nude mice, or in BALB/c mice with CD8 + T lymphocyte or NK cell depletion. Our investigation indicated that CXCL13 expression in TNBC triggered effective anti-tumor immunity by chemoattracting immune cell infiltrations, and could be considered as a novel prognostic marker for TNBC.