Human papillomavirus (HPV) infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers. Up to 38%–80% of head and neck squamous cell carcinoma (HNSCC) in oropharyngeal location (OPSCC) and nearly all cervical cancers contain the HPV genome which is implicated in causing cancer through its oncoproteins E6 and E7. Given by the biologically distinct HPV-related OPSCC and a more favorable prognosis compared to HPV-negative tumors, clinical trials on de-escalation treatment strategies for these patients have been studied. It is therefore raised the questions for the patient stratification if treatment de-escalation is feasible. Moreover, understanding the crosstalk of HPV-mediated malignancy and immunity with clinical insights from the proportional response rate to immune checkpoint blockade treatments in patients with HNSCC is of importance to substantially improve the treatment efficacy. This review discusses the biology of HPV-related HNSCC as well as successful clinically findings with promising candidates in the pipeline for future directions. With the advent of various sequencing technologies, further biomolecules associated with HPV-related HNSCC progression are currently being identified to be used as potential biomarkers or targets for clinical decisions throughout the continuum of cancer care.

Rationale: Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. Methods: To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAP GFAP -CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAP GFAP -CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor-β (TGF-β) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP. Results: We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β signaling pathway in YAP GFAP -CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAP GFAP -CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice. Conclusions: These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.

Immunotherapies such as immune checkpoint blockade benefit only a portion of patients with head and neck squamous cell carcinoma. The multidisciplinary field of nanomedicine is emerging as a promising strategy to achieve maximal anti-tumor effect in cancer immunotherapy and to turn non-responders into responders. Various methods have been developed to deliver therapeutic agents that can overcome bio-barriers, improve therapeutic delivery into the tumor and lymphoid tissues and reduce adverse effects in normal tissues. Additional modification strategies also have been employed to improve targeting and boost cytotoxic T cell-based immune responses. Here, we review the state-of-the-art use of nanotechnologies in the laboratory, in advanced preclinical phases as well as those running through clinical trials assessing their advantages and challenges.

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disease without a clear mechanism or drugs for treatment. Therefore, it is crucial to reveal the underlying molecular mechanism and identify potential drugs for PAH. In this study, we first integrated three human lung tissue datasets (GSE113439, GSE53408, GSE117261) from GEO. A total of 151 differentially expressed genes (DEGs) were screened, followed by KEGG and GO enrichment analyses and PPI network construction. Five hub genes (CSF3R, NT5E, ANGPT2, FGF7, and CXCL9) were identified by Cytoscape (Cytohubba). GSEA and GSVA were performed for each hub gene to uncover the potential mechanism. Moreover, to repurpose known and therapeutic drugs, the CMap database was retrieved, and nine candidate compounds (lypressin, ruxolitinib, triclabendazole, L-BSO, tiaprofenic acid, AT-9283, QL-X-138, huperzine-a, and L-741742) with a high level of confidence were obtained. Then ruxolitinib was selected to perform molecular docking simulations with ANGPT2, FGF7, NT5E, CSF3R, JAK1, JAK2, JAK3, TYK2. A certain concentration of ruxolitinib could inhibit the proliferation and migration of rat pulmonary artery smooth muscle cells (rPASMCs) in vitro . Together, these analyses principally identified CSF3R, NT5E, ANGPT2, FGF7 and CXCL9 as candidate biomarkers of PAH, and ruxolitinib might exert promising therapeutic action for PAH.

The incidence of high-risk Human Papillomavirus (HR-HPV)-driven head and neck squamous cell carcinoma (HNSCC) is on the rise globally. HR-HPV-driven HNSCC displays molecular and clinical characteristics distinct from HPV-uninvolved cases. Therapeutic strategies for HR-HPV-driven HNSCC are under investigation. HR-HPVs encode the oncogenes E6 and E7, which are essential in tumorigenesis. Meanwhile, involvement of E6 and E7 provides attractive targets for developing new therapeutic regimen. Here we will review some of the recent advancements observed in preclinical studies and clinical trials on HR-HPV-driven HNSCC, focusing on nanotechnology related methods. Materials science innovation leads to great improvement for cancer therapeutics including HNSCC. This article discusses HPV-E6 or -E7- based vaccines, based on plasmid, messenger RNA or peptide, at their current stage of development and testing as well as how nanoparticles can be designed to target and access cancer cells and activate certain immunology pathways besides serving as a delivery vehicle. Nanotechnology was also used for chemotherapy and photothermal treatment. Short interference RNA targeting E6/E7 showed some potential in animal models. Gene editing by CRISPR-CAS9 combined with other treatments has also been assessed. These advancements have the potential to improve the outcome in HR-HPV-driven HNSCC, however breakthroughs are still to be awaited with nanomedicine playing an important role.

Pulmonary arterial hypertension (PAH) is a chronic progressive cardiovascular disease characterized by vascular remodeling and leading to right heart failure. The purpose of this research was to further study the pathogenesis of PAH and to detect potential prognostic signatures. Differentially expressed genes (DEGs) selected from GSE38267 were mostly enriched in inflammation-related pathways, suggesting inflammation may be involved in the occurrence and development of PAH. Through the prediction and verification of related miRNAs and lncRNAs using online databases and GEO datasets, CCR7 and its related molecules, including hsa-let-7e-5p and SNHG12, were identified as possible targets. The expression levels of CCR7, hsa-let-7e-5p and SNHG12 were then verified by qRT-PCR in vivo and in vitro. Further study showed that silencing of SNHG12 decreased the expression of CCR7 under hypoxia treatment in vitro. Dual-luciferase reporter assays were utilized to verify the relationship between hsa-let-7e-5p and SNHG12. Collectively, our research reveals that a lncRNA/miRNA/mRNA interaction network may be involved in the pathogenesis of PAH, and suggest SNHG12, hsa-let-7e-5p and CCR7 as potential biomarkers for PAH.

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