Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer.

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.

EZH2 in hepatocellular carcinoma: progression, immunity, and potential targeting therapies.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death. The accumulation of genetic and epigenetic changes is closely related to the occurrence and development of HCC. Enhancer of zeste homolog 2 (EZH2, a histone methyltransferase) is suggested to be one of the principal factors that mediates oncogenesis by acting as a driver of epigenetic alternation. Recent studies show that EZH2 is widely involved in proliferation and metastasis of HCC cells. In this review, the functions of EZH2 in HCC progression, the role of EZH2 in tumor immunity and the application of EZH2-related inhibitors in HCC therapy are summarized.

Automatic Time Picking for Weak Seismic Phase in the Strong Noise and Interference Environment: An Hybrid Method Based on Array Similarity.

The extraction of travel-time curve of seismic phase is very important for the subsequent inference of the structural properties of underground media in seismology. In recent years, with the increase in the amount of data, manual processing is facing significant challenges, and automatic signal processing has gradually become the mainstream. According to the similarity of array signals and considering the elimination of outliers, we propose an improved multi-channel cross-correlation method using the L1 norm measure to obtain preliminary results, which builds on a new controllable measurement mode. Then, the post-correction step is carried out in combination with the signal gain property of beamforming technique. Based on these two methods, this paper proposes a new scheme of automatic arrival time picking. We apply the scheme to actual data to verify the effects of the two methods step by step. The entire scheme achieves fine results: direct water waves, seismic waves refracted by the crust and seismic waves reflected by the upper mantle are automatically detected. In addition, compared with the two traditional methods, the scheme proposed in this paper has a better overall effect and a reasonable computation cost.

The role of YAP1 in liver cancer stem cells: proven and potential mechanisms.

YAP1 (Yes-associated protein 1) is one of the principal factors that mediates oncogenesis by acting as a driver of gene expression. It has been confirmed to play an important role in organ volume control, stem cell function, tissue regeneration, tumorigenesis and tumor metastasis. Recent research findings show that YAP1 is correlated with the stemness of liver cancer stem cells, and liver cancer stem cells are closely associated with YAP1-induced tumor initiation and progression. This article reviews the advancements made in research on the mechanisms by which YAP1 promotes liver cancer stem cells and discusses some potential mechanisms that require further study.

In situ biomimetic lyotropic liquid crystal gel for full-thickness cartilage defect regeneration.

There is a great challenge in regenerating cartilage defects, which usually involve absent bearing capacity and poor adaptation to joint movement, further exacerbating subchondral bone damage. Therefore, ideal tissue-engineering cartilage scaffolds should be endowed with biomimetic and sustained-release function for promoting long-term chondrogenesis while protecting subchondral bone. Herein, in situ self-assembling gel based on glyceryl monooleate (GMO)-hyaluronic acid (HA) composite lyotropic liquid crystal (HLC) was developed as the biomimetic scaffold to deliver kartogenin for long-term cartilage regeneration. Compared to the GMO based (LLC) gel, HLC gel with modified lattice structure exhibited improved rheological properties for better joint protection by increasing mechanical strength, elasticity and lubrication. Besides, HLC gel successfully prolonged drug release and retention in the joint cavity over 4 weeks to provide combined effect of kartogenin and HA for cartilage repair. Pharmacodynamic studies demonstrated that HLC gel was the most effective to promote chondrogenesis and protect subchondral bone, making the damaged bone tissue restored to normal in divergent features as evidenced by the MRI, Micro-CT and histological results. Therefore, the HLC gel with joint protection and controlled drug release can serve as a firm scaffold for providing long-term cartilage repair.

Comparative transcriptome profiling and co-expression network analysis uncover the key genes associated withearly-stage resistance to Aspergillus flavus in maize.

BACKGROUND: The fungus Aspergillus flavus (A. flavus) is a serious threat to maize (Zea mays) production worldwide. It causes considerable yield and economic losses, and poses a health risk to humans and livestock due to the high toxicity of aflatoxin. However, key genes and regulatory networks conferring maize resistance to A. flavus are not clear, especially at the early stage of infection. Here, we performed a comprehensive transcriptome analysis of two maize inbred lines with contrasting resistance to A. flavus infection. RESULTS: The pairwise comparisons between mock and infected kernels in each line during the first 6 h post inoculation (hpi) showed that maize resistance to A. flavus infection was specific to the genotype and infection stage, and defense pathways were strengthened in the resistant line. Further comparison of the two maize lines revealed that the infection-induced up-regulated differentially expressed genes (DEGs) in the resistant line might underlie the enhanced resistance. Gene co-expression network analysis by WGCNA (weighted gene co-expression network analysis) identified 7 modules that were significantly associated with different infection stages, and 110 hub genes of these modules. These key regulators mainly participate in the biosynthesis of fatty acid and antibiotics. In addition, 90 candidate genes for maize resistance to A. flavus infection and/or aflatoxin contamination obtained in previous studies were confirmed to be differentially expressed between the resistant and susceptible lines within the first 6 hpi. CONCLUSION: This work unveiled more A. flavus resistance genes and provided a detailed regulatory network of early-stage resistance to A. flavus in maize.

Identifying a melanogenesis-related candidate gene by a high-quality genome assembly and population diversity analysis in Hypsizygus marmoreus.

Hypsizygus marmoreus is one of the most important edible fungi in Basidiomycete division and includes white and gray strains. However, very limited knowledge is known about the genomic structures and the genetic basis for the white/gray diversity of this mushroom. Here, we report the near-complete high-quality H. marmoreus genome at the chromosomal level. Comparative genomics analysis indicates that chromosome structures were relatively conserved, and variations in collinearity and chromosome number were mainly attributed by chromosome split/fusion events in Aragicales, whereas the fungi genome experienced many genomic chromosome fracture, fusion, and genomic replication events after the split of Aragicales from Basidiomycetes. Resequencing of 57 strains allows us to classify the population into four major groups and associate genetic variations with morphological features, indicating that white strains were not originated independently. We further generated genetic populations and identified a cytochrome P450 as the candidate causal gene for the melanogenesis in H. marmoreus based on bulked segregant analysis (BSA) and comparative transcriptome analysis. The high-quality H. marmoreus genome and diversity data compiled in this study provide new knowledge and resources for the molecular breeding of H. marmoreus as well as the evolution of Basidiomycete.