第9卷，第5期

The liver is the largest internal organ that has vital roles in many processes, including digestion, detoxification, immunity, metabolism, blood clotting, and iron storage. It is susceptible to many pathological conditions that result in liver diseases. Liver cancer, ranking sixth in cancer incidence, is the fourth most common cause of cancer-related death worldwide and is the second most lethal cancer after pancreatic cancer. The 5-year survival rate is 18%. Unfortunately, liver cancer barely responds to chemotherapy andradiotherapy. Atpresent, surgicalresectionand transplantation are recommended for patients with earlystage liver cancer, but for patients with advanced liver cancer and poor liver function, systemic therapy is the only treatment option. Sorafenib is the first frontline drug approved by the Food and Drug Administration (FDA) for the treatment of hepatocellular carcinoma (HCC), which only prolongs the overall survival by approximately 3 months. Thus far, phase 3 clinical trials of most systemic therapies have not performed better than sorafenib in HCC. Recently, clinical trials of the combination of immune checkpoint inhibitors and anti-angiogenesis drugs have shown promising results in HCC, leading to FDA approval in 2020; however, this therapy only benefits a subset of HCC patients without predictive markers available.

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Metastasis is the primary cause of HCC-related death. Neutrophils can activate the antitumor immune response and promote tumor cell clearance. However, most studies show that neutrophils support tumor progression and metastasis. The accumulation of neutrophils contributes to HCC progression and is associated with poor prognosis. Metabolic reprogramming is one of the significant hallmarks of cancers, and immune cells in the tumor microenvironment (TME) undergo complex metabolic alterations. Accumulating evidence indicates that high lipid content and increased fatty acid oxidation (FAO) support neutrophils' immunosuppressive functions of neutrophils. However, the role of neutrophils lipid metabolism in HCC metastasis remains largely unclear. In the present study, we sought to evaluate lipid metabolism in metastasisassociated neutrophils (MANs) and found that de novo lipogenesis (DNL) endows neutrophils with a prolonged lifetime and immunosuppressive phenotype that contribute to HCC metastasis.

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N⁶-methyladenosine (m⁶A) is the most prevalent posttranscriptional RNA modification in mRNA and long noncoding RNAs of eukaryotes, and its biological functions are mediated by m⁶A writers, erasers and readers. A nuclear methyltransferase complex consisting of METTL3, METTL14, WTAP, VIRMA, ZC3H13, RBM15 (or RBM15B), YWHAG, TRA2A and CAPRIN1 catalyzes the m⁶A modifications, acting as m⁶A writers. m⁶A demethylase ALKBH5 as well as m⁶A demethylase FTO mediate the demethylation of m⁶As, acting as the m⁶A erasers. A variety of proteins including YTH domain-containing proteins can bind m⁶A marks as the m⁶A readers. The role of mRNA m⁶A methylation in COVID-19 patients is of great concern due to reports that m⁶A may provide potential new strategies for the development of vaccine and antiviral drug. For instance, Jun'e et al reported that m⁶A regulators regulate m⁶A during SARS-CoV-2 infection in Huh7 cells. Other studies also show that m⁶A regulators METTL3 and RBM15 are able to regulate host cell innate immune responses during SARS-CoV-2 infection in Caco-2 cells and HuT 78 cells, respectively. Hannah et al found that METTL3 affects SARS-CoV-2 replication in A549 cells, and they found that targeting the m⁶A RNA modification pathway can block SARS-CoV-2 replication. Although many studies have focused on the function and molecular mechanism of m⁶A in cell lines infected with SARS-CoV-2, the clinical relevance and basic molecular characterization of m⁶A in vivo have been neglected, which deserves further exploration.

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Heart failure (HF) is a global health problem with a high mortality rate. The various stimuli associated with HF can cause maladaptive remodeling, gradually weakening cardiac functions. Left ventricular assist device (LVAD) can improve advanced HF patients' cardiac functions, termed "reverse remodeling". However, only a small percentage of patients who have received LVAD have experienced reverse remodeling. Moreover, heart failure relapses in many patients after LVAD explantation, indicating that current biomarkers may not be sufficient to provide a complete view of pathological status. In this study, we identified a 6-gene panel (6GP; positive correlation: MYC, FOXO1, and ZFP36; negative correlation: LONRF1, FRZB, and NPPA), which demonstrated outstanding potential for predicting cardiac recovery, by combining weighted gene co-expressionanalysis (WGCNA) anddifferential gene expression analysis.6GP was highly correlated with key molecular signatures related to cardiac recovery, including myogenesis, axonogenesis, and epidermis development.

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In the past, contradictory statements have been made about the age of cancer genes. While phylostratigraphic studies suggest that cancer genes emerged during the transitional period from unicellularians (UC) to early metazoans (EM), life cycle studies suggest that they arose earlier. This controversy could not be resolved. Phylostratigraphic methods use data from somatic tumor gene collections containing or lacking polyploidy genes (PGCC genes) and compare them to genes from evolutionary node taxa. I analyze whether the selected taxa are suitable to resolve the above contradiction or not. Both cancer and amoebae life cycles have a reproductive asexual germline that produces germline stem cells (GSCs) and somatic cell lines that cannot. When the germline loses its reproductive function, the soma-to-germ transition forms a new reproductive germline. The reproductive polyploidy of cancer is homologous to the reproductive polyploidy of unicellular cysts. PGCCs repair DNA defects, reorganize the involved genome architecture and produce new GSCs. The present study refutes the dogma of the early metazoan origin of cancer. Cancer has a unicellular life cycle that was adopted by early metazoans to rescue themselves from evolutionary dead ends. Early metazoans controlled the unicellular life cycle through suppressor and anti-suppressor genes that could suspend or reactivate it. They are the archetypes of tumor suppressor genes and oncogenes. Cells of mammalians and humans that reach a similar impasse as early metazoans can reactivate the conserved life cycle of unicellularians.

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