A prognostic and immune related risk model based on zinc homeostasis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The dysfunction of zinc homeostasis participates in the early and advancing malignancy of HCC. However, the prognostic ability of zinc homeostasis in HCC has not been clarified yet. Here, we showed a zinc-homeostasis related risk model in HCC. Five signature genes including ADAMTS5, PLOD2, PTDSS2, KLRB1, and UCK2 were screened out via survival analyses and regression algorithms to construct the nomogram with clinical characteristics. Experimental researches indicated that UCK2 participated in the progression of HCC. Patients with higher risk scores always had worse outcomes and were more associated with immune suppression according to the analyses of immune related-pathway activation, cell infiltration, and gene expression. Moreover, these patients were likely to exhibit more sensitivity to sorafenib and other antitumor drugs. This study highlights the significant prognostic role of zinc homeostasis and suggests potential treatment strategies in HCC.

Pharmacological inhibition of neddylation impairs long interspersed element 1 retrotransposition.

Aberrant long interspersed element 1 (LINE-1 or L1) activity can cause insertional mutagenesis and chromosomal rearrangements and has been detected in several types of cancers. Here, we show that neddylation, a post-translational modification process, is essential for L1 transposition. The antineoplastic drug MLN4924 is an L1 inhibitor that suppresses NEDD8-activating enzyme activity. Neddylation inhibition by MLN4924 selectively impairs ORF2p-mediated L1 reverse transcription and blocks the generation of L1 cDNA. Consistent with these results, MLN4924 treatment suppresses the retrotransposition activity of the non-autonomous retrotransposons short interspersed nuclear element R/variable number of tandem repeat/Alu and Alu, which rely on the reverse transcription activity of L1 ORF2p. The E2 enzyme UBE2M in the neddylation pathway, rather than UBE2F, is required for L1 ORF2p and retrotransposition. Interference with the functions of certain neddylation-dependent Cullin-really interesting new gene E3 ligases disrupts L1 reverse transcription and transposition activity. Our findings provide insights into the regulation of L1 retrotransposition and the identification of therapeutic targets for L1 dysfunctions.

Methyl jasmonate regulation of pectin polysaccharides in Cosmos bipinnatus roots: A mechanistic insight into alleviating cadmium toxicity.

Methyl jasmonate (MeJA), a crucial phytohormone, which plays an important role in resistance to Cadmium (Cd) stress. The cell wall (CW) of root system is the main location of Cd and plays a key role in resistance to Cd toxicity. However, the mechanism effect of MeJA on the CW composition and Cd accumulation remain unclear. In this study, the contribution of MeJA in regulating CW structure, pectin composition and Cd accumulation was investigated in Cosmos bipinnatus. Phenotypic results affirm MeJA's significant role in reducing Cd-induced toxicity in C. bipinnatus. Notably, MeJA exerts a dual impact, reducing Cd uptake in roots while increasing Cd accumulation in the CW, particularly bound to pectin. The molecular structure of pectin, mainly uronic acid (UA), correlates positively with Cd content, consistent in HC1 and cellulose, emphasizing UA as pivotal for Cd binding. Furthermore, MeJA modulates pectin methylesterase (PME) activity under Cd stress, influencing pectin's molecular structure and homogalacturonan (HG) content affecting Cd-binding capacity. Chelate-soluble pectin (CSP) within soluble pectins accumulates a substantial Cd proportion, with MeJA regulating both UA content and the minor component 3-deoxy-oct-2-ulosonic acid (Kdo) in CSP. The study delves into the intricate regulation of pectin monosaccharide composition under Cd stress, revealing insights into the CW's physical defense and Cd binding. In summary, this research provides novel insights into MeJA-specific mechanisms alleviating Cd toxicity in C. bipinnatus, shedding light on complex interactions between MeJA, and Cd accumulation in CW pectin polysaccharide.

SARS-CoV-2 and oncolytic EV-D68-encoded proteases differentially regulate pyroptosis.

Pyroptosis, a pro-inflammatory programmed cell death, has been implicated in the pathogenesis of coronavirus disease 2019 and other viral diseases. Gasdermin family proteins (GSDMs), including GSDMD and GSDME, are key regulators of pyroptotic cell death. However, the mechanisms by which virus infection modulates pyroptosis remain unclear. Here, we employed a mCherry-GSDMD fluorescent reporter assay to screen for viral proteins that impede the localization and function of GSDMD in living cells. Our data indicated that the main protease NSP5 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) blocked GSDMD-mediated pyroptosis via cleaving residues Q29 and Q193 of GSDMD. While another SARS-CoV-2 protease, NSP3, cleaved GSDME at residue G370 but activated GSDME-mediated pyroptosis. Interestingly, respiratory enterovirus EV-D68-encoded proteases 3C and 2A also exhibit similar differential regulation on the functions of GSDMs by inactivating GSDMD but initiating GSDME-mediated pyroptosis. EV-D68 infection exerted oncolytic effects on human cancer cells by inducing pyroptotic cell death. Our findings provide insights into how respiratory viruses manipulate host cell pyroptosis and suggest potential targets for antiviral therapy as well as cancer treatment.IMPORTANCEPyroptosis plays a crucial role in the pathogenesis of coronavirus disease 2019, and comprehending its function may facilitate the development of novel therapeutic strategies. This study aims to explore how viral-encoded proteases modulate pyroptosis. We investigated the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory enterovirus D68 (EV-D68) proteases on host cell pyroptosis. We found that SARS-CoV-2-encoded proteases NSP5 and NSP3 inactivate gasdermin D (GSDMD) but initiate gasdermin E (GSDME)-mediated pyroptosis, respectively. We also discovered that another respiratory virus EV-D68 encodes two distinct proteases 2A and 3C that selectively trigger GSDME-mediated pyroptosis while suppressing the function of GSDMD. Based on these findings, we further noted that EV-D68 infection triggers pyroptosis and produces oncolytic effects in human carcinoma cells. Our study provides new insights into the molecular mechanisms underlying virus-modulated pyroptosis and identifies potential targets for the development of antiviral and cancer therapeutics.

cGAS-STING-mediated novel nonclassic antiviral activities.

Stimulatorof interferon genes (STING) is an intracellular sensor of cyclic dinucleotides involved in the innate immune response against pathogen- or self-derived DNA. For years, interferon (IFN) induction of cyclic GMP-AMP synthase (cGAS)-STING has been considered as a canonical pattern defending the host from viral invasion. The mechanism of the cGAS-STING-IFN pathway has been well-illustrated. However, other signalling cascades driven by cGAS-STING have emerged in recent years and some of them have been found to possess antiviral ability independent of IFN. Here, we summarize the current progress on cGAS-STING-mediated nonclassic antiviral activities with an emphasis on the nuclear factor-κB and autophagy pathways, which are the most-studied pathways. In addition, we briefly present the primordial function of the cGAS-STING pathway in primitive species to show the importance of IFN-unrelated antiviral activity from an evolutionary angle. Finally, we discuss open questions that need to be solved for further exploitation of this field.

Effects of straw return with potassium fertilizer on the stem lodging resistance, grain quality and yield of spring maize (Zea mays L.).

This experiment aimed to study the effects of straw return combined with potassium fertilizer on stem lodging resistance, grain quality, and yield of spring maize. The objective was to provide a scientific basis for the rational utilization of Inner Mongolia spring maize straw and potassium fertilizer resources. The test material used was 'Xianyu 335', and the study was conducted in three ecological regions from east to west of Inner Mongolia (Tumochuan Plain Irrigation Area, Hetao Plain Irrigation Area, and Lingnan Warm Dry Zone). A split-plot design was employed, with the straw return method as the main plot and potassium fertilizer dosage as the secondary plot. We determined the stem resistance index, grain quality, and yield. The results showed that both straw return and potassium application improved stem lodging resistance, grain quality, and maize yield. Combining straw return with the reasonable application of potassium fertilizer enhanced the effectiveness of potassium fertilizer, increased lodging resistance, maize yield, and improved grain quality and yield stability. Under the straw return treatment, with potassium application compared to no potassium application, significant increases were observed in maize plant height, stem diameter, dry weight of stems, stem compressive strength, stem bending strength, grain protein content, yield, straw potassium accumulation content, and soil available potassium content. These increases were up to 30.79 cm, 2.63 mm, 15.40 g, 74.93 N/mm2, 99.65 N/mm2, 13.68%, 3142.43 kg/hm2, 57.97 kg/hm2, and 19.80 mg/kg, respectively. Therefore, the interaction of straw return and potassium fertilizer was found to be the most effective measure for maintaining high-yield and stress-resistant cultivation, improving grain quality, and optimizing the management of straw and potassium fertilizer resources. This approach is suitable for promotion and application in the spring maize growing areas of Inner Mongolia.

TRAF3 activates STING-mediated suppression of EV-A71 and target of viral evasion.

Innate immunity represents one of the main host responses to viral infection.1-3 STING (Stimulator of interferon genes), a crucial immune adapter functioning in host cells, mediates cGAS (Cyclic GMP-AMP Synthase) sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown. In the present study, we discovered that human enterovirus A71 (EV-A71) infection triggered STING activation in a cGAS dependent manner. EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells. However, during EV-A71 infection, cGAS-STING activation was attenuated. EV-A71 proteins were screened and the viral protease 2Apro had the greatest capacity to inhibit cGAS-STING activation. We identified TRAF3 as an important factor during STING activation and as a target of 2Apro. Supplement of TRAF3 rescued cGAS-STING activation suppression by 2Apro. TRAF3 supported STING activation mediated TBK1 phosphorylation. Moreover, we found that 2Apro protease activity was essential for inhibiting STING activation. Furthermore, EV-D68 and CV-A16 infection also triggered STING activation. The viral protease 2Apro from EV-D68 and CV-A16 also had the ability to inhibit STING activation. As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication, blocking EV-A71-mediated STING suppression represents a new anti-viral target.

SARS-CoV-2, HIV, and HPV: Convergent evolution of selective regulation of cGAS-STING signaling.

Recognizing aberrant cytoplasmic double-stranded DNA and stimulating innate immunity is essential for the host's defense against viruses and tumors. Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that synthesizes the second messenger 2'3'-cGAMP and subsequently activates stimulator of interferon genes (STING)-mediated activation of TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) and the production of type I interferon (IFN-I). Both the cGAS-STING-mediated IFN-I antiviral defense and the countermeasures developed by diverse viruses have been extensively studied. However, recent studies have revealed a convergent evolutionary feature of severe acute respiratory syndrome coronavirus 2 and human immunodeficiency virus (HIV) viral proteins in terms of the selective regulation of cGAS-STING-mediated nuclear factor-κB (NF-κB) signaling without any effect on cGAS-STING-mediated TBK1/IRF3 activation and IFN production. The potential beneficial effect of this cGAS-STING-mediated, NF-κB-dependent antiviral effect, and the possible detrimental effect of IFN-I in the pathogenesis of coronavirus disease 2019 and HIV infection deserve more attention and future investigation.

SARS-CoV-2 ORF3a inhibits cGAS-STING-mediated autophagy flux and antiviral function.

Recognizing aberrant cytoplasmic dsDNA and stimulating cGAS-STING-mediated innate immunity is essential for the host defense against viruses. Recent studies have reported that SARS-CoV-2 infection, responsible for the COVID-19 pandemic, triggers cGAS-STING activation. cGAS-STING activation can trigger IRF3-Type I interferon (IFN) and autophagy-mediated antiviral activity. Although viral evasion of STING-triggered IFN-mediated antiviral function has been well studied, studies concerning viral evasion of STING-triggered autophagy-mediated antiviral function are scarce. In the present study, we have discovered that SARS-CoV-2 ORF3a is a unique viral protein that can interact with STING and disrupt the STING-LC3 interaction, thus blocking cGAS-STING-induced autophagy but not IRF3-Type I IFN induction. This novel function of ORF3a, distinct from targeting autophagosome-lysosome fusion, is a selective inhibition of STING-triggered autophagy to facilitate viral replication. We have also found that activation of bat STING can induce autophagy and antiviral activity despite its defect in IFN induction. Furthermore, ORF3a from bat coronaviruses can block bat STING-triggered autophagy and antiviral function. Interestingly, the ability to inhibit STING-induced autophagy appears to be an acquired function of SARS-CoV-2 ORF3a, since SARS-CoV ORF3a lacks this function. Taken together, these discoveries identify ORF3a as a potential target for intervention against COVID-19.

DNA virus oncoprotein HPV18 E7 selectively antagonizes cGAS-STING-triggered innate immune activation.

Cellular infections by DNA viruses trigger innate immune responses mediated by DNA sensors. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway has been identified as a DNA-sensing pathway that activates interferons in response to viral infection and, thus, mediates host defense against viruses. Previous studies have identified oncogenes E7 and E1A of the DNA tumor viruses, human papillomavirus 18 (HPV18) and adenovirus, respectively, as inhibitors of the cGAS-STING pathway. However, the function of STING in infected cells and the mechanism by which HPV18 E7 antagonizes STING-induced Interferon beta production remain unknown. We report that HPV18 E7 selectively antagonizes STING-triggered nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation but not IRF3 activation. HPV18 E7 binds to STING in a region critical for NF-κB activation and blocks the nuclear accumulation of p65. Moreover, E7 inhibition of STING-triggered NF-κB activation is related to HPV pathogenicity but not E7-Rb binding. HPV18 E7, severe acute respiratory syndrome coronavirus-2 open reading frame 3a, human immunodeficiency virus-2 viral protein X, and Kaposi's sarcoma-associated herpesvirus KSHV viral interferon regulatory factor 1 selectively inhibited STING-triggered NF-κB or IRF3 activation, suggesting a convergent evolution among these viruses toward antagonizing host innate immunity. Collectively, selective suppression of the cGAS-STING pathway by viral proteins is likely to be a key pathogenic determinant, making it a promising target for treating oncogenic virus-induced tumor diseases.

Community succession and functional prediction of microbial consortium with straw degradation during subculture at low temperature.

To systematically explore and analyze the microbial composition and function of microbial consortium M44 with straw degradation in the process of subculture at low temperature. In this study, straw degradation characteristics of samples in different culture stages were determined. MiSeq high-throughput sequencing technology was used to analyze the evolution of community structure and its relationship with degradation characteristics of microbial consortium in different culture periods, and the PICRUSt function prediction analysis was performed. The results showed that straw degradation rate, endoglucanase activity, and filter paper enzyme activity of M44 generally decreased with increasing culture algebra. The activities of xylanase, laccase, and lignin peroxidase, as well as VFA content, showing a single-peak curve change with first an increase and then decrease. In the process of subculture, Proteobacteria, Bacteroidetes, and Firmicutes were dominant in different culture stages. Pseudomonas, Flavobacterium, Devosia, Brevundimonas, Trichococcus, Acinetobacter, Dysgonomonas, and Rhizobium were functional bacteria in different culture stages. It was found by PICRUSt function prediction that the functions were concentrated in amino acid transport and metabolism, carbohydrate transship and metabolism related genes, which may contain a large number of fibers and lignin degrading enzyme genes. In this study, the microbial community succession and the gene function in different culture periods were clarified and provide a theoretical basis for screening and rational utilization of microbial consortia.

Potentials of straw return and potassium supply on maize (Zea mays L.) photosynthesis, dry matter accumulation and yield.

Maize (Zea mays L.) is considered one of the most important grains in the world. Straw return has the effect of reducing soil bulk density and increasing soil porosity. Straw returning and potassium fertilizer can supplement soil potassium content. The improvement of soil structure and the optimization of soil nutrient levels provide a good environment for high yield and high efficiency of maize. Therefore, three field experiments were carried out over a three-year period (2018-2020) to study the effects of straw returning on photosynthesis, dry matter accumulation and yield of maize 'Xianyu 335' under two different fertilization methods and four potassium application levels. The results showed that straw returning and potassium application had significant effects on the above indicators. The above indicators were significantly improved by deep tillage straw returning compared with no tillage straw returning. Increasing potassium supply can promote the effect of straw returning. The photosynthesis, dry matter accumulation and yield parameters of maize treated with straw returning and deep tillage combined with 60 kg/hm2 potassium fertilizer (SFK60) reached the highest in the three harvest seasons. The corn planting profit of SFK45 treatment is the highest, which is $1868.92 per ha. Therefore, SFK45 is an effective way to ensure stable and high yield of corn and maximize farmers' income.

Chaihu Guizhi Decoction plus or minus formula combined with capecitabine inhibits IL-6/STAT3 signaling to suppress triple-negative breast cancer xenografts in nude mice / 南方医科大学学报

OBJECTIVE@#To investigate the effect of Chaihu Guizhi Decoction (CHGZD) combined with capecitabine on growth and apoptosis of subcutaneous triple-negative breast cancer xenografts in nude mice and explore the possible mechanism.@*METHODS@#Nude mouse models bearing subcutaneous triple-negative breast cancer xenografts were randomized into 6 groups (n=10) for treatment with distilled water (model group), low (10.62 g/kg), medium (21.23 g/kg) and high (42.46 g/kg) doses of CHGZD, capecitabine (0.2 mg/kg), or the combination of CHGZD (42.46 g/kg) and capecitabine (0.2 mg/k) once daily for 21 consecutive days. The general condition of mice was observed, and after 21-day treatments, the tumors were dissected for measurement of tumor volume and weight and histopathological examination with HE staining. Serum IL-6 levels of the mice were determined with enzyme-linked immunosorbent assay (ELISA), and the expression levels of IL-6, STAT3, p-STAT3, Bax, Bcl-2 and cyclin D1 in the tumor tissues were detected using real-time PCR and Western blotting.@*RESULTS@#Compared with those in the model group, the tumor-bearing mice receiving treatments with CHGZD showed significantly increased food intake with good general condition, sensitive responses, increased body weight, and lower tumor mass (P < 0.01). Compared with capecitabine treatment alone, treatment with CHGZD alone at the medium and high doses and the combined treatment all resulted in significantly higher tumor inhibition rates (P < 0.01), induced obvious tumor tissue degeneration and reduced the tumor cell density. Treatments with CHGZD, both alone and in combination with capecitabine, significantly decreased serum IL-6 level, lowered the mRNA expression levels of IL-6 and STAT3, the protein expressions of IL-6, STAT3 and P-STAT3 (P < 0.05), and the mRNA and protein expressions of Bcl-2 and cyclin D1 (P < 0.05), and increased the mRNA and protein expressions of Bax in the tumor tissues (P < 0.05).@*CONCLUSION@#CHGZD combined with capecitabine can significantly inhibit tumor growth in nude mice bearing triple-negative breast cancer xenografts, the mechanism of which may involve the inhibition of IL-6/STAT3 signaling pathway and regulation of Bax, Bcl-2 and cyclin D1 expressions to suppress tumor cell proliferation and differentiation and induce cell apoptosis.

Regulation of subsoiling tillage on the grain filling characteristics of maize varieties from different eras.

Grain filling is the key stage for achieving high grain yield. Subsoiling tillage, as an effective conservation tillage, has been widely used in the maize planting region of China. This study was conducted to explore the effects of subsoiling on the grain filling characteristics of maize varieties of different eras. Five typical maize varieties from different eras (1970s, 1980s, 1990s, 2000s and 2010s) were used as experimental materials with two tillage modalities (rotation tillage and subsoiling tillage). The characteristic parameters (Tmax: the time when the maximum grouting rate was reached, Wmax: the grain weight at the maximum filling rate, Rmax: the maximum grouting rate, P: the active grouting stage, Gmean: the average grouting rate; A: the ultimate growth mass) and rate parameters (T1: the grain filling duration of the gradually increasing stage, V1: the average grain filling rate of the gradually increasing stage, T2: he grain filling duration of the rapidly increasing stage, V2: the average grain filling rate of the rapidly increasing stage, T3: the grain filling duration of the slowly increasing stage, V3: the average grain filling rate of the slowly increasing stage) of grain filling of two tillage modalities were analyzed and compared. The results showed that the filling parameters closely correlated with the 100-kernel weight were significantly different among varieties from different eras, and the grain filling parameters of the 2010s variety were better than those of the other varieties, the P and Tmax prolonged by 4.06-19.25%, 5.88-27.53% respectively, the Rmax and Gmean improved by 5.68-14.81%, 4.76-12.82% and the Wmax increased by 10.14-32.58%. Moreover, the 2010s variety helped the V2 and V3 increase by 6.49-13.89%, 4.55-15.00%. In compared with rotation tillage, the grain yield of maize varieties from different eras increased by 4.28-7.15% under the subsoiling condition, while the 100-kernel weight increased by 3.53-5.06%. Under the same contrast conditions, subsoiling improved the Rmax, Wmax and Gmean by 1.23-4.86%, 4.01-5.96%, 0.25-2.50% respectively, delayed the Tmax by 4.04-5.80% and extended the P by 1.19-4.03%. These differences were major reasons for the significant increases in 100-kernel dry weight under the subsoiling condition. Moreover, subsoiling enhanced the V2 and V3 by 0.70-4.29%, 0.00-2.44%. The duration of each filling stage and filling rate of maize varieties from different eras showed different responses to subsoiling. Under the subsoiling condition, the average filling rate of the 1970-2010s varieties were improved by 1.18%, 0.34%, 0.57%, 1.57% and 2.69%. In the rapidly increasing period, the grain filling rate parameters of the 2010s variety were more sensitive to subsoiling than those of the other varieties. The rapidly increasing and slowly increasing period are the key period of grain filling. Since the 2010s variety and subsoiling all improve the grain filling rate parameters of two periods, we suggest that should select the variety with higher grain filling rate in the rapidly increasing and slowly increasing period, and combine subsoiling measures to improve the grain filling characteristic parameters of maize in production, so as to achieve the purpose of increasing 100 grain weight and yield.

Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins.

The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

Human endogenous retroviruses in cancer: Expression, regulation and function.

Human endogenous retroviruses (HERVs) are the remnants of ancient retroviruses that infected human germline cells and became integrated into the human genome millions of years ago. Although most of these sequences are incomplete and silent, several potential pathological roles of HERVs have been observed in numerous diseases, such as multiple sclerosis and rheumatoid arthritis, and especially cancer, including breast cancer and pancreatic carcinoma. The present review investigates the expression signatures and complex regulatory mechanisms of HERVs in cancer. The long terminal repeats-driven transcriptional initiation of HERVs are regulated by transcription factors (such as Sp3) and epigenetic modifications (such as DNA methylation), and are influenced by environmental factors (such as ultraviolet radiation). In addition, this review focuses on the dual opposing effects of HERVs in cancer. HERVs can suppress cancer via immune activation; however, they can also promote cancer. HERV env gene serves a prime role in promoting carcinogenesis in certain malignant tumors, including breast cancer, pancreatic cancer, germ cell tumors, leukemia and Kaposi's sarcoma. Also, HERV ENV proteins can promote cancer via immune suppression. Targeting ENV proteins is a potential future antitumor treatment modality.

Meta-omics characteristics of intestinal microbiota associated to HBeAg seroconversion induced by oral antiviral therapy.

Tenofovir and entecavir are currently designated as the preferred oral antiviral drugs for chronic hepatitis B. However, only less than 40% of patients can achieve HBeAg seroconversion. We aim at investigating the role of intestinal microbiome in HBeAg seroconversion induced by oral antiviral therapy and describe multi-omics characteristics of HBeAg seroconversion associated intestinal flora. In this study, we prospectively collected fecal samples at baseline from the patients with HBeAg positive chronic hepatitis B who would have oral antiviral therapy. 16S rDNA sequencing and metabolomics were performed. We identified HBeAg seroconversion-related microbial signature and constructed prediction model for HBeAg seroconversion. Thirty-seven of these subjects achieved HBeAg seroconversion within 156 weeks after the initiation of oral antiviral therapy, while 41 subjects remained HBeAg positive even after over 156 weeks of therapy. A computational statistical and machine learning approach allowed us to identify a microbial signature for HBeAg seroconversion. Using random forest method, we further constructed a classifier based on the microbial signature, with area under curve being 0.749 for the test set. Patients who achieved HBeAg seroconversion tended to have lower abundance of certain fecal metabolites such as essential amino acids, and several dipeptides. By analyzing the fecal microbiota from the patients with and without HBeAg seroconversion, we showed intestinal microbiome play a critical role in HBeAg seroconversion induced by oral antiviral therapy. We also identified intestinal microbial signature that is associated with HBeAg seroconversion after oral antiviral therapy.

Nicotinamide N-Methyltransferase Is a Prognostic Biomarker and Correlated With Immune Infiltrates in Gastric Cancer.

Gastric cancer (GC) is the third most common cause of cancer-related death in the word. Immunotherapy is a promising treatment of cancer. However, it is unclear which GC subpopulation would benefit most from immunotherapy and it is necessary to develop effective biomarkers for predicting immunotherapy response. Nicotinamide N-methyltransferase (NNMT) is a metabolic regulator of cancer-associated fibroblast (CAF) differentiation and cancer progression. In this study, we explored the correlations of NNMT to tumor-infiltrating immune cells (TIICs) and immune marker sets in The Cancer Genome Atlas Stomach Adenocarcinoma STAD (TCGA-STAD). Subsequently, we screened the NNMT correlated genes and performed the enrichment analysis of these genes. We eventually predicted the 19 most potential small-molecule drugs using the connectivity map (CMap) and Comparative Toxicogenomics Database (CTD). Also, nadolol, tranexamic acid, felbinac and dapsone were considered the four most promising drugs for GC. In summary, NNMT can be used as a prognostic biomarker that reflect immune infiltration level and a novel therapeutic target in GC.

Integrated Analysis of Distant Metastasis-Associated Genes and Potential Drugs in Colon Adenocarcinoma.

Background: Most colon adenocarcinoma (COAD) patients die of distant metastasis, though there are some therapies for metastatic COAD. However, the genes exclusively expressed in metastatic COAD remain unclear. This study aims to identify prognosis-related genes associated with distant metastasis and develop therapeutic strategies for COAD patients. Methods: Transcriptomic data from The Cancer Genome Atlas (TCGA; n = 514) cohort were analyzed as a discovery dataset. Next, the data from the GEPIA database and PROGgeneV2 database were used to validate our analysis. Key genes were identified based on the differential miRNA and mRNA expression with respect to M stage. The potential drugs targeting candidate differentially expressed genes (DEGs) were also investigated. Results: A total of 127 significantly DEGs in patients with distant metastasis compared with patients without distant metastasis were identified. Then, four prognosis-related genes (LEP, DLX2, CLSTN2, and REG3A) were selected based on clustering analysis and survival analysis. Finally, three compounds targeting the candidate DEGs, including ajmaline, TTNPB, and dydrogesterone, were predicted to be potential drugs for COAD. Conclusions: This study revealed that distant metastasis in COAD is associated with a specific group of genes, and three existing drugs may suppress the distant metastasis of COAD.