Development of a Novel Prognostic Model for Esophageal Squamous Cell Carcinoma: Insights into Immune Cell Interactions and Drug Sensitivity.

Esophageal squamous cell carcinoma (ESCC) presents a five-year survival rate below 20%, underscoring the need for improved prognostic markers. Our study analyzed ESCC-specific datasets to identify consistently differentially expressed genes. A Venn analysis followed by gene network interactions revealed 23 key genes, from which we built a prognostic model using the COX algorithm (p = 0.000245, 3-year AUC = 0.967). This model stratifies patients into risk groups, with high-risk individuals showing worse outcomes and lower chemotherapy sensitivity. Moreover, a link between risk scores and M2 macrophage infiltration, as well as significant correlations with immune checkpoint genes (e.g., SIGLEC15, PDCD1LG2, and HVCR2), was discovered. High-risk patients had lower Tumor Immune Dysfunction and Exclusion (TIDE) values, suggesting potential responsiveness to immune checkpoint blockade (ICB) therapy. Our efficient 23-gene prognostic model for ESCC indicates a dual utility in assessing prognosis and guiding therapeutic decisions, particularly in the context of ICB therapy for high-risk patients.

KIFC1 promotes proliferation and pseudo-bipolar division of ESCC through the transportation of Aurora B kinase.

Esophageal squamous cell carcinoma (ESCC) accounts for over 90% of total in China, and the five-year survival rate for patients is less than 30%. Accordingly, the identification of novel, effective early diagnosis markers and therapeutic targets for ESCC is of paramount importance. KIFC1 has been identified as highly expressed in several types of cancer, although its prognostic value is inconsistent, and no research has been conducted specifically on its effect on ESCC. To investigate the expression and function of KIFC1 in ESCC, we conducted immunohistochemical staining on 30 pairs of para-carcinoma tissue and cancerous tissues, revealing a significant increase in KIFC1 expression in ESCC tissues. Using siRNA to knock down KIFC1 significantly reduced the proliferation of EC109 ESCC cells both in vitro and in vivo. Bioinformatics analysis revealed a highly significant positive correlation between KIFC1 overexpression and signaling pathways associated with tumor proliferation pathways. In EC109 cells, overexpression of KIFC1 significantly increased the rate of centrosome amplification and the likelihood of pseudo-bipolar division. Furthermore, the expression of KIFC1 and the rate of centrosome amplification in ESCC tissues were also positively correlated. In order to explore the underline molecular mechanisms, we identified, through proteomics, that KIFC1 binds to the protein Aurora B. The knockdown of KIFC1 significantly reduced the distribution of Aurora B on the metaphase plate and substantially inhibited the phosphorylation of its classical substrate, Histone H3. In conclusion, these findings indicate the potential utility of KIFC1 as both a tumor marker and a promising target for therapeutic interventions.

Epstein-Barr virus microRNA miR-BART2-5p accelerates nasopharyngeal carcinoma metastasis by suppressing RNase â ¢ endonuclease DICER1.

The development and progression of nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. NPC is usually asymptomatic until it spreads to other sites, and more than 70% of cases are classified as locally advanced disease at diagnosis. EBV-positive nasopharyngeal cancer tissues express only limited viral latent proteins, but express high levels of the EBV-encoded BamHI-A rightward transcript (BART) miRNA molecules. Here, we report that EBV-miRNA-BART2-5p (BART2-5p) promotes NPC cell invasion and metastasis in vivo and in vitro but has no effect on NPC cell proliferation and apoptosis. In addition, BART2-5p altered the mRNA and miRNA expression profiles of NPC cells. The development of human tumors has been reported to be associated with altered miRNAs expression, and overall miRNAs expression is reduced in many types of tumors. We found that BART2-5p downregulated the expression of several miRNAs that could exert oncogenic functions. Mechanistically, BART2-5p directly targets the RNase III endonuclease DICER1, inhibiting its function of cleaving double-stranded stem-loop RNA into short double-stranded RNA, which in turn causes altered expression of a series of key epithelial-mesenchymal transition molecules, and reverting DICER1 expression can rescue this phenotype. Furthermore, analysis from clinical samples showed a negative correlation between BART2-5p and DICER1 expression. According to our study, high expression of BART2-5p in tissues and plasma of patients with NPC is associated with poor prognosis. Our results suggest that, BART2-5p can accelerate NPC metastasis through modulating miRNA profiles which are mediated by DICER1, implying a novel role of EBV miRNAs in the pathogenesis of NPC.

Polydopamine-Decorated PLCL Conduit to Induce Synergetic Effect of Electrical Stimulation and Topological Morphology for Peripheral Nerve Regeneration.

Due to the limited self-repairing capacity after peripheral nerve injuries (PNI), artificial nerve conduits are widely applied to facilitate neural regeneration. Exogenous electrical stimulation (ES) that is carried out by the conductive conduit regulates the biological behavior of Schwann cells (SCs). Meanwhile, a longitudinal surface structure counts to guide axonal growth to accelerate the end-to-end connection. Currently, there are no conduits equipped with both electrical conduction and axon-guiding surface structure. Herein, a biodegradable, conductive poly(l-lactide-co-caprolactone)/graphene (PLCL/GN) composite conduit is designed. The conduit with 20.96 ± 1.26 MPa tensile strength has a micropatterned surface of 20 µm groove fabricated by microimprint technology and self-assembled polydopamine (PDA). In vitro evaluation shows that the conduits with ES effectively stimulate the directional cell migration, adhesion, and elongation, and enhance neuronal expression of SCs. The rat sciatic nerve crush model demonstrates that the conductive micropatterned conduit with ES promotes the growth of myelin sheath, faster nerve regeneration, and 20-fold functional recovery in vivo. These discoveries prove that the PLCL(G)/PDA/GN composite conduit is a promising tool for PNI treatment by providing the functional integration of physical guidance, biomimetic biological regulation, and bioelectrical stimulation, which inspires a novel therapeutic approach for nerve regeneration in the future.

Deficiency of Lactoferrin aggravates lipopolysaccharide-induced acute inflammation via recruitment macrophage in mice.

Lactoferrin (Lf), a multiple functional natural immune protein, is widely distributed in mammalian milk and glandular secretions (bile, saliva, tears and nasal mucosal secretions, etc.). In the previous study, we found that Lf plays an anti-inflammatory and anti-tumorigenesis role in AOM/DSS (azoxymethane/dextran sulfate sodium) induced mouse colitis-associated colon cancer model. Although we found that Lf has anti-inflammatory effects in chronic inflammation, its specific role and mechanisms in acute inflammation have not been clarified. Here, we reported that the expression levels of Lf were significantly increased when the organism was infected by Gram-negative bacteria. We then explored the role and potential mechanism of Lf in lipopolysaccharide (LPS)-induced acute inflammation. In the LPS-induced acute abdominal inflammation model, Lf deficiency aggravated inflammatory response and promoted macrophage chemotaxis to the inflammation site. Lf inhibited macrophage chemotaxis by suppressing the expression of macrophage-associated chemokines Ccl2 and Ccl5. Highly activated NF-κB signaling in Lf-/- mice was responsible for the high expression of Ccl2 and Ccl5. Our results suggested that the anti-inflammatory effect of Lf offers a new potential treatment for acute inflammatory diseases.

Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer.

Metabolic disorders and abnormal immune function changes occur in tumor tissues and cells to varying degrees. There is increasing evidence that reprogrammed energy metabolism contributes to the development of tumor suppressive immune microenvironment and influences the course of gastric cancer (GC). Current studies have found that tumor microenvironment (TME) also has important clinicopathological significance in predicting prognosis and therapeutic efficacy. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors and key enzymes of immune metabolism, have been involved in the treatment of GC. However, the interaction between GC cells metabolism and immune metabolism and how to make better use of these immunotherapy methods in the complex TME in GC are still being explored. Here, we discuss how metabolic reprogramming of GC cells and immune cells involved in GC immune responses modulate anti-tumor immune responses, as well as the effects of gastrointestinal flora in TME and GC. It is also proposed how to enhance anti-tumor immune response by understanding the targeted metabolism of these metabolic reprogramming to provide direction for the treatment and prognosis of GC.

N6-methyladenosine regulates ATM expression and downstream signaling.

N6-methyladenosine (m6A) is the most abundant modification in eukaryotic mRNAs, which plays an important role in regulating multiple biological processes. ATM is a major protein kinase that regulates the DNA damage response. Here, we identified that ATM is a m6A-modificated gene. METTL3 (a m6A "writer") and FTO (a m6A "eraser") oppositely regulated ATM expression and its downstream signaling. Mechanically, m6A "readers" YTHDFs and eIF3A suppressed ATM expression in the post-transcriptional levels. We also revealed the oncogenic potential of METTL3 and YTHDF1 related to ATM modulation. This is the first report that ATM, a master in the DNA damage response, is modified by m6A epigenetic modification, and METTL3 disrupts the ATM stability via m6A modification, thereby affecting the DNA-damage response.

Clinical characteristics and risk factors of Talaromyces marneffei infection in human immunodeficiency virus-negative patients: A retrospective observational study.

BACKGROUND: To investigate the clinical characteristics and risk factors of human immunodeficiency virus (HIV)-negative patients with Talaromyces marneffei (T. marneffei) infection. METHODS: We retrospectively collected the clinical information of HIV-negative patients with T. marneffei infection from January 1, 2010 to June 30, 2019, and analyzed the related risk factors of poor prognosis. RESULTS: Twenty-five cases aging 22 to 79 years were included. Manifestations of T. marneffei infection included fever, cough, dyspnea, chest pain or distress, lymphadenopathy, ear, nose, and throat (ENT) and/or skin lesions, bone or joint pain, edema and pain in the lower extremities, digestive symptoms, icterus, malaise, and hoarseness. Two cases had no comorbidity, while 23 cases suffered from autoimmune disease, pulmonary disease, cancer, and other chronic diseases. Sixteen cases had a medication history of glucocorticoids, chemotherapy or immunosuppressors. Pulmonary lesions included interstitial infiltration, nodules, atelectasis, cavitary lesions, pleural effusion or hydropneumothorax, bronchiectasis, pulmonary fibrosis, pulmonary edema, and consolidation. The incidence of osteolytic lesions was 20%. Eight patients received antifungal monotherapy, and 11 patients received combined antifungal agents. Fifteen patients survived and ten patients were dead. The Cox regression analysis showed that reduced eosinophil counts, higher levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), myoglobin (Mb), procalcitonin (PCT), and galactomannan were related to poor prognosis (hazard ratio [HR]>1, P<0.05). CONCLUSIONS: Bone destruction is common in HIV-negative patients with T. marneffei infection. Defective cell-mediated immunity, active infection, multiple system, and organ damage can be the risk factors of poor prognosis.

Protective effects of recombinant 53-kDa protein of Trichinella spiralis on acute lung injury in mice via alleviating lung pyroptosis by promoting M2 macrophage polarization.

Trichinella spiralis represents an effective treatment for autoimmune and inflammatory diseases. The effects of recombinant T. spiralis (TS) 53-kDa protein (rTsP53) on acute lung injury (ALI) remain unclear. Here, mice were divided randomly into a control group, LPS group, and rTsP53 + LPS group. ALI was induced in BALB/c mice by LPS (10 mg/kg) injected via the tail vein. rTsP53 (200 µl; 0.4 µg/µl) was injected subcutaneously three times at an interval of 5 d before inducing ALI in the rTsP53+LPS group. Lung pathological score, the ratio and markers of classic activated macrophages (M1) and alternatively activated macrophages (M2), cytokine profiles in alveolar lavage fluid, and pyroptosis protein expression in lung tissue were investigated. RTsP53 decreased lung pathological score. Furthermore, rTsP53 suppressed inflammation by increasing IL-4, IL-10, and IL-13. There was an increase in alveolar M2 macrophage numbers, with an increase in CD206 and arginase-1-positive cells and a decrease in alveolar M1 markers such as CD197 and iNOS. In addition, the polarization of M2 macrophages induced by rTsP53 treatment could alleviate ALI by suppressing lung pyroptosis. RTsP53 was identified as a potential agent for treating LPS-induced ALI via alleviating lung pyroptosis by promoting M2 macrophage polarization.

Lactoferrin is required for early B cell development in C57BL/6 mice.

Lactoferrin (Lf) is widely distributed in mammalian milk, various tissues, and their exocrine fluids and has many physiological functions, such as bacteriostasis, antivirus, and immunoregulation. Here, we provide evidence that lactoferrin is required for early stages of B cell development in mice. Lactoferrin-deficient (Lf-/-) C57BL/6 mice showed systematic reduction in total B cells, which was attributed to the arrest of early B cell development from pre-pro-B to pro-B stage. Although the Lf-/- B cell "seeds" generated greater pro-B cells comparing to wild type (WT) littermates, the Lf-/- mice bone marrow had less stromal cells, and lower CXCL12 expression, produced a less favorable "microenvironment" for early B cell development. The underlying mechanism was mediated through ERK and AKT signalings and an abnormality in the transcription factors related to early differentiation of B cells. The Lf-/- mice also displayed abnormal antibody production in T cell-dependent and T cell-independent immunization experiments. In a pristane-induced lupus model, Lf-/- mice had more serious symptoms than WT mice, whereas lactoferrin treatment alleviated these symptoms. This study demonstrates a novel role of lactoferrin in early B cell development, suggesting a potential benefit for using lactoferrin in B cell-related diseases.

RNA m6 A methylation regulates virus-host interaction and EBNA2 expression during Epstein-Barr virus infection.

INTRODUCTION: N6 -methyladenosine (m6 A) is the most prevalent modification that occurs in messenger RNA (mRNA), affecting mRNA splicing, translation, and stability. This modification is reversible, and its related biological functions are mediated by "writers," "erasers," and "readers." The field of viral epitranscriptomics and the role of m6 A modification in virus-host interaction have attracted much attention recently. When Epstein-Barr virus (EBV) infects a human B lymphocyte, it goes through three phases: the pre-latent phase, latent phase, and lytic phase. Little is known about the viral and cellular m6 A epitranscriptomes in EBV infection, especially in the pre-latent phase during de novo infection. METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-RT-qPCR were used to determine the m6 A-modified transcripts during de novo EBV infection. RIP assay was used to confirm the binding of EBNA2 and m6 A readers. Quantitative reverse-transcription polymerase chain reaction (RT-qPCR) and Western blot analysis were performed to test the effect of m6 A on the host and viral gene expression. RESULTS: Here, we provided mechanistic insights by examining the viral and cellular m6 A epitranscriptomes during de novo EBV infection, which is in the pre-latent phase. EBV EBNA2 and BHRF1 were highly m6 A-modified upon EBV infection. Knockdown of METTL3 (a "writer") decreased EBNA2 expression levels. The emergent m6 A modifications induced by EBV infection preferentially distributed in 3' untranslated regions of cellular transcripts, while the lost m6 A modifications induced by EBV infection preferentially distributed in coding sequence regions of mRNAs. EBV infection could influence the host cellular m6 A epitranscriptome. CONCLUSIONS: These results reveal the critical role of m6 A modification in the process of de novo EBV infection.

The Effectiveness of Clinical Pharmacist-Led Consultation in the Treatment of Infectious Diseases: A Prospective, Multicenter, Cohort Study.

BACKGROUND: Antimicrobial resistance (AMR) is a serious global health threat and leads to a huge challenge to infectious diseases (ID) treatment. To tackle AMR, regional 'Antimicrobial Stewardship Programs' (ASP) have been implemented in many countries. Due to insufficient clinical pharmacy resources, a major intervention mode of ASP in China is through clinical pharmacist-led consultation (CPC). The current study aims to prospectively evaluate this intervention and compare the effectiveness of CPC served by ID and non-ID clinical pharmacists. METHODS: We conducted a prospective and multicenter cohort study based on a regional registry database in 17 hospitals in Western China, including consecutive patients with ID between April 2017 and December 2019. Baseline characteristics including sex, age, liver and kidney function, comorbidity, infection severity were prospectively collected and recorded. The main exposure of interest was whether the attending physician adopted recommendations of the clinical pharmacist in the therapeutic scheme. The outcome was the infection effective response, assessed during day 3-7 after completing CPC. Multivariate analyses were performed by generalized linear mixed models. RESULTS: A total of 2,663 ID patients were included in the final analysis according to the predesigned inclusion and exclusion criteria. The number of patients whose treatment followed and did not follow the pharmacists' suggestion was 2,529 and 134, respectively. CPC intervention could improve the ID patient prognosis in the context of other confounders controlled (Adjusted Odds ratio(AOR)=1.838, 95%Confidence Interval(CI)=[1.212, 2.786]), and the effectiveness of CPC served by ID and non-ID clinical pharmacists might be equivalent (AOR=0.958, 95%CI[0.740, 1.240]). Special consultation (AOR=1.832, 95%CI[1.106, 3.035]) and surgical treatment of infectious sites (AOR=1.380, 95%CI[1.039, 1.834]) had positive influences on the patient prognosis, while hypoalbuminemia (AOR=0.694, 95%CI[0.523, 0.921]), liver dysfunction (AOR=0.705, 95%CI[0.559, 0.889]), presence of high-risk factors (AOR=0.775, 95%CI[0.613, 0.980]), and increased infection severity (AOR=0.631, 95%CI[0.529, 0.753])were associated with a decrease in effective response rate, independently. CONCLUSION: This study suggests that CPC is a promising pharmacist-led intervention to improve ID treatment, and it can achieve standardization among clinical pharmacists with different backgrounds by some measures. Policy/decision-makers should promote this intervention mode in developing countries or regions where there is an insufficient number of clinical pharmacists.

Proinflammatory S100A8 Induces PD-L1 Expression in Macrophages, Mediating Tumor Immune Escape.

S100A8 is a damage-associated molecular pattern protein released by monocytes, playing a decisive role in the development of inflammation. Nonresolving inflammation is viewed as a driving force in tumorigenesis, and its role in tumor immune escape also attracted attentions. PD-1/PD-L1 axis is a critical determinant of physiological immune homeostasis, and anti-PD-1 or PD-L1 therapy has becoming the most exciting field of oncology. Multiple regulation mechanisms have been contributed to PD-L1 expression modulation including inflammatory mediators. In this study we reported that S100A8 significantly induced PD-L1 expression in monocytes/macrophages but not in tumor cells. S100A8 induced PD-L1 transcription through the TLR4 receptor and multiple crucial pathways of inflammation process. S100A8 modulated the histone modification of the PD-L1 promoter in monocytes/macrophages. S100A8-pretreated macrophages had immunosuppressive function and attenuated the antitumor ability of CTLs both in vitro and in vivo. A highly positive correlation existed between S100A8 expression and PD-L1 expression in human cancer specimens. To our knowledge, our study uncovers a novel molecular mechanism for regulating PD-L1 transcription by an inflammatory mediator S100A8, and reveals the importance of comprehensive understanding the role of inflammation in tumorigenesis as well as in tumor immune escape.

A significant role of transcription factors E2F in inflammation and tumorigenesis of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor from head and neck with characteristics in remarkable geographic and racial distribution worldwide, which has the important features of vigorous proliferation and inflammatory cells infiltration. By analyzing the expression profile data of NPC, we found that the E2F-related gene sets were highly enriched in NPC tissues. E2F transcription factor family is an important cycle regulator, which can promote the malignant proliferation and tumorigenesis. Here, we showed that E2Fs accelerated malignant phenotypes of NPC cells. RNA sequencing revealed that E2Fs can significantly up-regulate the inflammatory pathways in NPC cells. E2F1, as a transcription factor, can active the transcription activity of IL-6 promoter, and modulate macrophage function through a microenvironment manner. Thus, this study characterized a significant role of E2Fs in inflammation and tumorigenesis of NPC, which provided a promising anti-tumor target in NPC, since E2Fs are highly expressed and activated in NPC.

Phase Separation of Epstein-Barr Virus EBNA2 and Its Coactivator EBNALP Controls Gene Expression.

Biological macromolecule condensates formed by liquid-liquid phase separation (LLPS) have been discovered in recent years to be prevalent in biology. These condensates are involved in diverse processes, including the regulation of gene expression. LLPS of proteins have been found in animal, plant, and bacterial species but have scarcely been identified in viral proteins. Here, we discovered that Epstein-Barr virus (EBV) EBNA2 and EBNALP form nuclear puncta that exhibit properties of liquid-like condensates (or droplets), which are enriched in superenhancers of MYC and Runx3. EBNA2 and EBNALP are transcription factors, and the expression of their target genes is suppressed by chemicals that perturb LLPS. Intrinsically disordered regions (IDRs) of EBNA2 and EBNALP can form phase-separated droplets, and specific proline residues of EBNA2 and EBNALP contribute to droplet formation. These findings offer a foundation for understanding the mechanism by which LLPS, previously determined to be related to the organization of P bodies, membraneless organelles, nucleolus homeostasis, and cell signaling, plays a key role in EBV-host interactions and is involved in regulating host gene expression. This work suggests a novel anti-EBV strategy where developing appropriate drugs of interfering LLPS can be used to destroy the function of the EBV's transcription factors.IMPORTANCE Protein condensates can be assembled via liquid-liquid phase separation (LLPS), a process involving the concentration of molecules in a confined liquid-like compartment. LLPS allows for the compartmentalization and sequestration of materials and can be harnessed as a sensitive strategy for responding to small changes in the environment. This study identified the Epstein-Barr virus (EBV) proteins EBNA2 and EBNALP, which mediate virus and cellular gene transcription, as transcription factors that can form liquid-like condensates at superenhancer sites of MYC and Runx3. This study discovered the first identified LLPS of EBV proteins and emphasized the importance of LLPS in controlling host gene expression.

Lactoferrin deficiency induces a pro-metastatic tumor microenvironment through recruiting myeloid-derived suppressor cells in mice.

Lactoferrin, an innate immunity molecule, is involved in anti-inflammatory, anti-microbial, and anti-tumor activities. We previously reported that lactoferrin is downregulated in specimens of nasopharyngeal carcinoma and negatively associated with tumor progression and metastasis of patients with nasopharyngeal carcinoma. However, the relationship between lactoferrin and the pro-metastatic microenvironment has not been reported yet. Here, by using the lactoferrin knockout mouse, we found that lactoferrin deficiency facilitated melanoma cells metastasizing to lungs, through recruiting myeloid-derived suppressor cells (MDSCs) in the lungs. Mechanistic studies showed that in the lung microenvironment of the lactoferrin knockout mice, the TLR9 signaling was the most repressed signaling. Lactoferrin can induce MDSCs differentiation and apoptosis, as well as upregulate TLR9 expression. TLR9 agonist or lactoferrin treatment can rescue this phenotype in the tumor metastasis mouse model. Our results suggest a protective role of lactoferrin in cancer metastasis, along with a deficiency in certain components of the innate immune system, may lead to a pro-metastatic tumor microenvironment.

Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer.

Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here, we report that EBV-miR-BART3-3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by an oncogene (RASG12V) or chemotherapy (irinotecan). LMP1 and EBNA3C encoded by EBV have also been reported to have antisenescence effects; however, in EBVaGC specimens, LMP1 expression is very low, and EBNA3C is not expressed. BART3-3p inhibits senescence of gastric cancer cells in a nude mouse model and inhibits the infiltration of natural killer cells and macrophages in tumor by altering the senescence-associated secretory phenotype (SASP). Mechanistically, BART3-3p directly targeted the tumor suppressor gene TP53 and caused down-regulation of p53's downstream target, p21. Analysis from clinical EBVaGC samples also showed a negative correlation between BART3-3p and TP53 expression. It is well known that mutant oncogene RASG12V or chemotherapeutic drugs can induce senescence, and here we show that both RASG12V and a chemotherapy drug also can induce BART3-3p expression in EBV-positive gastric cancer cells, forming a feedback loop that keeps the EBVaGC senescence at a low level. Our results suggest that, although TP53 is seldom mutated in EBVaGC, its expression is finely regulated such that EBV-encoded BART3-3p may play an important role by inhibiting the senescence of gastric cancer cells.