Publications by authors named "Yulong He"

226 Publications

Cross-Talk of Focal Adhesion-Related Gene Defines Prognosis and the Immune Microenvironment in Gastric Cancer.

Front Cell Dev Biol 2021 1;9:716461. Epub 2021 Oct 1.

Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.

Focal adhesion, as the intermediary between tumor cells and extracellular matrix communication, plays a variety of roles in tumor invasion, migration, and drug resistance. However, the potential role of focal adhesion-related genes in the microenvironment, immune cell infiltration, and drug sensitivity of gastric cancer (GC) has not yet been revealed. The genetic and transcriptional perspectives of focal adhesion-related genes were systematically analyzed. From a genetic perspective, the focal adhesion index (FAI) was constructed based on 18 prognosis-related focus adhesion-related genes to evaluate the immune microenvironment and drug sensitivity. Then three prognosis-related genes were used for consistent clustering to identify GC subtypes. Finally, use FLT1, EGF, COL5A2, and M2 macrophages to develop risk signatures, and establish a nomogram together with clinicopathological characteristics. Mutations in the focal adhesion-related gene affect the survival time and clinical characteristics of GC patients. FAI has been associated with a shorter survival time, immune signaling pathways, M2 macrophage infiltration, epithelial-mesenchymal transition (EMT) signaling, and diffuse type of GC. FAI recognizes ALK, cell cycle, and BMX signaling pathways inhibitors as sensitive agents for the treatment of GC. FLT1, EGF, and COL5A2 may distinguish GC subtypes. The established risk signature is of great significance to the prognostic evaluation of GC based on FLT1, EGF, and COL5A2 and M2 macrophage expression. The focal adhesion-related gene is a potential biomarker for the evaluation of the immune microenvironment and prognosis. This work emphasizes the potential impact of the focal adhesion pathway in GC therapy and highlights its guiding role in prognostic evaluation.
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http://dx.doi.org/10.3389/fcell.2021.716461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517448PMC
October 2021

FLT4/VEGFR3 activates AMPK to coordinate glycometabolic reprogramming with autophagy and inflammasome activation for bacterial elimination.

Autophagy 2021 Oct 10:1-16. Epub 2021 Oct 10.

State Key Laboratory of Cell Biology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Macrophages rapidly undergo glycolytic reprogramming in response to macroautophagy/autophagy, inflammasome activation and pyroptosis for the clearance of bacteria. Identification the key molecules involved in these three events will provide critical potential therapeutic applications. Upon infection, FLT4/VEGFR3 and its ligand VEGFC were inducibly expressed in macrophages, and FLT4 signaling inhibited CASP1 (caspase 1)-dependent inflammasome activation and pyroptosis but enhanced MAP1LC3/LC3 activation for elimination of the bacteria. Consistently, FLT4 mutants lacking the extracellular ligand-binding domain increased production of the proinflammatory metabolites such as succinate and lactate, and reduced antimicrobial metabolites including citrate and NAD(P)H in macrophages and liver upon infection. Mechanistically, FLT4 recruited AMP-activated protein kinase (AMPK) and phosphorylated Y247 and Y441/442 in the PRKAA/alpha subunit for AMPK activation. The AMPK agonist AICAR could rescue glycolytic reprogramming and inflammasome activation in macrophages expressing the mutant FLT4, which has potential translational application in patients carrying mutations to prevent recurrent infections. Collectively, we have elucidated that the FLT4-AMPK module in macrophages coordinates glycolytic reprogramming, autophagy, inflammasome activation and pyroptosis to eliminate invading bacteria.
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http://dx.doi.org/10.1080/15548627.2021.1985338DOI Listing
October 2021

Identification of an Immune-Related Long Noncoding RNA Pairs Model to Predict Survival and Immune Features in Gastric Cancer.

Front Cell Dev Biol 2021 21;9:726716. Epub 2021 Sep 21.

Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.

Gastric cancer (GC) remains one of the most malignant tumors around the world, and an accurate model that reliably predicts survival and therapeutic efficacy is urgently needed. As a novel predictor for prognosis in a variety of cancers, immune-related long noncoding RNA pairs (IRlncRNAPs) have been reported to predict tumor prognosis. Herein, we integrated an IRlncRNAPs model to predict the clinical outcome, immune features, and chemotherapeutic efficacy of GC. Based on the GC data obtained from The Cancer Genome Atlas (TCGA) database and the Immunology Database and Analysis Portal (ImmPort), differentially expressed immune-related long noncoding RNAs (DEIRlncRNAs) were identified. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression analysis were used to select the most appropriate overall survival (OS)-related IRlncRNAPs to develop a prognostic signature. The riskScore of each sample was calculated by comparing the long noncoding RNA expression level in each IRlncRNAP. Based on the riskScore for each patient, GC patients were divided into high- and low-risk groups. Then, the correlation of the signature and riskScore with OS, clinical features, immune cell infiltration, immune-related gene (IRG) expression and chemotherapeutic efficacy in GC was analyzed. A total of 107 DEIRlncRNAs were identified which formed 4297 IRlncRNAPs. Fifteen OS-related IRlncRNAPs were selected to develop a prognostic model. GC patients could be accurately classified into high- and low-risk groups according to the riskScore of the prognostic model. The 1-, 2-, 3-, and 5-year receiver operating characteristic (ROC) curves for the riskScore were drawn and the area under the curve (AUC) values were found to be 0.788, 0.810, 0.825, and 0.868, respectively, demonstrating a high sensitivity and accuracy of this prognostic signature. Moreover, the immune-related riskScore was an independent risk factor. Patients showed a poorer outcome within the high-risk group. In addition, the riskScore was found to be significantly correlated with the clinical features, immune infiltration status, IRG expression, and chemotherapeutic efficacy in GC. The prognostic model of IRlncRNAPs offers great promise in predicting the prognosis, immune infiltration status, and chemotherapeutic efficacy in GC, which might be helpful for the selection of chemo- and immuno-therapy of GC.
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http://dx.doi.org/10.3389/fcell.2021.726716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491937PMC
September 2021

Metabolic syndrome and its component traits present gender-specific association with liver cancer risk: a prospective cohort study.

BMC Cancer 2021 Oct 7;21(1):1084. Epub 2021 Oct 7.

Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.

Background & Aims: Little is known on the gender-specific effect and potential role of non-linear associations between metabolic syndrome (MetS) components and liver cancer risk. We evaluated these associations based on the UK Biobank cohort.

Methods: We included 474,929 individuals without previous cancer based on the UK Biobank cohort. Gender-specific hazard ratios (HRs) and 95% confidence interval (CIs) were calculated by Cox proportional hazards regression, adjusting for potential confounders. Non-linear associations for individual MetS components were assessed by the restricted cubic spline method.

Results: Over a median follow-up of 6.6 years, we observed 276 cases of liver cancer (175 men, 101 women). MetS [HR 1.48, 95% CI 1.27-1.72] and central obesity [HR 1.65, 95% CI 1.18-2.31] were associated with higher risk of liver cancer in men but not in women. Participants with hyperglycaemia has higher risk of liver cancer. High waist circumference and blood glucose were dose-dependently associated with increased liver cancer risk in both genders. For high density lipoprotein (HDL) cholesterol (both genders) and blood pressure (women), U-shaped associations were observed. Low HDL cholesterol (< 1.35 mmol/L) in men and high HDL cholesterol in women (> 1.52 mmol/L) were associated with increased liver cancer risk.

Conclusions: MetS components showed gender-specific linear or U- shaped associations with the risk of liver cancer. Our study might provide evidence for individualized management of MetS for preventing liver cancer.
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http://dx.doi.org/10.1186/s12885-021-08760-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499577PMC
October 2021

p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in Mice.

Cell Mol Gastroenterol Hepatol 2021 Sep 17. Epub 2021 Sep 17.

Department of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, Germany.

Background & Aims: Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis.

Approach & Results: Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA-based silencing of p70S6K in HSC lines, experiments with p70S6K cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K mice developed significantly less fibrosis upon exposure to CCl.

Conclusions: We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment.
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http://dx.doi.org/10.1016/j.jcmgh.2021.09.001DOI Listing
September 2021

Developing the surgical technique reporting checklist and standards: a study protocol.

Gland Surg 2021 Aug;10(8):2591-2599

Editorial Office, AME Publishing Company, Hong Kong, China.

Background: Standardized and transparent reporting of surgical technique is the cornerstone of effective dissemination, implementation and improvement. However, current reporting of surgical techniques is inadequate. The existing guidelines potentially applied to guide surgical technique reporting are with a minimal highlight of the surgical technique, lack requirements explaining what extent and dimensions need to be described in detail, or are unlikely to extrapolate to a wide range of surgical techniques. This study aims to formulate a rigorous protocol to develop a surgical technique reporting checklist and standards (SUPER) that defines what a clear, comprehensive and detailed surgical technique report should be contained.

Methods: This protocol is designed following the classic guidance for developing reporting guidelines recommended by the EQUATOR network.

Results: The development team will consist of surgeons (~80%), methodologists, and journal editors. The draft checklist sources will include a scoping review of existing reporting guidelines related to surgical technique, surgical technique articles from 15 top journals published in the last year, and brainstorming by the multidisciplinary development team. The final SUPER checklist will be formed after three rounds of Delphi surveys, one round of face-to-face meeting, and a month-long pilot test. The SUPER checklist will be published as open-access and be used in combination with existing reporting guidelines related to surgical techniques (e.g., IDEAL). This protocol will steer the SUPER checklist's development, allowing us to further elaborate surgical technique reporting for all surgical specialties, and enabling a more favorable experience for surgeons, nurses, medical students, residents, editors, and reviewers.

Trial Registration: This trial is registered at the EQUATOR network on December 18th, 2020. Available at: https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-other-study-designs/.
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http://dx.doi.org/10.21037/gs-21-312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411094PMC
August 2021

PARP1 Inhibitor Combined With Oxaliplatin Efficiently Suppresses Oxaliplatin Resistance in Gastric Cancer-Derived Organoids via Homologous Recombination and the Base Excision Repair Pathway.

Front Cell Dev Biol 2021 23;9:719192. Epub 2021 Aug 23.

Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.

Oxaliplatin (OXA) resistance in the treatment of different types of cancer is an important and complex problem. The culture of tumor organoids derived from gastric cancer can help us to provide a deeper understanding of the underlying mechanisms that lead to OXA resistance. In this study, our purpose was to understand the mechanisms that lead to OXA resistance, and to provide survival benefits to patients with OXA through targeted combination therapies. Using sequence analysis of OXA-resistant and non-OXA-resistant organoids, we found that PARP1 is an important gene that mediates OXA resistance. Through the patients' follow-up data, it was observed that the expression level of PARP1 was significantly correlated with OXA resistance. This was confirmed by genetic manipulation of PARP1 expression in OXA-resistant organoids used in subcutaneous tumor formation. Results further showed that PARP1 mediated OXA resistance by inhibiting the base excision repair pathway. OXA also inhibited homologous recombination by CDK1 activity and importantly made cancers with normal BRCA1 function sensitive to PARP inhibition. As a result, combination of OXA and Olaparib (PARP-1/2/3 inhibitor), inhibited and OXA resistant organoid growth and viability.
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http://dx.doi.org/10.3389/fcell.2021.719192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419238PMC
August 2021

Poor Prognosis and Therapeutic Responses in LILRB1-Expressing M2 Macrophages-Enriched Gastric Cancer Patients.

Front Oncol 2021 9;11:668707. Epub 2021 Aug 9.

Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.

Immunosuppressive molecules are valuable prognostic biomarkers across different cancer types. Leukocyte immunoglobulin like receptor subfamily B1 (LILRB1) is considered to be an immunosuppressive molecule, which is an important receptor of human leukocyte antigen G. However, the clinical significance of LILRB1 expression in gastric cancer remains unexplored. We analyzed the immunohistochemistry data of 166 gastric cancer patients to determine the clinicopathologic and survival significance of LILRB1. Immunofluorescence was conducted to detect the co-localization of LILRB1 with infiltrating immune cells. Additionally, we also assessed the immune contexture, immune cell functions and tumor microenvironment state related to LILRB1. We found that LILRB1 was mainly present in tumor stroma which was higher in tumor tissues compared with matched adjacent tissues. High-LILRB1 expression was associated with more advanced tumor stage, higher recurrence risk and worse survival. Immunohistochemistry and bioinformatic analysis showed that LILRB1 had a significant positive correlation with M2 tumor-associated macrophages (TAMs) infiltration. Immunofluorescence confirmed that M2 TAMs were the primary immune cells expressing LILRB1. Dense infiltration of LILRB1+ M2 TAMs yielded an immunosuppressive microenvironment manifested as enriched exhausted CD8+ T cells and increased immunosuppressive cytokines. Moreover, patients with high infiltration of both LILRB1+ cells and M2 TAMs indicated poor prognosis and inferior therapeutic responsiveness to adjuvant chemotherapy. In conclusion, LILRB1+ M2 TAMs were associated with a pro-tumor immune contexture and determine poor prognosis in gastric cancer. Further studies are essential to explore therapeutic targeting LILRB1+ M2 TAMs.
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http://dx.doi.org/10.3389/fonc.2021.668707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415088PMC
August 2021

A Genetically Engineered Mouse Model of Venous Anomaly and Retinal Angioma-like Vascular Malformation.

Bio Protoc 2021 Aug 5;11(15):e4117. Epub 2021 Aug 5.

Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, National Clinical Research Center for Hematologic Diseases, State Key Laboratory of Radiation Medicine and Protection, Cam-Su Genomic Resources Center, Soochow University, Suzhou 215123, China.

Characterization of key regulators in vein development will advance our understanding of mechanisms underlying venous anomalies and provide therapeutic targets for the treatment of vascular malformations. Here, we provide a detailed protocol for the generation of genetically engineered mouse models targeting the gene for the analysis of vein formation and vein-associated vascular diseases at the embryonic and postnatal stages. It includes steps involved in the whole-mount processing of mouse skin, mesentery, and retina for the examination of vascular malformation during embryonic and postnatal development.
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http://dx.doi.org/10.21769/BioProtoc.4117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376502PMC
August 2021

Virulence effector SidJ evolution in is driven by positive selection and intragenic recombination.

PeerJ 2021 17;9:e12000. Epub 2021 Aug 17.

The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Effector proteins translocated by the Dot/Icm type IV secretion system determine the virulence of (). Among these effectors, members of the SidE family (SidEs) regulate several cellular processes through a unique phosphoribosyl ubiquitination mechanism mediated by another effector, SidJ. Host-cell calmodulin (CaM) activates SidJ to glutamylate the SidEs of ubiquitin (Ub) ligases and to make a balanced Ub ligase activity. Given the central role of SidJ in this regulatory process, studying the nature of evolution of is important to understand the virulence of and the interaction between the bacteria and its hosts. By studying from a large number of strains and using various molecular evolution algorithms, we demonstrated that intragenic recombination drove the evolution of and contributed to diversification. Additionally, we showed that four codons of which are located in the N-terminal (NTD) (codons 58 and 200) and C-terminal (CTD) (codons 868 and 869) domains, but not in the kinase domain (KD) had been subjected to strong positive selection pressure, and variable mutation profiles of these codons were identified. Protein structural modeling of SidJ provided possible explanations for these mutations. Codons 868 and 869 mutations might engage in regulating the interactions of SidJ with CaM through hydrogen bonds and affect the CaM docking to SidJ. Mutation in codon 58 of SidJ might affect the distribution of main-chain atoms that are associated with the interaction with CaM. In contrast, mutations in codon 200 might influence the -helix stability in the NTD. These mutations might be important to balance Ub ligase activity for different hosts. This study first reported that intragenic recombination and positive Darwinian selection both shaped the genetic plasticity of , contributing to a deeper understanding of the adaptive mechanisms of this intracellular bacterium to different hosts.
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http://dx.doi.org/10.7717/peerj.12000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378335PMC
August 2021

The prognostic impact of pretreatment anemia in patients with gastric cancer and nonhypoalbuminemia undergoing curative resection: a retrospective study.

Ann Transl Med 2021 Jul;9(13):1046

Digestive Disease Center, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Background: The influence of pretreatment anemia on the prognosis of patients with advanced gastric cancer (GC) remains controversial. We retrospectively examined the impact of pretreatment anemia on the overall survival (OS) of patients with GC with nonhypoalbuminemia undergoing curative resection.

Methods: The clinicopathological data of 2,916 patients with advanced GC who received a radical gastrectomy from 1994 to 2015 were analyzed. The patients were divided into two subgroups by hemoglobin level, <120 and ≥120 g/L. OS was analyzed using the Kaplan-Meier method, and a multivariate Cox proportional hazards model was used to identify the independent prognostic factor.

Results: A total of 1,099 patients were included in our study. The median follow-up duration was 43 (IQR, 24-66) months. The prevalence of anemia was 40.9%. Among these 1,099 patients, 505 (46.0%) had nonhypoalbuminemia. Kaplan-Meier survival analysis showed that patients with GC who were anemic had a poorer OS than patients who were not (5-year OS rate: 58.4% 66.8%, P<0.0001). Multivariate analysis revealed that pretreatment anemia was an independent prognostic factor [hazard ratio (HR) =1.455, 95% CI, 1.013-2.09; P=0.043].

Conclusions: Our findings indicate that pretreatment anemia may serve as an independent prognostic factor for patients with advanced GC with nonhypoalbuminemia after radical gastrectomy, especially those with larger tumor size and pT3 disease.
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http://dx.doi.org/10.21037/atm-21-1649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339834PMC
July 2021

Ethaselen synergizes with oxaliplatin in tumor growth inhibition by inducing ROS production and inhibiting TrxR1 activity in gastric cancer.

J Exp Clin Cancer Res 2021 Aug 19;40(1):260. Epub 2021 Aug 19.

Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China.

Background: Oxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro.

Methods: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect.

Results: We found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis.

Conclusions: This study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy.
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http://dx.doi.org/10.1186/s13046-021-02052-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375208PMC
August 2021

Regular Use of Proton Pump Inhibitor and the Risk of Inflammatory Bowel Disease: Pooled Analysis of 3 Prospective Cohorts.

Gastroenterology 2021 Aug 11. Epub 2021 Aug 11.

Clinical Research Center, Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China; Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China. Electronic address:

Background & Aims: Proton pump inhibitors (PPIs) have a major impact on gut microbiome and immune function, which in turn, may increase the risk of inflammatory bowel disease (IBD). Our aim in this study was to evaluate PPI use and subsequent risk of IBD and subtypes (ie, Crohn's disease and ulcerative colitis).

Methods: This was a pooled analysis of the Nurses' Health Study (NHS, n = 82,869), NHS II (n = 95,141), and UK Biobank (n = 469,397). We included participants with information on personal use of PPIs and free of IBD or cancer at baseline. We evaluated hazard ratios and 95% confidence intervals (CIs) with Cox regression adjusting for lifestyle factors, PPI indications, comorbidities, and other medications.

Results: We documented 271 cases of IBD (median follow-up, 12 years) in the pooled NHS cohorts and 1419 cases (median follow-up, 8.1 years) in the UK Biobank. For both pooled NHS cohorts and UK Biobank, regular use of PPIs consistently showed a significantly positive association with IBD, Crohn's disease, and ulcerative colitis risk. Combined analyses of 3 cohorts showed that regular PPI users had an increased risk of IBD as compared with nonusers (hazard ratio, 1.42; 95% CI, 1.22-1.65; number needed to harm, 3770; 95% CI, 3668-4369). Direct comparison with H2 receptor antagonist, a less potent acid suppressor, showed that PPI use was also associated with higher IBD risk (hazard ratio, 1.38; 95% CI, 1.16-1.65).

Conclusions: Regular use of PPIs was associated with an increased risk of IBD and its subtypes. The findings should be interpreted with caution because the absolute risk was low and the clinical benefits of PPIs are substantial.
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http://dx.doi.org/10.1053/j.gastro.2021.08.005DOI Listing
August 2021

No Associations Between Regular Use of Proton Pump Inhibitors and Risk of All-Cause and Cause-Specific Mortality: A Population-Based Cohort of 0.44 Million Participants.

Am J Gastroenterol 2021 Jul 27. Epub 2021 Jul 27.

Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.

Introduction: The association between proton pump inhibitors' (PPIs) use and mortality remains unclear.

Methods: This was a prospective analysis of 440,840 UK residents and 13,154 deaths. We evaluated the associations with multivariate Cox regression.

Results: After adjusting for confounders, such as over health status and longstanding diseases, the regular use of PPIs was not associated with an increased risk of all-cause mortality and mortality due to neoplasms, circulatory system diseases, respiratory system diseases, digestive system diseases, external causes, and other causes.

Discussion: Regular use of PPIs was not associated with an increased risk of all-cause and cause-specific mortality.
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http://dx.doi.org/10.14309/ajg.0000000000001377DOI Listing
July 2021

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

Lancet Oncol 2021 08 9;22(8):1081-1092. Epub 2021 Jul 9.

Department of General Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China.

Background: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy.

Methods: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral capecitabine 1000 mg/m twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546.

Findings: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported.

Interpretation: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer.

Funding: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00297-7DOI Listing
August 2021

MRPS17 promotes invasion and metastasis through PI3K/AKT signal pathway and could be potential prognostic marker for gastric cancer.

J Cancer 2021 11;12(16):4849-4861. Epub 2021 Jun 11.

Digestive Disease Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Zhenyuan Road 628, Guangming District, Shenzhen 518000, Guangdong, China.

In this study, the molecular mechanisms through which Mitochondrial Ribosomal Protein S17 (MRPS17) contributes to gastric cancer (GC) and its prognostic significance in GC have been explored. As a protein encoding gene, MRPS17 encodes a 28s proteins belonging the ribosomal protein S17P family. The specific roles and molecular mechanisms of MRPS17 in cancers remain ambiguous. It was revealed by analyzing data from TCGA and GEO that elevated expression of MRPS17 was significantly associated with invasion of GC and poor survival of GC patients. Then through univariate and multivariate Cox regression analyses it was demonstrated that MRPS17 an independent prognostic factor for GC patients (<0.001). It was demonstrated by differentially expressed gene analysis and functional enrichment analysis that MPRS17 is related to PI3K/AKT pathway and Cell adhesion molecules (CAMs), while its function is mediated by collagen-containing extracellular matrix and receptor ligand/regulator activity. Then it was proven by in-vitro experiments that knocking down of MRPS17 gene in AGS and SGC7901 cells would significantly inhibit proliferation and invasion capability of these cells. Furthermore, it was revealed by cell immunofluorescence assay that as a ribosomalprotein, MRPS17 was mainly distributed in the cytoplasmic surface of cell membrane. Additionally, activation of PI3K/AKT pathway is responsible for malignant progression of glioma that was promoted by MRPS17. In conclusion, it was revealed in the present study that MRPS17 promoted invasion and metastasis of GC and potential molecular mechanisms through which it exerted its influences on GC were explored, suggesting its potential as a novel prognostic biomarker for GC.
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http://dx.doi.org/10.7150/jca.55719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247386PMC
June 2021

Porcine Epidemic Diarrhea Virus Induces Vero Cell Apoptosis via the p53-PUMA Signaling Pathway.

Viruses 2021 06 24;13(7). Epub 2021 Jun 24.

College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China.

Porcine Epidemic Diarrhea Virus (PEDV) is the causative agent of swine epidemic diarrhea. In order to study the pathogenic mechanism of PEDV, PEDV was inoculated into Vero cells cultured in vitro, and the total RNA of Vero cells was extracted to construct a library for Illumina high-throughput sequencing and screening of differentially expressed genes ( < 0.05). Five differentially expressed genes for qRT-PCR verification analysis were randomly selected, and the verification results were consistent with the transcriptome sequencing results. The Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment analysis was performed on the differentially expressed genes screened above. The results showed that the target gene annotations of differentially expressed genes in the African green monkey genome were mainly enriched in the TNF signaling pathway, the P53 signaling pathway, the Jak-STAT signaling pathway, the MAPK signaling pathway, and immune inflammation. In addition, it has been reported that Puma can promote apoptosis and is a key mediator of P53-dependent and non-dependent apoptosis pathways. However, there is no report that PEDV infection can activate Puma and induce apoptosis in a P53-dependent pathway. It was found by flow cytometry that PEDV infection induced apoptosis, and by Western Blotting detection, PEDV infection significantly increased the expression of p53, BAX, and Puma apoptosis-related proteins. Treatment Vero cells with the p53 inhibitor, PFT-α, could significantly inhibit PEDV-induced apoptosis. Studies have shown that PEDV infection can activate Puma and induce apoptosis in a P53-dependent pathway. These findings provide data support for further elucidating the pathogenic mechanism of PEDV and developing an effective vaccine against PEDV.
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http://dx.doi.org/10.3390/v13071218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310168PMC
June 2021

Steroids Enable Mesenchymal Stromal Cells to Promote CD8 T Cell Proliferation Via VEGF-C.

Adv Sci (Weinh) 2021 06 2;8(12):2003712. Epub 2021 May 2.

CAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China.

Mesenchymal stromal cells (MSCs) function as a formidable regulator of inflammation and tissue homeostasis and expanded MSCs are shown to be effective in treating various inflammatory diseases. Their therapeutic effects require the existence of certain inflammatory cytokines. However, in the absence of sufficient proinflammatory stimuli or in the presence of anti-inflammatory medications, MSCs are animated to promote immune responses and unable to alleviate inflammatory disorders. In this study, it is demonstrated that steroid co-administration interferes the efficacy of MSCs in treating acute graft-versus-host disease (aGvHD). Molecular analysis reveals that vascular endothelial growth factor C (VEGF-C) is highly induced in MSCs by steroids and TNF and VEGF-C in turn promotes CD8 T cell response. This immune promoting effect is abolished by blockade or specific genetic ablation of VEGFR3 in CD8 T cells. Additionally, administration of VEGF-C alone exacerbates aGvHD progression through eliciting more vigorous CD8 T cell activation and proliferation. Further studies demonstrate that VEGF-C augments the PI3K/AKT signaling process and the expression of downstream genes, such as Cyclin D1. Thus, the data demonstrate that steroids can reverse the immunosuppressive effect of MSCs via promoting VEGF-C-augmented CD8 T cell response and provide novel information for designing efficacious MSC-based therapies.
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http://dx.doi.org/10.1002/advs.202003712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224440PMC
June 2021

Elderly Male With Cardiovascular-Related Comorbidities Has a Higher Rate of Fatal Outcomes: A Retrospective Study in 602 Patients With Coronavirus Disease 2019.

Front Cardiovasc Med 2021 7;8:680604. Epub 2021 Jun 7.

The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Elderly with comorbidities have shown a higher rate of fatal outcomes when suffering coronavirus disease 2019 (COVID-19). However, a delineation of clinical significances of hematologic indices and underlying comorbidities in the progression and outcome of COVID-19 remains undefined. Six hundred two COVID-19 patients with established clinical outcomes (discharged or deceased) from Hankou Hospital of Wuhan, China between January 14, 2020 and February 29, 2020 were retrospectively analyzed. Of the 602 patients with COVID-19, 539 were discharged and 63 died in the hospital. The deceased group showed higher leukocyte and neutrophil counts but lower lymphocyte and platelet counts. Longer activated partial thromboplastin time (APTT) and prothrombin time (PT), as well as higher D-dimer and C-reactive protein levels, were found in non-survivors. Our observations suggest that these parameters could serve as potential predictors for the fatal outcome and in the discharged group. A higher neutrophil count and D-dimer level but lower lymphocyte were associated with a longer duration of hospitalization. A multivariable Cox regression analysis showed that higher neutrophil count, prolonged PT, and low lymphocyte count were risk factors for patients with COVID-19. Also, we found an association of lower lymphocyte count and higher C-reactive protein levels with the elderly group and those with cardiovascular-related comorbidities. The significantly different hematologic profiles between survivors and non-survivors support that distinct hematologic signatures in COVID-19 patients will dictate different outcomes as a prognostic marker for recovery or fatality. Lymphopenia and aggressive inflammatory response might be major causes for fatal outcomes in the elderly male and especially those with cardiovascular-related comorbidities.
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http://dx.doi.org/10.3389/fcvm.2021.680604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215131PMC
June 2021

Deep learning wavefront sensing method for Shack-Hartmann sensors with sparse sub-apertures.

Opt Express 2021 May;29(11):17669-17682

In this letter, we proposed a deep learning wavefront sensing approach for the Shack-Hartmann sensors (SHWFS) to predict the wavefront from sub-aperture images without centroid calculation directly. This method can accurately reconstruct high spatial frequency wavefronts with fewer sub-apertures, breaking the limitation of d/r ≈ 1 (d is the diameter of sub-apertures and r is the atmospheric coherent length) when using SHWFS to detect atmospheric turbulence. Also, we used transfer learning to accelerate the training process, reducing training time by 98.4% compared to deep learning-based methods. Numerical simulations were employed to validate our approach, and the mean residual wavefront root-mean-square (RMS) is 0.08λ. The proposed method provides a new direction to detect atmospheric turbulence using SHWFS.
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http://dx.doi.org/10.1364/OE.427261DOI Listing
May 2021

Interfacially Engineered [email protected] Hollow Nanospheres for Glutathione Depleting Photothermally Enhanced Chemodynamic Therapy.

ACS Nano 2021 Jun 21. Epub 2021 Jun 21.

Department of Oncology, the First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230036, P. R. China.

Fenton-like reactions driven by manganese-based nanostructures have been widely applied in cancer treatment owing to the intrinsic physiochemical properties of these nanostructures and their improved sensitivity to the tumor microenvironment. In this work, [email protected] composites incorporating alloyed ZnMnS and polydopamine (PDA) were constructed, in which the Fenton-like reactions driven by Mn ions can be tuned by a controllable release of Mn ions and . As a result, the [email protected] exhibited good biocompatibility with normal cells but was specifically toxic to cancer cells. In addition, the shell thickness of PDA was carefully investigated to obtain excellent specific toxicity to cancer cells and promote synergistic chemodynamic and photothermal therapies. Overall, this work highlights an alternative strategy for fabricating high-performance, multifunctional composite nanostructures for a combined cancer treatment.
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http://dx.doi.org/10.1021/acsnano.1c01077DOI Listing
June 2021

Temporal phylogeny and molecular characterization of echovirus 30 associated with aseptic meningitis outbreaks in China.

Virol J 2021 06 6;18(1):118. Epub 2021 Jun 6.

WHO WPRO Regional Polio Reference Laboratory, National Health Commission Key Laboratory of biosafety, National Health Commission Key Laboratory of Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, People's Republic of China.

Background: An outbreak of aseptic meningitis occurred from June to August 2016, in Inner Mongolia Autonomous Region, China.

Methods: To determine its epidemiological characteristics, etiologic agent, and possible origin, specimens were collected for virus isolation and identification, followed by molecular epidemiological analysis.

Results: A total of 363 patients were clinically diagnosed from June 1st to August 31st 2016, and most cases (63.1%, n = 229) were identified between June 22nd and July 17th, with children aged 6 to 12 years constituting the highest percentage (68.9%, n = 250). All viral isolates from this study belonged to genotype C of echovirus 30 (E30), which dominated transmission in China. To date, two E30 transmission lineages have been identified in China, of which Lineage 2 was predominant. We observed fluctuant progress of E30 genetic diversity, with Lineage 2 contributing to increased genetic diversity after 2002, whereas Lineage 1 was significant for the genetic diversity of E30 before 2002.

Conclusions: We identified the epidemiological and etiological causes of an aseptic meningitis outbreak in Inner Mongolia in 2016, and found that Lineage 2 played an important role in recent outbreaks. Moreover, we found that Gansu province could play an important role in E30 spread and might be a possible origin site. Furthermore, Fujian, Shandong, Taiwan, and Zhejiang provinces also demonstrated significant involvement in E30 evolution and persistence over time in China.
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http://dx.doi.org/10.1186/s12985-021-01590-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182919PMC
June 2021

Association of body composition with risk of overall and site-specific cancers: A population-based prospective cohort study.

Int J Cancer 2021 10 4;149(7):1435-1447. Epub 2021 Jun 4.

Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.

Although excess adiposity has been linked with various cancers, association between body composition and some cancers remains unclear, like lung and prostate cancers. We investigated associations of body composition with risk of overall cancer and major site-specific cancers in a prospective cohort of 454 079 cancer-free participants from UK-Biobank. Body composition was measured with bioimpedance analysis. We evaluated hazard ratio (HR) and 95% confidence interval (CI) with multivariate Cox linear and nonlinear models in men and women separately. We identified 27 794 cancers over 7.6 years of follow-up. Multivariable adjusted models including fat-free mass (FFM) and fat mass (FM) showed that FFM was positively associated with overall cancer risk in men and women (HR 1.03, 95% CI 1.01-1.04 and 1.07, 1.04-1.10, respectively); while the association between FM and overall cancer disappeared after adjusting for FFM. FFM was associated with higher risks of obesity-related cancers combined, stomach (women only), malignant melanoma, postmenopausal breast, corpus uteri, prostate, kidney (men only), and blood cancers and lower risk of lung cancer. FM was associated with higher risks of obesity-related cancers combined, esophageal, colon, lung (men only), postmenopausal breast (at the lower end of FM range), and corpus uteri cancers and lower risks of rectal, malignant melanoma (women only), prostate and blood cancers. FFM and FM seemed to have different effects on cancer risk, and the effects varied substantially by cancer type, in both direction and size. Higher FM/FFM ratio was also associated with some cancers risk, and might be a useful predictor of cancer risk.
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http://dx.doi.org/10.1002/ijc.33697DOI Listing
October 2021

The Effect of Multidisciplinary Team Discussion Intervention on the Prognosis of Advanced Colorectal Cancer.

J Cancer 2021 7;12(11):3307-3314. Epub 2021 Apr 7.

Digestive Disease Center, Seventh Affiliated Hospital of Sun Yat-Sen University.

The effects of multidisciplinary team discussion intervention on the treatment and prognosis of advanced colorectal cancer are still controversial. Large sample size studies to evaluate the efficacy in patients with advanced colorectal cancer are lacking. We statistically analyzed the data of surgical patients diagnosed with advanced colorectal cancer from 2008 to 2014 by retrospective analysis. Patients were divided into two groups according to whether or not they received multidisciplinary team discussion intervention. After at least 3 years of follow up, differences between two groups were compared with respect to treatment process and patient prognosis. The time to treatment in intervention group was shorter (9.6 ± 4.2 days vs 10.7 ± 5.6 days; p= 0.002). There were no significant differences in recurrence and metastasis rate between the two groups. Multivariate survival analysis suggested that multidisciplinary team discussion intervention reduced the risk of death (HR = 0.677; p = 0.006). And it had significant interaction with tumor invasion and tumor stage, and especially had beneficial effects in the tumor stage IV subgroup (p=0.005) and tumor invasion T4 subgroup (p<0.001). Multidisciplinary team discussion intervention accelerated the treatment process and reduced the death risk of patients with advanced colorectal cancer, especially improved the overall survival of stage IV and invasion T4 patients. The clinical characteristics of tumor invasion and tumor stage must be the primary considerations when judging whether patients need to conduct multidisciplinary team discussions.
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http://dx.doi.org/10.7150/jca.56171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100813PMC
April 2021

Overexpression of ZNF460 predicts worse survival and promotes metastasis through JAK2/STAT3 signaling pathway in patient with colon cancer.

J Cancer 2021 2;12(11):3198-3208. Epub 2021 Apr 2.

Digestive Disease Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.

Zinc finger proteins (ZNFs) are a class of protein containing zinc finger domains, and they play an important role in tumor progression. However, as a member of the ZNFs family, the effect of ZNF460 in colon cancer remains unclear. In this study, we found that the expression of ZNF460 protein were markedly increased in clinical colon cancer tissues compared with para-cancer non-cancerous tissues by tissue immunohistochemistry (IHC) and western blot (WB). We also confirmed this result at the mRNA and protein levels of ZNF460 through bioinformatics analysis. In addition, high expression of ZNF460 was correlated with increased depth of invasion (P<0.05), increased lymph node metastasis (P<0.05), distant metastasis (P<0.05) and high blood serum CA19-9 level (P<0.05). High expression of ZNF460 predicted poor overall survival (OS) and recurrence free survival (RFS) in patients with colon cancer. Moreover, multivariate analyses revealed that ZNF460 was an independent prognostic factor in both OS (hazard ratio [HR]: 1.636; 95% confidence interval [CI], 1.028-2.603; P = 0.038) and RFS (HR: 2.215; 95% CI: 1.227-3.997; P = 0.008). The knockdown of ZNF460 suppressed the invasion and metastasis of colon cancer cells . Mechanistically, we revealed that ZNF460 promotes the activation of the JAK2/STAT3 signaling pathway in colon cancer cells. Taken together, overexpression of ZNF460 predicted worse survival and promoted metastasis through JAK2/STAT3 signaling pathway in patient with colon cancer, and could be a novel therapeutic target in colon cancer.
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http://dx.doi.org/10.7150/jca.55079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100796PMC
April 2021

KLF5 Is Activated by Gene Amplification in Gastric Cancer and Is Essential for Gastric Cell Proliferation.

Cells 2021 04 24;10(5). Epub 2021 Apr 24.

Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.

Gastric cancer is the third leading cause of cancer death worldwide. In this study, we tried to clarify the function of in gastric cancer. Copy number variation (CNV) and the expression of were interrogated in public datasets. The clinical significance of amplification and gene expression in gastric cancer were evaluated. The function of in cell proliferation was studied in gastric cancer cell lines and organoids. We found that amplification mainly occurred in the chromosome instable tumors (CIN) and was significantly associated with mutation. In addition, higher expression correlated with more locally invasive gastric cancer and higher T stage. Next, a gene expression signature was curated. The genes in the signature were involved in cell development, cell cycle regulation, cell death, suggesting potential roles played by . Functional studies using siRNAs revealed that was essential for the proliferation of gastric cancer cells. Finally, using gastric organoid models, we revealed that the proliferation of organoids was significantly inhibited after the down regulation of . Our study revealed that was amplified and over-expressed in gastric cancer, and it may play an oncogene-like role in gastric cancer by supporting cell proliferation.
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http://dx.doi.org/10.3390/cells10051002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152363PMC
April 2021

STIP1 knockdown suppresses colorectal cancer cell proliferation, migration and invasion by inhibiting STAT3 pathway.

Chem Biol Interact 2021 May 23;341:109446. Epub 2021 Mar 23.

Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China. Electronic address:

Stress-induced phosphoprotein 1 (STIP1) plays an important role in cancer tumorigenesis and progression. However, the role of STIP1 in colorectal cancer (CRC) remains unclear. This study aimed to explore clinical significance, biological function and potential molecular mechanism of STIP1 in CRC. Immunohistochemistry (IHC) and Western bolt were performed to detect STIP1 protein level in CRC and adjacent normal tissues. DLD1 and HCT116 cell lines were treated with shSTIP1, cell proliferation was detected by CCK8 and colony formation assays, and cell migration and invasion were detected by wound healing and transwell assays. Moreover, western blot and immunofluorescence assays were performed to explore the potential molecular mechanism of STIP1 in the progression of CRC. We found that STIP1 expression in CRC tissues was significantly higher than in adjacent normal tissues. High STIP1 expression was associated with poor overall survival (OS) in CRC patients. Furthermore, secreted STIP1 promoted CRC cell proliferation and invasion through STAT3 signaling pathway, while STIP1 knockdown inhibited the proliferation, migration and invasion of CRC cells. Mechanistically, STIP1 knockdown suppressed the activation of STAT3 signaling pathway in CRC. In conclusion, STIP1 knockdown suppresses CRC cell proliferation, migration and invasion by inhibiting the activation of STAT3 signaling, and STIP1 is a potential target for CRC therapy.
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http://dx.doi.org/10.1016/j.cbi.2021.109446DOI Listing
May 2021

Correction to: Long non-coding RNA H19 promotes colorectal cancer metastasis via binding to hnRNPA2B1.

J Exp Clin Cancer Res 2021 Mar 23;40(1):111. Epub 2021 Mar 23.

Center for Digestive Disease, the Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, 518000, Guangdong, China.

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http://dx.doi.org/10.1186/s13046-021-01911-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988987PMC
March 2021

Identification of Stemness Characteristics Associated With the Immune Microenvironment and Prognosis in Gastric Cancer.

Front Oncol 2021 3;11:626961. Epub 2021 Mar 3.

Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.

Background: Gastric cancer (GC) is a highly heterogeneous disease. In recent years, the prognostic value of the mRNA expression-based stemness index (mRNAsi) across cancers has been reported. We intended to identify stemness index-associated genes (SI-genes) for clinical characteristic, gene mutation status, immune response, and tumor microenvironment evaluation as well as risk stratification and survival prediction.

Methods: The correlations between the mRNAsi and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were evaluated. Weighted gene correlation network analysis (WGCNA) was performed to identify SI-genes from differentially expressed genes (DEGs) in The Cancer Genome Atlas (TCGA). Single-sample gene set enrichment analysis (ssGSEA) was employed to calculate the sample SI-gene-based ssGSEA score according to the SI-genes. Then, the correlations between the ssGSEA score and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were analyzed. Finally, the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to construct a prognostic signature with prognostic SI-genes. The ssGSEA score and prognostic signature were validated using the Gene Expression Omnibus (GEO) database.

Results: The mRNAsi could predict overall survival (OS), clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Fourteen positive SI-genes and 178 negative SI-genes were screened out using WGCNA. The ssGSEA score, similar to the mRNAsi, was found to be closely related to OS, clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Finally, a prognostic signature based on 18 prognostic SI-genes was verified to more accurately predict GC 1-year, 3-year, and 5-year OS than traditional clinical prediction models.

Conclusion: The ssGSEA score and prognostic signature based on 18 prognostic SI-genes are of great value for immune response evaluation, risk stratification and survival prediction in GC and suggest that stemness features are crucial drivers of GC progression.
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http://dx.doi.org/10.3389/fonc.2021.626961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966731PMC
March 2021

Derivation and Validation of a Prognostic Model for Cancer Dependency Genes Based on CRISPR-Cas9 in Gastric Adenocarcinoma.

Front Oncol 2021 25;11:617289. Epub 2021 Feb 25.

Digestive Disease Center, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

As a CRISPR-Cas9-based tool to help scientists to investigate gene functions, Cancer Dependency Map genes (CDMs) include an enormous series of loss-of-function screens based on genome-scale RNAi. These genes participate in regulating survival and growth of tumor cells, which suggests their potential as novel therapeutic targets for malignant tumors. By far, studies on the roles of CDMs in gastric adenocarcinoma (GA) are scarce and only a small fraction of CDMs have been investigated. In the present study, datasets of the differentially expressed genes (DEGs) were extracted from the TCGA-based (The Cancer Genome Atlas) GEPIA database, from which differentially expressed CDMs were determined. Functions and prognostic significance of these verified CDMs were evaluated using a series of bioinformatics methods. In all, 246 differentially expressed CDMs were determined, with 147 upregulated and 99 downregulated. Ten CDMs (ALG8, ATRIP, CCT6A, CFDP1, CINP, MED18, METTL1, ORC1, TANGO6, and PWP2) were identified to be prognosis-related and subsequently a prognosis model based on these ten CDMs was constructed. In comparison with that of patients with low risk in TCGA training, testing and GSE84437 cohort, overall survival (OS) of patients with high risk was significantly worse. It was then subsequently demonstrated that for this prognostic model, area under the ROC (receiver operating characteristic) curve was 0.771 and 0.697 for TCGA training and testing cohort respectively, justifying its reliability in predicting survival of GA patients. With the ten identified CDMs, we then constructed a nomogram to generate a clinically practical model. The regulatory networks and functions of the ten CDMs were then explored, the results of which demonstrated that as the gene significantly associated with survival of GA patients and Hazard ratio (HR), PWP2 promoted invasion and migration of GA cell lines through the EMT signaling pathway. Therefore, in conclusion, the present study might help understand the prognostic significance and molecular functions of CDMs in GA.
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http://dx.doi.org/10.3389/fonc.2021.617289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959733PMC
February 2021
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