Microbiome and its relevance to indigenous inflammatory bowel diseases in China.

BACKGROUND: Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with an unknown etiology. Although dysbiosis is implicated in its pathogenesis, deep sequencing and oral microbiota study in Chinese IBD patients is absent. AIM: To explore the role of oral / intestinal microbiota in patients with IBD and the potential associations therein. METHODS: Clinical data, fecal and saliva samples were harvested from 80 patients with IBD (Crohn's disease, CD, n = 69; Ulcerative colitis, UC, n = 11) and 24 normal controls. Microbiomics (16S rRNA sequencing and 16S rRNA full-length sequencing) were used to detect and analyze the difference between IBD patients and normal control. RESULTS: Compared with normal controls, a higher abundance of the intestinal Shigella spp. (Shigella flexneri and Shigella sonnei, which were positively relate to the severity of IBD), lower abundance of intestinal probiotics (Prevotella, Faecalibacterium and Roseburia), and higher abundance of oral Neisseria were present in IBD patients with microbiome. The higher inflammation-related markers, impaired hepatic and renal function, and dyslipidaemia were present in patients with IBD. A higher intake of red meat and increased abundance of Clostridium in the gut were found in CD patients, while the elevated abundance of Ruminococcus in the gut was showed in UC ones. The bacterial composition of saliva and fecal samples was completely different, yet there was some correlation in the distribution of dominant probiotics. CONCLUSION: Enteric dysbacteriosis and the infections of pathogenic bacteria (Shigella) may associate with the occurrence or development of IBD.

Forefronts and hotspots evolution of the nanomaterial application in anti-tumor immunotherapy: a scientometric analysis.

BACKGROUND: Tumor immunotherapy can not only eliminate the primary lesion, but also produce long-term immune memory, effectively inhibiting tumor metastasis and recurrence. However, immunotherapy also showed plenty of limitations in clinical practice. In recent years, the combination of nanomaterials and immunotherapy has brought new light for completely eliminating tumors with its fabulous anti-tumor effects and negligible side effects. METHODS: The Core Collection of Web of Science (WOSCC) was used to retrieve and obtain relevant literatures on antitumor nano-immunotherapy since the establishment of the WOSCC. Bibliometrix, VOSviewer, CiteSpace, GraphPad Prism, and Excel were adopted to perform statistical analysis and visualization. The annual output, active institutions, core journals, main authors, keywords, major countries, key documents, and impact factor of the included journals were evaluated. RESULTS: A total of 443 related studies were enrolled from 2004 to 2022, and the annual growth rate of articles reached an astonishing 16.85%. The leading countries in terms of number of publications were China and the United States. Journal of Controlled Release, Biomaterials, Acta Biomaterialia, Theranostics, Advanced Materials, and ACS Nano were core journals publishing high-quality literature on the latest advances in the field. Articles focused on dendritic cells and drug delivery accounted for a large percentage in this field. Key words such as regulatory T cells, tumor microenvironment, immune checkpoint blockade, drug delivery, photodynamic therapy, photothermal therapy, tumor-associated macrophages were among the hottest themes with high maturity. Dendritic cells, vaccine, and T cells tend to become the popular and emerging research topics in the future. CONCLUSIONS: The combined treatment of nanomaterials and antitumor immunotherapy, namely antitumor nano-immunotherapy has been paid increasing attention. Antitumor nano-immunotherapy is undergoing a transition from simple to complex, from phenotype to mechanism.

Validation of quercetin in the treatment of colon cancer with diabetes via network pharmacology, molecular dynamics simulations, and in vitro experiments.

This study built a prognostic model for CRC-diabetes and analyzed whether quercetin could be used for CRC-diabetes treatment through a network of pharmacology, molecular dynamics simulation, bioinformatics, and in vitro experiments. First, multivariate Cox proportional hazards regression was used to construct the prognosis modelof CRC-diabetes. Then, the intersection of quercetin target genes with CRC-diabetes genes was used to find the potential target for quercetin in the treatment of CRC-diabetes. Molecular docking and molecular dynamics simulations were used to screen the potential targets for quercetin in the treatment of CRC-diabetes. Finally, we verified the target and pathway of quercetin in the treatment of CRC-diabetes through in vitro experiments. Through molecular docking, seven proteins (HMOX1, ACE, MYC, MMP9, PLAU, MMP3, and MMP1) were selected as potential targets of quercetin. We conducted molecular dynamics simulations of quercetin and the above proteins, respectively, and found that the binding structure of quercetin with MMP9 and PLAU was relatively stable. Finally, according to the results of Western blot results, it was confirmed that quercetin could interact with MMP9. The experimental results show that quercetin may affect the JNK pathway, glycolysis, and epithelial-mesenchymal transition (EMT) to treat CRC-diabetes. Based on the TCGA, TTD, DrugBank, and other databases, a prediction model that can effectively predict the prognosis of colon cancer patients with diabetes was constructed. According to experiment results, quercetin can regulate the expression of MMP9. By acting on the JNK pathway, glycolysis, and EMT, it can treat colon cancer patients with diabetes.

A real-word study: is normothermic intraoperative intraperitoneal chemotherapy impactful as we expect?

Background: Patients with gastric cancer have a poor prognosis. Currently, intraperitoneal chemotherapy has been considered a therapeutic option to improve prognosis due to its appealing theoretical rationales. But there is no consensus on the choice of chemotherapeutic agents used in intraperitoneal chemotherapy for gastric cancer. The real-world efficacy of applying intraoperative chemotherapy in gastric cancer still remains undefined. Methods: Patients with gastric cancer who underwent radical gastrectomy at the Gastrointestinal Department of The First Affiliated Hospital of Anhui Medical University between 2012 and 2019 were enrolled in this study. Patients were divided into two groups based on whether they received intraperitoneal chemotherapy. The t-test (mean of two samples) was conducted to compare the difference in measurement data between the two groups, and the chi-square test was used to compare the difference in count data. Kaplan-Meier method with log-rank test was performed to analyze the overall survival of patients. Kaplan-Meier method with log-rank test was also performed in various subgroups to respectively compare the survival of patients. Multivariate Cox analysis was performed to analyze the prognosis factors of these patients. Results: A total of 1253 patients were included in the final analysis, in which 861 patients received intraperitoneal chemotherapy and 352 not received intraperitoneal chemotherapy. The clinicopathological features of the participants in the two groups were comparable. There was no significant difference between the two groups in overall survival (P > 0.05). Consistently, no significant difference was found between the two groups in each subgroup (P > 0.05). The multivariate Cox analysis demonstrated that only age, BMI, pathological type, TNM stage, and differentiation grade were independent risk factors of survival. Conclusion: Intraoperative intraperitoneal chemotherapy usage did not improve survival in patients with gastric cancer undergoing radical gastrectomy.

GRK2 Mediates Macrophage Polarization by Regulating EP4-cAMP-pCREB Signaling in Ulcerative Colitis and the Therapeutic Effect of Paroxetine on Mice with DSS-Induced Colitis.

G protein-coupled receptor kinase 2 (GRK2) is one of the cytosolic enzymes, and GRK2 translocation induces prostaglandin E2 receptor 4 (EP4) over-desensitization and reduces the level of cyclic adenosine monophosphate (cAMP) to regulate macrophage polarization. However, the role of GRK2 in the pathophysiology of ulcerative colitis (UC) remains unclear. In this study, we investigated the role of GRK2 in macrophage polarization in UC, using biopsies from patients, a GRK2 heterozygous mouse model with dextran sulfate sodium (DSS)-induced colitis, and THP-1 cells. The results showed that a high level of prostaglandin E2 (PGE2) stimulated the receptor EP4 and enhanced the transmembrane activity of GRK2 in colonic lamina propria mononuclear cells (LPMCs), resulting in a down-regulation of membrane EP4 expression. Then, the suppression of cAMP-cyclic AMP responsive element-binding (CREB) signal inhibited M2 polarization in UC. Paroxetine is acknowledged as one of the selective serotonin reuptake inhibitors (SSRI), which is also considered as a potent GRK2 inhibitor with a high selectivity for GRK2. We found that paroxetine could alleviate symptoms of DSS-induced colitis in mice by regulating GPCR signaling to affect macrophage polarization. Taken together, the current results show that GRK2 may act as a novel therapeutic target in UC by regulating macrophage polarization, and paroxetine as a GRK2 inhibitor may have therapeutic effect on mice with DSS-induced colitis.

Retracted: Long Chain Non-Coding RNA (lncRNA) HOTAIR Knockdown Increases miR-454-3p to Suppress Gastric Cancer Growth by Targeting STAT3/Cyclin D1.

This publication has been retracted by the Editor due to the identification of non-original figure images and manuscript content that raise concerns regarding the credibility and originality of the study and the manuscript. Reference: Jiang, He Li, Heping Xiang, Ming Gao, Chunlin Yin, Haiping Wang, Yuansong Sun, Maoming Xiong. Long Chain Non-Coding RNA (lncRNA) HOTAIR Knockdown Increases miR-454-3p to Suppress Gastric Cancer Growth by Targeting STAT3/Cyclin D1. Med Sci Monit, 2019; 25: 1537-1548. DOI: 10.12659/MSM.913087.

A novel signature based on CeRNA and immune status predicts prognostic risk and drug sensitivity in gastric cancer patients.

Background: At present, there is increasing evidence that both competitive endogenous RNAs (ceRNAs) and immune status in the tumor microenvironment (TME) can affect the progression of gastric cancer (GC), and are closely related to the prognosis of patients. However, few studies have linked the two to jointly determine the prognosis of patients with GC. This study aimed to develop a combined prognostic model based on ceRNAs and immune biomarkers. Methods: First, the gene expression profiles and clinical information were downloaded from TCGA and GEO databases. Then two ceRNA networks were constructed on the basis of circRNA. Afterwards, the key genes were screened by univariate Cox regression analysis and Lasso regression analysis, and the ceRNA-related prognostic model was constructed by multivariate Cox regression analysis. Next, CIBERSORT and ESTIMATE algorithms were utilized to obtain the immune cell infiltration abundance and stromal/immune score in TME. Furthermore, the correlation between ceRNAs and immunity was found out through co-expression analysis, and another immune-related prognosis model was established. Finally, combining these two models, a comprehensive prognostic model was built and visualized with a nomogram. Results: The (circRNA, lncRNA)-miRNA-mRNA regulatory network of GC was constructed. The predictive power of ceRNA-related and immune-related prognosis models was moderate. Co-expression analysis showed that the ceRNA network was correlated with immunity. The integrated model of combined ceRNAs and immunity in the TCGA training set, the AUC values of 1, 3, and 5-year survival rates were 0.78, 0.76, and 0.78, respectively; in the independent external validation set GSE62254, they were 0.81, 0.79, and 0.78 respectively; in GSE15459, they were 0.84, 0.88 and 0.89 respectively. Besides, the prognostic score of the comprehensive model can predict chemotherapeutic drug resistance. Moreover, we found that plasma variant translocation 1 (PVT1) and infiltrating immune cells (mast cells) are worthy of further investigation as independent prognostic factors. Conclusions: Two ceRNA regulatory networks were constructed based on circRNA. At the same time, a comprehensive prognosis model was established, which has a high clinical significance for prognosis prediction and chemotherapy drug selection of GC patients.

Survival nomogram for different grades of gastric cancer patients based on SEER database and external validation cohort.

Background: Influencing factors varied among gastric cancer (GC) for different differentiation grades which affect the prognosis accordingly. This study aimed to develop a nomogram to effectively identify the overall survival (OS). Methods: Totally, 9,568 patients with GC were obtained from the SEER database as the training cohort and internal validation cohort. We then retrospectively enrolled patients diagnosed with GC to construct the external validation cohort from the First Affiliated Hospital of Anhui Medical University. The prognostic factors were integrated into the multivariate Cox regression to construct a nomogram. To test the accuracy of the model, we used the calibration curves, receiver operating characteristics (ROC) curves, C-index, and decision curve analysis (DCA). Results: Race chemotherapy, tumor size, and other four factors were significantly associated with the prognosis of Grade III GC Patients. On this basis, we developed a nomogram. The discrimination of the nomogram revealed good prognostic accuracy The results of the area under the curve (AUC) calculated by ROC for five-year survival were 0.828 and 0.758 in the training set and external validation cohort, higher than that of the TNM staging system. The calibration plot revealed that the estimated risk was close to the actual risk. DCA also suggested an excellent predictive value of the nomogram. Similar results were obtained in Grade-I and Grade-II GC patients. Conclusions: The nomogram developed in this study and other findings could help individualize the treatment of GC patients and assist clinicians in their shared decision-making with patients.

Tumor-Derived Lactate Creates a Favorable Niche for Tumor via Supplying Energy Source for Tumor and Modulating the Tumor Microenvironment.

Tumor evolution is influenced by events involving tumor cells and the environment in which they live, known as the tumor microenvironment (TME). TME is a functional and structural niche composed of tumor cells, endothelial cells (ECs), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells (MSCs), and a subset of immune cells (macrophages, dendritic cells, natural killer cells, T cells, B cells). Otto Warburg revealed the Warburg effect in 1923, a characteristic metabolic mechanism of tumor cells that performs high glucose uptake and excessive lactate formation even in abundant oxygen. Tumor tissues excrete a large amount of lactate into the extracellular microenvironment in response to TME's hypoxic or semi-hypoxic state. High lactate concentrations in tumor biopsies have been linked to metastasis and poor clinical outcome. This indicates that the metabolite may play a role in carcinogenesis and lead to immune escape in TME. Lactate is now recognized as an essential carbon source for cellular metabolism and as a signaling molecule in TME, forming an active niche that influences tumor progression. This review summarized the advanced literature demonstrating the functional role of lactate in TME remodeling, elucidating how lactate shapes the behavior and the phenotype of both tumor cells and tumor-associated cells. We also concluded the intriguing interactions of multiple immune cells in TME. Additionally, we demonstrated how lactate functioned as a novel function factor by being used in a new histone modification, histone lysine lactylation, and to regulate gene expression in TME. Ultimately, because lactate created a favorable niche for tumor progression, we summarized potential anti-tumor strategies targeting lactate metabolism and signaling to investigate better cancer treatment.

A high bile acid environment promotes apoptosis and inhibits migration in pancreatic cancer.

Bile acids, the main organic solutes in bile, have been established to play an important role at physiological concentrations in gastrointestinal metabolism. However, under pathological conditions, such as cholestatic disease, cholestasis can damage hepatocytes/biliary epithelial cells leading to apoptosis or necrosis. Clinically, pancreatic head cancer usually presents with obstructive jaundice and increased serum bile acid levels, suggesting that pancreatic cancer is intricately correlated with a high bile acid environment in the human body. An increasing body of evidence suggests that bile acids are toxic to normal human and colon cancer cells. Nonetheless, the effect of bile acids on the occurrence and development of pancreatic cancer remains a matter of debate. In the present study, to explore the direct effects of high serum concentrations of bile acids on pancreatic cancer and the possible related mechanisms, human pancreatic cancer (PANC-1) cells were subject to different concentrations of bile acid mixtures to assess cell viability and the migration and invasion ability. Besides, we found that a high bile acid environment could inhibit the proliferation and migration of pancreatic cancer cells through ROS(Reactive oxygen species) induction and the EMT(epithelial-mesenchymal transition) pathway, thereby promoting the apoptosis of pancreatic cancer cells.Abbreviations BAs: Bile Acids; EMT: epithelial-mesenchymal transition; FBS: fatal bovine serum;CCK-8: Cell-Counting-Kit-8; ROS: reactive oxygen species; CA: cholic acid; CDCA: chenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; PVDF: Poly vinylidene fluoride.

Development and Validation of a Pyroptosis-Related Signature for Predicting Prognosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has emerged as a primary health problem and threat to global mortality, especially in China. Since pyroptosis as a new field for HCC prognosis is not well studied, it is important to open a specific prognostic model. In this study, consensus clustering method for 42 pyroptosis-related genes to classify 374 HCC patients in the TCGA database. After cox regression analysis of the differentially expressed genes between the two clusters, LASSO-Cox analysis was then performed to construct a pyroptosis-related prognostic model with 11 genes including MMP1, KPNA2, LPCAT1, NEIL3, CDCA8, SLC2A1, PSRC1, CBX2, HAVCR1, G6PD, MEX3A. The ICGC dataset was served as the validation cohort. Patients in the high-risk group had significantly lower overall survival (OS) rates than those in the low-risk group (p < 0.05). COX regression analysis showed that our model could be used as an independent prognostic factor to predict prognosis of patients and was significantly correlated with clinicopathological characteristics. Nomogram showing the stability of the model predicting the 1, 3, 5 year survival probability of patients. In addition, based on the risk model, ssGSEA analysis revealed significant differences in the level of immune cell infiltration and activation of immune-related functional pathways between high and low-risk groups, and patients with the high-risk score may benefit more from treatment with immune checkpoint inhibitors. Furthermore, patients in the high-risk group were more tend to develop chemoresistance. Overall, we identified a novel pyroptosis-related risk signature for prognosis prediction in HCC patients and revealed the overall immune response intensity of the tumor microenvironment. All these findings make the pyroptosis signature shed light upon a latent therapeutic strategy aimed at the treatment and prevention of cancers.

Hyperglycemia induces miR-26-5p down-regulation to overexpress PFKFB3 and accelerate epithelial-mesenchymal transition in gastric cancer.

Gastric cancer (GC) is one of the most deadly malignancies with high morbidity worldwide. Cancer cells exhibited higher level of glucose catabolism than normal cells to meet the needs for rapid growth. Emerging evidences indicated that hyperglycemia has positive effects on the progression of tumor. As a vital regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) was confirmed to have a higher expression level in tumor tissue and correlated with the prognosis of GC patients. However, the role of PFKFB3 in GC patients with hyperglycemia remains unclear. The data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were utilized to analyze the expression level of PFKFB3 and conducted survival analysis of GC patients. Western blot assay was used to detect gene expression at the protein level. Small interfering RNA (siRNA) transfection assay was conducted to down-regulate the expression of PFKFB3. Cell functional assays were carried out to reflect the ability of cell proliferation and migration. The results indicated that PFKFB3 was significantly upregulated and its overexpression was associated with poor prognosis of GC patients. Besides, hyperglycemia stimulated the higher expression of PFKFB3 along with the enhanced proliferation, migration and epithelial-mesenchymal transition (EMT) in GC cells. Knocking down of PFKFB3 effectively reversed the effects of high glucose concentration on GC malignant phenotype and the opposite results were gained when miR-26-5p was inhibited. Therefore, PFKFB3 down-regulated by miR-26-5p inhibited the malignant phenotype of GC with hyperglycemia.

Hypoxia-Related Gene-Based Signature Can Evaluate the Tumor Immune Microenvironment and Predict the Prognosis of Colon Adenocarcinoma Patients.

BACKGROUND: Colon adenocarcinoma (COAD) is a common gastrointestinal tumor and often occurs in the left colon with a poor prognosis. The progression of COAD is closely related to the tumor microenvironment, especially the hypoxia. Currently, few studies have reported the correlation between hypoxia-related genes and the prognosis of COAD patients. Furthermore, we constructed a prognostic model using four hypoxia-related genes to predict the prognosis of COAD patients. METHODS: The mRNA expression profiles and corresponding clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The string online analysis tool was used to construct a protein-protein interaction network (PPI) of hypoxia-related genes. Kaplan-Meier curve was used to analyze the relationship of hypoxia risk score and the overall survival of COAD patients, and the receiver operating characteristic (ROC) curve was used to assess the reliability. RESULTS: We screened out four hypoxia genes, including TKTL1 (transketolase like 1), SLC2A3 (solute carrier family 2 member 3), ALDOB (aldolase, fructose-bisphosphate B) and ENO3 (enolase 3), which were used to construct a hypoxia risk model to predict the overall survival of COAD patients. Besides, we also found that the hypoxia risk score was correlated with the immunosuppression of tumor microenvironment. CONCLUSION: The model we constructed with four survival-related hypoxia genes, including TKTL1, SLC2A3, ALDOB and ENO3, could be used to predict the overall survival of COAD patients with high stability.

Integrative analysis of prognostic value and immune infiltration of spindle and kinetochore-associated family members in breast cancer.

Spindle and kinetochore associated (SKA) complex subunit, which maintains the stability of mitotic metaphase, with emerging research implying its effect as a carcinogenic regulator in cancer. However, its potential role in BC has not been fully elucidated. ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, cBioPortal and TIMER databases were performed to analyze the expression, prognosis, mutation, immune infiltration and potential biological mechanisms of SKA1/2/3 in BC. Our results showed that SKA1/2/3 expression was upregulated in BC. Survival analysis reveals that SKA3 overexpression was associated with poor overall survival (OS), relapse-free survival (RFS), post-progression survival (PPS) and distant metastasis-free survival (DMFS). SKA1 overexpression was associated with poor OS, RFS and DMFS while SKA2 overexpression was only associated with RFS and DMFS. Notably, the results implied that SKA1 has a good prognostic value in HER2-positive BC. Besides, the genetic alterations of SKA were investigated and the altered group correlated with shorter progress-free survival (PFS) and disease-specific survival (DSS). GO and KEGG analysis showed that SKA1/2/3 were implicated in regulating cell cycle, p53 signaling pathway and DNA replication. The 10 Hub genes in the protein network were upregulated in BC and related to poorer prognosis. Additionally, SKA1/2/3 expression was negatively correlated with infiltration of various immune cells with antitumor effects, whereas positively correlated with the expression of immune checkpoints molecules. Further experiments revealed that SKA1/2/3 silencing markedly impeded the proliferation and migration of BC cells. Herein, our study firmly shows that SKA genes may serve as a promising therapeutic target for patients with BC.

Fenton/Fenton-like metal-based nanomaterials combine with oxidase for synergistic tumor therapy.

Chemodynamic therapy (CDT) catalyzed by transition metal and starvation therapy catalyzed by intracellular metabolite oxidases are both classic tumor treatments based on nanocatalysts. CDT monotherapy has limitations including low catalytic efficiency of metal ions and insufficient endogenous hydrogen peroxide (H2O2). Also, single starvation therapy shows limited ability on resisting tumors. The "metal-oxidase" cascade catalytic system is to introduce intracellular metabolite oxidases into the metal-based nanoplatform, which perfectly solves the shortcomings of the above-mentioned monotherapiesIn this system, oxidases can not only consume tumor nutrients to produce a "starvation effect", but also provide CDT with sufficient H2O2 and a suitable acidic environment, which further promote synergy between CDT and starvation therapy, leading to enhanced antitumor effects. More importantly, the "metal-oxidase" system can be combined with other antitumor therapies (such as photothermal therapy, hypoxia-activated drug therapy, chemotherapy, and immunotherapy) to maximize their antitumor effects. In addition, both metal-based nanoparticles and oxidases can activate tumor immunity through multiple pathways, so the combination of the "metal-oxidase" system with immunotherapy has a powerful synergistic effect. This article firstly introduced the metals which induce CDT and the oxidases which induce starvation therapy and then described the "metal-oxidase" cascade catalytic system in detail. Moreover, we highlight the application of the "metal-oxidase" system in combination with numerous antitumor therapies, especially in combination with immunotherapy, expecting to provide new ideas for tumor treatment.

FHL3 Contributes to EMT and Chemotherapy Resistance Through Up-Regulation of Slug and Activation of TGFß/Smad-Independent Pathways in Gastric Cancer.

BACKGROUND: Gastric cancer presents high risk of metastasis and chemotherapy resistance. Hence, it is important to understand the mechanisms of gastric cancer distant metastasis and chemotherapeutic resistance. Our previous study has revealed Four and a Half LIM Domains 3 (FHL3) plays as a binding partner of Glycogen Synthase Kinase 3 Beta (GSK3ß), promoted tumor metastasis in pancreatic cancer. However, the role of FHL3 in gastric cancer still remains unclear. METHODS: TCGA database and clinical samples are used for exploring the role of FHL3 in disease progression and prognosis. Oxaliplatin (OHP) resistance cell lines were established to study the role of FHL3 in chemotherapy resistance. The experiments about cell proliferation, apoptosis, and metastasis were performed to measure the chemotherapy effects of sh-FHL3 on gastric cancer cell lines and in vivo. That FHL3 changed the EMT phenotype was verified by western blot. Finally, we explored the mechanism of FHL3-mediated EMT and chemotherapy resistance. RESULTS: mRNA and protein level of FHL3 were significantly up-regulated in gastric cancer tissues when compared with adjacent tissue. FHL3 higher expression is always accompanied with higher TNM stage and worse overall survival. FHL3 over-expressed could lead to OHP resistance. Knockdown of FHL3 slightly inhibited the cell growth, while it obviously sensitized the chemotherapy in vivo and in vitro. In addition, down-regulation of FHL3 increased the mesenchymal markers, such as Slug, Snail, Twist Family BHLH Transcription Factor 1 (Twist1), and Vimentin, while it decreased the epithelial marker E-cadherin. Cell and animal experiments also proved that down-regulation of FHL3 can decrease cancer cell metastasis. For mechanism study, FHL3 knockdown down-regulated the expression level of Mitogen-Activated Protein Kinase (MAPK)/Extracellular Regulated Protein Kinase (ERK) pathway and Transforming Growth Factor-ß (TGFß)/Phosphatidylinositol 3-Kinase (PI3K)/protein kinase B(Akt)/GSK3ß-(Ring Finger Protein 146) RNF146/ubiquitin pathway. FHL3 competitively bonded the ubiquitin complex (Slug/GSK3ß/RNF146) with Slug and inhibited ubiquitination of Slug. Mesenchymal phenotype cells hold higher level of Multidrug Resistance Gene1 (MDR1), and the FHL3 knockdown reverts the MDR1 in this type cell. CONCLUSION: FHL3 high expression contributed to EMT and chemotherapy resistance via MAPK, and PI3K pathways were activated. FHL3 competitively bonded the ubiquitin complex with Slug, resulting in the up-regulation of Slug and leading to metastasis of gastric cancer.

A 4-gene-based hypoxia signature is associated with tumor immune microenvironment and predicts the prognosis of pancreatic cancer patients.

BACKGROUND: Pancreatic cancer (PAC) is one of the most devastating cancer types with an extremely poor prognosis, characterized by a hypoxic microenvironment and resistance to most therapeutic drugs. Hypoxia has been found to be one of the factors contributing to chemoresistance in PAC, but also a major driver of the formation of the tumor immunosuppressive microenvironment. However, the method to identify the degree of hypoxia in the tumor microenvironment (TME) is incompletely understood. METHODS: The mRNA expression profiles and corresponding clinicopathological information of PAC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, respectively. To further explore the effect of hypoxia on the prognosis of patients with PAC as well as the tumor immune microenvironment, we established a hypoxia risk model and divided it into high- and low-risk groups in line with the hypoxia risk score. RESULTS: We established a hypoxia risk model according to four hypoxia-related genes, which could be used to demonstrate the immune microenvironment in PAC and predict prognosis. Moreover, the hypoxia risk score can act as an independent prognostic factor in PAC, and a higher hypoxia risk score was correlated with poorer prognosis in patients as well as the immunosuppressive microenvironment of the tumor. CONCLUSIONS: In summary, we established and validated a hypoxia risk model that can be considered as an independent prognostic indicator and reflected the immune microenvironment of PAC, suggesting the feasibility of hypoxia-targeted therapy for PAC patients.

siMTA1-Loaded Exosomes Enhanced Chemotherapeutic Effect of Gemcitabine in Luminal-b Type Breast Cancer by Inhibition of EMT/HIF-α and Autophagy Pathways.

Advanced breast cancer holds a poor prognosis for chemotherapy and endocrine therapy resistance. Autophagy is one of the main causes of tumor drug-therapy failure, and increasing evidence shows that EMT also is responsible for that. Metastasis-associated protein1 (MTA1) is up regulated in lots of tumors, which leads to tumor progression and drug resistance. However, the role of MTA1 in chemotherapeutic resistance in luminal-b breast cancer is still unclear. In this paper, our research shows that higher expression of MTA1 accompanies with worse prognosis in luminal-b breast cancer. Knockdown of MTA1 enhances the sensitivity of MCF-7 to gemcitabine and weakens the metastasis ability of MCF-7 in vitro and in vivo. Further, we find that knockdown of MTA1 strengthens the gemcitabine-mediated tumor growth inhibition effect in vivo, through reversion of the EMT process and inhibition of the autophagy process. Furthermore, our research builds the siMTA1-loaded exosomes, which increases the gemcitabine-mediated tumor growth inhibition effect in vivo.

A Risk Prediction Model for Evaluating the Disease Progression of COVID-19 Pneumonia.

Background and Objective: The epidemic of coronavirus disease 2019 (COVID-19) pneumonia caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has expanded from China throughout the world. This study aims to estimate the risk of disease progression of patients who have been confirmed with COVID-19. Methods: Meta-analysis was performed in existing literatures to identify risk factors associated with COVID-19 pneumonia progression. Patients with COVID-19 pneumonia were admitted to hospitals in Wuhan or Hangzhou were retrospectively enrolled. The risk prediction model and nomogram were developed from Wuhan cohort through logistic regression algorithm, and then validated in Hangzhou and Yinchuan cohorts. Results: A total of 270 patients admitted to hospital between Dec 30, 2019, and Mar 30, 2020, were retrospectively enrolled (Table 1). The development cohort (Wuhan cohort) included 87 (43%) men and 115 (57%) women, and the median age was 53 years old. Hangzhou validation cohort included 20 (48%) men and 22 (52%) women, and the median age was 59 years old. Yinchuan validation cohort included 12 (46%) men and 14 (54%) women, and the median age was 44 years old. The meta-analysis along with univariate logistic analysis in development cohort have shown that age, fever, diabetes, hypertension, CREA, BUN, CK, LDH, and neutrophil count were significantly associated with disease progression of COVID-19 pneumonia. The model and nomogram derived from development cohort show good performance in both development and validation cohorts. Conclusion: The severe COVID-19 pneumonia is associated with various types of risk factors including age, fever, comorbidities, and some laboratory examination indexes. The model integrated with these factors can help to evaluate the disease progression of COVID-19 pneumonia.

The Oncolytic Virus in Cancer Diagnosis and Treatment.

Cancer has always been an enormous threat to human health and survival. Surgery, radiotherapy, and chemotherapy could improve the survival of cancer patients, but most patients with advanced cancer usually have a poor survival or could not afford the high cost of chemotherapy. The emergence of oncolytic viruses provided a new strategy for us to alleviate or even cure malignant tumors. An oncolytic virus can be described as a genetically engineered or naturally existing virus that can selectively replicate in cancer cells and then kill them without damaging the healthy cells. There have been many kinds of oncolytic viruses, such as herpes simplex virus, adenovirus, and Coxsackievirus. Moreover, they have different clinical applications in cancer treatment. This review focused on the clinical application of oncolytic virus and predicted the prospect by analyzing the advantages and disadvantages of oncolytic virotherapy.