Microbiome signatures associated with clinical stages of gastric Cancer: whole metagenome shotgun sequencing study.

BACKGROUND: Gastric cancer is one of the global health concerns. A series of studies on the stomach have confirmed the role of the microbiome in shaping gastrointestinal diseases. Delineation of microbiome signatures to distinguish chronic gastritis from gastric cancer will provide a non-invasive preventative and treatment strategy. In this study, we performed whole metagenome shotgun sequencing of fecal samples to enhance the detection of rare bacterial species and increase genome sequence coverage. Additionally, we employed multiple bioinformatics approaches to investigate the potential targets of the microbiome as an indicator of differentiating gastric cancer from chronic gastritis. RESULTS: A total of 65 patients were enrolled, comprising 33 individuals with chronic gastritis and 32 with gastric cancer. Within each group, the chronic gastritis group was sub-grouped into intestinal metaplasia (n = 15) and non-intestinal metaplasia (n = 18); the gastric cancer group, early stage (stages 1 and 2, n = 13) and late stage (stages 3 and 4, n = 19) cancer. No significant differences in alpha and beta diversities were detected among the patient groups. However, in a two-group univariate comparison, higher Fusobacteria abundance was identified in phylum; Fusobacteria presented higher abundance in gastric cancer (LDA scored 4.27, q = 0.041 in LEfSe). Age and sex-adjusted MaAsLin and Random Forest variable of importance (VIMP) analysis in species provided meaningful features; Bacteria_caccae was the most contributing species toward gastric cancer and late-stage cancer (beta:2.43, se:0.891, p:0.008, VIMP score:2.543). In contrast, Bifidobacterium_longum significantly contributed to chronic gastritis (beta:-1.8, se:0.699, p:0.009, VIMP score:1.988). Age, sex, and BMI-adjusted MasAsLin on metabolic pathway analysis showed that GLCMANNANAUT-PWY degradation was higher in gastric cancer and one of the contributing species was Fusobacterium_varium. CONCLUSION: Microbiomes belonging to the pathogenic phylum Fusobacteria and species Bacteroides_caccae and Streptococcus_anginosus can be significant targets for monitoring the progression of gastric cancer. Whereas Bifidobacterium_longum and Lachnospiraceae_bacterium_5_1_63FAA might be protection biomarkers against gastric cancer.

Loss of MTA2-mediated downregulation of PTK7 inhibits hepatocellular carcinoma metastasis progression by modulating the FAK-MMP7 axis.

The expression of metastasis tumor-associated protein 2 (MTA2) and protein tyrosine kinase 7 (PTK7) is associated with hepatocellular carcinoma (HCC) progression. However, the functional effect and mechanism through which MTA2 regulates PTK7-mediated HCC progression remains unclear. Here, we found that MTA2 knockdown significantly down-regulated PTK7 expression in HCC cells (SK-Hep-1 and PLC/PRF/5). Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases show that the PTK7 expression level was higher in HCC tissues than in normal liver tissues. In HCC patients, the PTK7 expression level clearly correlated with tumor stage and grade, lower overall survival (OS) correlated positively with MTA2 level, and PTK7 expression acted as a downstream factor for MTA2 expression. In addition, matrix metalloproteinase 7 (MMP7) expression was closely regulated by PTK7, and the mRNA and protein expression levels of MTA2 and PTK7 correlated positively with lower OS. MMP7 downregulation by PTK7 knockdown clearly decreased the migration and invasion abilities of HCC cells. In HCC cells, recombinant human MMP7 reversed the PTK7 knockdown-induced suppression of migration and invasion. Furthermore, deactivation of FAK using siFAK or FAK inhibitor (PF-573228, PF) synergistically contributed to PTK7 knockdown-inhibited FAK activity, MMP7 expression, and the migration and invasion abilities of HCC cells. Collectively, our findings show that PTK7 mediates HCC progression by regulating the MTA2-FAK-MMP7 axis and may be a diagnostic value for HCC patients.

Possible Strategies to Reduce the Tumorigenic Risk of Reprogrammed Normal and Cancer Cells.

The reprogramming of somatic cells to pluripotent stem cells has immense potential for use in regenerating or redeveloping tissues for transplantation, and the future application of this method is one of the most important research topics in regenerative medicine. These cells are generated from normal cells, adult stem cells, or neoplastic cancer cells. They express embryonic stem cell markers, such as OCT4, SOX2, and NANOG, and can differentiate into all tissue types in adults, both in vitro and in vivo. However, tumorigenicity, immunogenicity, and heterogeneity of cell populations may hamper the use of this method in medical therapeutics. The risk of cancer formation is dependent on mutations of these stemness genes during the transformation of pluripotent stem cells to cancer cells and on the alteration of the microenvironments of stem cell niches at genetic and epigenetic levels. Recent reports have shown that the generation of induced pluripotent stem cells (iPSCs) derived from human fibroblasts could be induced using chemicals, which is a safe, easy, and clinical-grade manufacturing strategy for modifying the cell fate of human cells required for regeneration therapies. This strategy is one of the future routes for the clinical application of reprogramming therapy. Therefore, this review highlights the recent progress in research focused on decreasing the tumorigenic risk of iPSCs or iPSC-derived organoids and increasing the safety of iPSC cell preparation and their application for therapeutic benefits.

Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.

Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor's phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Independent Signaling of Hepatoma Derived Growth Factor and Tumor Necrosis Factor-Alpha in Human Gastric Cancer Organoids Infected by Helicobacter pylori.

We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori (H. pylori). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFα) on the growth and invasion activity of H. pylori-infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori-infected cancer organoid. To clarify the role of HDGF and TNFα secreted from H. pylori-infected cancer organoids, we prepared recombinant HDGF and TNFα and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori, but TNFα decreased the cell viability in H. pylori-infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori-infected cancer organoid in a species-dependent manner. However, TNFα decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFα during infection by H. pylori. Recombinant HDGF and TNFα inhibited the development and invasion of H. pylori-infected gastric cancer differently. Thus, we propose that HDGF and TNFα are independent signals for development of H. pylori-infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells.

Heterogeneity of Phase II Enzyme Ligands on Controlling the Progression of Human Gastric Cancer Organoids as Stem Cell Therapy Model.

Gastric cancer (GC) organoids are frequently used to examine cell proliferation and death as well as cancer development. Invasion/migration assay, xenotransplantation, and reactive oxygen species (ROS) production were used to examine the effects of antioxidant drugs, including perillaldehyde (PEA), cinnamaldehyde (CA), and sulforaphane (SFN), on GC. PEA and CA repressed the proliferation of human GC organoids, whereas SFN enhanced it. Caspase 3 activities were also repressed on treatment with PEA and CA. Furthermore, the tumor formation and invasive activities were repressed on treatment with PEA and CA, whereas they were enhanced on treatment with SFN. These results in three-dimensional (3D)-GC organoids showed the different cancer development of phase II enzyme ligands in 2D-GC cells. ROS production and the expression of TP53, nuclear factor erythroid 2-related factor (NRF2), and Jun dimerization protein 2 were also downregulated on treatment with PEA and CA, but not SFN. NRF2 knockdown reversed the effects of these antioxidant drugs on the invasive activities of the 3D-GC organoids. Moreover, ROS production was also inhibited by treatment with PEA and CA, but not SFN. Thus, NRF2 plays a key role in the differential effects of these antioxidant drugs on cancer progression in 3D-GC organoids. PEA and CA can potentially be new antitumorigenic therapeutics for GC.

Betulinic Acid Inhibits the Stemness of Gastric Cancer Cells by Regulating the GRP78-TGF-ß1 Signaling Pathway and Macrophage Polarization.

Cancer stemness is the process by which cancer cells acquire chemoresistance and self-renewal in the tumor microenvironment. Glucose-regulated protein 78 (GRP78) is a biomarker for gastric cancer and is involved in cancer stemness. By inducing cancer stemness in various types of cancer, the polarization of macrophages into tumor-associated macrophages (TAMs) controls tumor progression. Betulinic acid (BA) is a bioactive natural compound with anticancer properties. However, whether GRP78 regulates TAM-mediated cancer stemness in the tumor microenvironment and whether BA inhibits GRP78-mediated cancer stemness in gastric cancer remain unknown. In this study, we investigated the role of GRP78 in gastric cancer stemness in a tumor microenvironment regulated by BA. The results indicated that BA inhibited not only GRP78-mediated stemness-related protein expression and GRP78-TGF-ß-mediated macrophage polarization into TAMs, but also TAM-mediated cancer stemness. Therefore, BA is a promising candidate for clinical application in combination-chemotherapy targeting cancer stemness.

Dimethyl sulfoxide stimulates the AhR-Jdp2 axis to control ROS accumulation in mouse embryonic fibroblasts.

The aryl hydrocarbon receptor (AhR) is a ligand-binding protein that responds to environmental aromatic hydrocarbons and stimulates the transcription of downstream phase I enzyme-related genes by binding the cis element of dioxin-responsive elements (DREs)/xenobiotic-responsive elements. Dimethyl sulfoxide (DMSO) is a well-known organic solvent that is often used to dissolve phase I reagents in toxicology and oxidative stress research experiments. In the current study, we discovered that 0.1% DMSO significantly induced the activation of the AhR promoter via DREs and produced reactive oxygen species, which induced apoptosis in mouse embryonic fibroblasts (MEFs). Moreover, Jun dimerization protein 2 (Jdp2) was found to be required for activation of the AhR promoter in response to DMSO. Coimmunoprecipitation and chromatin immunoprecipitation studies demonstrated that the phase I-dependent transcription factors, AhR and the AhR nuclear translocator, and phase II-dependent transcription factors such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) integrated into DRE sites together with Jdp2 to form an activation complex to increase AhR promoter activity in response to DMSO in MEFs. Our findings provide evidence for the functional role of Jdp2 in controlling the AhR gene via Nrf2 and provide insights into how Jdp2 contributes to the regulation of ROS production and the cell spreading and apoptosis produced by the ligand DMSO in MEFs.

Tailored susceptibility-guided therapy via gastric juice PCR for the first-line H. pylori eradication, a randomized controlled trial.

BACKGROUND/PURPOSE: Clarithromycin-based standard triple therapy is still commonly adopted by 81.4% of physicians in real-world practice but yields low eradication rates. Therefore, we conducted this study to compare the efficacy of gastric juice-guided therapy for first-line eradication with the standard triple therapy, in order to provide an alternative to real-world practice. METHODS: A total of 182 treatment-naïve Hp-infected patients were included and randomly allocated to either susceptibility-guided therapy (SGT) with gastric juice PCR or Clarithromycin-based standard triple therapy (STT) for 7 days. RESULTS: The intention-to-treat eradication rates were 89% (81/91) in SGT and 75.8% in STT (p < 0.031). The per-protocol eradication rates were 91.0% (81/89) in SGT and 79.3% (69/87) in STT (p < 0.034). Among the subgroups of different antibiotic resistance, patients with SGT demonstrated superior eradication rates (91.7% vs 45.5%, p < 0.027) in the subgroup of both clarithromycin resistance and levofloxacin resistance. CONCLUSION: This prospective randomized controlled trial demonstrated the reliable efficacy of susceptibility-guided therapy via gastric juice PCR for the first-line Hp eradication. In Asia-Pacific area, where standard triple therapy is still adopted by the majority of the physicians, it is a recommended alternative to overcome the increasing antibiotic resistance.

Targeting of Mcl-1 Expression by MiRNA-3614-5p Promotes Cell Apoptosis of Human Prostate Cancer Cells.

MicroRNA (miRNA) acts as a critical regulator of growth in various human malignancies. However, the role of miRNA-3614 in the progression of human prostate cancer remains unknown. In this study, our results demonstrated that miRNA-3614-5p exerts a significant inhibitory effect on cell viability and colony formation and induces sub-G1 cell cycle arrest and apoptosis in human prostate cancer cells. Myeloid cell leukemia-1 (Mcl-1) acts as a master regulator of cell survival. Using the miRNA databases, miRNA-3614-5p was found to regulate Mcl-1 expression by targeting positions of the Mcl-1-3' UTR. The reduction of Mcl-1 expression by miRNA-3614-5p was further confirmed using an immunoblotting assay. Pro-apoptotic caspase-3 and poly (ADP-ribose) polymerase (PARP) were significantly activated by miRNA-3614-5p to generate cleaved caspase-3 (active caspase-3) and cleaved PARP (active PARP), accompanied by the inhibited Mcl-1 expression. These findings were the first to demonstrate the anti-growth effects of miRNA-3614-5p through downregulating Mcl-1 expression in human prostate cancer cells.

The impact of urine microbiota in patients with lower urinary tract symptoms.

INTRODUCTION: Inflammation and infection are causative factors of benign prostatic hyperplasia (BPH). Urine is not sterile, and urine microbiota identified by DNA sequencing can play an important role in the development of BPH and can influence the severity of lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: We collected mid-stream voided urine samples from BPH patients and control participants and stored them in a freezer at - 80 °C. All enrolled participants were requested to provide information about their clinical characteristics and complete the International Prostate Symptom Score (IPSS) questionnaire. Each step of the procedure, including the extraction of the genomic DNA from the urine samples; the amplification by polymerase chain reaction (PCR); PCR product quantification, mixing, and purification; DNA library preparation; and sequencing was performed with quality control (QC) measures. Alpha diversity was indicative of the species complexity within individual urine samples, and beta diversity analysis was used to evaluate the differences among the samples in terms of species complexity. Pearson's correlation analysis was performed to calculate the relationship between the clinical characteristics of the participants and the microbiota species in the urine samples. RESULTS: We enrolled 77 BPH patients and 30 control participants who reported no recent antibiotic usage. Old age, high IPSS and poor quality of life were observed in the participants of the BPH group. No significant differences were observed in the alpha diversity of the samples. In the beta diversity analysis, there was a significant difference between the microbiota in the samples of the BPH and control groups according to ANOSIM statistical analysis. On comparing the groups, the ten bacterial genera present in the samples of the BPH group in descending order of abundance were: Sphingomonas, Bacteroides, Lactobacillus, Streptococcus, Alcaligenes, Prevotella, Ruminococcaceae UCG-014, Escherichia_Shigella, Akkermansia, and Parabacteroides. Spearman's correlation analysis revealed that urine samples showing the presence of the bacterial genera Haemophilus, Staphylococcus, Dolosigranulum, Listeria, Phascolarctobacterium, Enhydrobacter, Bacillus, [Ruminococcus]torques, Faecalibacterium, and Finegoldia correlated with a high IPSS, and severe storage and voiding symptoms (P < 0.05). CONCLUSION: Our current study shows that dysbiosis of urine microbiota may be related to the development of BPH and the severity of LUTS. Further research targeting specific microbes to identify their role in the development of diseases is necessary and might provide novel diagnostic biomarkers and therapeutic options.

Modulating the ERK1/2-MMP1 Axis through Corosolic Acid Inhibits Metastasis of Human Oral Squamous Cell Carcinoma Cells.

Corosolic acid (CA; 2α-hydroxyursolic acid) is a natural pentacyclic triterpenoid with antioxidant, antitumour and antimetastatic activities against various tumour cells during tumourigenesis. However, CA's antitumour effect and functional roles on human oral squamous cell carcinoma (OSCC) cells are utterly unknown. In this study, our results demonstrated that CA significantly exerted an inhibitory effect on matrix metalloproteinase (MMP)1 expression, cell migration and invasion without influencing cell growth or the cell cycle of human OSCC cells. The critical role of MMP1 was confirmed using the GEPIA database and showed that patients have a high expression of MMP1 and have a shorter overall survival rate, confirmed on the Kaplan-Meier curve assay. In the synergistic inhibitory analysis, CA and siMMP1 co-treatment showed a synergically inhibitory influence on MMP1 expression and invasion of human OSCC cells. The ERK1/2 pathway plays an essential role in mediating tumour progression. We found that CA significantly inhibits the phosphorylation of ERK1/2 dose-dependently. The ERK1/2 pathway played an essential role in the CA-mediated downregulation of MMP1 expression and in invasive motility in human OSCC cells. These findings first demonstrated the inhibitory effects of CA on OSCC cells' progression through inhibition of the ERK1/2-MMP1 axis. Therefore, CA might represent a novel strategy for treating OSCC.

Silencing PROK2 Inhibits Invasion of Human Cervical Cancer Cells by Targeting MMP15 Expression.

Cervical cancer is the second most frequent type of gynecologic cancer worldwide. Prokineticin 2 (PROK2) is reported to be involved in tumor progression in some malignant tumors. However, the role of PROK2 in the development of cervical cancer remains unknown. Our results indicate that PROK2 is overexpressed in the human cervical cancer. Cervical cancer patients with high PROK2 expression have a shorter overall survival rate (OS) and disease-free survival rate (DFS). PROK2 acts as a potential biomarker for predicting OS and DFS of cervical cancer patients. We further show that PROK2 is important factor for oncogenic migration and invasion in human cervical cancer cells. Knockdown PROK2 significantly inhibited cell migration, invasion, and MMP15 protein expression in HeLa cells. High expression of MMP15 is confirmed in the human cervical cancer, is significantly associated with the shorter overall survival rate (OS) and is correlated with PROK2 expression. Overexpression of PROK2 using PROK2 plasmid significantly reverses the function of knockdown PROK2, and further upregulates MMP15 expression, migration and invasion of human cervical cancer cells. In conclusion, our findings are the first to demonstrate the role of PROK2 as a novel and potential biomarker for clinical use, and reveal the oncogenic functions of PROK2 as therapeutic target for cervical cancer.

Antiproliferative and Antimetastatic Effects of Praeruptorin C on Human Non-Small Cell Lung Cancer Through Inactivating ERK/CTSD Signalling Pathways.

Praeruptorin C (PC) reportedly has beneficial effects in terms of antiinflammation, antihypertension, and antiplatelet aggregation, and it potentially has anticancer activity. However, the effect of PC on human non-small cell lung cancer (NSCLC) is largely unknown. Compared with the effects of praeruptorin A and praeruptorin B, we observed that PC significantly suppressed cell proliferation, colony formation, wound closure, and migration and invasion of NSCLC cells. It induced cell cycle arrest in the G0/G1 phase, downregulated cyclin D1 protein, and upregulated p21 protein. PC also significantly reduced the expression of cathepsin D (CTSD). In addition, the phosphorylation/activation of the ERK1/2 signalling pathway was significantly suppressed in PC-treated NSCLC cells. Cotreatment with PC and U0126 synergistically inhibited CTSD expression, cell migration, and cell invasion, which suggests that the ERK1/2 signalling pathway is involved in the downregulation of CTSD expression and invasion activity of NSCLC cells by PC. These findings are the first to demonstrate the inhibitory effects of PC in NSCLC progression. Therefore, PC may represent a novel strategy for treating NSCLC.

Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer.

CYP19A1/aromatase (Ar) is a prognostic biomarker of gastric cancer (GCa). Ar is a critical enzyme for converting androstenedione to oestradiol in the steroidogenesis cascade. For decades, Ar has been targeted with Ar inhibitors (ARIs) in gynaecologic malignancies; however, it is unexplored in GCa. A single-cohort tissue microarray examination was conducted to study the association between Ar expression and disease outcome in Asian patients with GCa. The results revealed that Ar was a prognostic promoter. Bioinformatics analyses conducted on a Caucasian-based cDNA microarray databank showed Ar to be positively associated with GCa prognosis for multiple clinical modalities, including surgery, 5-Fluorouracil (5-FU) for adjuvant chemotherapy, or HER2 positivity. These findings imply that targeting Ar expression exhibits a potential for fulfilling unmet medical needs. Hence, Ar-targeting compounds were tested, and the results showed that exemestane exhibited superior cancer-suppressing efficacy to other ARIs. In addition, exemestane down-regulated Ar expression. Ablating Ar abundance with short hairpin (sh)Ar could also suppress GCa cell growth, and adding 5-FU could facilitate this effect. Notably, adding oestradiol could not prevent exemestane or shAr effects, implicating a nonenzymatic mechanism of Ar in cancer growth. Regarding translational research, treatment with exemestane alone exhibited tumour suppression efficacy in a dose-dependent manner. Combining subminimal doses of 5-FU and exemestane exerted an excellent tumour suppression effect without influencing bodyweight. This study validated the therapeutic potentials of exemestane in GCa. Combination of metronomic 5-FU and exemestane for GCa therapy is recommended.

Gastric juice-based PCR assay: An alternative testing method to aid in the management of previously treated Helicobacter pylori infection.

BACKGROUND: Culture of Helicobacter pylori with previous eradication failure has been emphasized in clinical guidelines. The current unmet need to manage previously treated H pylori is one tool with diagnostic accuracy and ability for antibiotics susceptibility. Gastric juice PCR can provide diagnosis and antibiotics susceptibility; however, whether treatment failure affects its accuracy remains uninvestigated. Our study aimed to investigate diagnostic accuracy and antibiotics susceptibility of juice PCR in previously treated H pylori and to compare with the current standard of culture. METHODS: We categorized all 547 patients into treatment-naïve, post-1st treatment, post-2nd treatment, and post-3rd treatment. Helicobacter pylori infection was confirmed using gold standards. Sensitivity, specificity, positive predictive value, negative predictive value, receiver operating characteristic (ROC) curve and area under ROC curve (AUC) of juice PCR and culture were calculated. Intra-gastric H pylori density was evaluated. Lastly, the antibiotics susceptibility results of gastric juice and culture were compared. RESULTS: Our findings demonstrated AUC was higher in juice PCR than culture in all patients (96.7% vs 91.3%, P < 0.0001). The superiority of juice PCR was statistically significant in previously treated patients (P < 0.0001) but not in treatment-naïve patients (P = 0.13). Antral H pylori density was less marked in previously treated patients (P = 0.014). The comparisons of PCR-RFLP and E-test for Clarithromycin resistance showed reliable AUC = 89.8%. CONCLUSION: Compared with the current standard of culture, the gastric juice PCR contains the strengths of performing the antibiotics susceptibility and overcomes the shortcomings of low accuracy. Consequently, gastric juice PCR suits the unmet need to manage previously treated H pylori.

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells.

Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115-2128.

Levels of malondialdehyde in the gastric juice: Its association with Helicobacter pylori infection and stomach diseases.

BACKGROUND: Helicobacter pylori (H. pylori) infection causes elevation of lipid peroxidation product malondialdehyde (MDA) and this association may be due to the bacterium causing reactive oxygen species-mediated damage to DNA in the gastric epithelium. The aim of this study was to investigate the gastric juice MDA levels in relation to H. pylori infection and associated gastric diseases. METHODS: Gastric juice samples were obtained from 117 patients undergoing endoscopy, and gastric juice MDA levels were determined by high-performance liquid chromatography (HPLC) system. We compared the MDA levels between patients with and without H. pylori infection and assessed the differences of MDA levels between chronic gastritis, gastric intestinal metaplasia, and gastric cancer postsurgical resection. RESULTS: Malondialdehyde levels in gastric juice were significantly higher in chronic gastritis patients with H. pylori infection than in those without H. pylori infection (P < .0001). In patients without H. pylori infection, patients with gastric intestinal metaplasia and gastric cancer postsurgical resection had significantly higher gastric juice MDA level than patients with chronic gastritis. As a whole, patients with gastric intestinal metaplasia and gastric cancer postsurgical resection also had significantly higher MDA levels in gastric juice as compared to patients with chronic gastritis (P < .01). However, the difference of gastric juice MDA levels between gastric intestinal metaplasia and gastric cancer postsurgical resection was not significant. CONCLUSION: Malondialdehyde in gastric juice could be used as a potential diagnostic biomarker for H. pylori infection and associated gastric diseases. The gastric juice MDA levels increased proportionally with the severity of gastric diseases.

Synergistic antimetastatic effect of cotreatment with licochalcone A and sorafenib on human hepatocellular carcinoma cells through the inactivation of MKK4/JNK and uPA expression.

To improve the clinical outcome of tumor chemotherapy, more effective combination treatments against tumor metastasis and recurrence are required. Licochalcone A (LicA) is the root of Glycyrrhiza inflata and has been reported to possess anti-inflammatory, antimicrobial, and antitumor effects. Sorafenib (Sor), a multikinase inhibitor, is used to treat patients with solid tumors such as advanced hepatocellular carcinoma (HCC). However, the synergistic effects of LicA and Sor on the metastasis of human HCC cells have not been reported. We found that LicA and Sor did not have cytotoxic effects or arrest growth in human SK-Hep-1 and Huh-7 cells. In addition, treatment with LicA or Sor alone inhibited migration and invasion in human SK-Hep-1 and Huh-7 HCC cells. Furthermore, cotreatment with LicA and Sor synergistically inhibited the migration and invasion of HCC cells and significantly inhibited uPA protein expression. Notably, cotreatment of LicA and Sor synergistically and significantly downregulated MKK4-JNK expression. Through tail vein injection in nude mice, the aforementioned cotreatment synergistically suppressed SK-Hep-1 cell-mediated lung metastasis. These findings first revealed the synergistic effects of LicA and Sor cotreatment against human HCC cells, further suggesting that beneficial effects on tumor regression could be confirmed through prospective clinical trials.

Recent Advances in the Pharmacological Management of Gastroesophageal Reflux Disease.

The management of proton pump inhibitor-refractory GERD (rGERD) is a challenge in clinical practice. Since up to one-third of patients with typical GERD symptoms (heartburn and/or acid regurgitation) are not satisfied with proton pump inhibitor (PPI) therapy, new drug development targeting different pathophysiologies of GERD is imperative. At present, no other drugs serve as a more potent acid suppression agent than PPIs. As an add-on therapy, histamine type-2 receptor antagonists, alginates, prokinetics and transient lower esophageal sphincter relaxation inhibitors have some impact on the subgroups of rGERD, but greater effectiveness and fewer adverse effects for widespread use are required. Visceral hypersensitivity also contributes to the perception of GERD symptoms, and neuromodulators including antidepressants play a role in this category. Esophageal pH-impedance monitoring helps to distinguish functional heartburn from true GERD, and psychologic medication and cognitive behavior therapy are further therapy options instead of PPIs.