Microbial treatment of alcoholic liver disease: A systematic review and meta-analysis.

Background and aims: Alcoholic liver disease (ALD) is characterized by impaired liver function due to chronic alcohol consumption, even fatal in severe cases. We performed a meta-analysis to determine whether microbial agents have therapeutic potential for ALD and elucidate the underlying mechanisms. Methods and results: Forty-one studies were eligible for this meta-analysis after searching the PubMed, Cochrane, and Embase databases. The combined analysis showed that microbial therapy significantly decreased hepatic enzymatic parameters, including alanine transaminase [standardized mean difference (SMD): -2.70, 95% confidence interval (CI): -3.33 to -2.07], aspartate aminotransferase (SMD: -3.37, 95% CI: -4.25 to -2.49), γ-glutamyl transpeptidase (SMD: -2.07, 95% CI: -3.01 to -1.12), and alkaline phosphatase (SMD: -2.12, 95% CI: -3.32 to -0.92). Microbial agents endotoxin to enter the portal circulation and increasing reduced total cholesterol (SMD = -2.75, 95%CI -4.03 to -1.46) and triglycerides (SMD = -2.64, 95% CI: -3.22 to -2.06). Microbial agents increased amounts of the beneficial flora Lactobacillus (SMD: 4.40, 95% CI: 0.97-7.84) and Bifidobacteria (SMD: 3.84, 95% CI: 0.22-7.45), Bacteroidetes (SMD: 2.51, 95% CI: 0.29-4.72) and decreased harmful Proteobacteria (SMD: -4.18, 95% CI: -6.60 to -1.77), protecting the integrity of the intestinal epithelium and relieving endotoxin (SMD: -2.70, 95% CI: -3.52 to -2.17) into the portal vein, thereby reducing the production of inflammatory factors such as tumor necrosis factor-α (SMD: -3.35, 95% CI: -4.31 to -2.38), interleukin-6 (SMD: -4.28, 95% CI: -6.13 to -2.43), and interleukin-1ß (SMD: -4.28, 95% CI: -6.37 to -2.19). Oxidative stress was also relieved, as evidenced by decreased malondialdehyde levels (SMD: -4.70, 95% CI: -6.21 to -3.20). Superoxide dismutase (SMD: 2.65, 95% CI: 2.16-3.15) and glutathione levels (SMD: 3.80, 95% CI: 0.95-6.66) were elevated. Conclusion: Microbial agents can reverse dysbiosis in ALD, thus significantly interfering with lipid metabolism, relieving inflammatory response and inhibiting oxidative stress to improve liver function.

Neoantigen-reactive T cells exhibit effective anti-tumor activity against colorectal cancer.

Neoantigens play a crucial role in cancer immunotherapy. However, the effectiveness and safety of neoantigen-based immunotherapies in patients with colorectal cancer (CRC), particularly in the Chinese population, have not been well studied. This study explored the feasibility and effectiveness of neoantigens in the treatment of CRC. Whole-exome sequencing (WES) and transcriptome sequencing were used to identify somatic mutations, RNA expression, and human leukocyte antigen (HLA) alleles. Neoantigen candidates were predicted, and immunogenicity was assessed. The neoantigens TSHZ3-L523P, RARA-R83H, TP53-R248W, EYA2-V333I, and NRAS-G12D from Patient 4 (PW4); TASP1-P161L, RAP1GAP-S215R, MOSPD1-V63I, and NAV2-D1973N from Patient 10 (PW10); and HAVCR2-F39V, SEC11A-R11L, SMPDL3B-T452M, LRFN3-R118Q, and ULK1-S248L from Patient 11 (HLA-A0201+PW11) induced a heightened neoantigen-reactive T cell (NRT) response as compared with the controls in peripheral blood lymphocytes (PBLs) isolated from patients with CRC. In addition, we identified neoantigen-containing peptides SEC11A-R11L and ULK1-S248L from HLA-A0201+PW11, which more effectively elicited specific CTL responses than the corresponding native peptides in PBLs isolated from HLA-A0201+PW11 as well as in HLA-A2.1/Kb transgenic mice. Importantly, adoptive transfer of NRTs induced by vaccination with two mutant peptides could effectively inhibit tumor growth in tumor-bearing mouse models. These data indicate that neoantigen-containing peptides with high immunogenicity represent promising candidates for peptide-mediated personalized therapy.Abbreviations: CRC: colorectal cancer; DCs: dendritic cells; ELISPOT: enzyme-linked immunosorbent spot; E:T: effector:target; HLA: human leukocyte antigen; MHC: major histocompatibility complex; Mut: mutant type; NGS: next-generation sequencing; NRTs: neoantigen-reactive T cells; PBMCs: peripheral blood mononuclear cells; STR: short tandem repeat; PBLs: peripheral blood lymphocytes; PBS: phosphate-buffered saline; PD-1: programmed cell death protein 1; TILs: tumor-infiltrating lymphocytes; RNA-seq: RNA sequencing; Tg: transgenic; TMGs: tandem minigenes; WES: whole-exome sequencing; WT: wild-type.

Duodenal ulcer caused by coil wiggle after digital subtraction angiography-guided embolization: A case report.

BACKGROUND: Acute gastrointestinal bleeding (GIB) is a life-threatening medical emergency with high morbidity and mortality. Transcatheter embolization with endovascular coils under digital subtraction angiography guidance is a common and effective method for the treatment of GIB with high technical success rates. Duodenal ulcers caused by coils wiggled from the branch of the gastroduodenal artery, which is a rare complication, have not previously been reported in a patient with right intrathoracic stomach. CASE SUMMARY: A 62-year-old man had undergone thoracoscopy-assisted radical resection of esophageal cancer and gastroesophageal anastomosis 3 years ago, resulting in right intrathoracic stomach. He was admitted to the hospital 15 mo ago for dizziness and suffered acute GIB during his stay. Interventional surgery was urgently performed to embolize the branch of the gastroduodenal artery with endovascular coils. After 15 mo, the patient was re-admitted with a chief complaint of melena for 2 d, esophagogastroduodenoscopy and abdominal computed tomography revealed that some endovascular coils had migrated into the duodenal bulb, leading to a deep ulcer. Bleeding was controlled after conservative treatment. Seven months later, duodenal balloon dilatation was performed to relieve the stenosis after the removal of a few coils, and the patient was safely discharged with only one coil retained in the duodenum due to difficulties in complete removal and risk of bleeding. Mild melena recurred once during the long-term follow-up. CONCLUSION: Although rare, coil wiggle after interventional therapy requires careful attention, effective precautionary measures, and more secure alternative treatment methods.

Effectiveness of Probiotics and Prebiotics Against Acute Liver Injury: A Meta-Analysis.

Background and Aims: Acute liver injury (ALI) is a clinical syndrome characterized by rapid loss of liver function, which may progress to life-threatening liver failure. We conducted this meta-analysis to examine the evidence on the effects of probiotics or prebiotics on ALI. Methods and Results: Several databases, including PubMed, EMBASE, and Cochrane Library, were scrutinized from the inception through February 2021 by combining key search terms, yielding 26 eligible studies, which concluded that modulation of gut microbiota significantly decreased aspartate transaminase [standardized mean difference (SMD): -1.51, 95% confidence interval (CI): -2.03 to -1.00], alanine aminotransferase (SMD: -1.42, 95% CI: -1.85 to -0.98), and bilirubin (SMD: -0.91, 95% CI: -1.33 to -0.49). In addition, administration of probiotics or prebiotics also promoted proliferation of Bifidobacterium (SMD: 1.21, 95% CI: -0.18 to 2.60) and inhibited Enterococcus (SMD: -1.00, 95% CI: -1.39 to -0.61), contributing to lower levels of endotoxin (SMD: -2.14, 95% CI: -2.91 to -1.37). Tight junction protein ZO-1 (SMD: 1.95, 95% CI: 0.14 to 3.76) was upregulated after intervention, thereby reducing bacterial translocation to the liver [odds ratio (OR) = 0.23, 95% CI: 0.13-0.44] and mesenteric lymph node (OR = 0.14, 95% CI: 0.08 to 0.26), with decreased tumor necrosis factor-α (SMD: -2.84, 95% CI: -3.76 to -1.93) and interleukin-6 (SMD: -2.62, 95% CI: -4.14 to -1.10). Oxidative stress was also relieved by reducing malondialdehyde (SMD: -1.83, 95% CI: -2.55 to -1.10) while elevating superoxide dismutase (SMD: 1.78, 95% CI: 1.00-2.55) and glutathione (SMD: 1.83, 95% CI: 0.76-2.91). Conclusion: Our findings suggest that probiotics and prebiotics could be a promising therapeutic strategy in ALI and possess a potential for clinical applications. Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=255888, CRD42021255888.

IncRNA LUCAT1 acts as a Potential Biomarker and Demonstrates Malignant Biological Behaviors in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) remains the fourth-leading malignancy worldwide and has a high mortality rate. Accumulating evidence reveals that long noncoding RNAs (lncRNAs) play essential roles in tumorigenesis and metastasis and can be used as potential biomarkers for diagnosis and prognosis. METHODS: We downloaded gene expression profiles from the National Center of Biotechnology Information Gene Expression Omnibus (GEO), screened lncRNAs differentially expressed in gastric cancer tissues and adjacent tissues, and then constructed a lncRNA-miRNA-mRNA network. Seventy patients with gastric cancer were divided into two groups according to different clinical characteristics. The expression of lncRNA LUCAT1 in gastric cancer was detected by reverse transcription polymerase chain reaction (RT-PCR). The AGS and SGC-7901 cell lines were used in CCK8 assay, apoptosis, cell cycle test, transwell assay, and wound healing assay. RESULTS: The expression level of LUCAT1 was associated with tumor diameter (p < 0.001), tissue differentiation grade (p = 0.026), and LNM status (p = 0.020) in GC. The results showed that the lncRNA LUCAT1 could promote the proliferation, invasion, and migration of GC cells, inhibit the apoptosis of GC cells, and affect the process of cell cycles. CONCLUSIONS: The lncRNA LUCAT1 may be used as a potential biomarker for early signs of LNM in GC and may play a crucial role in the development of GC.

Hybrid Nanoparticles Modified by Hyaluronic Acid Loading an HSP90 Inhibitor as a Novel Delivery System for Subcutaneous and Orthotopic Colon Cancer Therapy.

BACKGROUND: As a therapeutic target for cancer treatment, HSP90 has been explored extensively. However, the significant side effects of the HSP90 inhibitor 17AAG have limited its clinical use. METHODS: In this study, we used hyaluronic acid (HA)-decorated DOTAP-PLGA hybrid nanoparticles (HA-DOTAP-PLGA NPs) as 17AAG-delivery carriers for targeted colon cancer therapy. RESULTS: Different methods were used to characterize the successful fabrication of these hybrid PLGA NPs. Our results demonstrated that internalization of HA-NPs in colon cancer cells was governed by CD44receptor-mediated endocytosis. Annexin V-propidium iodide staining experiments revealed that cell apoptosis induced by HA-NPs-17AAG in colon cancer cells was more efficient than free 17AAG. In two animal models used to screen anticancer efficacy (Luc-HT29 subcutaneous xenograft and AOM/DSS-induced orthotopic tumor model), HA-NPs-17AAG significantly inhibited xenograft and orthotopic tumor growth, demonstrating HA-NPs-17AAG had much better therapeutic efficiency than free 17AAG. It is worth noting that great biocompatibility of HA-DOTAP-PLGA NPs was observed both in vitro and in vivo. CONCLUSION: Our research offers a preclinical proof of concept for colon cancer therapy with DOTAP-PLGA NPs as a creative drug-delivery system.

Antiperistaltic effect and safety of l-menthol oral solution on gastric mucosa for upper gastrointestinal endoscopy in Chinese patients: Phase III, multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: The topical antispasmodic agent l-menthol is commonly used for gastric peristalsis suppression during diagnostic upper gastrointestinal (GI) endoscopy. We evaluated the efficacy and safety of a single dose l-menthol solution in suppressing gastric peristalsis during upper GI endoscopy in Chinese patients. METHODS: In this phase III, multicenter, randomized, double-blind, placebo-controlled study (ClinicalTrials.gov: NCT03263910), 220 patients scheduled to undergo upper GI endoscopy at five Chinese referral centers received a single dose of either 160 mg of l-menthol (n = 109) or placebo (n = 111). Both treatments were sprayed endoscopically on the gastric mucosa. An independent committee evaluated the degree of gastric peristalsis (peristaltic score: grade 1-5). RESULTS: At baseline, the proportion of patients with grade 1 peristalsis (no peristalsis) did not differ between the groups. The proportion of patients with grade 1 peristalsis post-treatment was significantly higher in the l-menthol group (40.37%, 44/109) versus the placebo group (16.22%, 18/111; P < 0.001); the difference between the groups was 24.15% (95% confidence interval: 12.67%-35.63%; P < 0.001). In the l-menthol group, 61.47% of patients had grade 1 peristalsis after endoscopy versus 24.55% in the placebo group (P < 0.001). The ease of intragastric examination correlated significantly with the grade of peristalsis. The incidence of adverse events was comparable between the groups (P = 0.340). CONCLUSIONS: During upper GI endoscopy, a single dose of l-menthol solution (160 mg) sprayed on the gastric mucosa significantly attenuated gastric peristalsis versus placebo, thereby improving the visual stability without any safety concerns.

Association between the non-HDL-cholesterol to HDL-cholesterol ratio and non-alcoholic fatty liver disease in Chinese children and adolescents: a large single-center cross-sectional study.

BACKGROUND: The non-HDL-cholesterol to HDL-cholesterol (NHDLC/HDLC) ratio is closely related to a variety of dyslipidemia-related diseases. This study examined the relationship between the NHDLC/HDLC ratio and non-alcoholic fatty liver (NAFLD) in children and adolescents. METHODS: This cross-sectional survey included a total of 7759 eligible Chinese children and adolescents (5692 boys and 2067 girls) who received routine medical examinations. The anthropometric and laboratory data of the subjects were collected. NAFLD was diagnosed by liver ultrasonography. Binary logistic regression analysis was performed on the NHDLC/HDLC ratio, NHDLC, HDLC and NAFLD. Receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic significance of the above parameters for NAFLD. RESULTS: The total prevalence of NAFLD was 4.36%, and the prevalence in boys was higher than that in girls (5.61% vs. 1.9%, P < 0.001). The prevalence of NAFLD was positively correlated with the NHDLC/HDLC ratio (P < 0.001). The binary logistic regression analysis demonstrated that the OR was 8.61 (95% CI, 5.90-12.57, P < 0.001) in tertile 3 (highest NHDLC/HDLC ratio) compared with tertile 1 (lowest NHDLC/HDLC ratio). After adjustment for age, sex, body mass index (BMI), alanine aminotransferase (ALT), uric acid (UA), total bilirubin (TB), fasting plasma glucose (FPG) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), the OR for tertile 3 (OR = 1.83, 95% CI, 1.04-3.22, P = 0.035) was still significantly higher than that of tertile 1. The area under the curve (AUC) of the NHDLC/HDLC ratio of boys was 0.787, which was significantly greater than NHDLC and HDLC (0.719 and 0.726, P < 0.001). For girls, the AUC of the NHDLC/HDLC ratio was 0.763, which was also significantly greater than NHDLC (0.661, P < 0.001). The cutoff point of the NHDLC/HDLC ratio was 2.475 in boys and 2.695 in girls. In addition, the AUC of the NHDLC/HDLC ratio was 0.761 in subjects with normal ALT levels (ALT ≤40 U/L), which was significantly higher than NHDLC (0.680, P < 0.001) and HDLC (0.724, P = 0.007). For subjects with elevated ALT levels (ALT > 40 U/L), the AUC of the NHDLC/HDLC ratio (0.746) was also significantly greater than NHDLC (0.646, P < 0.001). CONCLUSIONS: The NHDLC/HDLC ratio was positively correlated with NAFLD in Chinese children and adolescents. It may serve as an effective indicator to help identify NAFLD in children and adolescents.

Accessory spleen originating from the intrinsic muscularis of the stomach misdiagnosed as gastrointestinal stromal tumor: a case report.

A 34-year-old man presented to our hospital with a 2-month history of repeated dull upper abdominal pain. Gastroscopy and endoscopic ultrasonography indicated a hemispherical mass at the junction of the greater curvature and the gastric fundus, with hypoechogenicity originating from the intrinsic muscular layer. He was diagnosed with a gastric body submucosal lesion and gastrointestinal stromal tumor, and underwent endoscopic full-thickness resection. However, postoperative pathological examination of the mass unexpectedly revealed heterotopic spleen tissue (accessory spleen). Intragastric ectopic spleen tissue originating from the intrinsic muscular layer of the stomach is a rare clinical condition, with no specific clinical symptoms. This finding is of great clinical significance for the identification of gastric submucosal tumors.

Prognostic Value of Lymphovascular Invasion in Patients with Stage III Colorectal Cancer: A Retrospective Study.

BACKGROUND Lymph node metastasis and tumor progression depend on lymphovascular invasion (LVI). This study aimed to investigate the prognostic role of LVI in patients with stage III colorectal cancer (CRC) and to develop a prognostic nomogram. MATERIAL AND METHODS A retrospective study included 437 patients with stage III CRC. The impact of LVI on overall survival (OS) was analyzed with the Kaplan-Meier method and Cox regression model. A nomogram was constructed, and its predictive accuracy was evaluated using the concordance index (C-index) and the calibration plot. RESULTS LVI was found in 19.7% of cases of stage III CRCs and was significantly correlated with high tumor grade (poor differentiation) and advanced tumor stage (all P<0.05). Patients age, a family history of cancer in a first-degree relative, pre-treatment levels of carcinoembryonic antigen (CEA), prognostic nutritional index (PNI), histological tumor grade, tumor-node-metastasis (TNM) stage, and LVI were independent prognostic indicators (all P<0.05). Compared with the LVI(-) group, patients in the LVI(+) group showed a 1.748-fold increased risk of death (P=0.004) and a significantly reduced OS rate (P<0.001). In the prognostic nomogram, the C-index was significantly increased with LVI compared with the TNM stage alone (0.742 vs. 0.593; P<0.001). Calibration plots showed good fitness of the nomogram for prediction of survival. Comparison of the nomograms with and without LVI showed that inclusion of LVI improved the C-index from 0.715 to 0.742. CONCLUSIONS LVI was an indicator of more aggressive biological behavior and poor prognosis in patients with stage III CRC.

Overexpression of calpain­1 predicts poor outcome in patients with colorectal cancer and promotes tumor cell progression associated with downregulation of FLNA.

Several studies have demonstrated that calpain­1 is involved in a variety of pathophysiological processes, including tumorigenesis. However, the clinical relevance and role of calpain­1 in colorectal cancer (CRC) are unclear. Filamin A (FLNA) is an actin­binding protein that participates in cancer progression and can be cleaved by calpain­1. In the present study, the protein expression levels of calpain­1 and FLNA were detected by immunohistochemistry in 467 matched cancerous and paracancerous tissues from patients with CRC. The staining results and the clinicopathological characteristics of the patients were comprehensively analyzed. A high expression level of calpain­1 was strongly associated with age, metastasis, Dukes stage and survival time but not with sex, histologic grade, tumour location or tumor size. By contrast, a low expression level of FLNA was significantly associated with tumor size, histological grade, metastasis, Dukes stage and survival time, but not with age, sex, or tumor location. Kaplan­Meier survival analysis demonstrated that patients with calpain­1 overexpression had a shorter mean overall survival (OS) than patients with lower levels of calpain­1 expression. Unlike high levels of calpain­1, high levels of FLNA were associated with longer OS than lower levels of FLNA expression. Furthermore, calpain­1 expression was inversely correlated with FLNA expression. The relationship between calpain­1 and FLNA was further confirmed using CRC cell lines in vitro. When calpain­1 expression decreased in CRC cells, FLNA expression increased. Furthermore, calpain­1 knockdown in CRC cells resulted in decreased proliferation, colony formation, migration and invasion. The present findings suggest that calpain­1 overexpression predicted a poor outcome in patients with CRC and promoted tumor progression, possibly via FLNA downregulation.

Therapeutic Effect of Tanshinone IIA on Liver Fibrosis and the Possible Mechanism: A Preclinical Meta-Analysis.

BACKGROUND: Liver fibrosis is a serious human health problem, and there is a need for specific antifibrosis drugs in the clinic. Tanshinone IIA has recently been reported to have a role in the treatment of liver fibrosis. However, the evidence supporting its antifibrotic effect is not sufficient, and the underlying mechanism is not clear. We thus performed this meta-analysis of animal research to assess the therapeutic effect of tanshinone IIA on liver fibrosis and analyzed the possible associated mechanism to provide a reference for further clinical drug preparation and clinical research. METHODS: We collect related articles from the databases PubMed, Web of Science, Embase, Wanfang, VIP, and CNKI. The quality of the included studies was evaluated according to the SYRCLE risk of bias tool for animal studies. Data were analyzed using RavMan 5.3 and Stata 12.0 software. RESULTS: A total of 404 articles were retrieved from the databases. After screening, 11 articles were included in the analysis. The included studies' methodological quality was generally low, and an obvious publication bias was found. The results showed that tanshinone IIA significantly improved liver function in experimental animals and reduced the level of liver fibrosis by reducing inflammation and inhibiting immunity, antiapoptotic processes, and HSC activation. CONCLUSION: Tanshinone IIA can effectively improve liver fibrosis and liver function in animal models and is worthy of future higher quality animal studies and clinical drug trials.

Targeted delivery of miRNA-204-5p by PEGylated polymer nanoparticles for colon cancer therapy.

AIM: miRNAs have been recognized for their potential in cancer therapeutics, and multiple miRNAs were suggested to affect target genes expression. To overcome limitations of free synthetic miRNAs, such as easily degraded in biofluids and limited in cellular uptake, novel miRNAs delivery systems need to be developed. MATERIALS & METHODS: Using surface-functionalizing technique, poly(D,L-lactide-co-glycolide)/poly(L-lactide)-block-poly(ethylene glycol)-folate polymer nanoparticle (PLGA/PLA-PEG-FA) loaded with miR-204-5p (FA-NPs-miR-204) was developed. The therapeutic efficacy of FA-NPs-miR-204 was evaluated in the Luc-HT-29 xenograft tumor model in vivo. RESULTS: FA-NPs-miR-204 could be taken up by HT-29  and HCT-116 cells efficiently, resulting in significant inhibitory effect on cell proliferation and promotive effect on cell apoptosis. In vivo study showed that FA-NPs-miR-204 could exert tumor suppressive function in Luc-HT-29 xenograft model. CONCLUSION: Our study demonstrates a convenient miRNA delivery system that targets tumor tissue and exerts tumor suppressive function, thus demonstrating a potential new therapeutic option for colon cancer.

Andrographolide ameliorates d-galactosamine/lipopolysaccharide-induced acute liver injury by activating Nrf2 signaling pathway.

Andrographolide (ADH), a diterpenoid lactone extracted from Andrographis paniculata, has been found to have anti-inflammatory and anti-oxidative effects. However, its protective effects and mechanisms on liver injury have not been investigated clearly. This study takes an attempt to reveal the protective effects and mechanism of ADH on lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced acute liver injury in mice. The mice liver injury model was induced by LPS (60 mg/kg) and D-GalN (800 mg/kg), and ADH was given 1 h after LPS and D-GalN treatment. Hepatic tissue histology was measured by H&E staining. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected by detection kits. The levels of TNF-α and IL-1ß were detected by ELISA. Moreover, malondialdehyde (MDA) and reactive oxygen species (ROS) contents were also detected. Meanwhile, the expression of Nrf2, HO-1, and NF-κB were detected by western blot analysis. The results showed that ADH treatment improved liver histology and decreased the levels of ALT, AST, MPO, IL-1ß, TNF-α, as well as MDA and ROS levels of hepatic tissues in a dose-dependent manner. ADH also inhibited LPS/D-GalN-induced NF-κB activation. The expression of Nrf2 and HO-1 were increased by treatment of ADH. In conclusion, ADH protected against LPS/D-GalN-induced liver injury by inhibiting NF-κB and activating Nrf2 signaling pathway.

High expression of atonal homolog 8 predicts a poor clinical outcome in patients with colorectal cancer and contributes to tumor progression.

Hitherto, it has been identified that numerous basic-helix-loop-helix (bHLH) transcription factors play vital roles in tumor initiation and progression. Atonal homolog 8 (ATOH8) is a member of the bHLH family of transcription factors, which participates in embryogenesis and the development of various tissues. Several studies have demonstrated that ATOH8 is involved in the progression of malignancies; however, the effects of ATOH8 in colorectal cancer (CRC) remain unknown. The aim of the present study was to explore the expression and function of ATOH8 in CRC. The present study included 106 paired CRCs and peritumoral samples. The expression of ATOH8 was evaluated by immunohistochemistry, and the results were compared with the clinical outcomes of the patients. Furthermore, cell proliferation, cell cycle distribution, wound healing and cytotoxicity assays were performed in colon cancer cell line SW620. Immunohistochemical analyses revealed that the expression of ATOH8 in CRC tissues was significantly increased compared with the peritumoral tissues, and that the high expression of ATOH8 was associated with a high serum carcinoembryonic antigen (CEA) level and a worse overall survival. In vitro assays revealed that ATOH8 knockdown in colon cancer cells inhibited cell proliferation, induced cell cycle arrest at the S phase, and increased the percentage of apoptotic cells and sensitivity to 5-fluorouracil (5-FU). The present study suggests that ATOH8 promotes the progression of CRC and may potentially serve as a novel prognostic predictor and potential therapeutic target in CRC.

High Rab11-FIP4 expression predicts poor prognosis and exhibits tumor promotion in pancreatic cancer.

Some studies have demonstrated that Rab11-family interacting proteins (Rab11-FIPs) are connected with the tumorigenesis, and they may act as tumor promoters in some cancers. The clinicopathological significance of Rab11-family interacting protein 4 (Rab11-FIP4 ) expression and its possible effects on pancreatic cancer (PC) are still undiscovered. In this study, Rab11-FIP4 protein expression level in 60 PC specimens and pair-matched non-cancerous samples were detected by immunohistochemistry analysis. The results were analysed and compared with each patients' clinical data. Rab11-FIP4 expression in PC tissues increased significantly more than that of adjacent non-cancerous tissues (P=0.0001). Overexpression of Rab11-FIP4 in the PC tissues was significantly related to tumor size (P=0.0001), histological grade (P=0.028), metastasis (P=0.001) and TNM stage (P=0.004) but not with age (P=0.832), gender (P=0.228) or tumor site (P=0.875). Kaplan-Meier survival analysis showed that overexpression of Rab11-FIP4 was significantly related to overall survival time (P=0.0036). In addition, Rab11-FIP4 in PANC-1 pancreatic cancer cells were successfully knocked-out using the CRISPR/Cas9 system. Rab11-FIP4 knockout in PANC-1 cells inhibited cell growth, invasion and metastasis, and arrested cell cycle progression, but did not alter apoptosis. Our findings suggest that overexpression of Rab11-FIP4 predicts poor clinical outcomes for pancreatic cancer and contributes to pancreatic tumor progression.

The Benefits of Combination Therapy with Esomeprazole and Rebamipide in Symptom Improvement in Reflux Esophagitis: An International Multicenter Study.

BACKGROUND/AIMS: To investigate the effects of esomeprazole and rebamipide combination therapy on symptomatic improvement in patients with reflux esophagitis. METHODS: A total of 501 patients with reflux esophagitis were randomized into one of the following two treatment regimens: 40 mg esomeprazole plus 300 mg rebamipide daily (combination therapy group) or 40 mg esomeprazole daily (monotherapy group). We used a symptom questionnaire that evaluated heartburn, acid regurgitation, and four upper gastrointestinal symptoms. The primary efficacy end point was the mean decrease in the total symptom score. RESULTS: The mean decreases in the total symptom score at 4 weeks were estimated to be -18.1±13.8 in the combination therapy group and -15.1±11.9 in the monotherapy group (p=0.011). Changes in reflux symptoms from baseline after 4 weeks of treatment were -8.4±6.6 in the combination therapy group and -6.8±5.9 in the monotherapy group (p=0.009). CONCLUSIONS: Over a 4-week treatment course, esomeprazole and rebamipide combination therapy was more effective in decreasing the symptoms of reflux esophagitis than esomeprazole monotherapy.

Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer.

AIM: To assess human cytomegalovirus-encoded US28 gene function in colorectal cancer (CRC) pathogenesis. METHODS: Immunohistochemical analysis was performed to determine US28 expression in 103 CRC patient samples and 98 corresponding adjacent noncancerous samples. Patient data were compared by age, sex, tumor location, histological grade, Dukes' stage, and overall mean survival time. In addition, the US28 gene was transiently transfected into the CRC LOVO cell line, and cell proliferation was assessed using a cell counting kit-8 assay. Cell cycle analysis by flow cytometry and a cell invasion transwell assay were also carried out. RESULTS: US28 levels were clearly higher in CRC tissues (38.8%) than in adjacent noncancerous samples (7.1%) (P = 0.000). Interestingly, elevated US28 amounts in CRC tissues were significantly associated with histological grade, metastasis, Dukes' stage, and overall survival (all P < 0.05); meanwhile, US28 expression was not significantly correlated with age, sex or tumor location. In addition, multivariate Cox regression data revealed US28 level as an independent CRC prognostic marker (P = 0.000). LOVO cells successfully transfected with the US28 gene exhibited higher viability, greater chemotherapy resistance, accelerated cell cycle progression, and increased invasion ability. CONCLUSION: US28 expression is predictive of poor prognosis and may promote CRC.

Latexin exhibits tumor-suppressor potential in pancreatic ductal adenocarcinoma.

Recent studies suggest that latexin (Lxn) expression is involved in stem cell regulation and that it plays significant roles in tumor cell migration and invasion. The clinicopathological significance of Lxn expression and its possible correlation with CD133 expression in pancreatic ductal adenocarcinoma (PDAC) is currently unknown. In the present study, immunohistochemical analysis was performed to determine Lxn and CD133 expression in 43 PDAC patient samples and in 32 corresponding adjacent non-cancerous samples. The results were analyzed and compared with patient age, gender, tumor site and size, histological grade, clinical stage and overall mean survival time. Lxn expression was clearly decreased in the PDAC tissues compared with that in the adjacent non-cancerous tissues, while CD133 expression was increased. Low Lxn expression in the PDAC tissues was significantly correlated with tumor size (P=0.002), histological grade (P=0.000), metastasis (P=0.007) and clinical stage (P=0.018), but not with age (P=0.451), gender (P=0.395) or tumor site (P=0.697). Kaplan-Meier survival analysis revealed that low Lxn expression was significantly correlated with reduced overall survival time (P=0.000). Furthermore, Lxn expression was found to be inversely correlated with CD133 expression (r=-0.485, P=0.001). Furthermore, CD133-positive MIA PaCa-2 pancreatic tumor cells were sorted by magnetic-activated cell sorting (MACS), and those that overexpressed Lxn exhibited a significantly higher rate of apoptosis and lower proliferative activity. Our findings suggest that Lxn may function as a tumor suppressor that targets CD133-positive pancreatic cancer cells.

Latexin inhibits the proliferation of CD133+ miapaca-2 pancreatic cancer stem-like cells.

BACKGROUND: An increasing number of evidence suggests that pancreatic cancer contains cancer stem cells (CSCs), which may be relevant to the resistance of chemotherapy. Latexin (Lxn) is a negative regulator of stem cell proliferation and we investigate the effects of Lxn on CD133+ pancreatic cancer stem-like cells. METHODS: CD133+ miapaca-2 cells, a human pancreatic carcinoma cell line, were isolated and sorted by magnetic activated cell sorting and flow cytometry. The capacity for self-renewal, proliferation, and tumorigenicity of CD133+ miapaca-2 cells was determined by the floating spheres test and tumor xenograft assays. Protein and mRNA expression of Lxn in CD133+ and CD133- miapaca-2 cells were detected by Western blotting and qRT-PCR, respectively. After CD133+ miapaca-2 cells were treated with Lxn in serum-free medium (SFM), cell proliferation was assayed with a Cell Counting Kit 8 (CCK-8) and apoptosis was analyzed by flow cytometry. The protein and mRNA expression levels of Bcl-2, bax, and c-myc were also analyzed. RESULTS: We successfully isolated CD133+ miapaca-2 cells that exhibited the capacity for self-renewal in SFM, a proliferation potential in DMEM supplemented with FBS, and high tumorigenicity in nude mice. Lxn protein and mRNA expression levels in CD133+ miapaca-2 cells were significantly lower than those in CD133- cells. Lxn-treated CD133+ miapaca-2 cells exhibited increased apoptosis and low proliferation activity, down-regulation of Bcl-2 and c-myc expression, and up-regulation of Bax expression in a dose-dependent manner. CONCLUSIONS: Lxn induces apoptosis and inhibits the proliferation of CD133+ miapaca-2 cells. These changes are associated with down-regulation of Bcl-2 and c-myc and up-regulation of Bax.