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Background For the past two decades, dispute on whether proton pump inhibitor (PPI) leads to digestive tract cancer remains, and emerging studies in recent years still demonstrate inconsistent results, which continues to perpetuate concerns over the safety of PPI use. We performed a systematic review and meta-analysis, with comprehensive evaluation by Bradford Hill criteria of causation, to assess the effect of PPI use on digestive tract cancers. Methods Medline, Embase and Web of Science databases were searched for observational studies published up to 15th January 2021. Pooled relative risks (RRs) were estimated via random effects models. Cumulative defined daily dose- and duration-risk relationships using restricted cubic spline and fractional polynomial models were investigated. Bradford Hill criteria were applied to evaluate causation. PROSPERO Registration: CRD42020211103. Results Thirty-two publications containing 4,355,254 participants were included. PPI use is associated with an increased risk of overall digestive tract cancers (RR = 1.63, 95% confidence interval (CI) 1.33 to 2.00). PPI use is correlated with increased risks of gastric cancer (RR = 1.78, 95% CI 1.38 to 2.31), pancreatic cancer (RR = 1.72, 95% CI 1.05 to 2.82) and liver cancer (RR = 1.62, 95% CI 1.04 to 2.52), but not of esophageal cancer (RR = 2.06, 95% CI 0.65 to 6.57) and colorectal cancer (RR = 1.24, 95% CI 0.93 to 1.66). The association between PPI and digestive tract cancers is stronger in people with minimal exposure. When cumulative defined daily dose or duration increases, the risks decline and become non-significant. Evaluation by Bradford Hill criteria indicates weak evidence of causation. Conclusions A causal relationship between PPI use and digestive tract cancers is not supported by the evidence in the current review. Concerns over carcinogenic side-effects of PPI might be unfounded.

Necrotizing enterocolitis (NEC) is a devastating disease predominately affecting neonates. Despite therapeutic advances, NEC remains the leading cause of mortality due to gastrointestinal conditions in neonates. Stem cells have been exploited in various diseases, and the application of different types of stem cells in the NEC therapy is explored in the past decade. However, stem cell transplantation possesses several deficiencies, and exosomes are considered potent alternatives. Exosomes, especially those derived from stem cells and breast milk, demonstrate beneficial effects for NEC both in vivo and in vitro and emerge as promising options for clinical practice. In this review, the function and therapeutic effects of stem cells and exosomes for NEC are investigated and summarized, which provide insights for the development and application of novel therapeutic strategies in pediatric diseases. Further elucidation of mechanisms, improvement in preparation, bioengineering, and administration, as well as rigorous clinical trials are warranted.

Treatment options for necrotizing enterocolitis (NEC) remain inadequate. Here we examined if and how prolyl hydroxylase 2 (PHD2) silencing enhances the paracrine effects of bone-marrow-derived mesenchymal stem cells (BM-MSCs) on NEC. In this study, BM-MSCs were transduced with lentiviruses containing GFP (GFP-MSC) or shPHD2-GFP constructs (PHDMSC), followed by intraperitoneal injection of the PHDMSC-conditioned medium (PHDMSC-CM) or the GFP-MSC-conditioned medium (MSC-CM) into a rat pup model of NEC. Our results showed that systemic infusion of PHDMSC-CM, but not MSC-CM, significantly improved intestinal damage and survival of NEC rats. Such benefits may involve the modulation of epithelial regeneration and inflammation, as indicated by the regeneration of intestinal epithelial/stem cells, the regulation of Treg cells function and pro-/anti-inflammatory cytokine balance. The mechanism for the superior paracrine efficacy of PHDMSC is related to a higher release of pivotal factor IGF-1 and TGF-β2. NF-κB activation was induced by PHD2 silencing to induce IGF-1 and TGF-β2 secretion via binding to IGF-1 and TGF-β2 gene promoter. Our work indicated that PHD2 silencing enhanced the paracrine effect of BM-MSCs on NEC via the NF-κB-dependent mechanism which may be a novel strategy for stem cell therapy on NEC.

Duodenal ulcers, especially caused by increasingly drug-resistant Helicobacter pylori, are a concern in Asia. We compared oral vonoprazan versus lansoprazole for efficacy (healing duodenal ulcers) and safety in non-Japanese Asian patients.In this phase 3, randomized (1:1), double-blind, double-dummy, parallel-group, non-inferiority study (April 5, 2017, to July 19, 2019), patients with ≥ 1 endoscopically confirmed duodenal ulcer, at 52 hospitals (China, South Korea, and Taiwan), received vonoprazan 20 mg once daily (QD) or lansoprazole 30 mg QD for 6 weeks maximum. Patients with H. pylori received bismuth-containing quadruple therapy including vonoprazan 20 mg twice daily (BID) or lansoprazole 30 mg BID, for 2 weeks, followed by vonoprazan or lansoprazole monotherapy QD (4 weeks maximum). Endpoints were endoscopically confirmed duodenal ulcer healing (Week 4/6; primary) and H. pylori eradication (4 weeks post-treatment; secondary); non-inferiority margins were -6% and -10%, using a two-sided 95% confidence interval (CI).Of 533 enrolled patients, one was lost to follow-up and one withdrew (full analysis set: 531 patients [vonoprazan, n = 263; lansoprazole, n = 268]; 85.4% = H. pylori positive). Vonoprazan was non-inferior to lansoprazole for duodenal ulcer healing (96.9% vs 96.5%; difference 0.4% [95% CI -3.00, 3.79]). H. pylori eradication rates were 91.5% (vonoprazan) and 86.8% (lansoprazole; difference 4.7% [95% CI -1.28, 10.69]). Vonoprazan and lansoprazole were well tolerated, with similar safety profiles, no new safety signals; no deaths occurred.Vonoprazan was well tolerated and non-inferior to lansoprazole for duodenal ulcer healing and achieved H. pylori eradication above the clinically meaningful threshold (90%), in non-Japanese Asian patients.

In the past decade, the study of extracellular vesicles (EVs), especially exosomes (50–150 nm) have attracted growing interest in numerous areas of cancer and tissue regeneration due to their unique biological features. A low isolation yield and insufficient targeting abilities limit their therapeutic applicability. Recently, superparamagnetic iron oxide nanoparticles (SPIONs) with magnetic navigation have been exploited to enhance the targeting ability of EVs. To construct targeted EV delivery systems engineered by SPIONs, several groups have pioneered the use of different techniques, such as electroporation, natural incubation, and cell extrusion, to directly internalize SPIONs into EVs. Furthermore, some endogenous ligands, such as transferrins, antibodies, aptamers, and streptavidin, were shown to enable modification of SPIONs, which increases binding with EVs. In this review, we summarized recent advances in targeted EV delivery systems engineered by SPIONs and focused on the key methodological approaches and the current applications of magnetic EVs. This report aims to address the existing challenges and provide comprehensive insights into targeted EV delivery systems. Statement of significance Targeted extracellular vesicle (EV) delivery systems engineered by superparamagnetic iron oxide nanoparticles (SPIONs) have attracted wide attention and research interest in recent years. Such strategies employ external magnet fields to manipulate SPION-functionalized EVs remotely, aiming to enhance their accumulation and penetration in vivo. Although iron oxide nanoparticle laden EVs are interesting, they are controversial at present, hampering the progress in their clinical application. A thorough integration of these studies is needed for an advanced insight and rational design of targeted EV delivery systems. In this review, we summarize the latest advances in the design strategies of targeted EV delivery systems engineered by SPIONs with a focus on their key methodological approaches, current applications, limitation and future perspectives, which may facilitate the development of natural theranostic nanoplatforms.

AIM To identify functional proteins involved in pancreatic-duodenal homeobox-1 (PDX1)-mediated effects on gastric carcinogenesis. METHODS A PDX1-overexpressed model was established by transfecting gastric cancer cell line SGC7901 with pcDNA3.1(+)-PDX1 vector (SGC-PDX1). Transfection with empty pcDNA3.1 vector (SGC-pcDNA) served as control. Comparative protein profiles of the two groups were analyzed by two-dimensional electrophoresis based-proteomics (2DE gel-based proteomics). The differential proteins identified by 2DE were further validated by qRT-PCR and immunoblotting. Finally, co-immunoprecipitation was used to determine any direct interactions between PDX1 and the differential proteins. RESULTS 2DE gel proteomics identified seven differential proteins in SGC-PDX1 when compared with those in SGC-pcDNA. These included four heat shock proteins (HSPs; HSP70p1B, HSP70p8, HSP60, HSP27) and three other proteins (ER60, laminin receptor 1, similar to epsilon isoform of 14-3-3 protein). Immunoblotting validated the expression of the HSPs (HSP70, HSP60, HSP27). Furthermore, their expressions were lowered to 80%, 20% and 24%, respectively, in SGC-PDX1, while PDX1 exhibited a 9-fold increase, compared to SGC-pcDNA. However, qRT-PCR analysis revealed that mRNA levels of the HSPs were increased in SGC-PDX1, suggesting that the expression of the HSPs was post-translationally regulated by the PDX1 protein. Finally, co-immunoprecipitation failed to identify any direct interaction between PDX1 and HSP70 proteins. CONCLUSION This study demonstrates the potential involvement of HSPs in PDX1-mediated effects on the genesis of gastric cancer.

Cancer stem cells (CSCs) and epithelial‑mesenchymal transition (EMT) are critical factors contributing to tumor metastasis and recurrence. The BMI1 proto‑oncogene (Bmi‑1) promotes the development and progression of hematologic malignancies and of several types of solid tumors. The aim of the present study was to explore the mechanism by which Bmi‑1 may promote invasion and migration of hepatocellular carcinoma Hep G2 cells. CD133 antigen is a transmembrane glycoprotein and regarded as a cancer stem cells marker in hepatocellular carcinoma. CD133+Hep G2 cells were enriched by magnetic‑activated cell sorting and exhibited greater viability compared with CD133‑Hep G2 cells, as measured by Cell Counting kit‑8 assay. Then, Bmi‑1 was overexpressed in CD133+Hep G2 cells by transfection with the Bmi‑1/pcDNA3.1(+) expression plasmid, and overexpression was confirmed by reverse‑transcription‑polymerase chain reaction and western blotting. Overexpression of Bmi‑1in CD133+Hep G2 cells resulted in the downregulation of E‑cadherin and upregulation of Vimentin at the protein level. The invasion and migration abilities of CD133+Hep G2 cells were increased in the Bmi‑1/pcDNA3.1(+)‑transfected group, as measured by Transwell invasion and wound healing assays, respectively. In conclusion, Bmi‑1 promoted invasion and migration of CD133+Hep G2 cells most likely through inducing EMT. The present findings may offer a potential novel target for the development of hepatocellular carcinoma therapies.

Objective PD98059 is a potent and selective inhibitor of mitogen-activated protein kinase. Substantial preclinical evidence has shown an anti-tumor effect of curcumin on various solid tumors. This study aimed to investigate whether curcumin synergistically acts with PD98059 in exerting anti-gastric cancer effects. Methods The cell counting kit-8 assay was used to detect cell proliferation of the human gastric cancer MGC-803 cell line. Flow cytometry was performed to detect apoptosis. Western blotting was used to detect phosphatase and tensin homolog (PTEN) and phosphorylated Akt (p-Akt) expression levels. Quantitative reverse transcription-polymerase chain reaction was used to determine microRNA-21 (miR-21). Results A dose of 5 to 40 µM curcumin inhibited proliferation of MGC-803 cells in a dose- and time-dependent manner. A high dose of curcumin strongly inhibited p-Akt protein expression. With increasing curcumin levels, PTEN expression increased and miR-21 levels decreased. These results suggest that curcumin negatively modulated the miR-21/PTEN/Akt pathway. Moreover, after pretreatment with PD98059, cell apoptosis induced by curcumin was significantly increased. Additionally, the inhibitory effects of curcumin on the miR-21/PTEN/Akt pathway were significantly enhanced. Conclusion PD98059 combined with curcumin may be a potential strategy for managing gastric cancer.

Metastasis and recurrence are the challenges of cancer therapy. Recently, mounting evidence has suggested that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical factors in tumor metastasis and recurrence. The oncogene, Bmi-1, promotes the development of hematologic malignancies and many solid tumors. The aim of the present study was to elucidate the mechanisms through which Bmi-1 promotes the invasion and migration of colon CSCs (CCSCs) using the HCT116 colon cancer cell line. Sphere formation medium and magnetic-activated cell sorting were used to enrich and screen the CCSCs. CD133 and CD44 were regarded as markers of CCSCs and they were found to be co-expressed in the HCT116 colon cancer cell line. Colony formation assay, cell proliferation assay and viability assay using the Cell Counting Kit-8, and transplantation assay using nude mice injected with CCSCs were used to examine the CCSCs. The CD133+CD44+ HCT116 cells exhibited greater cloning efficiency, an enhanced proliferative ability, increased cell viability and stronger tumorigenicity; these cells were used as the CCSCs for subsequent experiments. In addition, the invasive and migratory abilities of the CD133+CD44+ HCT116 cells were markedly decreased when Bmi-1 was silenced by small interfering RNA (siRNA). The results of RT-qPCR and western blot analysis suggested that Bmi-1 had a negative effect on E-cadherin expression. On the whole, our findings suggest that Bmi-1 promotes the invasion and migration of CCSCs through the downregulation of E-cadherin, possibly by inducing EMT. Our findings thus indicate that Bmi-1 may be a novel therapeutic target for the treatment of colon cancer.

Trastuzumab has been approved for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction cancers (GC and GJC) in combination with chemotherapy. The aim of this HER2 early/advanced gastric epidemiology (HER-EAGLE) study was to evaluate the frequency of HER2 over-expression and to evaluate agreement on HER2 status assessment in GC and GJC patients in local laboratories versus a central laboratory in China. Tumor samples from 734 GC or GJC patients who were enrolled at 11 different hospitals in China were examined. HER2 status was assessed by immunohistochemistry (IHC), and followed by dual-color silver-enhanced in Situ hybridization (DSISH) in IHC 2+ cases. Clinicopathologic characteristics were collected from all of the patients. HER2-positive tumors were identified in 12.0% (88/734) of the GC and GJC cases. There were significantly higher rates of HER2 positivity in patients with GJC (GJC: 18.1%, GC: 9.7%, P=0.002), and intestinal-type cancers using the Lauren classification (intestinal: 23.6%, diffuse/mixed: 4.3%, P

Recently, Gastroesophageal Reflux Disease Questionnaire (GerdQ) has been developed for diagnosis of GERD. However, no study investigated its value in real-world practice. This study aimed to investigate whether GerdQ can be used for diagnosis of GERD in China.A national multicenter survey was undertaken; all patients who underwent first diagnostic upper endoscopy for upper gastrointestinal (GI) symptoms were included. Data including the gender, age, symptoms, and endoscopic findings were prospectively recorded. The GerdQ score was measured before endoscopic procedure.Totally, 8065 patients were included. One thousand four hundred and thirty-five patients (17.8%) had reflux esophagitis. Among them, 620 (43.2%) patients' GerdQ score was ≥ 8. For 2025 patients with GerdQ ≥ 8, 620 (30.6%) were found to have reflux esophagitis, but the remaining 69.4% (1405/2025) were normal. Proportions of patients with reflux esophagitis increased in cut-off range from 3-18 for GerdQ. However, 22.2% of the patients with a GerdQ score ≤ 2 also had reflux esophagitis. Twenty-eight (0.3%) patients were diagnosed to have upper GI malignancies, and 10 out of these 28 (35.7%) patients' GerdQ score was ≥ 8.The study suggests the proportions of Chinese patients with reflux esophagitis rise up with the increase of GerdQ score, and GerdQ may be used for diagnosis of GERD. However, low GerdQ score cannot exclude the possibility of reflux esophagitis. A minority of Chinese patients has high GerdQ score but is diagnosed with malignancies, even in the absence of alarm features.

Aim: The aim of this study was to assess gastric slow waves, antral and duodenal motility simultaneously, and determine the correlation among all these measures in patients with functional dyspepsia. Methods: Thirty-one patients with functional dyspepsia were assessed for severity of upper gastrointestinal symptoms with the electrogastrography (EGG) and antroduodenal manometry. The EGG and manometry were recorded for 3 to 4 hours in the fasting state and for 2 hours after a solid meal. Computerized spectral analysis methods were used to compute various EGG parameters. Results: The EGG was abnormal in 71.0% of patients. The abnormalities included normal slow waves lower than 70% in the fasting state (51.6% of patients) and in the fed state (48.4% of patients), a decrease in dominant power in 28.9% of patients. Antral motility was abnormal in 80.6% of patients and duodenal motility was abnormal in 74.2% of patients. For the EGG and antral motility, 19 of 31 patients had both abnormal EGG and abnormal antral motility; 2 of 31 patients had both normal EGG and normal antral motility. For the EGG and duodenal motility, these values were 16/31 and 2/31, respectively. By both EGG and antroduodenal manometry, abnormal gastric motor function was found in 93.5% of patients. However, quantitative one-to-one correlation between any of the EGG parameters and the antroduodenal dysmotility was not noted. The patients showed high symptom scores particularly to upper abdominal pain, nausea, and belch. No one-to-one correlation was noted between the symptom scores and any of the EGG or motility parameters. Conclusions: More than two-thirds of patients with functional dyspepsia have abnormalities in the EGG and antral/duodenal motility. The sensitivity of these 2 different methods is essentially the same. EGG and antroduodenal manometry can complement each other in demonstrating gastric motor dysfunction in patients with functional dyspepsia.

The objectives of this study were to assess differences in gastric slow waves measured by a newly approved multichannel electrogastrogram (EGG) device between patients with functional dyspepsia (FD) and healthy controls.Gastric myoelectrical activity was measured by multichannel EGG for 1 hour preprandially and for 2 hours postprandially in 72 FD patients and 16 healthy volunteers. Computerized spectral analysis methods were used to compute various EGG parameters.(1) Multichannel EGG was abnormal in 83.3% of patients. (2) The regularity of the gastric slow wave was significantly lower in the FD patients in both fasting and fed states; the lowest regularity was seen in channel 3. (3) There was a significantly higher incidence of arrhythmia and tachygastria in FD patients. The highest percentage of arrhythmia and tachygastria were both seen in channel 3. (4) The FD patients showed a significantly lower percentage of slow wave coupling among the 4-channel EGGs in the fed state. (5) The postprandial-preprandial power ratio was significantly less in FD patients. (6) These patients had high symptom scores particularly to nausea, upper abdominal pain, and bloating. However, no significant correlation was noted between the EGG parameters and the symptoms.Gastric myoelectrical activity is impaired in most patients with FD. The impairment is reflected as a decreased percentage of normal slow waves and an excessive amount of arrhythmia as well as an abnormal spatial distribution of EGG parameters among the 4 channels, suggesting an impaired coordination of gastric slow waves.

To investigate the prevalence of functional dyspepsia (FD) and the psychological disorders in Chinese population and their relation.A total of 1016 apparently healthy people (study population) randomly selected from population were interviewed. A general questionnaire, Zung self-rating depression scales (SDS), and anxiety scales (SAS) were given to each subject. Seventy-two inpatients with confirmed diagnosis of FD, 84 with organic dyspepsia, and 197 with other organic diseases were also studied.Among the study population, 23.5% had FD and 9. 1% had disturbances of depression and/or anxiety. The prevalence of psychological disturbances in FD group (15.5%) differed significantly from that in non-FD group (7.1%, P0.01 ) . In the survey of inpatients, the rate of depression/anxiety in FD group (54.2%) was greater than that in organic dyspepsia group (19.0%) and other organic diseases group (28.9%), P0.05, and was also significantly higher than that of the FD cases in the study population (15.5%), P0.01. Further analysis showed that some psychosocial disturbances were risk factors of FD.Both FD and depression/anxiety disturbances are common in China, and there is a link between them.

Background and Objective Irritable Bowel Syndrome (IBS) has a substantial impact on health-related quality of life (HR-QoL) but high-quality data pre- and post-treatment using the IBS–Quality of Life (IBS-QOL) measure are limited. The objective of this study was to evaluate the changes from baseline of the IBS-QOL scores, symptom scores and health economic data in IBS patients, after 4 and 8 weeks of treatment with mebeverine hydrochloride or pinaverium bromide. Methods This was a prospective observational cohort study in patients with IBS, diagnosed using the Rome III criteria in four countries (Poland, Egypt, Mexico and China). Results A total of 607 patients were enrolled. At baseline, the IBS-QOL total scores were 52.0 in Poland, 48.9 in Egypt, 51.9 in Mexico, 76.4 in China and 56.4 overall. Increases in IBS-QOL total score were statistically significant at Weeks 4 and 8 overall and in each country (overall: 11.8 at Week 4, 24.3 at Week 8; p