Synergistic Effects of Matrix Biophysical Properties on Gastric Cancer Cell Behavior via Integrin-Mediated Cell-ECM Interactions.

The biophysical properties of the extracellular matrix (ECM) play a pivotal role in modulating cancer progression via cell-ECM interactions. However, the biophysical properties specific to gastric cancer (GC) remain largely unexplored. Pertinently, GC ECM shows significantly heterogeneous metamorphoses, such as matrix stiffening and intricate restructuring. By combining collagen I and alginate, this study designs an in vitro biomimetic hydrogel platform to independently modulate matrix stiffness and structure across a physiological stiffness spectrum while preserving consistent collagen concentration and fiber topography. With this platform, this study assesses the impacts of matrix biophysical properties on cell proliferation, migration, invasion, and other pivotal dynamics of AGS. The findings spotlight a compelling interplay between matrix stiffness and structure, influencing both cellular responses and ECM remodeling. Furthermore, this investigation into the integrin/actin-collagen interplay reinforces the central role of integrins in mediating cell-ECM interactions, reciprocally sculpting cell conduct, and ECM adaptation. Collectively, this study reveals a previously unidentified role of ECM biophysical properties in GC malignant potential and provides insight into the bidirectional mechanical cell-ECM interactions, which may facilitate the development of novel therapeutic horizons.

Cell response to mechanical microenvironment cues via Rho signaling: From mechanobiology to mechanomedicine.

Mechanical cues in the cell microenvironment such as those from extracellular matrix properties, stretching, compression and shear stress, play a critical role in maintaining homeostasis. Upon sensing mechanical stimuli, cells can translate these external forces into intracellular biochemical signals to regulate their cellular behaviors, but the specific mechanisms of mechanotransduction at the molecular level remain elusive. As a subfamily of the Ras superfamily, Rho GTPases have been recognized as key intracellular mechanotransduction mediators that can regulate multiple cell activities such as proliferation, migration and differentiation as well as biological processes such as cytoskeletal dynamics, metabolism, and organ development. However, the upstream mechanosensors for Rho proteins and downstream effectors that respond to Rho signal activation have not been well illustrated. Moreover, Rho-mediated mechanical signals in previous studies are highly context-dependent. In this review, we systematically summarize the types of mechanical cues in the cell microenvironment and provide recent advances on the roles of the Rho-based mechanotransduction in various cell activities, physiological processes and diseases. Comprehensive insights into the mechanical roles of Rho GTPase partners would open a new paradigm of mechanomedicine for a variety of diseases. STATEMENT OF SIGNIFICANCE: In this review, we highlight the critical role of Rho GTPases as signal mediators to respond to physical cues in microenvironment. This article will add a distinct contribution to this set of knowledge by intensively addressing the relationship between Rho signaling and mechanobiology/mechanotransduction/mechanomedcine. This topic has not been discussed by the journal, nor has it yet been developed by the field. The comprehensive picture that will develop, from molecular mechanisms and engineering methods to disease treatment strategies, represents an important and distinct contribution to the field. We hope that this review would help researchers in various fields, especially clinicians, oncologists and bioengineers, who study Rho signal pathway and mechanobiology/mechanotransduction, understand the critical role of Rho GTPase in mechanotransduction.

Extracellular matrix physical properties govern the diffusion of nanoparticles in tumor microenvironment.

Nanoparticles (NPs) are confronted with limited and disappointing delivery efficiency in tumors clinically. The tumor extracellular matrix (ECM), whose physical traits have recently been recognized as new hallmarks of cancer, forms a main steric obstacle for NP diffusion, yet the role of tumor ECM physical traits in NP diffusion remains largely unexplored. Here, we characterized the physical properties of clinical gastric tumor samples and observed limited distribution of NPs in decellularized tumor tissues. We also performed molecular dynamics simulations and in vitro hydrogel experiments through single-particle tracking to investigate the diffusion mechanism of NPs and understand the influence of tumor ECM physical properties on NP diffusion both individually and collectively. Furthermore, we developed an estimation matrix model with evaluation scores of NP diffusion efficiency through comprehensive analyses of the data. Thus, beyond finding that loose and soft ECM with aligned structure contribute to efficient diffusion, we now have a systemic model to predict NP diffusion efficiency based on ECM physical traits and provide critical guidance for personalized tumor diagnosis and treatment.

Non-invasive model for predicting esophageal varices based on liver and spleen volume.

BACKGROUND: Upper endoscopy is the gold standard for predicting esophageal varices in China. Guidelines and consensus suggest that patients with liver cirrhosis should undergo periodic upper endoscopy, most patients undergo their first upper endoscopy when esophageal variceal bleeds. Therefore, it is important to develop a non-invasive model to early diagnose esophageal varices. AIM: To develop a non-invasive predictive model for esophageal varices based on liver and spleen volume in viral cirrhosis patients. METHODS: We conducted a cross-sectional study based on viral cirrhosis crowd in the Second Affiliated Hospital of Xi'an Jiaotong University. By collecting the basic information and clinical data of the participants, we derived the independent risk factors and established the prediction model of esophageal varices. The established model was compared with other models. Area under the receiver operating characteristic curve, calibration plot and decision curve analysis were used to test the discriminating ability, calibration ability and clinical practicability in both the internal and external validation. RESULTS: The portal vein diameter, the liver and spleen volume, and volume change rate were the independent risk factors of esophageal varices. We successfully used the factors to establish the predictive model [area under the curve (AUC) 0.87, 95%CI: 0.80-0.95], which showed better predictive value than other models. The model showed good discriminating ability, calibration ability and the clinical practicability in both modelling group and external validation group. CONCLUSION: The developed non-invasive predictive model can be used as an effective tool for predicting esophageal varices in viral cirrhosis patients.

The Effects of Psychological Interventions on Symptoms and Psychology of Functional Dyspepsia: A Systematic Review and Meta-Analysis.

Background: The effects of psychological interventions on symptoms and psychology of functional dyspepsia (FD) remain unclear. We aimed to comprehensively evaluate the effects of psychological interventions on symptoms and psychology of FD. Methods: We searched the PubMed, Cochrane Library, and Embase electronic databases for randomized controlled trials (RCTs) evaluating the role of psychological interventions in FD patients published before July 2021. Standardized mean differences (SMDs), risk ratios (RRs) and 95% confidence intervals (CIs) were calculated by a random effects model. Subgroup analyses and sensitivity analyses were also performed. Results: Fourteen RCTs with a total of 1,434 FD patients were included. Compared with the control group, psychological interventions were significantly more likely to symptom improvement [RR = 1.74, 95% CI (1.12, 2.72), p = 0.01], relieve gastrointestinal symptoms scores at follow up [SMD = -1.06, 95% CI (-1.55, -0.57), p < 0.0001], relieve gastrointestinal symptoms scores at end of treatment [SMD = -0.98, 95% CI (-1.29, -0.67), p < 0.001], decrease anxiety [SMD = -0.8, 95% CI (-1.38, -0.22), p = 0.006] and depression levels [SMD = -1.11, 95% CI (-1.62, -0.61), p < 0.001]. The results of the subgroup analysis showed that psychotherapy was more likely to symptom improvement, relieve gastrointestinal symptoms scores and decreased depression levels compared to the control. Conclusions: Psychological interventions may be effective in alleviating the symptoms and psychology of FD, but the effect appears to be limited to psychotherapy with fewer trials for other psychological interventions. More data from high-quality RCTs are needed to confirm their use in the treatment of FD.

Predictive value of alarm symptoms in Rome IV irritable bowel syndrome: A multicenter cross-sectional study.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disease that shares features with many organic diseases and cannot be accurately diagnosed by symptom-based criteria. Alarm symptoms have long been applied in the clinical diagnosis of IBS. However, no study has explored the predictive value of alarm symptoms in suspected IBS patients based on the latest Rome IV criteria. AIM: To investigate the predictive value of alarm symptoms in suspected IBS patients based on the Rome IV criteria. METHODS: In this multicenter cross-sectional study, we collected data from 730 suspected IBS patients evaluated at 3 tertiary care centers from August 2018 to August 2019. Patients with IBS-like symptoms who completed colonoscopy during the study period were initially identified by investigators through medical records. Eligible patients completed questionnaires, underwent laboratory tests, and were assigned to the IBS or organic disease group according to colonoscopy findings and pathology results (if a biopsy was taken). Independent risk factors for organic disease were explored by logistic regression analysis, and the positive predictive value (PPV) and missed diagnosis rate were calculated. RESULTS: The incidence of alarm symptoms in suspected IBS patients was 75.34%. Anemia [odds ratio (OR) = 2.825, 95% confidence interval (CI): 1.273-6.267, P = 0.011], fecal occult blood [OR = 1.940 (95%CI: 1.041-3.613), P = 0.037], unintended weight loss (P = 0.009), female sex [OR = 0.560 (95%CI: 0.330-0.949), P = 0.031] and marital status (P = 0.030) were independently correlated with organic disease. The prevalence of organic disease was 10.41% in suspected IBS patients. The PPV of alarm symptoms for organic disease was highest for anemia (22.92%), fecal occult blood (19.35%) and unintended weight loss (16.48%), and it was 100% when these three factors were combined. The PPV and missed diagnosis rate for diagnosing IBS were 91.67% and 74.77% when all alarm symptoms were combined with Rome IV and 92.09% and 34.10% when only fecal occult blood, unintended weight loss and anemia were combined with Rome IV, respectively. CONCLUSION: Anemia, fecal occult blood and unintended weight loss have high predictive value for organic disease in suspected IBS patients and can help identify patients requiring further examination but are not recommended as exclusion criteria for IBS.

Identification of SRGAP2 as a potential oncogene and a prognostic biomarker in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the common malignancies worldwide. Slit-Robo GTPase-activating proteins (SRGAPs) have been shown to regulate the occurrence and development of various tumors. However, their specific roles in HCC remain elusive. METHODS: The expression pattern, genetic alteration and prognostic value of SRGAPs in HCC are analyzed by bioinformatics tools. The biological functions of SRGAP2 in HCC cells are demonstrated by in vitro experiments. The high-throughput RNA sequencing is conducted to explore the underlying molecular mechanisms of SRGAP2 in HCC cells. RESULTS: The expression levels of SRGAP1 and SRGAP2 are significantly elevated in HCC tissues compared to the normal both in Oncomine and TCGA datasets, and SRGAP2 are dramatically upregulated both in mRNA and protein levels. Moreover, higher SRGAP2 is significantly related to the clinical stages of HCC. Meanwhile, SRGAP2 might be an independent prognostic indicator, as it correlates negatively with the clinical outcomes of HCC patients. Further SRGAP2-silencing experiments imply that SRGAP2 might remarkably promote the migration and invasion of HCC cells in an EMT-independent pattern. Based on the high-throughput RNA sequencing of SRGAP2-knockdown HCC cells, enrichment and network analyses demonstrate that SRGAP2 is closely associated with cellular metabolic signaling. CONCLUSIONS: Our study firstly illustrates the crucial role of SRGAP2 in the metastasis of HCC and explores its underlying molecular mechanisms. We identify SRGAP2 as a promising prognostic biomarker and a novel therapeutic target for HCC patients.

MicroRNA-302s Might Regulate ARL4C-Mediated Gastric Cancer Progression via p53 Signaling: Bioinformatics Analysis and Experiments Validation.

BACKGROUND: Our previous studies demonstrate that ARL4C is the most critical clinical biomarker for gastric cancer (GC) patients among ARL family members (ARLs) and functions as an oncogene in GC. However, its underlying mechanisms in GC need to be further illustrated. In this study, we aim to explore the upstream and downstream molecular mechanisms of ARL4C in GC cells. METHODS: The genetic alteration of ARL4C in GC is analyzed by cBioPortal database. Potential ARL4C-targeted microRNAs (miRs) are predicted by three databases. The high-throughput RNA sequencing is performed to explore the underlying mechanisms of ARL4C in GC cells. The effects of predicted microRNAs on ARL4C, the RNA-sequencing results validation and the biological functions of ARL4C in GC cells are illustrated by in vitro experiments. RESULTS: Genetic analyses indicate that ARL4C is significantly upregulated in GC, which is not caused by gene amplification. MicroRNAs prediction shows the high relevance between ARL4C and miR-302 members. Moreover, miR-302c or miR-302d transfection reduces ARL4C protein expression in GC cells. Based on the high-throughput RNA sequencing of ARL4C-knockdown cells, enrichment analyses demonstrate that ARL4C is closely related to cell growth and involved in p53 signaling. Moreover, there are strong gene-gene interactions between ARL4C and genes in p53 signaling, and ARL4C downregulation could inhibit the protein expression of MDM2, a critical gene in p53 pathway. Further functional experiments demonstrate that ARL4C silencing leads to cell cycle arrest and increased cell apoptosis in AGS and MKN45 cells. CONCLUSION: Our data suggest that miR-302c and miR-302d may function as the upstream regulators of ARL4C. And, ARL4C might promote GC cell cycle progression via regulating p53 signaling. Our findings provide novel insights into the key role of ARL4C and the underlying mechanisms in GC progression, thus facilitating the development of ARL4C-targeted therapy.

Predictive value of alarm symptoms in patients with Rome IV dyspepsia: A cross-sectional study.

BACKGROUND: No studies have evaluated the predictive value of alarm symptoms for organic dyspepsia and organic upper gastrointestinal (GI) diseases based on Rome IV criteria in the Chinese population. AIM: To evaluate the predictive value of alarm symptoms for dyspeptic patients based on Rome IV criteria. METHODS: We performed a cross-sectional study of dyspepsia patients who met the inclusion and exclusion criteria at two academic urban tertiary-care centers from March 2018 to January 2019. Basic demographic data, dyspeptic information, alarm symptoms, lifestyle, examination results, family history and outpatient cost information were collected. Dyspepsia patients with normal findings on upper GI endoscopy, epigastric ultrasound and laboratory examination and without Helicobacter pylori-associated dyspepsia were classified as functional dyspepsia. RESULTS: A total of 381 patients were enrolled in the study, including 266 functional dyspepsia patients and 115 organic dyspepsia patients. There were 24 patients with organic upper GI disease among patients with organic dyspepsia. We found that based on the Rome IV criteria, alarm symptoms were of limited value in differentiating organic dyspepsia and organic upper GI diseases from functional dyspepsia. Age (odds ratio (OR) = 1.056, P = 0.012), smoking (OR = 4.714, P = 0.006) and anemia (OR = 88.270, P < 0.001) were independent predictors for organic upper GI diseases. For the comparison of epigastric pain syndrome, postprandial distress syndrome and epigastric pain syndrome combined with postprandial distress syndrome, the results showed that there were statistically significant differences in anorexia (P = 0.021) and previous visits (P = 0.012). The ClinicalTrials.gov number is NCT03479528. CONCLUSION: Most alarm symptoms had poor predictive value for organic dyspepsia and organic upper GI diseases based on Rome IV criteria. Gastroscopic screening should not be based solely on alarm symptoms.

Non-invasive prediction model for high-risk esophageal varices in the Chinese population.

BACKGROUND: There are two types of esophageal varices (EVs): high-risk EVs (HEVs) and low-risk EVs, and HEVs pose a greater threat to patient life than low-risk EVs. The diagnosis of EVs is mainly conducted by gastroscopy, which can cause discomfort to patients, or by non-invasive prediction models. A number of non-invasive models for predicting EVs have been reported; however, those that are based on the formula for calculation of liver and spleen volume in HEVs have not been reported. AIM: To establish a non-invasive prediction model based on the formula for liver and spleen volume for predicting HEVs in patients with viral cirrhosis. METHODS: Data from 86 EV patients with viral cirrhosis were collected. Actual liver and spleen volumes of the patients were determined by computed tomography, and their calculated liver and spleen volumes were calculated by standard formulas. Other imaging and biochemical data were determined. The impact of each parameter on HEVs was analyzed by univariate and multivariate analyses, the data from which were employed to establish a non-invasive prediction model. Then the established prediction model was compared with other previous prediction models. Finally, the discriminating ability, calibration ability, and clinical efficacy of the new model was verified in both the modeling group and the external validation group. RESULTS: Data from univariate and multivariate analyses indicated that the liver-spleen volume ratio, spleen volume change rate, and aspartate aminotransferase were correlated with HEVs. These indexes were successfully used to establish the non-invasive prediction model. The comparison of the models showed that the established model could better predict HEVs compared with previous models. The discriminating ability, calibration ability, and clinical efficacy of the new model were affirmed. CONCLUSION: The non-invasive prediction model for predicting HEVs in patients with viral cirrhosis was successfully established. The new model is reliable for predicting HEVs and has clinical applicability.

Rome III, Rome IV, and Potential Asia Symptom Criteria for Functional Dyspepsia Do Not Reliably Distinguish Functional From Organic Disease.

INTRODUCTION: Although the Rome criteria were created primarily for research purposes, it was an important question whether the Rome criteria can distinguish organic dyspepsia from functional dyspepsia (FD). We evaluated the accuracy of the Rome IV criteria in identifying patients with FD and compared the differences between the Rome IV, Rome III, and potential Asia criteria in identifying patients with FD. METHODS: In this cross-sectional study, we analyzed data from patients who met the inclusion and exclusion criteria from March 2018 to January 2019 at 2 tertiary hospitals. RESULTS: A total of 600 patients were enrolled in this study, including 381 individuals met the Rome IV criteria for FD, 438 individuals met the Rome III criteria for FD, and 525 individuals met the potential Asia criteria for FD. The Rome IV criteria identified patients with FD with 67.3% sensitivity and 38.4% specificity, and the positive and negative likelihood ratios of FD identified by Rome IV criteria were 1.09 (95% confidence interval 0.97-1.24) and 0.85 (95% confidence interval 0.67-1.08), respectively. There was no significant difference in the area under Rome IV, Rome III, or potential Asia criteria receiver operating characteristic curves in identifying FD (P > 0.05). DISCUSSION: The Rome IV criteria were no better than the Rome III or potential Asia criteria in identifying FD and were not helpful in identifying patients with FD. Hence, although the Rome criteria remain useful for defining patients with FD for inclusion into clinical treatment trials, they should not be used for diagnosing FD.

Prognostic value of risk scoring systems for cirrhotic patients with variceal bleeding.

BACKGROUND: Acute variceal bleeding is one of the deadliest complications of cirrhosis, with a high risk of in-hospital rebleeding and mortality. Some risk scoring systems to predict clinical outcomes in patients with upper gastrointestinal bleeding have been developed. However, for cirrhotic patients with variceal bleeding, data regarding the predictive value of these prognostic scores in predicting in-hospital outcomes are limited and controversial. AIM: To validate and compare the overall performance of selected prognostic scoring systems for predicting in-hospital outcomes in cirrhotic patients with variceal bleeding. METHODS: From March 2017 to June 2019, cirrhotic patients with acute variceal bleeding were retrospectively enrolled at the Second Affiliated Hospital of Xi'an Jiaotong University. The clinical Rockall score (CRS), AIMS65 score (AIMS65), Glasgow-Blatchford score (GBS), modified GBS (mGBS), Canada-United Kingdom-Australia score (CANUKA), Child-Turcotte-Pugh score (CTP), model for end-stage liver disease (MELD) and MELD-Na were calculated. The overall performance of these prognostic scoring systems was evaluated. RESULTS: A total of 330 cirrhotic patients with variceal bleeding were enrolled; the rates of in-hospital rebleeding and mortality were 20.3% and 10.6%, respectively. For in-hospital rebleeding, the discriminative ability of the CTP and CRS were clinically acceptable, with area under the receiver operating characteristic curves (AUROCs) of 0.717 (0.648-0.787) and 0.716 (0.638-0.793), respectively. The other tested scoring systems had poor discriminative ability (AUROCs < 0.7). For in-hospital mortality, the CRS, CTP, AIMS65, MELD-Na and MELD showed excellent discriminative ability (AUROCs > 0.8). The AUROCs of the mGBS, CANUKA and GBS were relatively small, but clinically acceptable (AUROCs > 0.7). Furthermore, the calibration of all scoring systems was good for either in-hospital rebleeding or death. CONCLUSION: For cirrhotic patients with variceal bleeding, in-hospital rebleeding and mortality rates remain high. The CTP and CRS can be used clinically to predict in-hospital rebleeding. The performances of the CRS, CTP, AIMS65, MELD-Na and MELD are excellent at predicting in-hospital mortality.

Association of proton pump inhibitors with risk of hepatic encephalopathy in advanced liver disease: A meta-analysis.

BACKGROUND: Several studies have explored the association between the use of proton pump inhibitors (PPIs) and the risk of developing hepatic encephalopathy (HE) in patients with advanced liver disease. However, the evidence-based conclusions are controversial. We hypothesized that using PPIs may increase the risk of HE in patients with advanced liver disease. If confirmed, clinicians must strictly adhere to the indications for PPI treatment in this population. AIM: To evaluate the pooled risk of HE in patients with advanced liver disease who use PPIs. METHODS: Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from the date of database inception through January 8, 2019 to identify comparative studies evaluating the association between PPI use and the risk of HE. Data from the included studies were extracted. The random-effects model was used for pooling risk estimates and the corresponding 95% confidence intervals (CIs). Subgroup and sensitivity analyses were also performed. RESULTS: In total, 4342 patients from five case-control studies and 188053 patients from four cohort studies were included in this analysis. In patients with advanced liver disease, PPI use was associated with an elevated risk of developing HE, with significant heterogeneity. The pooled odds ratio for case-control studies was 2.58 (95%CI: 1.68-3.94, I 2 = 72%). The pooled RR for cohort studies was 1.67 (95%CI: 1.30-2.14, I 2 = 67%). The results of the subgroup analyses suggested that the heterogeneity may be the result of differences in the study designs and the definitions of PPI use. The sensitivity and subgroup analyses did not alter our findings. CONCLUSION: In patients with advanced liver disease, PPI use is associated with an elevated risk of HE. Future large prospective studies are needed to confirm this association.

The effects of curcumin on the metabolic parameters of non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

AIMS: Evidence indicates that curcumin seems to improve outcomes in non-alcoholic fatty liver disease (NAFLD). A meta-analysis was performed to evaluate the effects of curcumin inNAFLD. METHODS: We searched PubMed, EMBASE, and the Cochrane Library from inception through March 2018 to identify randomized controlled trials (RCTs) evaluating the role of curcumin inNAFLD. The mean difference (MD) and 95% confidence interval (CI) were calculated. RESULTS: Four RCTs with a total of 229 NAFLD patients were included. Curcumin was more likely to lower LDL-C, triglycerides, FBS, HOMA-IR, weight and AST levels compared with placebo, and the difference was statistically significant [MD = - 27.02, 95% CI (- 52.30, - 1.74); MD = - 33.20, 95% CI (- 42.30, - 24.09); MD = - 5.63, 95% CI (- 10.36, - 0.90); MD = - 0.53, 95% CI (- 1.00, - 0.05); MD = - 2.27, 95% CI (- 3.11, - 1.44); MD = - 7.43, 95% CI (- 11.31, - 3.54), respectively]. However, the beneficial effect of curcumin did not achieve statistical significance in lowering total cholesterol, HDL-C, HbA1c, ALT or insulin levels [MD = - 30.47,95% CI (- 60.89. - 0.06); MD = - 0.98, 95% CI (- 2.88, 0.92); MD = - 0.41, 95% CI (- 1.41, 0.59); MD = - 6.02, 95% CI (- 15.61, 3.57); MD = - 0.92, 95% CI (- 2.33, 0.49)]. CONCLUSIONS: Curcumin is effective in lowering LDL-C, triglycerides, FBS, HOMA-IR, weight, and AST levels in NAFLD patients, and it is well tolerated. Further RCTs are required to confirm our findings.