Gastroenterology and Hepatology from Bed to Bench

Background: miR-125 family (including miR-125a, miR-125b) have been reported as pivotal prognostic biomarkers of gastric cancer (GC). However, there is controversy about the role of miR-125 family in progression prediction of GC.

Aim: We design this meta-analysis to reassess the prognostic and clinicopathologic values of microRNA-125 family in GC patients.

Methods: Studies were systemically searched from electronic databases of PubMed, ISI Web of Science, Scopus and Cochrane library. The overall hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) was calculated to evaluate the association between miR-125 family expression with prognosis and susceptibility to gastric cancer. The quality of evidence was evaluated using Newcastle-Ottava Scale (NOS).

Results: Totally 1203 GC patients in ten studies were analyzed in this meta-analysis. The results showed a high significant association between the ratio of low/high expression of miR-125a (HR= 1.7; 95% CI: 1.38 to 2.08; P< 0.001) and poor OS in patients with GC, while, this ratio for miR-125b (HR= 1.16; 95% CI: 0.71 to 1.89; P= 0.53) was not significant. Further, low miR-125 family expression was associated with clinicopathological features of liver metastasis (OR= 6.3; 95% CI: 1.1 to 36.3; P= 0.03). The sensitivity analysis shows that our results were completely powerful and stable. No potential publication bias was observed using Begg’s (P = 0.72) and Egger’s (P = 0.95) tests.

Conclusion: The low expression of miR-125 family predicts poor OS in GC patients. Thus, miR-125 family may be helpful as a potential biomarker for the prognosis of gastric cancer.

The liver plays a principal role in the human body as a metabolic and detoxifying unit. Liver diseases are the world’s major health problems and affect millions of people worldwide. Early detection of liver diseases is certainly effective in timely treatment and prevention of their progression. Liver injury is associated with significant alterations in immune responses and pattern changes in various tissue-related gene expressions and cytokine production. Increasing or decreasing the specific spectrum of non-coding RNAs in different phases of liver disease can be a criterion for diagnosis. Novel diagnostic biomarkers are needed for liver diseases. Currently, micro-RNAs (miRNAs) are known to play important roles in the diagnosis of liver diseases. Circulating biomarkers such as miRNA-assisted diagnosis can conceivably be helpful for the early treatment of liver diseases. In this review, we look at miRNAs and their potential applications in liver diseases as diagnostic biomarkers were investigated.

Celiac disease (CD) is an autoimmune disorder of the gastrointestinal tract in a genetically susceptible person. Gluten is the most crucial trigger factor for CD, and environmental factors such as microbiota and opportunistic infection risk its pathogenesis.

Coronavirus disease 19 (COVID-19) spread rapidly and became a problem for healthcare systems worldwide. Little is known about the risk of severe COVID-19 and the role of dysbiosis among patients with CD. There is also a lack of knowledge about the effects of CD gut microbiota on COVID-19 infection. Therefore, the current review discusses the relationship between CD and risk factors such as microbiota for susceptibility to COVID-19.

Aim: Search for SMAD4 mutations in Colorectal cancer (CRC) or polyp in Iran.

Background: Colorectal cancer is one of the five prevalent cancers among the Iranian population; however, its molecular mechanisms are not fully understood. The vast majority of CRCs arise from neoplastic polyp

Methods: Colorectal cancer and polyp lesions with matched normal tissues from patients who had undergone colonoscopy in Taleghani Hospital (January 2009 – November 2010) were included in the study. DNA extraction and PCR-sequencing for exons 5-11 of the SMAD-4 gene were carried out on 39 and 30 specimens of polyp and adenocarcinoma, respectively.

Results Of cancer and polyp specimens, 33.3% and 28.2%, respectively, were mutated in the Smad-4 gene. The majority of SMAD4 mutations, especially in the MH₂ domain were missense mutations (63.6% and 68.75, respectively). In cancer, codon 435 and in polyp, codons 435 and 399 were the most common alterations. Unlike cancer specimens, transversion was found frequently in the polyp (56.25% vs. 35.7%). CG>TA transition was about 18.75% and 14.3% in cancer and polyp samples, respectively. Mutations of codon 264 and C.483-4 were seen both in cancer and neoplastic polyps.

Conclusion: As frequent alterations, missense mutations are presumably selected during tumorigenesis and polyposis due to their structural impacts on SMAD4 functions and TGF-ß signaling pathway. The lower frequency of CG>TA can be attributed to global genome hypomethylation. Presumably, SMAD4 mutations had occurred in the primary polyps, and some of these mutated cells then developed into carcinoma. On the other hand, polyp-specific mutations may lower the risk of CRC.

Aim: The present study aimed to detect key candidate genes and pathways involved in colorectal aberrant crypt foci-to-adenoma-to-carcinoma progression.

Background: Although colorectal cancer (CRC) is the third most common type of cancer, the involved signaling pathways and driver-genes remain largely unclear. CRC begins with the malignant transformation of precancerous lesions including aberrant crypt foci (ACF) and benign adenomatous polyp or adenoma

Methods: A list of formerly reported ACF, adenoma, and CRC-associated proteins was obtained from GeneCards, and then the data in online David Bioinformatics Resources was analyzed. The protein-protein interactions were surveyed utilizing String database and Cytoscape software. After hubs and bottlenecks were recognized, the key genes and pathways were identified through different bioinformatics analysis.

Results The most important pathways associated with colorectal aberrant crypt foci-to-adenoma progression were attributed to “pathways in cancer” and “chemokine signaling pathway” and those in adenoma-to-carcinoma progression were related to “pathways in cancer,” “chemokine signaling pathway,” and “Ras signaling pathway.” The genes participating in these pathways are key ones. Furthermore, PRKACB, CUL2, and GSK3B were significant as the seed in the clusters related to adenoma and GNB1, RALBP1, ROCK1, and IKBKG in the clusters related to cancer.

Conclusion: The key candidate genes and pathways in progress CRC formed precursor lesions were identified by integrated bioinformatics analysis. The results could lead to a better understanding of the cause and underlying molecular events as well as detection of therapeutic targets for CRC.

Aim: The current study aimed to assess and compare colon cancer dysregulated genes from the GEO and STRING databases.

Background: Colorectal cancer is known as the third most common kind of cancer and the second most important reason for global cancer-related mortality rates. There have been many studies on the molecular mechanism of colon cancer

Methods: From the STRING database, 100 differentially expressed proteins related to colon cancers were retrieved and analyzed by network analysis. The central nodes of the network were assessed by gene ontology. The findings were compared with a GSE from GEO.  

Results: Based on data from the STRING database, TP53, EGFR, HRAS, MYC, AKT1, GAPDH, KRAS, ERBB2, PTEN, and VEGFA were identified as central genes. The central nodes were not included in the significant DEGs of the analyzed GSE.

Conclusion: A combination of different database sources in system biology investigations provides useful information about the studied diseases.

Aim: In the current study, it was hypothesized that single nucleotide polymorphisms (SNPs) in the regulatory region of the IL-22 signaling pathway genes, including IL-22 and IL-22RA1 variants, may be associated with CRC susceptibility.

Background: The important role of pro-inflammatory cytokines during tumorigenesis is well-established. In recent years, IL-22 has been linked with colorectal cancer (CRC) through a number of mechanistic and observational studies

Methods: The association of four polymorphisms in the IL-22 (rs1179251 and rs1179246) and IL-22RA1 (rs4648936 and rs10794665) genes with CRC risk were studied using a case-control design with 304 cases and 345 controls from the Iranian population. All 649 subjects were evaluated by PCR–RFLP method.

Results: No significant difference was found in genotype and allele frequencies between the cases and controls for either IL-22 and IL-22RA1 gene variants or CRC risk before or after adjusting for confounders.

Conclusion: The current findings do not present any significant evidence for associations between variants in IL-22 signaling pathway genes and CRC. Complementary studies with greater sample sizes may be necessary to fully elucidate the nature of these associations.

Aim: Description of the inflammatory bowel disease natural history in Tehran province.

Background: Inflammatory bowel disease (IBD) is a non-homogeneous disorder with an unpredictable natural history that impairs a patient's quality of life over the course of their life. As a result, providing evidence for efficient patient management is critical.

Methods: In this case series study, 198 IBD patients who were visited in our clinic at least three times routinely from Oct 2015 to May 2020 were included. Then, two panel-based approaches, the Multi-State Model (MSM) and random-effect ordered logistic, were used to deduce the clinical course of IBD, which included remission, mild, moderate to severe, and surgical states.

Results For ulcerative colitis (UC), women had a slightly poorer condition for remission but better for moderate to severe and a faster transition from moderate to severe to mild (HR=1.490, 95% CI: 1.02-2.16) compared to men. For Crohn's disease (CD), they had a better condition for remission but a slightly poorer condition for the severe state and higher transition from mild to moderate to severe (HR=1.221, 95% CI: 0.471-3.22) than men. Oral 5-ASA had better efficacy in people with remission and/or mild states but not for those with moderate to severe states, especially in CD (mild to moderate to serve, HR=1.526, 95% CI: 0.59-3.89). Immunosuppressive drugs were better for patients with lower disease severity, especially with UC (mild to remission, HR=1.258, 95% CI: 0.75-2.09).

Conclusion: Panel approaches have the potential efficacy to tackle the unpredictable clinical course of IBD (UC/CD). Hence, we highly recommend that our findings be included into the Iranian routine clinical environment of IBD and/or that related studies be conducted in Iran and other regions to gain a better understanding of the natural history of IBD.

Aim: The present study implemented an RT-qPCR assay for the detection and quantification of human cosavirus in stool specimens from pediatric patients involved in acute gastroenteritis.

Background: Human cosavirus is a newly recognized virus that seems to be partly related to acute gastroenteritis in pediatric patients. However, the relationship between human cosavirus and diseases in humans is unclear

Methods: From January 2018 to December 2019, a total of 160 stool samples were collected from pediatric patients presenting with acute gastroenteritis in a hospital in Karaj, Iran. After viral RNA extraction, RT-qPCR was performed to amplify the 5’UTR region of the human cosavirus genome and viral load was analyzed.

Results The human cosavirus genomic RNA was detected in 4/160 (2.5%) stool samples tested. The maximum viral load was determined to be 4.6×10⁶ copies/ml in one sample obtained from a 4-year-old patient.

Conclusion: The human cosavirus as a new member of the Picornaviridae family was illustrated in fecal samples from pediatric patients with acute gastroenteritis in Iran. This is the first documentation of human cosavirus circulation in Iranian children.

Aim: The aim of this study was to introduce biomarkers commonly involved in pancreatic cancer metastasis to the liver.

Background: The liver is affected by metastatic disease in pancreatic cancer.

Methods: Two cancer biomarkers were distinguished through a STRING database protein query. The dysregulated proteins of the two cancers were included in 2 networks drawn by Cytoscape software v 3.2.7. 20 top nodes and achieved by the Network analyzer application of Cytoscape based on degree value. The common hub nodes were determined, and action maps were analyzed.

Results: Among 20 hubs of each studied cancer, 18 common hub nodes (90% of hubs) were identified and screened by action maps. Four proteins, AKT1, CDKN2A, ERBB2, and IL6, were identified as common central proteins related to the two studied diseases.

Conclusion: AKT1, CDKN2A, ERBB2, and IL6 are common protein core of liver and pancreatic cancers, while STAT3, CASP3, NOTCH1, and CTNNB1 are possible differential proteins to discriminate these cancers.

Aim: This study aimed to introduce the main biomarkers related to NFLD and diabetes II to determine common pathogenic and metabolite factors linking NFLD to diabetes II.

Background: Nonalcoholic fatty liver disease (NFLD) is chronic hepatic failure with a broad range of hepatic disorders. NFLD and diabetes type 2 coexist regularly to drive adverse outcomes such as hepatocellular carcinoma and vascular complications

Methods: The proteins related to NFDL and diabetes mellitus were extracted from String database. Proteins related to each disease were included in protein-protein interaction networks in Cytoscape software. Obtained networks were analyzed using Cytoscape network analyzer. The central nodes were determined as top hubs based on degree value. The top hubs related to NFLD and diabetes mellites were compared.

Results: In total, 200 proteins related to NFDL and diabetes mellitus were found separately in String database and connected through undirected edges in individual networks. Central nodes based on degree value were determined for each disease. Ten percent of top nodes were selected based on degree value as the 20 top hubs for each disease. Target common hub proteins between NFDL and diabetes mellitus comprised INS, AKT1, ALB, PPARG, IL6, GPDPH, LEP, TNF, ADIPOQ, IGF1, TP53, MAPK3, and SIRT1.

Conclusion: According to the results, 13 common and 14 discriminatory central dysregulated proteins were determined for NAFLD and diabetes mellitus.

Aim: This study aimed to identify the risk factors of metabolic (dysfunction)-associated fatty liver disease (MAFLD) among adults in northeastern Iran.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and hepatic manifestation of metabolic syndrome that threatens global public health. Recently, MAFLD has been proposed as a new terminology updated from NAFLD and diagnosed based on modified criteria.

Methods: A nested case-control study was performed on the participants of the first phase of the Persian Sabzevar Cohort Study (PSCS), a survey that was conducted in northeastern Iran and enrolled 4,242 participants aged 35-70 years. In total, 968 MAFLD cases and 964 controls adjusted for age and sex were recruited. Data including demographic, lifestyle, anthropometric, biochemical, sleep pattern, and dietary intake information was collected.

Results The mean (SD [standard deviation]) age of participants was 49.2 (8.8) years, and 39.9% of the participants were males. The prevalence of MAFLD was 22.8% (95% CI [confidence interval] 19.2 – 26.3%). Increased body mass index (BMI) (OR [odds ratios] 5.51, 95% CI 2.73 – 11.10), waist circumference (WC) (OR 1.85, 95% CI 1.44 – 2.38), blood concentrations of triglycerides (TG) (OR 1.10, 95% CI 1.06 – 1.15), total cholesterol (TC) (OR 1.02, 95% CI 1.003 – 1.04), and alanine aminotransferase (AST) (OR 1.10, 95% CI 1.05 – 1.16) were significantly associated with an increased risk of the MAFLD (p-value <0.05). Furthermore, the odds of MAFLD risk was 43% higher in subjects who slept ≤ 5 hrs/day than those with ≥ 7 hrs per day of sleep (OR 1.43; 95% CI 1.07 – 1.92, p-value = 0.01).

Conclusion: In this study, it was found that MAFLD was best predicted by BMI, WC, and serum levels of TG, total cholesterol, and AST. Sleeping ≤ 5hrs/day compared to ≥ 7hrs/day was associated with an increased risk of MAFLD.

Aim: The present study was performed on patients with large bile duct stones to compare clinical outcomes and complications of balloon dilatation treatment between two sizes of balloons, < 15 mm and ≥ 15 mm.

Background: in 1982, the endoscopic papillary balloon dilatation (EPBD) method was presented by Staritz to reduce bleeding and perforation risk of large bile duct stones.

Methods: Patients with large bile duct stones admitted to Taleghani hospital from December 2018 to December 2019 who were the candidates for balloon dilation with limited sphincterotomy. Patients were randomly divided into two groups. In group B, a ≥ 15 mm balloon was used, and in group A, a balloon <15 mm was used. The clinical results of balloon dilation and its complications were recorded and compared.

Results: Most patients had 1 or 2 large bile duct stones, and there was no significant difference in the number of stones. Extraction was successful in 92.8% of group B and 85.7% of group A without significant differences (P = 0.8). Pancreatitis, hemorrhage, cholangitis, and perfusion occurred in 8%, 4.2%, 1.4%, and 2.8% of group B subjects and also in 10%, 2.8%, 0%, and 1.4% of group A subjects, respectively, and the difference between the two groups was not significant.

Conclusion: Generally, this study results showed that balloon size did not have a significant effect on the success rate of bile duct stones. Moreover, considering the lack of significant association between balloon dilatation size and the occurrence of post-endoscopic complications such as pancreatitis, it seems that large-size dilatation has no serious clinical risk.

Aim: The present study aimed to introduce a possible biomarker to differentiate between severe and fatal conditions of COVID-19.

Background: The COVID-19 pandemic, appearing as a complicated health problem, has changed the lifestyle of people in recent years. Clinical findings indicate mild, severe, and fatal conditions of this disease. Prediction of disease severity is a significant point in managing COVID-19 infection

Methods: In this study, 195 differentially expressed genes (DEGs) that discriminate between fatal and severe conditions in patients were extracted from the literature and screened to determine the significant ones. The significant DEGs plus the 90 first neighbors added from the STRING database were included in the interactome using Cytoscape software v 3.7.2. The central nodes of the analyzed network were identified and assessed.

Results: Ten significant DEGs were candidates for assessment, of which 9 were recognized by the STRING database. IL6, ALB, TNF, CRP, INS, MPO, C3, CXCL8, TTR, and TLR4 were determined as central nodes; IL6, CRP, and TTR were highlighted as the critical genes related to the severity of COVID-19 infection.

Conclusion: CRP was identified as the best possible biomarker with levels related to the severity and fatality of COVID-19 infection.

Aim: This multicenter study is the first one on Iranian children with very early onset ulcerative colitis (UC) and one of the few studies about the effect of biological therapy in children with UC under 7 years of age.

Background: Children with very early onset inflammatory bowel disease (IBD) are diagnosed before 6 years of age

Methods: The current study was performed on 14 children under 7 years of age with severe UC. Children with severe UC whose therapy with corticosteroid and azathioprine as conventional treatment had failed were treated with infliximab (IFX) and later with adalimumab (ADA).

Results: Among the total 14 participants, 6 (43%) patients were female. Mean patient age was 4.9 years (range = 3–7 years), mean age at diagnosis was 3.4 years (range = 1.5–6 years), and mean duration of illness was 1.5 years. At the end of 54 weeks of therapy with IFX, 2 (14%) patients were in remission, 2 (14%) patients were mild, and 4 (29%) patients were moderate, with no secondary treatment failure (during the maintenance phase). A total of 6 (43%) patients had primary treatment failure (no response after 14 weeks of therapy). These patients were treated with ADA. At the end of 52 weeks of therapy, 3 (50%) of those 6 (100%) patients were referred for colectomy, 1 (17%) was in remission, and 2 (33%) patients had mild severity.

Conclusion: The current study has shown that IFX is a safe and effective therapy for children with very early onset UC. ADA may be effective in the treatment of children with UC who are refractory to IFX.

NEW ZEALAND SOCIETY OF GASTROENTEROLOGY Abstracts of Annual Scientific Meeting 2021; 17 - 19 November 2021