SUFU promotes GLI activity in a Hedgehog-independent manner in pancreatic cancer.

Aberrant activation of the Hedgehog (Hh) signaling pathway, through which the GLI family of transcription factors (TF) is stimulated, is commonly observed in cancer cells. One well-established mechanism of this increased activity is through the inactivation of Suppressor of Fused (SUFU), a negative regulator of the Hh pathway. Relief from negative regulation by SUFU facilitates GLI activity and induction of target gene expression. Here, we demonstrate a novel role for SUFU as a promoter of GLI activity in pancreatic ductal adenocarcinoma (PDAC). In non-ciliated PDAC cells unresponsive to Smoothened agonism, SUFU overexpression increases GLI transcriptional activity. Conversely, knockdown (KD) of SUFU reduces the activity of GLI in PDAC cells. Through array PCR analysis of GLI target genes, we identified B-cell lymphoma 2 (BCL2) among the top candidates down-regulated by SUFU KD. We demonstrate that SUFU KD results in reduced PDAC cell viability, and overexpression of BCL2 partially rescues the effect of reduced cell viability by SUFU KD. Further analysis using as a model GLI1, a major TF activator of the GLI family in PDAC cells, shows the interaction of SUFU and GLI1 in the nucleus through previously characterized domains. Chromatin immunoprecipitation (ChIP) assay shows the binding of both SUFU and GLI1 at the promoter of BCL2 in PDAC cells. Finally, we demonstrate that SUFU promotes GLI1 activity without affecting its protein stability. Through our findings, we propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a new mechanism of Hh/GLI signaling pathway regulation in cancer cells.

The Abdominal Ultrasonography Results of Cappadocia Cohort Study of Turkey Reveals High Prevalence of Fatty Liver.

BACKGROUND: There is limited data about the prevalence of frequent gastrointestinal diseases in developing parts of the world based on community-based screening studies. Therefore, we aimed to present the detailed transabdominal ultrasonography results of the previously completed Turkey Cappadocia cohort study, which included a population-based evaluation of gastrointestinal symptoms and diseases in adults. METHODS: This cross-sectional study was conducted in Cappadocia cohort. The transabdominal ultrasonography, anthropometric measurements, and disease questionnaires were applied to cohort persons. RESULTS: Transabdominal ultrasonography was performed in 2797 subjects (62.3% were female and the mean age was 51 ± 15 years). Among them, 36% were overweight, 42% were obese, and 14% had diabetes mellitus. The most common pathological finding in transabdominal ultrasonography was hepatic steatosis (60.1%). The severity of hepatic steatosis was mild in 53.3%, moderate in 38.8%, and severe in 7.9%. Age, body mass index, liver size, portal vein, splenic vein diameter, hypertension, diabetes mellitus, and hyperlipidemia were significantly higher while physical activities were significantly lower in hepatic steatosis group. Ultrasonographic grade of hepatic steatosis was positively correlated with liver size, portal vein and splenic vein diameter, frequency of diabetes mellitus, hypertension, and coronary artery disease. Hepatic steatosis was observed in none of the underweight, 11.4% of the normal weights, 53.3% of the overweight, and 86.7% of the obese subjects. The percentage of hepatic steatosis cases with normal weight (lean nonalcoholic fatty liver disease) was 3.5%. The rate of lean nonalcoholic fatty liver disease in the entire cohort was 2.1%. Regression analysis revealed male gender (hazard ratio [HR]: 3.2), hypertension (HR: 1.5), and body mass index (body mass index: 25-30 HR: 9.3, body mass index >30 HR: 75.2) as independent risk factors for hepatic steatosis. The second most common ultrasonographic finding was gallbladder stone (7.6%). In the regression analysis, female gender (HR: 1.4), body mass index (body mass index: 25-30 HR: 2.1, body mass index >30 HR: 2.9), aging (30-39 age range HR: 1.5, >70 years HR: 5.8), and hypertension (HR: 1.4) were the most important risk factors for gallbladder stone. CONCLUSIONS: Cappadocia cohort study in Turkey revealed a high prevalence of hepatic steatosis (60.1%) while the prevalence of gallbladder stones was 7.6% among the participants. The results of the Cappadocia cohort located in central Anatolia, where overweight and lack of physical activity are characteristic, showed that Turkey is one of the leading countries in the world for nonalcoholic fatty liver disease.

Epigenetics of Inflammatory Bowel Diseases.

Inflammatory bowel diseases are multifactorial, chronic, continuous, relapsing, and immune-mediated diseases of the gastrointestinal tract. It has been believed that mechanisms underlying inflammatory bowel diseases include genetic predisposition, environmental factors, and altered immune response to the gut microbiome. The epigenetic modulation takes place via chromatin modifications, including phosphorylation, acetylation, methylation, sumoylation, and ubiquitination. The methylation levels of colonic tissue were found well correlated to blood samples in inflammatory bowel diseases. Moreover, the methylation level of specific genes was different between Crohn's disease and ulcerative colitis. It has been shown that the enzymes affecting histone modifications like histone deacetylases and histone acetyltransferases do not act solely on histones but also affect the acetylation of many proteins such as p53 and STAT3. It has been already shown that a nonselective histone deacetylase inhibitor, Vorinostat (SAHA), which is currently being used in several cancer treatments, showed anti-inflammatory activities in mouse models. Among epigenetic alterations, long non-coding RNAs and microRNAs play significant roles in T-cell maturation, differentiation, activation, and senility. The long non-coding RNA and microRNA expression profiles can perfectly separate inflammatory bowel disease patients from healthy controls and are remarked as biomarkers of inflammatory bowel diseases. Overall, many studies have shown that epigenetic inhibitors can target significant signal pathways in the pathogenesis of inflammatory bowel diseases, and the impact of epigenetic inhibitors is being studied in clinical trials. In conclusion, exploring more epigenetic pathways regarding inflammatory bowel disease pathogenesis will help us to discover therapeutic targets and new drugs and agents targeting miRNAs in inflammatory bowel diseases. In general, discovering epigenetic targets could improve the diagnosis and treatment of inflammatory bowel diseases.

GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1.

Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process.

Non-invasive fibrosis markers for assessment of liver fibrosis in chronic hepatitis delta.

Assessment of liver fibrosis by non-invasive means is clinically important. Studies in chronic hepatitis delta (CHD) are scarce. We evaluated the performance of eight serum fibrosis markers [fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), age-platelet index (API), AST-to platelet-ratio-index (APRI), Goteborg University Cirrhosis Index (GUCI), Lok index, cirrhosis discriminant score (CDS) and Hui score] in CHD and chronic hepatitis B (CHB). Liver stiffness was assessed by transient elastography (TE) in CHD. The ability of fibrosis markers to detect significant fibrosis and cirrhosis were evaluated in 202 CHB and 108 CHD patients using published and new cut-offs through receiver operating characteristics (ROC) analysis. The latter was also applied to obtain cut-offs for TE. APRI, Fib-4, API and Hui score were assessed for significant fibrosis, and APRI, GUCI, Lok index, CDS and AAR for cirrhosis determination. Fibrosis markers displayed weak performance in CHB for significant fibrosis with area under ROC (AUROC) curves between 0.62 and 0.71. They did slightly better for CHD. TE displayed an AUROC of 0.92 and performed better than serum fibrosis markers (p < 0.05 for fibrosis markers). For cirrhosis determination, CDS and Lok Index displayed an AUROC of 088 and 0.89 in CHB and GUCI, Lok index and APRI displayed AUROCs around 0.90 in CHD. TE displayed the best AUROC (0.95). Hence TE is superior to serum fibrosis markers for diagnosing significant liver fibrosis and cirrhosis. GUCI, Lok index and APRI displayed a reasonable performance in CHD, which needs further confirmation.

Management of iron-deficiency anemia following acute gastrointestinal hemorrhage: A narrative analysis and review.

Many patients experiencing acute gastrointestinal bleeding (GIB) require iron supplementation to treat subsequent iron deficiency (ID) or iron-deficiency anemia (IDA). Guidelines regarding management of these patients are lacking. We aimed to identify areas of unmet need in patients with ID/IDA following acute GIB in terms of patient management and physician guidance. We formed an international working group of gastroenterologists to conduct a narrative review based on PubMed and EMBASE database searches (from January 2000 to February 2021), integrated with observations from our own clinical experience. Published data on this subject are limited and disparate, and those relating to post-discharge outcomes, such as persistent anemia and re-hospitalization, are particularly lacking. Often, there is no post-discharge follow-up of these patients by a gastroenterologist. Acute GIB-related ID/IDA, however, is a prevalent condition both at the time of hospital admission and at hospital discharge and is likely underdiagnosed and undertreated. Despite limited data, there appears to be notable variation in the prescribing of intravenous (IV)/oral iron regimens. There is also some evidence suggesting that, compared with oral iron, IV iron may restore iron levels faster following acute GIB, have a better tolerability profile, and be more beneficial in terms of quality of life. Gaps in patient care exist in the management of acute GIB-related ID/IDA, yet further data from large population-based studies are needed to confirm this. We advocate the formulation of evidence-based guidance on the use of iron therapies in these patients, aiding a more standardized best-practice approach to patient care.

Culture media composition influences patient-derived organoid ability to predict therapeutic responses in gastrointestinal cancers.

BACKGROUNDA patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO's ability to predict clinical response to gastrointestinal (GI) cancers.METHODSWe generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments.RESULTSWe report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures.CONCLUSIONWhile we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.TRIAL REGISTRATIONNot applicable.FUNDINGThe Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research, GI Cancer program of the Mayo Clinic Cancer Center, Mayo Clinic SPORE in Pancreatic Cancer, Center of Individualized Medicine (Mayo Clinic), Department of Laboratory Medicine and Pathology (Mayo Clinic), Incyte Pharmaceuticals and Mayo Clinic Hepatobiliary SPORE, University of Minnesota-Mayo Clinic Partnership, and the Early Therapeutic program (Department of Oncology, Mayo Clinic).

The Impact of Inflammatory Bowel Diseases and Related Medications on COVID-19 Severity and Outcome: A Tertiary Referral Center Experience from Turkey.

BACKGROUND: Coronavirus disease-2019 has become a serious pandemic, and still remains a risk despite vaccines that have been devel- oped. Among inflammatory bowel disease patients old age, inflammatory bowel disease activation, the existence of the comorbid dis- ease, and using steroids are known risk factors for severe coronavirus disease-2019. But there are different data for drugs other than corticosteroids used. The aims of the study are to evaluate the prevalence and risk factors of severe coronavirus disease-2019 and the effect of inflammatory bowel disease drugs on severe coronavirus disease-2019. METHODS: In this study among 1195 inflammatory bowel disease patients, 130 patients who were found to be positive for severe acute respiratory syndrome coronavirus-2 between March 2020 and May 2021 were evaluated. Patients were divided into 3 groups as mild, moderate, and severe coronavirus disease-2019. RESULTS: Among 130 patients, 91 (70%) had mild, 16 (12.3%) had moderate, and 23 (17.7%) had severe coronavirus disease-2019. Being 60 years of age or older (P = .009), having at least 1 comorbid disease (P = .002), and having active inflammatory bowel disease (P = .001) were factors that increased the risk for severe coronavirus disease-2019. The use of mesalazine (P = .35), biologic agents (P = .23), and corticosteroids (P = .42) did not increase the risk of severe coronavirus disease-2019. The use of azathioprine seemed to decrease the risk of severe disease with univariate regression analysis however the significance disappeared with multivariate analysis. CONCLUSION: Older age, active inflammatory bowel disease, and existence of at least 1 comorbid disease are risk factors for severe coro- navirus disease-2019. However, drugs used in inflammatory bowel disease management do not increase the risk of severe coronavirus disease-2019. But due to the small number of patients, it is difficult to reach a definite conclusion about corticosteroids.

Evaluation of periodontal status and cytokine levels in saliva and gingival crevicular fluid of patients with inflammatory bowel diseases.

BACKGROUND: Periodontal diseases and inflammatory bowel diseases (IBD, ulcerative colitis [UC] and Crohn disease [CD]) have been reported to present with increased salivary and gingival crevicular fluid (GCF) concentrations of cytokines. The aim of this study was to evaluate the salivary and GCF levels of TNF-α, IL-1ß, IL-10, and IL-17A and their associations with the periodontal statuses of UC, CD, and non-IBD patients, and to analyze the interrelationships among these cytokines, IBD conditions, and periodontal diseases. METHODS: This cross-sectional study was performed with a total of 131 patients (62 women and 69 men, mean age 42.96±13.02 years). Patients were divided into three groups: UC, CD, and non-IBD. Periodontal status was defined according to the 2017 World Workshop Disease Classification. Salivary and GCF cytokine levels were analyzed using ELISA. RESULTS: UC and CD patients diagnosed as having periodontitis and gingivitis presented with significantly higher levels of TNF-α and lower levels of IL-10 as compared with non-IBD patients (p<0.05). UC patients diagnosed with periodontitis exhibited significantly higher scores of bleeding on probing (p = 0.011) and increased salivary and GCF IL-1ß levels as compared with CD patients (p = 0.005, and 0.012, respectively). Considering the active and remission status of IBD, salivary IL-1ß was found to be correlated with the parameters representing the severity of periodontal diseases in active UC and CD patients. CONCLUSION: In the presence of periodontal diseases, UC and CD patients showed different expression levels of TNF-α, IL-1ß, and IL-10 in oral secretions as compared with non-IBD patients.

Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility.

Irritable bowel syndrome with diarrhoea (IBS-D) and functional diarrhoea (FDr) are the two major functional bowel disorders characterized by diarrhoea. In spite of their high prevalence, IBS-D and FDr are associated with major uncertainties, especially regarding their optimal diagnostic work-up and management. A Delphi consensus was performed with experts from 10 European countries who conducted a literature summary and voting process on 31 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation criteria. Consensus (defined as >80% agreement) was reached for all the statements. The panel agreed with the potential overlapping of IBS-D and FDr. In terms of diagnosis, the consensus supports a symptom-based approach also with the exclusion of alarm symptoms, recommending the evaluation of full blood count, C-reactive protein, serology for coeliac disease, and faecal calprotectin, and consideration of diagnosing bile acid diarrhoea. Colonoscopy with random biopsies in both the right and left colon is recommended in patients older than 50 years and in presence of alarm features. Regarding treatment, a strong consensus was achieved for the use of a diet low fermentable oligo-, di-, monosaccharides and polyols, gut-directed psychological therapies, rifaximin, loperamide, and eluxadoline. A weak or conditional recommendation was achieved for antispasmodics, probiotics, tryciclic antidepressants, bile acid sequestrants, 5-hydroxytryptamine-3 antagonists (i.e. alosetron, ondansetron, or ramosetron). A multinational group of European experts summarized the current state of consensus on the definition, diagnosis, and management of IBS-D and FDr.

Perception of COVID-19 Pandemic Among IBD Clinicians and IBD Surgeons in Black Sea Region: A Cross-Sectional Questionnaire Study.

BACKGROUND: Since December 2019, the COVID-19 pandemic has created an increasing challenge in managing inflammatory bowel dis- ease patients both medically and surgically. Although several international and national medical/surgical associations published guide- lines in this area, there is still a huge difference between daily practices and these guidelines, especially depending on regional practices and governmental policies. Therefore, we aimed to investigate and define gastroenterologists' and surgeons' fear of COVID-19 and how they have managed inflammatory bowel disease patients during this pandemic in the Black Sea region. METHODS: A 20-question survey was administered to 70 gastroenterology specialists and 80 general surgeons who are mainly focused on the management of inflammatory bowel disease in 5 countries in the Black Sea region. RESULTS: The majority of respondents (81.3%) mentioned that they have concerns that their inflammatory bowel disease patients were at risk of contracting COVID-19. In addition, the majority of respondents (80.3%) believed that inflammatory bowel disease itself, inde- pendent of medications, might increase the risk of contracting COVID-19. The majority of gastroenterologists told that they did not stop inflammatory bowel disease medications due to the COVID-19 pandemic unless patients had COVID-19 disease. Surgeons overwhelm- ingly reached a consensus on how to test patients for COVID-19 perioperatively and came to a conclusion on which of the patients can- not wait to be operated. Both gastroenterologists and general surgeons, usually have similar perceptions. CONCLUSION: Despite the increasing number of definitive studies, it seems that there are still regional differences in the perception of COVID-19 and inflammatory bowel disease patient care during the pandemic.

Improvement of Work Productivity and Quality of Life with Anti-Tumor Necrosis Factor Treatment Used in Crohn's Disease in Routine Clinical Practice in Turkey.

BACKGROUND: Patients with Crohn's disease experience major deterioration in work productivity and quality of life. We aimed to provide the long-term effects of anti-tumor necrosis factor agents on work productivity and activity impairment and quality of life in patients with Crohn's disease using the Inflammatory Bowel Disease Questionnaire and the Short-Form Health Survey-36. METHODS: Patients with Crohn's disease and initiated an anti-tumor necrosis factor treatment were included and followed up for 12 months in this observational study. RESULTS: A total of 106 patients were included in this study, and 64.2% of the patients were males. Mean [± standard deviation] age was 36.8 [± 10.9] years. At baseline, mostly perianal fistulas [65.7%] were observed [n = 23]. Intestinal stenosis was detected in 34.9% of the patients [n = 37], and most of the stenosis was located in the ileum [70.6%] followed by the colon [20.6%]. Extraintestinal symp- toms were observed in 24 patients [22.6%]. Most frequent extraintestinal symptom was arthritis with 71.4% [n = 15]. Mean time from first symptom to initiation of anti-tumor necrosis factor treatment was 6.3 [± 5.0] years. Improvements in work productivity and activ- ity impairment scores throughout 12 months were -24.1% [P = .003] for work time missed, -18.0% [P = .006] for impairment at work, -8.5% [P = .160] for overall work impairment, and -17.0% [P < .001] for daily activity impairment. Similarly, significant improvements [P < .001] were detected in all components of the Inflammatory Bowel Disease Questionnaire when compared to baseline. Statistically sig- nificant improvements [P < .05] were detected for all components of Short-Form Health Survey-36 except for mental health [P = .095]. CONCLUSION: Our study indicates the significant improvement in work productivity and activity impairment and quality of life of patients with Crohn's disease who receive long-term anti-tumor necrosis factor treatment.

Assessment of Imaging Features of Crohn's Disease with MR Enterography.

BACKGROUND: To evaluate the frequency of pathological findings determined on magnetic resonance (MR) enterography (MRE) in patients with Crohn's Disease. METHODS: A retrospective analysis of the MRE images was made in 34 female and 41 male patients (mean age 41 years) with Crohn's disease. The prevalence of bowel wall (mural thickening, mural edema, mural fat deposits, mucosal enhancement, ulceration, cobblestone appearance, pseudopolyps) and mesenteric fatty tissue alterations (fatty tissue proliferation, mesenteric hypervascularity, enlarged lymph nodes, peri-enteric inflammation, reactive fluid), complications due to penetrating (fistula, sinus tract, abscess) and stenosing processes (fibrotic and inflammatory stenosis, obstruction, dilatation), and involvement of the colon were determined. RESULTS: The most frequently observed changes in the bowel wall and mesenteric fatty tissue were mural thickening (98.7%) and enlargement of mesenteric lymph nodes (76%), respectively. Stenosis was the most common complication (76%). The most frequently seen pathology of the colon was ileocecal valve thickening and enhancement (74.7%). CONCLUSION: MR enterography is a useful imaging modality for the evaluation of changes in both the mesenteric fatty tissue and the bowel wall. As there is no use of ionizing radiation, MR enterography should be the preferred imaging modality during follow-up of patients with Crohn's disease.

The association of anti-CD74 antibody with spondyloarthropathies.

OBJECTIVE: The etiopathogenesis of spondyloarthropathies (SpA) is still unclear. Recently, anti-CD74 antibody has been suspected to play a role in SpA etiopathogenesis. This study aimed to examine the levels of anti-CD74 antibody in patients with SpA and investigate their association with disease activity. METHODS: This study was conducted using data from patients who were treated at the departments of rheumatology and gastroenterology between June 2013 and November 2013. The demographic and clinical characteristics of the participants and their serum IgG-type antibodies against anti-CD74 were analyzed. RESULTS: We analyzed 111 patients with ankylosing spondylitis (AS), 108 patients with inflammatory bowel disease (IBD), and 101 healthy controls. The rate of human leukocyte antigen-B27 positivity was 86.5% in patients with AS and 21.3% in patients with IBD. The mean levels of anti-CD74 antibodies in the AS, IBD, and control groups were 6.99±3.24 ng/mL, 6.25±3.34 ng/mL, and 7.83±4.72 ng/mL, respectively. Anti-CD74 levels were higher in healthy controls than in patients with IBD (p=0.009). There was no significant difference in anti-CD74 levels between the AS and IBD groups and the AS and control groups. In addition, there was no correlation between anti-CD74 levels and disease activity. CONCLUSION: This study could not find an association between anti-CD74 levels and SpA in Turkish patients.

Turkish IBD Organization's Position Statement on Inflammatory Bowel Disease Management Recommendations During COVID-19 Pandemic.

The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2, has resulted in high mortality and morbidity worldwide and is still a growing problem. Inflammatory bowel disease (IBD) is a chronic inflammatory disease for which a substantial number of patients are treated with immunosuppressive medications, either occasionally or long-term. Despite the accumulating evidence, there is still a lack of knowledge about the impact of COVID-19 on IBD patients, especially those who are under immunosuppressive treatment. Moreover, following the emergence of several COVID vaccines, there are concerns regarding vaccine effectiveness and possible side effects in such patients. In this context, we tried to briefly summarize the accumulating evidence and recommendations for the management of IBD in the context of the COVID-19 pandemic.

Natural History of Cirrhosis: Changing Trends in Etiology Over the Years.

BACKGROUND AND GOALS: The aims of the present study were to investigate the natural history of cirrhosis and to determine trends in the etiology of cirrhosis. METHODS: Between January 2001 and January 2018, a total of 1,341 patients had been diagnosed with cirrhosis and were included. RESULTS: A total of 898 cirrhotic patients, who were followed up for at least 6 months were included into the analysis. The median age was 54 years. The median Child-Pugh and MELD scores were 7.5 and 11, respectively. Ascites (51%) was the most common causes of decompensation. Chronic viral hepatitis was the most frequent cause of cirrhosis (58%). Hepatitis B virus (HBV) infection was the main etiology (34%), followed by hepatitis C virus (HCV) infection (18%). Among 129 patients with cryptogenic cirrhosis (CC), 60 had metabolic abnormalities. If these 60 patients with CC were considered to have nonalcoholic fatty liver disease (NAFLD)-related cirrhosis, the proportion of NAFLD-related cirrhosis increased from 1.8 to 8.0%. At admission, 74 patients (8%) had been diagnosed with hepatocellular carcinoma (HCC). A new HCC developed in 80 patients during the follow-up period. The probability of developing HCC was 3.9% at 12 months. Logistic regression analysis showed that the development of HCC was significantly associated with older age (p < 0.001), male gender (p < 0.001), viral etiology (p = 0.026), and baseline high aspartate aminotransferase level (p = 0.01). Overall, 104 cirrhotic patients died. CONCLUSION: HBV and HCV remain the leading causes of etiology in cirrhosis and HCC. However, NAFLD-related cirrhosis is recognized as a growing burden.

New Aspects of the Epigenetics of Pancreatic Carcinogenesis.

Pancreatic cancer remains among the deadliest forms of cancer with a 5 year survival rate less than 10%. With increasing numbers being observed, there is an urgent need to elucidate the pathogenesis of pancreatic cancer. While both contribute to disease progression, neither genetic nor environmental factors completely explain susceptibility or pathogenesis. Defining the links between genetic and environmental events represents an opportunity to understand the pathogenesis of pancreatic cancer. Epigenetics, the study of mitotically heritable changes in genome function without a change in nucleotide sequence, is an emerging field of research in pancreatic cancer. The main epigenetic mechanisms include DNA methylation, histone modifications and RNA interference, all of which are altered by changes to the environment. Epigenetic mechanisms are being investigated to clarify the underlying pathogenesis of pancreatic cancer including an increasing number of studies examining the role as possible diagnostic and prognostic biomarkers. These mechanisms also provide targets for promising new therapeutic approaches for this devastating malignancy.

Incidence of suboptimal response to tumor necrosis factor antagonist therapy in inflammatory bowel disease in newly industrialised countries: The EXPLORE study.

BACKGROUND: Incidence of inflammatory bowel disease (IBD) is increasing in newly industrialised countries (NICs); however, data on suboptimal response to anti-tumor necrosis factor (anti-TNF) agents are limited. OBJECTIVES: To assess incidence and indicators of suboptimal response to first anti-TNF therapy in IBD patients in NICs. METHODS: A chart review was conducted in ten countries from Asia-Pacific (APAC), Latin America (LatAm), and Russia and the Middle East (RME) regions among patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD), initiating anti-TNF therapy in 2010-2015. The cumulative incidence of suboptimal response to anti-TNF therapy was assessed using the following indicators: dose escalation or discontinuation, augmentation with non-biologic therapy, IBD-related hospitalization, or surgery. RESULTS: The study included 1,674 patients (570 UC; 1,104 CD). At 24 months, 32.9% of UC (APAC: 45.1%; LatAm: 38.2%; RME: 23.8%) and 41.2% of CD patients (APAC: 54.1%; LatAm: 42.5%; RME: 29.5%) had experienced suboptimal response. The most frequent first indicator was non-biologic therapy augmentation in LatAm (41.7%), IBD-related hospitalization in RME (UC: 50.7%; CD:37.3%) and in APAC for CD (39.1%), and anti-TNF discontinuation in APAC for UC (38.3%). CONCLUSION: Suboptimal response to anti-TNF agents is common in IBD patients in NICs. Observed regional differences in the incidence and indicators may reflect local practice and anti-TNF restrictions in IBD management. NCT REGISTRATION NUMBER: NCT03090139.

Population-based assessment of gastrointestinal symptoms and diseases: Cappadocia Cohort, Turkey.

BACKGROUND/AIMS: The aim of this study was to determine the prevalence of symptoms and diseases of the lower and upper gastrointestinal system (GIS) in a population-based sample. MATERIALS AND METHODS: The cross-sectional cohort study was conducted in Cappadocia cohort comprising the Gülsehir and Avanos districts. The "Gastrointestinal Symptom Questionnaire" was applied to persons over the age of 18 years. RESULTS: The GI Symptom Questionnaire was applied to 3369 subjects, and height and body weight were measured in 2797 consenting subjects. Of the participants, 61% were female and the mean patient age was 50±15 years. At least one GI symptom was present in 70.6% of the cohort. The most common upper GI symptoms were gastric bloating (31.0%) and heartburn (29.1%). The most common lower GI symptom was abnormal defecation (33.5). The prevalence of upper GIS and lower GIS diseases was 32.7% and 12.9%, respectively, and the prevalence of togetherness of upper and lower GIS diseases was 9.9%. Prevalence of GIS disease was approximately 3 times higher in females (p<0.001). All of the upper and lower GI symptoms and the prevalence of upper GIS disease increased in line with Body mass index (BMI). CONCLUSION: This first population-based, cross-sectional cohort study revealed that the prevalence of GIS diseases is critically high for optimal public health. Special attention must be paid to these diseases while planning health policies and reimbursements.