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The International Rome Committee defines Disorders of Gut-Brain Interactions (DGBI) based upon distinct combinations of chronic and/or recurrent unexplained gastrointestinal symptoms. Yet patients often experience overlapping DGBI. Patients with DGBI frequently also suffer from extraintestinal symptoms, including fatigue, sleep disturbances, anxiety, and depression. Patients with overlapping DGBI typically experience more severe GI symptoms and increased psychosocial burden. Concerning the pathophysiology, DGBI are associated with disruptions in gut motility, function of the brain and enteric neurons, immune function, and genetic markers, with recent findings revealing gut microbiome alterations linked to these mechanisms of DGBI. Emerging evidence summarized in this review suggests that the microbiome influences various established disease mechanisms of different DGBI groups. Overall, changes in the gastrointestinal microbiome do not seem to be linked to a specific DGBI subgroup but may play a key role in the manifestation of different DGBI and, subsequently, overlap of DGBI. Understanding these shared mechanisms and the role of the gastrointestinal microbiome, particularly for overlapping DGBI, might aid in developing more precise diagnostic criteria and treatment strategies while developing personalized interventions that target specific mechanisms to improve patient outcomes.

Abstract Background/aims Bile reflux (BR) can influence the gastric environment by altering gastric acidity and possibly the gastric microbiota composition. This study investigated the correlation between bile acids and microbial compositions in the gastric juice of 50 subjects with differing gastric pathologies. Methods This study included 50 subjects, which were categorized into three groups based on the endoscopic BR grading system. The primary and secondary bile acid concentrations in gastric juice samples were measured, and microbiota profiling was conducted using 16 S rRNA gene sequencing. Results Significant differences were observed in each bile acid level in the three endoscopic BR groups (P

Abstract Background Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency. Methods To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD–GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls. Results iMGs from FTD–GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD–GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines. Conclusions Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.

Abstract The TARDBP gene variant is a known major cause of amyotrophic lateral sclerosis (ALS), with limited reports of Korean patients with ALS harboring the variants in TARDBP. This large cohort study introduces four ALS patients who share the p.M337V variant of the TARDBP, allowing for an investigation of clinical characteristics and prognosis by analyzing previously reported cases with the same variant. From November 2014 to August 2022, participants were recruited from two tertiary hospitals in Seoul, Korea. Clinical characteristics of patients diagnosed with ALS carrying the variant in TARDBP were evaluated. Previous articles demonstrating subjects’ characteristics were reviewed. Four patients were identified with the pathogenic missense variant (c.1009A>G; p.M337V) in the TARDBP. The mean age of onset was 55 years old, and none of the patients showed severe cognitive impairment. Sixty-three patients carrying the p.M337V variant in TARDBP from this study and previous reports delineated young age of onset (51.6 years), high frequency of bulbar onset patients (61.9%), and low comorbidity of frontotemporal dementia. This study reveals the presence of pathogenic variant of TARDBP in Korea and emphasizes the importance of genetic screening of the TARDBP gene, in diagnosing ALS and evaluating prognosis among familial and simplex ALS patients in Korea.

Gastric acid-related disorders are commonly encountered in clinical practice. Acetylcholine, gastrin, and histamine are physiological agonists that stimulate acid secretion from parietal cells. Histamine plays a decisive role in the transformation of parietal cells into acid-secreting forms. The H+, K+- ATPase proton pump, which represents the final step of acid secretion, translocates from cytoplasmic tubulovesicles to secretory canaliculi upon parietal cell stimulation and facilitates exchange of intracellular H+ with extracellular K+ in a 1:1 ratio. Histamine-2 receptor antagonists and proton pump inhibitors (PPIs) are widely used in clinical practice, and potassium-competitive acid blockers (P-CABs) have gained attention in recent times. P-CABs address the unmet needs of patients who receive conventional PPIs and have broadened the spectrum of drug choices; however, further research is warranted to confirm long-term safety of these drugs. Comprehensive understanding of the mechanisms of actions, characteristics, advantages and disadvantages, and the adverse effect profile is essential for appropriate prescription of gastric acid-suppressive drugs. In this review, we provide a developing history and outline the pharmacological mechanisms underlying various gastric acid-suppressive drugs used in clinical settings.

Patients frequently report that stress causes or exacerbates gastrointestinal (GI) symptoms, indicating a functional relationship between the brain and the GI tract. The brain and GI tract are closely related embryologically and functionally, interacting in various ways. The concept of the brain–gut axis was originally established in the 19th and early 20th centuries based on physiological observations and experiments conducted in animals and humans. In recent years, with the growing recognition that gut microbiota plays a vital role in human health and disease, this concept has been expanded to the brain–gut–microbiota axis. The brain influences the motility, secretion, and immunity of the GI tract, with consequent effects on the composition and function of the gut microbiota. On the other hand, gut microbiota plays an essential role in the development and function of the brain and enteric nervous system. Although knowledge of the mechanisms through which the gut microbiota influences distant brain function is incomplete, studies have demonstrated communication between these organs through the neuronal, immune, and endocrine systems. The brain–gut–microbiota axis is an essential aspect of the pathophysiology of functional GI disorders such as irritable bowel syndrome, and is also involved in other GI diseases, including inflammatory bowel disease. This review summarizes the evolving concept of the brain–gut–microbiota axis and its implications for GI diseases, providing clinicians with new knowledge to apply in clinical practice.

Abstract Objectives Gastric cancer (GC) is the fourth most common cancer worldwide, with the highest incidence and mortality regardless of sex. Despite technological advances in diagnosing and treating gastric cancer, GC still has high incidence and mortality rates. Therefore, continuous research is needed to overcome GC. In various studies, cell lines are used to find and verify the cause of specific diseases. Large-scale genomic studies such as ENCODE and Roadmap epigenomic projects provide multiomics data from various organisms and samples. However, few multi-omics data for gastric tissues and cell lines have been generated. Therefore, we performed RNA-seq, Exome-seq, and ChIP-seq with several gastric cell lines to generate a multi-omics data set in gastric cancer. Data description Multiomic data, such as RNA-seq, Exome-seq, and ChIP-seq, were produced in gastric cancer and normal cell lines. RNA-seq data were generated from nine GC and one normal gastric cell line, mapped to a human reference genome (hg38) using the STAR alignment tool, and quantified with HTseq. Exome sequence data were produced in nine GC and two normal gastric lines. Sequenced reads were mapped and processed using BWA-MEM and GATK, variants were called by stralka2, and annotation was performed using ANNOVAR. Finally, for the ChIP-seq, nine GC cell lines and four GC cell lines were used in two experimental sets; chip-seq was performed to confirm changes in H3K4me3 and H3K27me3. Data was mapped to human reference hg38 with BWA-MEM, and peak calling and annotation were performed using the Homer tool. Since these data provide multi-omics data for GC cell lines, it will be useful for researchers who use the GC cell lines to study.

Background/Aims Histamine-2 receptor antagonists (H2RA) are used to treat acid-related disorders and functional dyspepsia. In contrast to other H2RAs, nizatidine promotes gastric emptying (GE). We investigated the effects of nizatidine and famotidine on intragastric pH and the GE rate in rats exposed to stress. Materials and Methods We used 8-week-old male Wistar rats. Based on administration of water or drugs after an overnight fast, the animals were categorized into the nonstress-water, stress-water, stress-nizatidine, stress-famotidine, and stress-nizatidine with mosapride groups. The rats had access to pre-weighed food for 10 minutes, and those in the stress groups were exposed to 1 hour of restraint stress. Intragastric pH was measured under isoflurane anesthesia, and the GE rate was measured after the rats were sacrificed. Results The GE rate was significantly lower in the stress-water and stress-famotidine groups than in the nonstress-water group. However, GE in the stress-nizatidine and stress-nizatidine with mosapride group did not significantly differ from that in the nonstress- water group. The GE rate was significantly higher in the stress-nizatidine with mosapride than in the stress-famotidine group. Intragastric pH was significantly higher in the stress-nizatidine and stress-famotidine groups than in the stress-water group. Nonetheless, there was no significant difference in pH between the stress-nizatidine and stress-famotidine groups. The intragastric pH was slightly but significantly higher in the stress-nizatidine with mosapride group than in the stress-nizatidine and stress-famotidine groups. Conclusions In contrast to famotidine, nizatidine prevents stress-induced GE delay, which suggests that nizatidine is superior to other H2RAs for treatment of functional dyspepsia associated with delayed GE.

Abstract Background/Objectives The hormone-dependent effect of MAP3K1 gene polymorphisms may explain sex-specific differences in gastric cancer (GC) risk. Phytoestrogens have been shown to interact with this genetic factor. Here, we investigated the association between MAP3K1 gene polymorphisms and GC risk by sex and whether these associations differ depending on soy products intake. Methods Participants aged 20–79 years were recruited from two hospitals between December 2002 and September 2006. In all, 440 cases and 485 controls were recruited, among, 246 pairs of cases and controls, matched by sex, age (± 5 years), study admission period (± 1 years), and hospital, were included for the analysis. Results In dominant model, men with the A allele of rs252902 showed significantly increased GC risk (odd ratio; OR=2.19, 95% confidence interval; CI=1.31–3.64) compared to GG homozygotes. When stratified by intake of soy products, men with the A allele of rs252902 and low intake of soy products showed significantly higher GC risk (OR=3.29, 95% CI=1.55–6.78) than that in GG homozygotes. Conclusions Men with the risk allele of MAP3K1 had a significantly increased GC risk compared to GG homozygotes; this trend was more pronounced in those with low intake of soy products.

Gastrointestinal (GI) prokinetic agents are drugs that increase GI motility and promote the movement of contents in the GI tract by amplifying and controlling the contraction of GI smooth muscle. Currently used prokinetics increase GI motility by acting as a dopamine D2 receptor antagonist (e.g., metoclopramide, domperidone, levosulpiride) and 5-HT4 receptor agonist (e.g., mosapride, prucalopride). Some prokinetics also have a cholinesterase inhibitory property (e.g., itopride), and herb-derived prokinetics (e.g., motilitone) affect multiple receptors. Depending on the type and distribution of receptors on which the prokinetics bind, the effect(s) may be regional or throughout the GI tract. Most prokinetics have been used for functional dyspepsia and gastroparesis because they mainly affect upper GI motility. However, prucalopride, a highly selective 5-HT4 receptor agonist, is used primarily to treat chronic constipation and pseudo-obstruction. Dopamine D2 receptor antagonists also inhibit the D2 receptor in the medulla oblongata chemoreceptor trigger zone; therefore, they can treat nausea and vomiting. However, short term use of dopamine D2 antagonists at an appropriate dose is recommended because of their potential for central nervous system side effects by penetrating the blood-brain barrier. It is necessary to know the mechanism of action, each clinical trial’s characteristics, and the side effects of prokinetics to obtain the best clinical outcomes. This article aims to summarize the results of clinical studies related to the impact of currently available prokinetic agents in Korea on GI motility.

PurposeCurrent evidence regarding the association between zinc intake and gastric cancer (GC)-specific survival in patients with intestinal-type GC is lacking. Therefore, this cohort study investigated the association between zinc intake and GC mortality through follow-up on GC death among patients with intestinal-type GC and whether these effects differ according to the source of zinc intake.MethodsA total of 185 patients with intestinal-type GC were enrolled from two hospitals between 2002 and 2006. Their survival or death was prospectively followed up until December 31, 2016, through a review of medical records and telephone surveys.ResultsA total of 178 patients were included and analyzed. The median follow-up period was 7.3 years. In the fully adjusted models, the highest tertile of total zinc intake showed a significantly lower GC mortality than the lowest tertile (hazard ratio, 0.22; 95% confidence interval: 0.08–0.64). In addition, the tertile of total zinc intake showed a dose-response association with GC mortality (p=0.015). Analysis of the source of zinc intake revealed that when zinc intake from staples (rice and noodles), animal, and plant food sources were combined, the results were similar to those of total zinc intake and GC mortality.ConclusionZinc intake through various foods may be effective in reducing GC mortality by achieving balance with other nutrients. Our results suggest that zinc improves the survival of patients with intestinal-type GC in Korea.

Background/Aims Studies in healthy humans have reported that the addition of mosapride to acid suppressants resulted in higher intragastric pH than acid suppressant administration alone. We investigated the effect of the addition of mosapride to famotidine on the intragastric pH and gastric emptying rate (GER) in rats. Materials and Methods Sixty male Wistar rats were used in this study. Experimental groups were divided into control, famotidine-only, mosapride-only, and famotidine with mosapride (combination). The first experiment was performed in non-stressed rats. Mosapride was administered by oral gavage 1 hour before the meal, and famotidine was administered just before the meal. The rats were provided with food for 30 minutes. The intragastric pH was measured under isoflurane anesthesia, and the GER was measured after harvesting the stomach. In the stress experiment, rats were exposed to 1-hour restraint stress immediately after mosapride administration and subjected to the same process as in the experiment with the non-stressed rats. Results The famotidine-only and combination groups showed significantly higher gastric pH levels than the control group in non-stressed (P

Eradication of Helicobacter pylori has contributed to the treatment of peptic ulcers and mucosa-associated lymphoid tissue lymphoma. Moreover, it has possibly decreased the prevalence of gastric cancer. However, eradication therapy is associated with various adverse effects, of which diarrhea is the most common. The incidence of diarrhea after eradication treatment varies from 8% to 48%. In particular, the incidence is higher in patients who receive first-line standard triple therapy compared with those who receive second-line therapy. Both antibiotics and proton pump inhibitors, components of eradication therapy, have short-term and long-term impacts on gut microbiota. The alterations of gut microbiota may not recover until 1 year after eradication therapy. Most cases of diarrhea that occur after eradication therapy are antibiotic-associated diarrhea caused by the destruction of the normal gut microbiota. In some cases, Clostridioides difficile-associated diarrhea occurs after eradication therapy. If bloody diarrhea occurs after eradication therapy and the Clostridioides difficile toxin is not detected, antibiotic-associated hemorrhagic colitis associated with Klebsiella oxytoca infection should be suspected. It is crucial to explain the possibility of diarrhea before initiating eradication therapy to increase compliance. Furthermore, probiotics may be administered to reduce diarrhea. If severe diarrhea or symptoms other than the usual antibiotic-associated diarrhea occur during or after eradication therapy, antibiotics should be discontinued. In addition, appropriate tests to determine the cause of diarrhea should be performed. This review summarizes the alteration of the gut microbiota, the causes of diarrhea after Helicobacter pylori eradication therapy, and its management.

Background/Aims: The incidence of peptic ulcer disease has decreased in past decades; however, the trends in peptic ulcer bleeding (PUB) are inconsistent among regions. This study aimed to investigate the trends in PUB incidence and the effect of risk factors on PUB in Korea. Methods: The records of patients hospitalized with PUB from 2006 to 2015 were retrieved from the Korean National Health Insurance Service Database. Standardized incidences of PUB were calculated, and the clinical characteristics such as age, sex, Helicobacter pylori infection, drug exposure, comorbidities, and mortality were obtained. Results: In total, 151,507 hospitalizations with PUB were identified. The overall annual hospitalization rate was 34.98 per 100,000 person-years. The incidence of PUB showed no significant change from 2006 to 2008 and decreased from 2008 to 2015, with an annual change of -2.7% (p

Background/Aims: This study aimed to characterize the changes in the gut microbiota of irritable bowel syndrome (IBS) patients and to investigate the consequent alterations in bacterial functions. Methods: We performed 16S rRNA metagenomic sequencing and a phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analyses using fecal samples from control (n=12) and diarrhea-dominant IBS patients (n=7). Results: The samples were clustered by the principal coordinates analysis depending on the presence of IBS (p=0.003). In the IBS patients, the abundances of Acidaminococcaceae, Sutterellaceae, and Desulfovibrionaceae were significantly increased, while those of Enterococcaceae, Leuconostocaceae, Clostridiaceae, Peptostreptococcaceae, and Lachnospiraceae were significantly decreased. The PICRUSt results indicated that two orthologues involved in secondary bile acid biosynthesis were significantly decreased in IBS patients. Modules involved in multidrug resistance, lipopolysaccharide biosynthesis, the reductive citrate cycle, and the citrate cycle were significantly increased in the IBS patients. In contrast, modules involved in cationic antimicrobial peptide resistance, and some transport systems were more abundant in controls than in IBS patients. Conclusions: Changes in the gut microbiota composition in IBS patients lead to alterations in bacterial functions, such as bile acid transformation and the induction of inflammation, which is a known pathophysiological mechanism of IBS.

Men and women are different, but this difference has not been well reflected in clinical trials and preclinical studies of biomedical science. Gender medicine, which systematically analyzes research results according to sex and gender, has been emphasized to overcome this problem. On the other hand, researchers still have difficulty in applying gender medicine to their research. To perform rigorous gender medicine, using correct terms, a thorough literature review during research planning, appropriate statistical analysis and reporting, and cautious interpretation of the results are necessary. Applying gender medicine will increase the reproducibility of studies, promote discoveries, expand the study relevance, and ultimately improve patient care in both men and women. Here, this study reviewed the practical issues on applying gender medicine to both preclinical and clinical studies in the field of biomedical science.

Background/Aims Effect of proton pump inhibitor (PPI) use on the risk of hip fracture is controversial. This study aimed to clarify the association between PPI use and hip fracture risk using a large cohort. Methods This study recruited participants from the nationwide cohort (n = 1,025,340). After exclusion of participants who had hip fractures or were aged less than 40 years during the baseline period (2002 to 2004), 371,806 participants were followed to 2013. Participants prescribed PPIs for more than 90 days during baseline period were defined as users. Fracture cases were defined when participants were hospitalized with claims of a hip fracture. Results During 4,159,343 person-years of follow-up, fractures developed more often in PPI users than in nonusers (relative risk [RR], 1.787; 95% confidence interval [CI], 1.260 to 2.534; p = 0.002). The results persisted after adjusting for age, sex, and many drugs relevant to osteoporosis or influential in bone health. Furthermore, fracture risk associated with PPI use increased with duration of use (p trend < 0.001). The fully adjusted RRs of hip fracture development were 1.350 (95% CI, 1.203 to 1.515) for 1- to 90-day users, 1.487 (95% CI, 0.957 to 2.311) for 91- to 180-day users, and 1.771 (95% CI, 0.931 to 3.368) for > 180-day users. The positive association between PPI use and fracture was also confirmed in a subgroup with health screening data where further adjustment for body mass index, smoking status, alcohol consumption, and physical activity was available (adjusted RR, 2.025; 95% CI, 1.151 to 3.564, p = 0.014). Conclusions PPI use is associated with hip fracture development.

Humans carry numerous symbiotic microorganisms in their body, most of which are present in the gut. Although recent technological advances have produced extensive research data on gut microbiota, there are various confounding factors (e.g., diet, race, medications) to consider. Sex is one of the important variables affecting the gut microbiota, but the association has not yet been sufficiently investigated. Although the results are inconsistent, several animal and human studies have shown sex differences in gut microbiota. Herein, we review these studies to discuss the sex-dependent differences as well as the possible mechanisms involved.

Ischemic colitis primarily affects the elderly with underlying disease, but it rarely occurs in young adults with risk factors, such as coagulopathy or vascular disorder. Moreover, it is extremely rare in the very young without risk factors. This paper presents a patient with ischemic colitis associated with heat stroke and rhabdomyolysis after intense exercise under high-temperature conditions. A 20-year-old man presented with mental deterioration after a vigorous soccer game for more than 30 minutes in sweltering weather. He also presented with hematochezia with abdominal pain. The laboratory tests revealed the following: AST 515 U/L, ALT 269 U/L, creatine kinase 23,181 U/L, BUN 29.1 mg/dL, creatinine 1.55 mg/dL, and red blood cell >50/high-power field in urine analysis. Sigmoidoscopy showed ischemic changes at the rectum and rectosigmoid junction. A diagnosis of ischemic colitis and rhabdomyolysis was made, and the patient recovered after conservative and fluid therapy. This case showed that a diagnosis of ischemic colitis should be considered in patients who present with abdominal pain and bloody diarrhea after intense exercise, and appropriate treatment should be initiated immediately.

Gut microbiota have been known to play an essential role in host immunity and metabolism. Dysbiosis is associated with various gastrointestinal (GI) and other diseases such as cancers, metabolic diseases, allergies, and immunological disorders. So far, the role of gut microbiota has been studied mainly in lower GI disease but has recently been reported in upper GI diseases other than Helicobacter pylori infection, including Barrett’s esophagus, esophageal carcinoma, gastric cancer, functional dyspepsia, and nonsteroidal anti-inflammatory drug-induced small intestinal mucosal injury. Probiotics have some beneficial effect on these diseases, but the effects are strain specific.

Abstract Background Mechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs. Methods We established patient-derived xenograft (PDX) lines from diffuse-type GCs, and searched for drugs that suppressed their growth. Diffuse-type GCs were classified into subtypes by their gene expression profiles. Results mTOR inhibitor temsirolimus strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells, which was regulated via Wnt-mTOR axis. These cells were microsatellite unstable (MSI) or chromosomally unstable (CIN), inconsistent with TCGA report. Diffuse-type GCs in TCGA cohort could be classified into two clusters, and GS subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived diffuse-type GC cells were included. We estimated that about 9 and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively, by identifying PIK3CA mutations and MSI condition in TCGA cohort. These ratios were far greater than those of diffuse-type GCs in cluster I or intestinal-type GCs. Further analysis suggested that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells. Conclusion mTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.

Background : /Aims: Behavioral factors, such as smoking and heavy alcohol consumption, increase the risk of gastric cancer (GC), but their effects on survival are not clear. We examined associations between prediagnostic smoking and alcohol drinking behavior and GC death by long-term follow-up. Methods : : The participants were 508 GC patients enrolled at Chungnam University Hospital and Hanyang University Guri Hospital from 2001 to 2006. Information on clinicopathologic and behavioral risk factors was collected, and patient survival was prospectively followed until 2016 by medical chart review and telephone survey. Results : : During above 10 years follow-up period, overall death was 46.2% (n=226) and GC deaths was 38.2% (n=187) among the 489 GC patients included in the analysis. No significant association was found between smoking habits and overall or GC survival. However, after stratification by histological type, the hazard ratio (HR) of GC death for current smokers tended to be higher for the diffuse type (HR 1.61, 95% CI 0.57-4.59 for current vs. never) rather than for the intestinal type (HR 0.78, 95% CI 0.28-2.19 for current vs. never). Light alcohol consumption was found to be associated with a significantly lower risk of GC death (HR 0.52, 95% CI 0.36-0.75 for

The pathophysiology of functional gastrointestinal disorders (FGIDs) is still unclear and various complex mechanisms have been suggested to be involved. In many cases, improvement of symptoms and quality of life (QoL) in patients with FGIDs is difficult to achieve with the single-targeted treatments alone and clinical application of these treatments can be challenging owing to the side effects. Herbal preparations as complementary and alternative medicine can control multiple treatment targets of FGIDs simultaneously and relatively safely. To date, many herbal ingredients and combination preparations have been proposed across different countries and together with a variety of traditional medicine. Among the herbal therapies that are comparatively considered to have an evidence base are iberogast (STW-5) and peppermint oil, which have been mainly studied and used in Europe, and rikkunshito and motilitone (DA-9701), which are extracted from natural substances in traditional medicine, are the focus of this review. These herbal medications have multi-target pharmacology similar to the etiology of FGIDs, such as altered intestinal sensory and motor function, inflammation, neurohormonal abnormality, and have displayed comparable efficacy and safety in controlled trials. To achieve the treatment goal of refractory FGIDs, extensive and high quality studies on the pharmacological mechanisms and clinical effects of these herbal medications as well as efforts to develop new promising herbal compounds are required.

Using data from the real world to solve clinical questions that cannot be answered using data from clinical trials is attracting more attention. Clinical outcomes for patients with esophageal cancer in a real-world setting might be different from data in randomized controlled trials. This study aimed to provide real world data on treatment and prognosis in Korean patients with esophageal cancer. This retrospective cancer cohort included newly diagnosed cases of esophageal cancer at 19 tertiary hospitals between January 1, 2005 and December 31, 2017. Cancer staging was defined according to the 7th edition of the American Joint Committee on Cancer criteria. We identified 6,354 patients with newly diagnosed esophageal cancer (mean age: 64.9 ± 9.0 years, 96.9% squamous cell carcinoma). The proportion of early esophageal cancer increased from 24.7% in 2005 to 37.2% in 2015 (p

Stomach cancer: DNA methylation of hormone receptor genes A sequencing study reveals abnormal changes to DNA that set the stage for stomach cancer development. DNA methylation, the addition of methyl groups to alter DNA activity, is often disrupted in human cancers. Yong Sung Kim at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) in Daejeon, South Korea, and co-workers used sequencing technogy to identify critical methylation changes in stomach epithelial cells, intestinal metaplasia lesion and tumor cells during early-stage gastric cancer. The team found 3,035 abnormally methylated DNA regions related to the expression of particular genes. Further analysis identified six hormone receptor genes directly involved with stomach acid secretion, whose altered expression was linked to over-methylated DNA regions. Loss of function within these six genes may lead to gastric cancer, and their expression levels could be valuable biomarkers for the disease.

Abstract Epigenetic dysregulation is a major driver of tumorigenesis. To identify tumor‐suppressive microRNAs repressed by DNA methylation in gastric cancer (GC), we analyzed the genome‐wide DNA methylation and microRNA expression profiles of EpCAM+/CD44+ GC cells. Among the set of microRNAs screened, miR‐1271 was identified as a microRNA repressed by DNA methylation in GC. Forced miR‐1271 expression substantially suppressed the growth, migration, and invasion of GC cells. To identify candidate target genes and signaling pathways regulated by miR‐1271, we performed RNA sequencing. Among the genes down‐regulated by miR‐1271, MAP2K1 (MEK1) was significantly repressed by miR‐1271, and the associated ERK/MAPK signaling pathway was also inhibited. TEAD4 was also repressed by miR‐1271, and the associated YAP1 signatures within genes regulated by miR‐1271 were significantly enriched. These findings uncovered MEK1 and TEAD4 as novel miR‐1271 targets and suggest that the epigenetic silencing of miR‐1271 is crucial for GC development.

Background/Aims: This study was performed to evaluate the relationship between family history of gastrointestinal (GI) cancers and incidence of any GI cancer in the Korean population. Methods : : Between January 2015 and July 2016, 711 GI cancer patients and 849 controls in 16 hospitals in Korea were enrolled. Personal medical histories, life styles, and family history of GI cancers were collected via questionnaire. Results: There was a significant difference in the incidence of family history of GI cancer between GI cancer patients and controls (p=0.002). Patients with family history of GI cancer tended to be diagnosed as GI cancer at younger age than those without family history (p=0.016). The family members of GI cancer patients who were diagnosed before 50 years of age were more frequently diagnosed as GI cancer before the age of 50 years (p=0.017). After adjusting for major confounding factors, age (adjusted odds ratio [AOR] 1.065, 95% confidence interval [CI]; 1.053-1.076), male gender (AOR 2.270, 95% CI; 1.618-3.184), smoking (AOR 1.570, 95% CI; 1.130-2.182), and sibling’s history of GI cancer (AOR 1.973, 95% CI; 1.246-3.126) remained independently associated with GI cancers. Conclusions: GI cancer patients tended to have a first relative with a history of concordant GI cancer. Personal factors (old age and male) and lifestyle (smoking) contribute to the development of GI cancer, independently. Individuals with high risk for GI cancers may be advised to undergo screening at an earlier age.

Background/Aims: Stress has a role in the pathogenesis of functional dyspepsia (FD) and influences food intake in humans and animals. Prokinetic drugs have been used in FD, and some of these drugs reverse the feeding inhibition (FI) induced by acute restraint stress in rats. We aimed to evaluate the effect of DA-9701 on FI induced by acute restraint in rats. Materials and Methods: Male Sprague-Dawley rats were divided into 6 groups: Control (no stress), Stress+vehicle, and Stress+DA-9701 at doses of 1, 3, 10, and 30 mg/kg (n=6∼7). DA-9701 or vehicle was administered through gastric gavage 45 minutes before stress. After 60 minutes of stress, pre-weighed chow was given and the weight of remaining food was measured 30 and 60 minutes later. The effect of DA-9701 on FI was compared after pretreatment with WAY100635, a 5HT1A antagonist. Results: The restraint stress group had significantly less food intake than the control group. After feeding, rats given 1 and 3 mg/kg of DA-9701 showed increased food intake at 60 minutes, but this was not statistically significant. Rats given 10 mg/kg of DA-9701 showed significantly increased food intake at 30 minutes and 60 minutes (P＜0.05). Interestingly, rats given 30 mg/kg of DA-9701 showed a significant decrease in food intake, similar to that of the vehicle group. The beneficial effect of 10 mg/kg of DA-9701 on FI was abolished by the pretreatment with WAY100635. Conclusions: Acute restraint stress reduced food intake in rats and pretreatment with DA-9701 improved stress-induced FI.

Background/Aims: The eradication rate of Helicobacter pylori (H. pylori) has been decreasing recently in Korea due to antibiotics resistance. The aim of this study was to investigate the trend of eradication rate and clinical factors affecting the eradication rate of H. pylori in the last 10 years in west Gyeonggi-do, Korea. Methods: The trends of eradication rate of H. pylori, gender, age, concomitant mediations, and clinical factors were retrospectively evaluated in patients with H. pylori infection between 2006 and 2015 (n=2,485). Results: The overall H. pylori eradication rate for the standard triple therapy was 82.5%. The annual eradication rates from 2006 to 2015 were 90%, 77.9%, 75.8%, 83.2%, 85.6%, 90.1%, 81.3%, 81.1%, 78.7%, and 78.8%, respectively, showing a significant decrement during the last five years (p〈 0.001). Higher eradication rate was observed in males than in females (p〈 0.001). Esomeprazole showed a higher eradication rate compared with pantoprazole between 2006 and 2010 (p〈 0.022). Age and the use of probiotics and mucosal protective agents played no significant role in the H. pylori eradication rate. The overall eradication rate for bismuth-based quadruple therapy was 94.4%. Conclusions: The eradication rate of H. pylori over the last 10 years for first-line therapy ranged from 75.8 to 90.1%; the eradication rate for triple therapy has declined. However, the eradication rate for quadruple therapy has remained unchanged over the last 10 years.

Currently, Illumina sequencers are the globally leading sequencing platform in the next-generation sequencing market. Recently, MGI Tech launched a series of new sequencers, including the MGISEQ-2000, which promise to deliver high-quality sequencing data faster and at lower prices than Illumina’s sequencers. In this study, we compared the performance of two major sequencers (MGISEQ-2000 and HiSeq 4000) to test whether the MGISEQ-2000 sequencer delivers high-quality sequence data as suggested. We performed RNA sequencing of four human colon cancer samples with the two platforms, and compared the sequencing quality and expression values. The data produced from the MGISEQ-2000 and HiSeq 4000 showed high concordance, with Pearson correlation coefficients ranging from 0.98 to 0.99. Various quality control (QC) analyses showed that the MGISEQ-2000 data fulfilled the required QC measures. Our study suggests that the performance of the MGISEQ-2000 is comparable to that of the HiSeq 4000 and that the MGISEQ-2000 can be a useful platform for sequencing.

The crab-eating monkey is widely used in biomedical research for pharmacological experiments. Epigenetic regulation in the brain regions of primates involves complex patterns of DNA methylation. Previous studies of methylated CpG-binding domains using microarray technology or peak identification of sequence reads mostly focused on developmental stages or disease, rather than normal brains. To identify correlations between gene expression and DNA methylation levels that may be related to transcriptional regulation, we generated RNA-seq and whole-genome bisulfite sequencing data from seven different brain regions from a single crab-eating monkey. We identified 92 genes whose expression levels were significantly correlated, positively or negatively, with DNA methylation levels. Among them, 11 genes exhibited brain region-specific characteristics, and their expression patterns were strongly correlated with DNA methylation level. Nine genes (SLC2A5, MCM5, DRAM1, TTC12, DHX40, COR01A, LRAT, FLVCR2, and PTER) had effects on brain and eye function and development, and two (LHX6 and MEST) were previously identified as genes in which DNA methylation levels change significantly in the promoter region and are therefore considered brain epigenetic markers. Furthermore, we characterized DNA methylation of repetitive elements at the whole genome through repeat annotation at single-base resolution. Our results reveal the diverse roles of DNA methylation at single-base resolution throughout the genome and reflect the epigenetic variations in adult brain tissues.

Controversies exist regarding the impact of age on gastric cancer-related mortality according to cancer stage. In our prospective cohort study, we evaluated the impact of age on stage-specific mortality in patients with gastric cancer. Between 2002 and 2006, patients with newly diagnosed gastric cancer were recruited from two university-affiliated hospitals in Korea. Follow-up data were updated regularly based on medical records and telephone surveys. Patients were classified into four subgroups according to age:

Background/Aims To evaluate changes in gut microbiota composition following long-term proton pump inhibitor (PPI) treatment. Methods : Twenty-four-week-old F344 rats were fed diets with (n=6) or without (n=5) lansoprazole for 50 weeks. Profiles of luminal microbiota in the terminal ileum were then analyzed. Pyrosequencing of the 16S rRNA gene was performed using an FLX genome sequencer (454 Life Sciences/Roche). Results : Rats treated with lansoprazole showed significantly reduced body weights compared to controls (lansoprazole-treated rats and controls, 322.3±15.3 g vs 403.2±5.2 g, respectively, p

Background : /Aims: Peptic ulcer bleeding (PUB) is the most common cause of upper gastrointestinal bleeding in Korea but there has been no research done using big data. This study evaluates the optimal operational definition (OD) for big data research by analyzing clinical characteristics of PUB. Methods : : We reviewed the clinical characteristics of 92 patients with PUB confirmed on endoscopy in Wonkwang University Sanbon Hospital (January 2013 to December 2014). We calculated sensitivity and positive predictive value (PPV) to detect confirmed PUB patients using ODs developed by combining clinical features of patients with PUB. Results : : The mean patient age was 63 years. Men had higher prevalence of PUB than women. Bleeding gastric ulcer was proportionately common in the age range of 40s to 60s in men, while a significantly higher rate of bleeding occurred in women older than 70s. The rate of drug-induced ulcer was 28.2%, whereas the prevalence of Helicobacter pylori was 47.8%. Among the hospitalized patients with diagnostic code of PUB, we ruled out patients with endoscopic removal of gastric adenoma or peritonitis, and selected patients who had been administered intravenous proton pump inhibitor. The sensitivity in this setting was 82.6%, and PPV was 88.4%. Conclusion : s: PUB was more common in older patients, and there was a clear gender difference in gastric ulcer bleeding by age. With a proper OD using PUB diagnostic codes, we can identify true patients with sufficiently high sensitivity and PPV. (Korean J Gastroenterol 2016;68:77-86)

Background : /Aims: In Korea, there are no available multicenter data concerning the prevalence of or diagnostic approaches for non-responsive gastroesophageal reflux disease (GERD) which does not respond to practical dose of proton pump inhibitor (PPI) in Korea. The purpose of this study is to evaluate the prevalence and the symptom pattern of non-responsive GERD. Methods : : A total of 12 hospitals who were members of a Korean GERD research group joined this study. We used the composite score (CS) as a reflux symptom scale which is a standardized questionnaire based on the frequency and severity of typical symptoms of GERD. We defined "non-responsive GERD" as follows: a subject with the erosive reflux disease (ERD) whose CS was not decreased by at least 50% after standard-dose PPIs for 8 weeks or a subject with non-erosive reflux disease (NERD) whose CS was not decreased by at least 50% after half-dose PPIs for 4 weeks. Results : : A total of 234 subjects were analyzed. Among them, 87 and 147 were confirmed to have ERD and NERD, respectively. The prevalence of non-responsive GERD was 26.9% (63/234). The rates of non-responsive GERD were not different between the ERD and NERD groups (25.3% vs. 27.9%, respectively, p=0.664). There were no differences between the non-responsive GERD and responsive GERD groups for sex (p=0.659), age (p=0.134), or BMI (p=0.209). However, the initial CS for epigastric pain and fullness were higher in the non-responsive GERD group (p=0.044, p=0.014, respectively). Conclusion : s: In conclusion, this multicenter Korean study showed that the rate of non-responsive GERD was substantially high up to 26%. In addition, the patients with the non-responsive GERD frequently showed dyspeptic symptoms such as epigastric pain and fullness. (Korean J Gastroenterol 2016;68:16-22)

The present study aimed to identify molecules associated with lymphovascular invasion (LVI) and perineural invasion (PNI) and to examine their biological behavior in colorectal cancer (CRC). LVI- and PNI-associated molecules were identified and verified using sequential processes including (1) identification of 117 recurrence-associated genes differentially expressed on RNA-seq analysis using primary cancer tissues from 130 CRC patients with and without systemic recurrence; (2) analysis of molecules associated with LVI and PNI; (3) assessment of biological properties by measuring proliferation, anoikis, invasion/migration, epithelial-mesenchymal transition and autophagy flux; and (4) verification of disease-free survival using public datasets. Gelsolin (GSN) and 2'-5'-oligoadenylate synthetase 2 (OAS2) were associated with PNI and LVI, respectively. Invasion potential was >2-fold greater in GSN-overexpressing LoVo cells than in control cells (p

MicroRNAs (miRNAs) have been demonstrated to play an important role in carcinogenesis. Previous studies revealed that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity. In this study, we measured the plasma expression levels of three miRNAs (miR-21, miR-27a, and miR-155) to investigate the usefulness of miRNAs for gastric cancer detection. We initially examined plasma miRNA expression levels in a screening cohort consisting of 15 patients with gastric cancer and 15 healthy controls from Korean population, using TaqMan quantitative real-time polymerase chain reaction. We observed that the expression level of miR-27a was significantly higher in patients with gastric cancer than in healthy controls, whereas the miR-21 and miR-155a expression levels were not significantly higher in the patients with gastric cancer. Therefore, we further validated the miR-27a expression level in 73 paired gastric cancer tissues and in a validation plasma cohort from 35 patients with gastric cancer and 35 healthy controls. In both the gastric cancer tissues and the validation plasma cohort, the miR-27a expression levels were significantly higher in patients with gastric cancer. Receiver-operator characteristic (ROC) analysis of the validation cohort, revealed an area under the ROC curve value of 0.70 with 75% sensitivity and 56% specificity in discriminating gastric cancer. Thus, the miR-27a expression level in plasma could be a useful biomarker for the diagnosis and/or prognosis of gastric cancer.

The gastric accommodation reflex is an important mechanism in gastric physiology. However, the aging-associated structural and functional changes in gastric relaxation have not yet been established. Thus, we evaluated the molecular changes of interstitial cell of Cajal (ICC) and neuronal nitric oxide synthase (nNOS) and the function changes in the corpus of F344 rats at different ages (6-, 31-, 74-wk and 2-yr). The proportion of the c-Kit-positive area in the submucosal border (SMB) and myenteric plexus (MP) layer was significantly lower in the older rats, as indicated by immunohistochemistry. The density of the nNOS-positive immunoreactive area also decreased with age in the SMB, circular muscle (CM), and MP. Similarly, the percent of nNOS-positive neuronal cells per total neuronal cells and the proportion of nNOS immunoreactive area of MP also decreased in aged rats. In addition, the mRNA and protein expression of c-Kit and nNOS significantly decreased with age. Expression of stem cell factor (SCF) and the pan-neuronal marker PGP 9.5 mRNA was significantly lower in the older rats than in the younger rats. Barostat studies showed no difference depending on age. Instead, the change of volume was significantly decreased by L-NG63-nitroarginine methyl ester in the 2-yr-old rats compared with the 6-wk-old rats (P = 0.003). Taken together, the quantitative and molecular nNOS changes in the stomach might play a role in the decrease of gastric accommodation with age.

The colonic response to stress is greater in female rats than in male rats. The aim of this study was to evaluate the effect of probiotics in the repeated water avoidance stress (rWAS)-induced colonic microinflammation model of Wistar rats in a sex-specific manner. The three groups (no-stress, WAS, and WAS with probiotics) were exposed to r-WAS for 1 h daily for 10 days, and Lactobacillus farciminis was administered by oral gavage for 10 days to animals in the probiotics group. The visceromotor response (VMR) to colorectal distension (CRD) was assessed using a barostat and noninvasive manometry before and after WAS exposure. Immunohistochemistry for mast cells and real-time polymerase chain reaction (RT-PCR) for detection of mucosal cytokines were performed using distal colon tissue after the animals were sacrificed. Significant reduction of VMR to CRD (visceral analgesia) was observed at 60 mmHg in the female WAS group (P = 0.045), but not in males. In addition, the female WAS with probiotics group showed a significantly lower colonic mucosal mast cell count in comparison to the female WAS group (P = 0.013), but this phenomenon was not observed in the male group. The colonic mucosal mRNA levels of interferon-γ (IFNR), tumor necrosis factor-α (TNFA), interleukin (IL) 6, and IL17 were higher in the female WAS group than in the male WAS group. The mRNA levels of IFNR, TNFA, and IL6 were significantly decreased in WAS females who received probiotics (all P < 0.050). In conclusion, rWAS is induced in a sex-specific manner. A 10-day-long treatment with L. farciminis is an effective therapy for rWAS-induced colonic microinflammation in female rates, but not in male rats.

The aging-associated cellular and molecular changes in esophagus have not been established, yet. Thus we evaluated histological structure, interstitial cells of Cajal (ICCs), neuronal nitric oxide synthase (nNOS)-positive cells, and contractility in the esophagus of Fischer 344 rat at different ages (6-, 31-, 74-weeks, and 2-years). The lamina propria thickness and endomysial area were calculated. The immunoreactivity of c-Kit, nNOS and protein gene product (PGP) 9.5 was counted after immunohistochemistry. Expression of c-Kit, stem cell factor (SCF), nNOS and PGP 9.5 mRNA was measured by real-time PCR, and expression of c-Kit and nNOS protein was detected by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The lamina propria thickness increased (6 week vs 2 year, P = 0.005) and the endomysial area of longitudinal muscle decreased with aging (6 week vs 2 year, P

[This corrects the article DOI: 10.1371/journal.pone.0169113.].

Autoimmune hepatitis (AIH) has been reported in association with Sjögren's syndrome (SS). Drug-induced AIH has been rarely reported. A rare case of the co-development of AIH and SS in a 53-year-old woman after the consumption of herbal medicines is described. After admission, the patient complained of dryness in her mouth, and she was subsequently diagnosed with SS, which had not been detected previously. The patient's bilirubin and aminotransferase levels initially decreased following conservative management; however, they later began to progressively increase. A diagnosis of AIH was made based on the scoring system proposed by the International Autoimmune Hepatitis Group. The patient was administered a combination of prednisolone and azathioprine, and the results of follow-up liver-function tests were found to be within the normal range. This is an unusual case of AIH and SS triggered simultaneously by the administration of herbal medicines.

Background/AimsThe red-blood-cell distribution width (RDW) is a newly recognized risk marker in patients with cardiovascular disease, but its role in nonalcoholic fatty liver disease (NAFLD) has not been well defined. The aim of the present study was to determine the association between RDW values and the level of fibrosis in NAFLD according to BARD and FIB-4 scores.MethodsThis study included 24,547 subjects who had been diagnosed with NAFLD based on abdominal ultrasonography and questionnaires about alcohol consumption. The degree of liver fibrosis was determined according to BARD and FIB-4 scores. The association between RDW values and the degree of fibrosis in NAFLD was analyzed retrospectively.ResultsAfter adjusting for age, hemoglobin level, mean corpuscular volume, history of hypertension, history of diabetes, and high-sensitivity C-reactive protein, the RDW values were 12.61±0.41% (mean±SD), 12.70±0.70%, 12.77±0.62%, 12.87±0.82%, and 13.25±0.90% for those with BARD scores of 0, 1, 2, 3, and 4, respectively, and 12.71±0.72%, 12.79±0.66%, and 13.23±1.52% for those with FIB-4 scores of

Using our data set (GSE50760) previously established by RNA sequencing, the present study aimed to identify upregulated genes associated with colorectal cancer (CRC) liver metastasis (CLM) and verify their biological behavior. The potential roles of candidate genes in tumors were assessed using cell proliferation and invasion assays. Tissue samples were collected from 18 CRC patients with synchronous CLM and two CRC cell lines (SW480 and SW620) were used for transfection and cloning. The roles of the genes identified in CLM were verified using immunohistochemistry in 48 nude mice after intrasplenic transplantation of CRC cells. mRNA and protein expression was determined by quantitative real-time reverse transcription polymerase chain reaction and western blot, respectively. Nine genes were initially selected according to the relevance of their molecular function and biological process and, finally, ALDH1A1 and IGFBP1 were chosen based on differential mRNA expression and a positive correlation with protein expression. The overexpression of ALDH1A1 and IGFBP1 significantly and time-dependently decreased cell proliferation (p ≤ 0.001-0.003) and suppressed invasiveness by ≥3-fold over control cells (p < 0.001) in the SW480 cell line, whereas they had a slight effect on reducing SW620 cell proliferation. The protein expression levels of E-cadherin, N-cadherin, claudin-1, and vimentin were significantly higher in CLM than in primary tumor tissues (p < 0.05). However, the cadherin switch, namely, N-cadherin overexpression with reduced E-cadherin expression, was not observed in CLM tissues and transfected CRC cells. Irrespective of reduced proliferation and invasion found on in vitro cell assays, persistent overexpression of β-catenin, vimentin, and ZO-1 in IGFBP1-overexpressing SW480 cells possibly contributed to CLM development in mice implanted with IGFBP1-overexpressing SW480 cells (CLM occurrences: SW480/IGFBP1-transfected mice vs. SW480/vector- and SW480/ALDH1A1-transfected mice, 4/8 vs. 0/10, p = 0.023). In conclusion, ALDH1A1 and IGFBP1 are differentially overexpressed in CLM and may play a dual role, functioning as both tumor suppressors and metastasis promoters in CRC.

High-throughput genomic technologies (HGTs), including next-generation DNA sequencing (NGS), microarray, and serial analysis of gene expression (SAGE), have become effective experimental tools for cancer genomics to identify cancer-associated somatic genomic alterations and genes. The main hurdle in cancer genomics is to identify the real causative mutations or genes out of many candidates from an HGT-based cancer genomic analysis. One useful approach is to refer to known cancer genes and associated information. The list of known cancer genes can be used to determine candidates of cancer driver mutations, while cancer gene-related information, including gene expression, protein-protein interaction, and pathways, can be useful for scoring novel candidates. Some cancer gene or mutation databases exist for this purpose, but few specialized tools exist for an automated analysis of a long gene list from an HGT-based cancer genomic analysis. This report presents a new web-accessible bioinformatic tool, called CaGe, a cancer genome annotation system for the assessment of candidates of cancer genes from HGT-based cancer genomics. The tool provides users with information on cancer-related genes, mutations, pathways, and associated annotations through annotation and browsing functions. With this tool, researchers can classify their candidate genes from cancer genome studies into either previously reported or novel categories of cancer genes and gain insight into underlying carcinogenic mechanisms through a pathway analysis. We show the usefulness of CaGe by assessing its performance in annotating somatic mutations from a published small cell lung cancer study.