Sex-related differences in single nucleotide polymorphisms associated with dyslipidemia in a Korean population.

BACKGROUND: The prevalence of dyslipidemia has increased steadily in Korea, and the incidence of dyslipidemia differs by sex. In this study, we identified single nucleotide polymorphisms (SNPs) related to dyslipidemia in Korean cohorts through genome-wide association study (GWAS) analysis. METHODS: Genotyping was conducted to determine the genotypes of 72,298 participants and investigate genotypes for 7,079,946 SNPs. Sex, age, and BMI were set as covariates for GWAS, and significant SNPs were identified in the discovery and replication stages using logistic regression. RESULTS: GWAS of the entire cohort revealed a total of five significant SNPs: rs117026536 (LPL), rs651821 (APOA5), rs9804646 (APOA5), rs9926440 (CETP), and rs429358 (APOE). GWAS of the male subjects revealed a total of four significant SNPs. While rs9804646 (APOA5) and rs429358 (APOE) were significant for all the subjects, rs662799 (APOA5) and rs56156922 (CETP) were significant only for the male subjects. GWAS of the female subjects revealed two significant SNPs, rs651821 (APOA5) and rs9804646 (APOA5), both of which were significant in all the subjects. CONCLUSION: This is the first study to identify sex-related differences in genetic polymorphisms in Korean populations with dyslipidemia. Further studies considering environmental variables will be needed to elucidate these sex-related genetic differences in dyslipidemia.

Long-term outcome of endoscopic submucosal dissection is comparable to that of surgery for early gastric cancer: a propensity-matched analysis.

BACKGROUND: Data concerning the long-term outcomes of endoscopic submucosal dissection (ESD) versus surgery for early gastric cancer (EGC) are limited. We aimed to compare the long-term outcomes of ESD and surgery for patients with EGC. METHODS: Data were reviewed from patients treated by ESD or surgery for EGC in 2005-2010. The primary outcome was overall survival (OS). Secondary outcomes were disease-specific survival (DSS), disease-free survival (DFS), recurrence-free survival (RFS), treatment-related complications, and hospital stay duration. RESULTS: Among 617 patients, 342 underwent ESD and 275 underwent surgery. The 5-year OS rates were similar between the ESD group and the surgery group (96.9% vs 98.1%, P = 0.581). In a propensity-score-matched analysis of 117 pairs, there were no significant differences in the OS rates (96.5% vs 99.1%, P = 0.125) and DSS rates (100% vs 99.1%, P = 0.317) between the ESD group and the surgery group. The ESD group had a significantly lower DFS rate (90.3% vs 98.0%, P = 0.002), a significantly lower RFS rate (95.1% vs 98.0%, P = 0.033), a significantly higher early complication rate (6.7% vs 1.5%, P < 0.001), a significantly lower late complication rate (0% vs 9.1%, P < 0.001), and a significantly shorter median hospital stay (3 days vs 10 days, P < 0.001) than the surgery group. CONCLUSIONS: ESD and surgery have comparable OS rates in patients with EGC. ESD has benefits, including a lower late complication rate and shorter hospital stay. However, RFS and DFS rates might be lower after ESD than after surgery.

Endoscopic submucosal dissection for undifferentiated-type early gastric cancer: short- and long-term outcomes.

BACKGROUND AND AIMS: Application of endoscopic submucosal dissection (ESD) for undifferentiated-type early gastric cancers (EGCs) remains controversial owing to limited data regarding long-term outcomes. We aimed to evaluate the feasibility of ESD for undifferentiated-type EGCs that meet the expanded criteria (EC). METHODS: We performed a retrospective analysis of 66 patients who underwent ESD for undifferentiated-type EGC between January 2005 and December 2014. We evaluated the rates of en bloc, complete, and curative resections along with overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS). RESULTS: Of the 66 patients, the EC group included 38 patients and the beyond-EC group included 28 patients. The overall rates of en bloc, complete, and curative resection of the 66 lesions were 92.4% (61/66), 65.2% (43/66), and 48.5% (32/66), respectively. Of the 34 patients with non-curative resection, 18 underwent additional surgery. Local remnant cancer was detected in 1 patient (1/18, 5.6%), and none of the 18 patients had lymph node metastasis. On multivariate analysis, tumors > 2 cm [odd ratio (OR) 6.183, 95% confidence interval (CI) 1.279-29.880, p = 0.023) and submucosal invasion depth (OR 6.226, 95% CI 1.881-20.606, p = 0.003) were independent predictors of incomplete resection. All 26 patients with more than 1 year of follow-up after curative resection survived without any evidence of local or distant recurrences over a median follow-up period of 36 months. The OS, DSS, and RFS rates of patients with curative ESD were 93.8, 100, and 100%, respectively. CONCLUSIONS: ESD may have favorable long-term outcomes in patients with undifferentiated-type EGC after curative resection.

Endoscopic submucosal dissection for esophagogastric junction tumors: a single-center experience.

BACKGROUND: Surgical resection for esophagogastric junction (EGJ) tumors is more aggressive and worsens the quality of life of the patients and leads to poor prognosis even after surgery compared with tumors in other sites of the stomach. Endoscopic submucosal dissection (ESD) is a widely accepted treatment modality for premalignant lesions and early cancers in the stomach. However, EGJ tumor is one of the most technically difficult lesions to resect by ESD. Therefore, this study aimed to evaluate the therapeutic outcomes of ESD for EGJ epithelial neoplasms and to assess the predictive factors for incomplete resection. METHODS: We conducted a retrospective observational study of 48 patients who underwent ESD for adenomas and early cancers of the EGJ between March 2006 and November 2015 at the Pusan National University Hospital. Therapeutic outcomes of ESD and procedure-related adverse events were analyzed. RESULTS: En bloc resection, complete resection, and curative resection rates were 96, 77, and 71%, respectively. Multivariate analyses showed that the presence of ulceration was an independent predictive factor for incomplete resection (odds ratio 21.3, 95% confidence interval 1.51-298.49; p = 0.023). The procedure-related bleeding, perforation, and stenosis rates were 8, 4, and 0%, respectively; none of the adverse events required surgical intervention. During a median follow-up period of 25 months (range 6-72 months), local recurrence occurred in four patients with incomplete resection. CONCLUSION: ESD is an effective, safe, and feasible treatment for EGJ epithelial neoplasms. However, the complete resection rate decreases for tumors with ulceration.

Endoscopic submucosal dissection for papillary adenocarcinoma of the stomach: is it really safe?

BACKGROUND: Papillary adenocarcinoma of the stomach has been treated according to the same endoscopic submucosal dissection (ESD) indication criteria as other differentiated-type adenocarcinomas. We aimed to compare lymph node metastasis (LNM) in patients with early gastric cancer (EGC) with papillary adenocarcinoma (EGC-P) with that in patients with EGC with nonpapillary adenocarcinoma (EGC-NP) and to consider the potential limitation of current ESD indication criteria in the treatment of EGC-P. METHODS: In total, 1583 patients who underwent gastrectomy for EGC from 2005 to 2014 were included. Clinicopathologic characteristics of 56 patients with EGC-P were compared with those of 1527 patients with EGC-NP. The safety of ESD was evaluated, by application of current ESD indication criteria to EGC-P. RESULTS: The frequency of submucosal invasion was significantly higher in EGC-P than in both EGC-NP with differentiated-type histologic appearance and EGC-NP with undifferentiated-type histologic appearance (71.4% vs 50.8% and 37.6%, respectively). In addition, the frequency of LNM in EGC-P was 17.9%, higher than that in both EGC-NP with differentiated-type histologic appearance and EGC-NP with undifferentiated-type histologic appearance (9.7% and 11.1%, respectively). When the current ESD indication criteria were applied to the 56 patients with EGC-P, 17 patients met the current indications. Of these patients, two (11.8%) had LNM and three (17.6%) had lymphovascular invasion (LVI). When LNM and LVI were combined, one of seven patients (16.7%) meeting the absolute ESD indications and three of ten patients (30.0%) meeting the expanded ESD indications would not be cured after ESD. CONCLUSIONS: The use of ESD should be more carefully applied in patients with EGC-P meeting the ESD indication criteria, especially the expanded indication criteria, after pretreatment workup compared with other differentiated-type adenocarcinomas, owing to the higher frequencies of submucosal invasion, LNM, and LVI in EGC-P.

Clinicopathologic features of early gastric carcinoma with lymphoid stroma and feasibility of endoscopic submucosal dissection.

BACKGROUND: Gastric carcinoma with lymphoid stroma (GCLS) is a rare disease known to have unique features and a favorable prognosis. This study aimed to determine the clinicopathologic features of early GCLS (EGCLS) and define the feasibility of endoscopic submucosal dissection (ESD) for EGCLS. METHODS: We performed a retrospective analysis of 70 EGCLS patients treated via ESD or surgery and 1626 patients who underwent surgical resection for early non-GCLS (ENGCLS) between January 2007 and December 2014 at Pusan National University Hospital, Busan, Republic of Korea. RESULTS: The mean age of EGCLS patients was 58 years (range 36-77 years); a male predominance (3.7:1) was observed, and 81.4% showed Epstein-Barr virus positivity. Compared with ENGCLS, EGCLS was macroscopically more elevated (34.3 vs. 18.0%, P = 0.003) and located more proximally (upper third: 37.1 vs. 9.7%, P < 0.001). Tumor size was smaller (2.1 ± 1.1 vs. 3.1 ± 2.0 cm, P < 0.001), but submucosal invasion was more frequent (77.1 vs. 44.4%, P < 0.001) and deeper in the EGCLS group. Among the 59 EGCLS patients who were treated surgically, only two (3.4%) showed lymph node metastasis (LNM). Despite submucosal invasion, EGCLS showed a lower LNM rate (4.0 vs. 19.4%, P = 0.007) than ENGCLS, even in patients with SM3 EGCLS (5.3 vs. 24.5%, P = 0.007). There were no recurrences in the available ten patients who underwent ESD alone during a mean follow-up of 37.2 months. CONCLUSIONS: In this study, we observed unique clinicopathologic features with a very low LNM rate in EGCLS. We consider ESD a potentially curative treatment strategy for EGCLS despite deep submucosal invasion, especially in patients with poor performance status and significant comorbidities.

Sphingosine kinase 1 as a potential therapeutic target in epithelial ovarian cancer.

Sphingosine kinase 1 (SK1) is over-expressed in multiple types of human cancer. SK1 has growth-promoting effects and has been proposed as a potential therapeutic target. We investigated the therapeutic effects of SK1 inhibition in epithelial ovarian carcinoma (EOC). SK1 siRNA or inhibitors were tested in EOC cell lines, including A2780, SKOV3ip1, A2780-CP20, SKOV3-TR, ES2 and RMG2. Cells were treated with SK inhibitor or FTY720, and cell proliferation, apoptosis, angiogenesis and invasion were examined by MTT, FACS, ELISA and wound-healing assays, respectively. In vivo experiments were performed to test the effects of FTY720 on tumor growth in orthotopic mouse xenografts of EOC cell lines A2780 or SKOV3ip1 and a patient-derived xenograft (PDX) model of clear cell ovarian carcinoma (CCC). Blocking SK1 with siRNA or inhibitors significantly reduced proliferation, angiogenesis and invasion, and increased apoptosis in chemosensitive (A2780 and SKOV3ip1) and chemoresistant (A2780-CP20, SKOV3-TR, ES2 and RMG2) EOC cells. SK1 inhibitors also decreased the intracellular enzymatic activity of SK1. Furthermore, FTY720 treatment significantly decreased the in vivo tumor weight in xenograft models of established cell lines (A2780 and SKOV3ip1) and a PDX model for CCC compared to control (p < 0.05). These results support therapeutic targeting of SK1 as a potential new strategy for EOC.

Gastric epithelial dysplasia: characteristics and long-term follow-up results after endoscopic resection according to morphological categorization.

BACKGROUND: Gastric epithelial dysplasia (GED) can be morphologically categorized into adenomatous and foveolar types. To date, there have been few studies on the clinical characteristics of GEDs according to the morphologic types. Therefore, we here aimed to elucidate the clinicopathologic characteristics of patients with GED and the long-term follow-up results after endoscopic resection according to the morphologic characteristics of GEDs. METHODS: A total of 357 patients who underwent endoscopic resection for GEDs at Pusan National University Hospital between January 2008 and December 2009 were included in the study. GEDs were morphologically categorized into adenomatous, foveolar, and hybrid types on histologic examination. The clinicopathologic characteristics of patients with GEDs and outcomes of endoscopic resection were analyzed. RESULTS: Patients with GED were divided into 3 groups: adenomatous (n = 167, 46.8%), foveolar (n = 103, 28.9%), and hybrid (n = 87, 24.3%) types. Compared to the adenomatous type, foveolar type lesions were more frequently located in the antrum/pylorus, flat/depressed lesions, and normal/reddish in color; and showed more frequent high-grade dysplasia. During the follow-up period (median, 37.3 months), the overall incidence of synchronous and metachronous lesions was 20.8% and 20.1%, respectively; of these, the incidence of synchronous and metachronous gastric cancer was 8.7% and 5.4%, respectively. There were no significant differences in the incidence of synchronous and metachronous lesions according to morphologic types. CONCLUSION: GEDs appear to have different clinicopathologic characteristics according to morphologic types. Irrespective of the morphology, synchronous and metachronous gastric cancers are commonly found after endoscopic resection of GEDs. Therefore, close follow-up surveillance after endoscopic resection of GEDs should be performed for all patients.

Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma.

OBJECTIVE: The renin-angiotensin system (RAS) influences cardiovascular homeostasis, and Angiotensin II type 1 receptor (AGTR1) is the main effector of RAS, and AGTR2 antagonizes AGTR1. Accumulating evidence supports the role of RAS in the paracrine regulation of tumorigenesis in several cancer types. Although treatment with AGTR1 antagonist (losartan) or AGTR2 agonist (CGP42112A) inhibits tumor progression in several cancer cells, their combined treatment has not been reported. METHODS: In this study, we estimated the expression of AGTR1 and AGTR2 in epithelial ovarian cancer cells and tissues. Then, we evaluated the anti-cancer effects of combined treatment with losartan and/or CGP42112A in ovarian cancer cells and human umbilical vein endothelial cells (HUVEC). RESULTS: AGTR1 protein was detected in 86% of ovarian cancer tissues, while AGTR2 was not detected in immunohistochemistry. The mRNA expression of AGTR1 obtained from the cancer genome atlas (TCGA) dataset showed that AGTR1 overexpression was correlated with poor survival. Treatment with either losartan or CGP42112A reduced the angiotensin II (Ang II)-mediated cell survival in both ovarian cancer cells and HUVEC. Combined treatment with losartan and CGP42112A synergistically decreased cell survival. As a downstream pathway, phosphorylation of phospholipase C ß3 (PLC ß3) and expression of vascular endothelial growth factor (VEGF) decreased synergistically in combined treatment. CONCLUSION: The results suggest that dual regulation of AGTR1 and AGTR2 may be a novel therapeutic strategy for epithelial ovarian carcinoma through inhibition of cancer cell survival as well as anti-angiogenesis. TRANSLATIONAL RELEVANCE: This study investigated the expressions of AGTR1 and AGTR2 in epithelial ovarian carcinoma and the therapeutic potential of AGTR modulation with specific antagonist and/or agonist in epithelial ovarian cancer cells. Treatment of AGTR1 antagonist, losartan and/or AGTR2 agonist, CGP42112A synergistically mediated anti-cancer effects including the decrease of cell survival and down-regulation of VEGF.

Digital image analysis of endoscopic ultrasonography is helpful in diagnosing gastric mesenchymal tumors.

BACKGROUND: Endoscopic ultrasonography (EUS) is a valuable imaging tool for evaluating subepithelial lesions in the stomach. However, there are few studies on differentiation between gastrointestinal stromal tumors (GISTs) and benign mesenchymal tumors, such as leiomyoma or schwannoma, with the use of EUS. In addition, there are limitations in the analysis of the characteristic features of such tumors due to poor interobserver agreement as a result of subjective interpretation of EUS images. Therefore, the aim of this study was to evaluate the role of digital image analysis in distinguishing the features of GISTs from those of benign mesenchymal tumors on EUS. METHODS: We enrolled 65 patients with histopathologically proven gastric GIST, leiomyoma or schwannoma on surgically resected specimens who underwent EUS examination at our endoscopic unit from January 2007 to September 2010. After standardization of the EUS images, brightness values including the mean (Tmean), indicative of echogenicity, and the standard deviation (TSD), indicative of heterogeneity, in the tumors were analyzed. RESULTS: The Tmean and TSD were significantly higher in GIST than in leiomyoma and schwannoma (p < 0.001). However, there was no significant difference in the Tmean or TSD between benign and malignant GISTs. The sensitivity and specificity were almost optimized for differentiating GIST from leiomyoma or schwannoma when the critical values of Tmean and TSD were 65 and 75, respectively. The presence of at least 1 of these 2 findings in a given tumor resulted in a sensitivity of 94%, specificity of 80%, positive predictive value of 94%, negative predictive value of 80%, and accuracy of 90.8% for predicting GIST. CONCLUSIONS: Digital image analysis provides objective information on EUS images; thus, it can be useful in diagnosing gastric mesenchymal tumors.

A Case of Esophageal MALT Lymphoma Mimicking a Subepithelial Tumor.

Mucosa-associated lymphoid tissue (MALT) lymphoma, also known as extranodal marginal zone lymphoma, is a low-grade B-cell lymphoma that can develop in the mucosal layer of various organs, including the gastrointestinal tract, salivary glands, lungs, and skin. The most common site is the gastrointestinal tract, particularly the stomach. On the other hand, primary esophageal lymphomas are extremely rare. MALT lymphomas can undergo histological transformation into more aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma, resulting in a poor prognosis. This paper reports a rare case of primary esophageal MALT lymphoma mimicking a subepithelial tumor located in the lower esophagus that was treated successfully with radiotherapy. MALT lymphoma should be included in a differential diagnosis when subepithelial tumors are found in the esophagus, particularly if endoscopic ultrasonography reveals the tumor to be located in the deep mucosal and submucosal layers. Following the precise diagnosis, accurate staging and appropriate treatment are crucial. Regular follow-up is necessary to assess the possibility of recurrence or transformation to high-grade lymphoma.

Single-nucleotide polymorphisms link gout with health-related lifestyle factors in Korean cohorts.

Gout-a very painful inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints-is influenced by several factors. We identified the association of single- nucleotide polymorphisms (SNPs) that link gout with health-related lifestyle factors using genomic data from the Korean Genome and Epidemiology Study. We conducted a genome-wide association study (GWAS) on 18,927 samples of 438 Korean patients with gout and 18,489 controls for the discovery stage. For the replication stage, another batch containing samples of 326 patients with gout and 2,737 controls were analyzed. Lastly, a meta-analysis was performed using these two cohorts. We analyzed the effects of health-related lifestyle factors, including eating habits, physical activity, drinking behavior, and smoking behavior, on gout. After identifying the association between GWAS-derived SNPs and health-related lifestyle factors, we confirmed the interaction between the polygenic risk score (PRS) and health-related lifestyle factors. We identified 15 SNPs related to gout, among which rs1481012 of ABCG2 located on chromosome 4 has been newly discovered (P = 2.46e-11). On examining the interaction between SNPs and health-related lifestyles, rs3109823-located in ABCG2-was found to be associated with smoking status. In addition, rs11936395-located in SLC2A9-was significantly associated with the average momentum of exercise per session, whereas rs11066325 located in PTPN11, showed a significant association with the number of exercise sessions per week, smoking status, drinking status, and amount of soju drink per session. rs9421589-located in FAM35A-was significantly associated with the duration of smoking. In addition, we verified that the association between PRS and duration of smoking affects gout. Thus, in this study, we identified novel SNPs that link gout with health-related lifestyle factors in the Korean population.

Associations between the Genetic Heritability of Dyslipidemia and Dietary Patterns in Korean Adults Based on Sex Differences.

Dyslipidemia can be defined as an abnormality in serum lipid levels that is substantially linked to genetic variations and lifestyle factors, such as diet patterns, and has distinct sex-specific characteristics. We aimed to elucidate the genetic impact of dyslipidemia according to sex and explore the associations between genetic variants and dietary patterns in large-scale population-based cohorts. After performing genome-wide association studies (GWASs) in male, female, and entire cohorts, significant single nucleotide polymorphisms (SNPs) were identified in the three groups, and genetic risk scores (GRSs) were calculated by summing the risk alleles from the selected SNPs. After adjusting for confounding variables, the risk of dyslipidemia was 2.013-fold and 2.535-fold higher in the 3rd quartile GRS group in the male and female cohorts, respectively, than in the 1st quartile GRS group. While instant noodle and soft drink intake were significantly associated with GRS related to hyperlipidemia in male cohorts, coffee consumption was substantially related to GRS related to hyperlipidemia in female cohorts. Considering the influence of genetic factors and dietary patterns, the findings of this study suggest the potential for implementing sex-specific strategic interventions to avoid dyslipidemia.

Efficacy of Tegoprazan in Patients with Laryngopharyngeal Reflux Disease: A Preliminary Feasibility Study.

Tegoprazan is a novel, potent, and highly selective potassium-competitive acid blocker that inhibits gastric acid secretion with rapid onset of action and prolonged control of gastric acidity. We performed a preliminary feasibility study to evaluate whether tegoprazan could control symptoms more effectively than a placebo in patients with laryngopharyngeal reflux disease (LPRD). In this double-blind, randomized, placebo-controlled trial, 35 patients with LPRD were randomly assigned to two groups: tegoprazan 50 mg daily and placebo. The primary endpoint was the complete resolution rate of LPRD symptoms after 8 weeks of medication, and the secondary endpoints were the complete resolution rate of LPRD symptoms after 4 weeks of medication and changes in the reflux symptom index (RSI) and reflux finding score (RFS) from baseline at 4 and 8 weeks of medication. There was no difference in the complete symptom resolution rates at 8 weeks between the tegoprazan and placebo groups (29.4% [5/17] vs. 27.8% [5/18], p = 1.000). Moreover, there was no significant difference in the complete symptom resolution rates at 4 weeks between the two groups. Compared with the baseline, both tegoprazan and placebo significantly reduced the total RSI and RFS scores after 4 and 8 weeks of medication; however, tegoprazan was not superior to the placebo. In conclusion, tegoprazan (50 mg daily) administration improved LPRD symptoms and signs. However, tegoprazan did not show superiority over placebo. Considering the potential effectiveness of tegoprazan as an acid-suppressing therapy and the possibility of type II error due to a low number of included patients herein, prospective, large-scale, multi-center studies with a higher dose of tegoprazan for a prolonged duration are required to elucidate the efficacy of tegoprazan in patients with LPRD. (ClinicalTrials.gov: NCT05871398).

Magnifying Endoscopy with Narrow-Band Imaging for Duodenal Neuroendocrine Tumors.

Duodenal neuroendocrine tumors (NETs) are rare subepithelial tumors that arise from the neuroendocrine cells beneath the epithelial layer. However, an accurate histopathological diagnosis is difficult when tissue samples are obtained using conventional endoscopic forceps biopsy alone. This study aimed to evaluate the magnifying endoscopy with narrow-band imaging (ME-NBI) findings of duodenal NETs. We retrospectively analyzed a database of 22 duodenal NETs from 21 patients who underwent ME-NBI between January 2011 and June 2022. The ME-NBI, endosonographic, and histopathologic findings of duodenal NETs were analyzed. Nineteen lesions were located in the bulb, two were located in the superior duodenal angle, and one was located in the second portion of the duodenum. Eighteen lesions (82%) had IIa morphology, and nine (41%) had central depression on the surface. On endoscopic ultrasonography, almost all lesions (20/22, 91%) were located in the second and/or third layers, and the median tumor size was 6 mm. During ME-NBI, the microsurface pattern was regular in 18 lesions (82%) and absent in 4 (18%). The microvascular pattern was regular in 17 lesions (77%), irregular in 4 (18%), and absent in 1 (5%). Thickened subepithelial vessels were observed in 15 (68%) lesions. There was no difference in tumor size according to the presence or absence of thickened subepithelial vessels (6.1 ± 1.8 mm vs. 5.9 ± 3.8 mm, p = 0.860). In conclusion, the characteristic ME-NBI findings of duodenal NETs were regular microsurface and microvascular patterns and the presence of thickened subepithelial vessels. These ME-NBI features may be useful for differentiating duodenal NETs from other duodenal subepithelial lesions.

Reduced expression of FASN through SREBP-1 down-regulation is responsible for hypoxic cell death in HepG2 cells.

Cells under hypoxic stress either activate an adaptive response or undergo cell death. Although some mechanisms have been reported, the exact mechanism behind hypoxic cell death remains unclear. Recently, increased expression of fatty acid synthase (FASN) has been observed in various human cancers. In highly proliferating cells, tumor-associated FASN is considered necessary for both membrane lipids production and post-translational protein modification, but the exact mechanisms are not fully understood. Further, FASN overexpression is associated with aggressive and malignant cancer diseases and FASN inhibition induces apoptosis in cancer cells. For this reason, FASN is emerging as a key target for the potential diagnosis and treatment of various cancers. Here, we observed decreased FASN expression under hypoxic cell death conditions in HepG2 cells. Thus, we examined the effect of decreased FASN expression on hypoxia-induced cell death in HepG2 cells and also investigated the mechanism responsible for reduction of FASN expression under hypoxic cell death conditions. As a result, reduction of FASN expression resulted in hypoxic cell death via malonyl-CoA accumulation. In addition, SREBP-1 restored FASN reduction and hypoxia-induced apoptosis. Taken together, we suggest that hypoxic cell death is promoted by the reduced expression of FASN through SREBP-1 down-regulation.

The interactions between MicroRNA-200c and BRD7 in endometrial carcinoma.

OBJECTIVE: Increased expression of miR-200c was recently reported in endometrial carcinoma compared with normal tissues. In this study, we evaluated the role of miR-200c in cell growth and drug sensitivity in endometrial carcinoma and investigated the underlying mechanisms. METHODS: The expression of miR-200c in human endometrial tissues was detected by quantitative RT-PCR. The transfection with anti-miRNA (anti-miR) or the premature form of miRNA (pre-miR) was performed to regulate the level of expression of miRNA-200c in endometrial carcinoma cells, HEC-1A and Ishikawa. To identify the target genes for miR-200c, we performed mRNA microarray after pre-miR-200c transfection in HEC-1A cells. RESULTS: We found that miR-200c expression was increased in endometrial carcinoma compared with normal endometrial tissues. Anti-miR or pre-miR-200c could regulate cell survival, proliferation, and apoptosis and affect cytotoxicity in endometrial cancer cells. Through mRNA microarray analysis, we found that miR-200c inhibits the expression of BRD7, which was recently reported as a potential tumor suppressor gene. MiR-200c regulated the translocation of ß-catenin from the cytoplasm to the nucleus via inhibition of BRD7, resulting in increased expression of its transcriptional target genes, cyclinD1 and c-myc. CONCLUSION: The interaction between miR-200c and BRD7 might have important roles in controlling growth of endometrial of cancer cells and suggest a novel target pathway for treatment of this cancer.

Randomized Controlled Trial Comparing the Efficacy of Sustained-Release Formula of Mosapride-Plus-Esomeprazole Combination Therapy to Esomeprazole Monotherapy in Patients with Gastroesophageal Reflux Disease.

We aimed to evaluate whether adding a sustained-release (SR) formula of mosapride to proton-pump inhibitors (PPIs) would be more effective in controlling symptoms than PPI alone in patients with gastroesophageal reflux disease (GERD). Sixty patients with heartburn and/or regurgitation were randomly assigned to two groups: mosapride SR 15 mg combined with esomeprazole 20 mg once daily (ME group) and esomeprazole 20 mg once daily alone (E group). The primary endpoint was the complete-resolution rate of GERD symptoms after eight-week medication, and the secondary endpoints were the complete-resolution rate of GERD symptoms after four-week medication, symptom-improvement rates ≥ 50% after four- and eight-week medication, and change in reflux-disease-questionnaire (RDQ) and GERD-health-related quality-of-life (GERD-HRQL) scores from baseline at four- and eight-week medication. No significant differences in complete-symptom-resolution rates at eight weeks and four weeks or in the changes in RDQ and GERD-HRQL scores from baseline at four- and eight-week medication were observed between the ME and E groups. The symptom-improvement rate of ≥50% after four and eight weeks was comparable between both groups. Adding mosapride SR to esomeprazole in patients with GERD provides no additional benefits in controlling GERD symptoms.

Overexpression of Galectin-3 and its clinical significance in ovarian carcinoma.

BACKGROUND: Galectin-3 (Gal-3) is a ß-galactoside-binding lectin involved in regulating cell growth, angiogenesis, and tumor progression. We investigated the clinical significance of Gal-3 expression including its possible use as a prognostic marker or therapeutic target in epithelial ovarian carcinoma (EOC). METHODS: Gal-3 expression was evaluated by immunohistochemistry in 71 patients with 54 serous, 13 endometrioid, and 4 mucinous ovarian carcinomas. We assessed the correlation of Gal-3 expression with clinical characteristics including histology, optimal debulking, chemosensitivity, and survival. In vitro, Gal-3 was inhibited using siRNA to evaluate its role in cell growth and sensitivity to chemotherapeutic agents in ovarian carcinoma cell lines. RESULTS: Gal-3 protein, which was mainly cytoplasmic in location, was observed in a majority (63/71, 88.7%) of the EOCs but not in normal ovarian tissues (P < 0.001). High Gal-3 expression in EOCs correlated with shorter progression-free survival (PFS) of patients (P = 0.039; 43.1 and 49.5 months, respectively). Moreover, cotreatment with Gal-3 siRNA and paclitaxel showed an enhanced cytotoxic effect compared with control siRNA in SKOV3 cells. CONCLUSION: These findings suggest that Gal-3 expression can be a prognostic factor for PFS and may be involved in regulating the response to paclitaxel-based chemotherapy in the treatment of EOC.