Human soluble delta-like 1 homolog exerts antitumor effects in vitro and in vivo.

Proteolysis of delta-like 1 homolog (DLK1), a cell-surface transmembrane protein, produces an active soluble form of DLK1 (sDLK1). Both membrane-bound DLK1 and sDLK1 modulate multiple developmental processes including adipogenesis, osteogenesis, chondrogenesis and myogenesis. However, cancer-related functions of DLK1 have not yet been established. We thus evaluated the roles of extracellular sDLK1, comprising six EGF-like domains and juxtamembrane regions, in human pancreatic cancer MIA PaCa-2 cells in vitro and in vivo. We observed that sDLK1 exerted antitumor effects not only in cancer cell migration and anchorage-independent cell growth but also in in vivo tumor growth.

Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis.

The measurement of the hepatic venous pressure gradient (HVPG) for the estimation of portal hypertension (PH) in cirrhosis has some limitations, including its invasiveness. Hepatic vein arrival time (HVAT), as assessed by microbubble contrast-enhanced ultrasonography (CEUS), is negatively correlated with the histological grade of liver fibrosis because of the associated hemodynamic abnormalities. Anatomical and pathophysiological changes in liver microcirculation are the initial events leading to PH. However, the direct relationship between HVAT and PH has not been evaluated. The present study measured both HVPG and HVAT in 71 consecutive patients with compensated cirrhosis and analyzed the relationship between the two parameters (i.e., the derivation set). Results were validated in 35 compensated patients with cirrhosis at another medical center (i.e., the validation set). The derivation set had HVPG and HVAT values of 11.4 ± 5.0 mmHg (mean ± standard deviation; range, 2-23) and 14.1 ± 3.4 seconds (range, 8.4-24.2), respectively; there was a statistically significant negative correlation between HVPG and HVAT (r(2) = 0.545; P < 0.001). The area under the receiver operating characteristic curve (AUROC) was 0.973 for clinically significant PH (CSPH; HVPG, ≥ 10 mmHg), and the sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios for CSPH for an HVAT cut-off value of 14 seconds were 92.7%, 86.7%, 90.5%, 89.7%, 6.95, and 0.08, respectively. In addition, a shorter HVAT was associated with worse Child-Pugh score (P < 0.001) and esophageal varices (P = 0.018). In the validation set, there was also a significant negative correlation between HVAT and HVPG (r(2) = 0.538; P < 0.001), and AUROC = 0.953 for CSPH. HVAT was significantly correlated with PH. These results indicate that measuring HVAT is useful for the noninvasive prediction of CSPH in patients with compensated cirrhosis.

Half-dose rabeprazole has an equal efficacy to standard-dose rabeprazole on endoscopic submucosal dissection-induced ulcer.

BACKGROUND: Although endoscopic submucosal dissection (ESD)-induced ulcers heal faster and recur less often than non-iatrogenic gastric ulcers, the optimal dosage and duration of proton pump inhibitor treatment for ESD-induced ulcers remain unclear. AIMS: To evaluate the efficacy of half-dose rabeprazole on endoscopic submucosal dissection-induced ulcer compared with standard dose rabeprazole. METHODS: The study was a prospective randomized controlled double-blind trial at a single tertiary hospital. A total of 80 patients who underwent ESD for gastric neoplasia were enrolled. Of these patients, 10 were not followed to completion. Final analysis included the remaining 70 patients. Rabeprazole 20 or 10 mg, depending on randomization, was given orally for 4 weeks after ESD. RESULTS: Of the 70 patients, 45 (64 %) were men, and the median age was 65.2 ± 9.7 years. The mean ESD-induced ulcer area was 673 mm(2). No significant differences in ulcer area reduction ratio (p = 0.49) or ulcer-related symptoms (p = 0.91) were observed between the two groups at 4 weeks after ESD. CONCLUSION: For ESD-induced ulcers, treatment with 10 mg of rabeprazole daily produces a similar outcome as 20 mg of rabeprazole with regard to healing efficacy and symptom resolution.

Hepatogenous diabetes in cirrhosis is related to portal pressure and variceal hemorrhage.

BACKGROUND AND AIM: The clinical impact and complications of hepatogenous diabetes (HD) on cirrhosis have not been elucidated. This study aimed to evaluate the relationship of HD with portal hypertension (PHT) and variceal hemorrhage and to assess the prevalence of HD. METHODS: From July 2007 to December 2009, 75-g oral glucose tolerance test and insulin resistance (IR) were evaluated for 195 consecutive cirrhotic liver patients (M:F = 164:1, 53.0 ± 10.2 years) who had no history of diabetes mellitus. IR was calculated using the homeostasis model of assessment-insulin resistance (HOMA-IR) formula. Endoscopy for varices, hepatic venous pressure gradient (HVPG), and serologic tests were also conducted. RESULTS: HD was observed in 55.4 % (108/194) of the patients. Among them, 62.0 % required OGTT for diagnosis because they did not show an abnormal fasting plasma glucose level. The presence of HD showed a significant correlation with high Child-Pugh's score, variceal hemorrhage, and HVPG (p = 0.004, 0.002, and 0.019, respectively). In multivariate analysis, Child-Pugh's score (OR 1.43, 95 % CI 1.005-2.038) and HVPG (OR 1.15, 95 % CI 1.003-2.547) had significant relationships with HD. Patients with recent variceal hemorrhages (within 6 months) exhibited significantly higher glucose levels at 120 min in OGTT compared to patients without hemorrhages (p = 0.042). However, there was no difference in fasting glucose levels. The 120-min glucose level and HOMA-IR score were significantly and linearly correlated with HVPG (r (2) = 0.189, p < 0.001 and r (2) = 0.033, p = 0.011, respectively). CONCLUSION: HD and IR have significant relationships with PHT and variceal hemorrhage. Postprandial hyperglycemia in particular had a significant relationship with variceal hemorrhage.

Predictive factors affecting cecal intubation failure in colonoscopy trainees.

BACKGROUND: Successful cecal intubation (SCI) is not only a quality indicator but also an important marker in a colonoscopy trainee's progress. We conducted this study to determine factors predicting SCI in colonoscopy trainees, and to compare these factors before and after trainees achieve technical competence. METHODS: Design of this study was a cross-sectional studies of two time series design for one year at a single center. From March 2011 to February 2012, a total 2,050 subjects who underwent colonoscopy by four first-year gastrointestinal fellows were enrolled at Christian hospital, Wonju, Republic of Korea. Four gastrointestinal fellows have filled out the colonoscopic documentation. Main outcome measurement was predictive factors affecting cecal intubation failure and learning curves. RESULTS: Colonoscopy was successfully completed to the cecum in 1,720 patients (83.9%). Success rates gradually increased as trainees performed more colonoscopies: the rate of SCI was 62% in the first 50 cases, and grew to 93% by the 250th case. Logistic regression analysis of factors affecting cecal intubation failure showed that female gender, low BMI (BMI < 18.5 kg/m²), poor bowel preparation, and past history of stomach surgery were more often associated with cecal intubation failure, particularly before the trainees achieved technical competence. CONCLUSION: Several patient characteristics were identified that may predict difficulty of cecal intubation in colonoscopy trainees. Particularly, low BMI, inadequate bowel cleansing, and previous stomach operation were predictors of cecal intubation failure before the trainees have reached technical competency. The results could be informative so that trainees enhance the success rate regarding better colonoscopy training programs.

[A case of afferent loop syndrome treated by endoscopic drainage procedure using nasogastric tube].

Afferent loop syndrome is an uncommon complication which occurs in patients with Billroth II partial gastrectomy. Clinically, the diagnosis of afferent loop syndrome may be difficult to establish and thus, depends on the finding of computed tomography, abdominal ultrasound, barium studies and hepatobiliary scan. When the diagnosis is made, most of the cases are treated by surgical operation. We present a case of 67-year-old male patient with afferent loop syndrome associated with acute pancreatitis which was treated by endoscopic drainage procedure using a nasogastric tube.

An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases.

CONTEXT: The oncogenic RET/PTC tyrosine kinase causes papillary thyroid cancer (PTC). The use of inhibitors specific for RET/PTC may be useful for targeted therapy of PTC. OBJECTIVE: The objective of the study was to evaluate the efficacies of the recently developed kinase inhibitors SU11248, SU5416, and SU6668 in inhibition of RET/PTC. DESIGN: SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay. The inhibitory effects of the compounds on RET/PTC were evaluated by quantifying the autophosphorylation of RET/PTC, signal transducer and activator of transcription (STAT)-3 activation, and the morphological reversal of RET/PTC-transformed cells. RESULTS: An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC(50) of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248. Thus, SU11248 effectively inhibits the kinase activity of RET/PTC3. RET/PTC-mediated Y705 phosphorylation of STAT3 was inhibited by addition of SU11248, and the inhibitory effects of SU11248 on the tyrosine phosphorylation and transcriptional activation of STAT3 were very closely correlated with decreased autophosphorylation of RET/PTC. SU11248 caused a complete morphological reversion of transformed NIH-RET/PTC3 cells and inhibited the growth of TPC-1 cells that have an endogenous RET/PTC1. CONCLUSION: SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.

Regulation of protein kinase B tyrosine phosphorylation by thyroid-specific oncogenic RET/PTC kinases.

Papillary thyroid carcinoma (PTC) is a heterogenous disorder characterized by unique gene rearrangements and gene mutations that activate signaling pathways responsible for cellular transformation, survival, and antiapoptosis. Activation of protein kinase B (PKB) and its downstream signaling pathways appears to be an important event in thyroid tumorigenesis. In this study, we found that the thyroid-specific oncogenic RET/PTC tyrosine kinase is able to phosphorylate PKB in vitro and in vivo. RET/PTC-transfected cells showed tyrosine phosphorylation of endogenous and exogenous PKB, which was independent of phosphorylation of T308 and S473 regulated by the upstream kinases phosphoinositide-dependent kinase-1 and -2, respectively. The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity. The activation of PKB by RET/PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity. In summary, these observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.

[Effect of endoscopic sclerotherapy using N-butyl-2-cyanoacrylate in patients with gastric variceal bleeding].

BACKGROUND/AIMS: Gastric variceal bleeding is a severe complication of cirrhosis, and it has a high mortality rate. This study was conducted to evaluate the efficacy of n-butyl-2-cyanoacrylate injection therapy for patients suffering with gastric variceal bleeding. METHODS: A total of 86 patients diagnosed with gastric variceal bleeding underwent endoscopic n-butyl-2-cyanoacrylate (Histoacryl) injection therapy at our department between April, 2002 and July, 2005, with a mean follow-up period of 44 weeks (range: 2 to 136 weeks). The initial hemostasis rate and the rebleeding rate of endoscopic sclerotherapy were analyzed. Also, the cumulative survival rate was analyzed according to the status of hepatocellular carcinoma and hyponatremia, the MELD score, the Child-Pugh score and the amount of injected Histoacryl. RESULTS: The initial hemostasis rate of Histoacryl injection therapy was 93% and the 1 month rebleeding rate was 16.1%. The total number of session for treating the initial hemostasis was 1.2+/-0.4 and the total volume of Histoacryl was 2.7+/-1.2 mL. The cumulative rebleeding-free rates for the patients treated by the Histoacryl injection method at 1 month, 12 months and 34 months period were 95.1%, 83.2% and 74%, respectively. The cumulative survival rates were 78.3% at 1 month, 61.9% at 12 months and 54.6% at 34 months, respectively. No thromboembolic phenomenon occurred. According to the Cox's proportional hazards analysis, only the MELD score (<15) was an independent predicting factor for survival of the patients with gastric variceal bleeding. CONCLUSIONS: Endoscopic sclerotherapy using n-butyl-2-cyanoacrylate was a safe and effective hemostatic method for patients with gastric variceal bleeding. Also, the MELD score (<15) contributed to predicting survival of the patients with gastric variceal bleeding.

[Interequipment variability of Doppler ultrasonographic indices in patients with liver cirrhosis].

BACKGROUNDS/AIMS: Doppler ultrasongraphy is used to evaluate hemodynamic alternations in patients with liver cirrhosis. Purpose of this study was to determine the interequipment variability of Doppler indices in portal and splenic vein in cirrhosis. METHODS: Blood velocity, diameter, flow and congestive index in portal and splenic vein were measured by Doppler ultrasonography in 30 patients with cirrhosis using two different machines. RESULTS: Portal venous velocities measured by HDI-5000 and SSD-5000 were 8.72+/-3.69 cm/sec, 12.21+/-2.84 cm/sec, respectively which showed significant difference (P<0.001). Measured portal blood flows and congestive indices also had significant difference between HDI-5000 and SSD-5000 (P<0.01). Splenic venous velocity by HDI-5000 was 8.55+/-2.71 cm/sec, which was lower than that of 12.32+/-3.11 cm/sec by SSD-5000 (P<0.001). Splenic blood flows measured by HDI-5000 and SSD-5000 were 390.73+/-260.98 mL/min, 595.01+/-346.53 mL/min, respectively, showing significant difference (P=0.015). However, no differences were in the diameters of portal and splenic vein between HDI-5000 and SSD-5000. CONCLUSION: Doppler indices in portal and splenic vein showed significant interequipment variability. Therefore, in liver cirrhosis, hemodynamic investigations using different Doppler ultrasonographic machines is inappropriate.

Effect of propranolol on portal pressure and systemic hemodynamics in patients with liver cirrhosis and portal hypertension: a prospective study.

BACKGROUND/AIMS: Propranolol can prevent variceal bleeding by ameliorating portal hypertension. We conducted this study to determine the effect of propranolol on portal hypertension and the optimal required dose in Korean cirrhotic patients. METHODS: This study prospectively evaluated 50 patients with cirrhosis who exhibited variceal bleeding. The hepatic venous pressure gradient (HVPG), portal venous flow, heart rate (HR), and blood pressure were assessed both at baseline and at 3 months after the treatment. The initial dose of propranolol (20 mg) was subsequently adjusted until the target HR was reached. Patients in whom HVPG reduced by >20% or to less than 12 mmHg were defined as responders. RESULTS: Propranolol significantly (p<0.01) reduced the HVPG (-21+/-26%, mean+/-standard deviation), portal venous flow (-25+/-21%), HR (-20+/-13%), and blood pressure (-3+/-13%). Twenty-nine patients were responders, and the optimal required dose was 154.4 mg. The main complication was dizziness (24%), but this was not serious enough to require medication withdrawal. CONCLUSIONS: Propranolol is safe and effective at reducing portal pressure in Korean cirrhotic patients. An effective improvement in portal hypertension requires the dose to be increased until the target HR is reached.