Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice.

BACKGROUND & AIMS: Prostaglandin E2 (PGE2) is mediator of inflammation that regulates tissue regeneration, but its continual activation has been associated with carcinogenesis. Little is known about factors in the PGE2 signaling pathway that contribute to tumor formation. We investigated whether yes-associated protein 1 (YAP1), a transcriptional co-activator in the Hippo signaling pathway, mediates PGE2 function. METHODS: DLD-1 and SW480 colon cancer cell lines were transfected with vectors expressing transgenes or small hairpin RNAs and incubated with recombinant PGE2, with or without pharmacologic inhibitors of signaling proteins, and analyzed by immunoblot, immunofluorescence, quantitative reverse-transcription polymerase chain reaction, transcriptional reporter, and proliferation assays. Dextran sodium sulfate (DSS) was given to induce colitis in C57/BL6 (control) mice, as well as in mice with disruption of the hydroxyprostaglandin dehydrogenase 15 gene (15-PGDH-knockout mice), Yap1 gene (YAP-knockout mice), and double-knockout mice. Some mice also were given indomethacin to block PGE2 synthesis. 15-PGDH knockout mice were crossed with mice with intestine-specific disruption of the salvador family WW domain containing 1 gene (Sav1), which encodes an activator of Hippo signaling. We performed immunohistochemical analyses of colon biopsy samples from 26 patients with colitis-associated cancer and 51 age-and sex-matched patients with colorectal cancer (without colitis). RESULTS: Incubation of colon cancer cell lines with PGE2 led to phosphorylation of cyclic adenosine monophosphate-responsive element binding protein 1 and increased levels of YAP1 messenger RNA, protein, and YAP1 transcriptional activity. This led to increased transcription of the prostaglandin-endoperoxide synthase 2 gene (PTGS2 or cyclooxygenase 2) and prostaglandin E-receptor 4 gene (PTGER4 or EP4). Incubation with PGE2 promoted proliferation of colon cancer cell lines, but not cells with knockdown of YAP1. Control mice developed colitis after administration of DSS, but injection of PGE2 led to colon regeneration in these mice. However, YAP-knockout mice did not regenerate colon tissues and died soon after administration of DSS. 15-PGDH-knockout mice regenerated colon tissues more rapidly than control mice after withdrawal of DSS, and had faster recovery of body weight, colon length, and colitis histology scores. These effects were reversed by injection of indomethacin. SAV1-knockout or 15-PGDH-knockout mice did not develop spontaneous tumors after colitis induction, but SAV1/15-PGDH double-knockout mice developed polyps that eventually progressed to carcinoma in situ. Administration of indomethacin to these mice prevented spontaneous tumor formation. Levels of PGE2 correlated with those of YAP levels in human sporadic colorectal tumors and colitis-associated tumors. CONCLUSIONS: PGE2 signaling increases the expression and transcriptional activities of YAP1, leading to increased expression of cyclooxygenase 2 and EP4 to activate a positive signaling loop. This pathway promotes proliferation of colon cancer cell lines and colon tissue regeneration in mice with colitis. Constitutive activation of this pathway led to formation of polyps and colon tumors in mice.

Controlled release of bupivacaine HCl through microchannels of biodegradable drug delivery device.

Local and prolonged delivery of local analgesics is much desired for post-operative pain management. For delivery of local analgesics at a constant rate over couple of days, a microfluidic device comprised of a drug reservoir and microchannels for drug release was developed using a biodegradable polymer, 85/15 poly(lactic-co-glycolic acid). Unlike conventional methods relying on material property, this device enables convenient modulation of the release speed of drugs by a simple change of the channel geometry such as the length and cross-sectional area. Bupivacaine was selected as our model local analgesic drug and its diffusional transport through microchannels was studied using the microfluidic devices. However, since the salt form of bupivacaine, bupivacaine hydrochloride, has pH-dependent solubility, its precipitation in microchannels had an adverse impact on the release performance of the microfluidic drug delivery devices. Thus, in this investigation, the diffusional transport and precipitation of bupivacaine hydrochloride in microfluidic channels were studied using in vitro release experiments and optical analysis. Furthermore, a concept of co-delivery of bupivacaine hydrochloride together with acidic additives was demonstrated to achieve a zero-order delivery of bupivacaine hydrochloride without the clogging of microchannels by its precipitation.

Hepatocellular carcinoma screening in a hepatitis B virus-infected Korean population.

BACKGROUND: Hepatocellular carcinoma (HCC) screening has been recommended for hepatitis B virus (HBV)-infected individuals in an effort to detect HCC at a sufficiently early stage to provide potentially curative treatments. The study reported here is the first to address the rate of HCC screening use in an HBV endemic area. METHODS: Data were collected from 11,147 adults aged ≥40 years who participated in the 2007-2009 Korea National Health and Nutrition Examination Survey and had a valid HBV surface antigen test. Current HCC screening was defined as either receiving an ultrasonography or an α-fetoprotein measurement in the past year. Prevalence estimates were weighted. RESULTS: The response rate was 78.4 %, and 436 cases of HBV infection were identified. The overall seroprevalence of the HBV surface antigen was 4.1 % [95 % confidence interval (CI) 3.9-4.4 %]. Of the 436 HBV-infected subjects, only 23.2 % (95 % CI 19.5 -27.4 %) were aware that they had been infected, and approximately 27 % (27.1 %; 95 %CI 23.2-to 31.5 %) were up to date with their HCC screening tests; more than half (52.9 %, 95 % CI 48.2-57.5) had never been screened. In a multivariate analysis that included various sociodemographic variables, only self-reported awareness of HBV infection was significantly associated with current HCC screening tests (odds ratio 2.82; 95 % CI 1.64-4.84). CONCLUSIONS: Adoption of HCC screening as a standard practice among HBV-infected Korean adults aged ≥40 years is suboptimal. Evidence-based programs in communities and education for both healthcare providers and HBV-infected persons are needed to improve the implementation of HCC screening in clinical practice.

Obesity, insulin resistance, and the risk of an elevated alanine aminotransferase activity in the Korean adolescent population.

BACKGROUND: It is unclear to what extent insulin resistance (IR) modulates the association linking obesity to alanine aminotransferase (ALT) activity elevation. METHODS: We measured the homeostatic model assessment for IR (HOMA-IR) in 1591 participants aged 12-18 years from the 2008 to 2009 Korea National Health and Nutrition Examination Survey. RESULTS: Overweight adolescents had an odds ratio of 7.23 [95% confidence interval (95% CI), 4.33-12.10] for an elevated ALT activity compared with normal-weight adolescents, and the corresponding risk was 23.62 (95% CI, 12.98-42.98) in obese adolescents. Adjustments for other participant factors did not substantially affect the results. The addition of the HOMA-IR data decreased the estimate for overweight adolescents by 27% and for obese adolescents, the decrease was 47%. Both obesity and IR markers remained independent predictors of outcome. CONCLUSIONS: The greater the obesity level, the more that IR contributes to the association between obesity and an elevated ALT activity.

Secular trends in prevalence of alcohol use disorder and its correlates in Korean adults: results from Korea National Health and Nutrition Examination Survey 2005 and 2009.

The Alcohol Use Disorders Identification Test (AUDIT) has been found to provide an accurate measure for risk of hazardous and harmful alcohol use, as well as possible dependence. Data from 2 representative samples of 7693 adults in the Korea National Health and Nutrition Examination Survey (KNHANES) 2005 and 6276 participants in 2009 were analyzed. The overall age-adjusted prevalence of alcohol use disorder (AUD) in 2009 (38.8%) was higher than that in 2005 (32.7%), with a difference of 6.1% (95% confidence interval [CI], 2.9%-9.3%; P = .0002). Men were about 7 times as likely as women to meet the criteria for AUD (odds ratio [OR] = 7.16; 95% CI, 6.27-8.17). Current smoking was the most important correlate associated with AUD in both genders (women: OR = 6.03; 95% CI, 4.40-8.27; men: OR = 2.83; 95% CI, 2.29-3.48). Among women, unmarried (OR = 1.76; 95% CI, 1.35-2.31), less than high school education (OR = 2.71, 95% CI, 1.86-3.96), and lowest income (OR = 1.45, 95% CI, 1.06-1.97) were associated with AUD. These findings provide the most updated prevalence estimates of AUD in the Korean population and they highlight its strong association with smoking, gender differences, and lower socioeconomic status in the Korean population.

Prevalence of alcoholic liver disease among Korean adults: results from the fourth Korea National Health and Nutrition Examination Survey, 2009.

BACKGROUND/AIM: Alcohol consumption continues to be a common cause of acute and chronic liver disease. METHODS: Data from a representative sample of 7,893 adults in the Korean National Health and Nutrition Examination Survey 2009 were analyzed. Alcoholic liver disease (ALD) was defined through heavy alcohol consumption (≥40 g/day for men or ≥20 g/day for women) and through elevated liver tests. RESULTS: Approximately 6.7% (95% confidence interval [CI], 6.0-7.4) was at heavy alcohol consumption. Of these "heavy alcohol consumers", one quarter also had ALD. The prevalence of ALD was 1.7% (95% CI, 1.3-2.1). CONCLUSION: ALD is still a burden in the Korean population.

Electrospun Silk Fibroin Nanofibrous Scaffolds with Two-Stage Hydroxyapatite Functionalization for Enhancing the Osteogenic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells.

The development of functional scaffolds with improved osteogenic potential is important for successful bone formation and mineralization in bone tissue engineering. In this study, we developed a functional electrospun silk fibroin (SF) nanofibrous scaffold functionalized with two-stage hydroxyapatite (HAp) particles, using mussel adhesive-inspired polydopamine (PDA) chemistry. HAp particles were first incorporated into SF scaffolds during the electrospinning process, and then immobilized onto the electrospun SF nanofibrous scaffolds containing HAp via PDA-mediated adhesive chemistry. We obtained two-stage HAp-functionalized SF nanofibrous scaffolds with improved mechanical properties and capable of providing a bone-specific physiological microenvironment. The developed scaffolds were tested for their ability to enhance the osteogenic differentiation of human adipose-derived mesenchymal stem cells (hADMSCs) in vitro and repair bone defect in vivo. To boost their ability for bone repair, we genetically modified hADMSCs with the transcriptional coactivator with PDZ-binding motif (TAZ) via polymer nanoparticle-mediated gene delivery. TAZ is a well-known transcriptional modulator that activates the osteogenic differentiation of mesenchymal stem cells (MSCs). Two-stage HAp-functionalized SF scaffolds significantly promoted the osteogenic differentiation of TAZ-transfected hADMSCs in vitro and enhanced mineralized bone formation in a critical-sized calvarial bone defect model. Our study shows the potential utility of SF scaffolds with nanofibrous structures and enriched inorganic components in bone tissue engineering.

Giant Brunner's Gland Hamartoma of the Duodenal Bulb Presenting with Upper Gastrointestinal Bleeding and Obstruction.

Brunner's gland hamartomas are small benign lesions that are most commonly found in the bulb of the duodenum. They are very uncommon, and most are found incidentally during upper gastrointestinal series or esophagogastroduodenoscopy. The lesions tend to be asymptomatic, but patients may present with symptoms of duodenal obstruction or hemorrhage secondary to ulceration. Histologically, a Brunner's gland hamartoma consists of the components of Brunner's gland cells, as well as glandular, adipose and muscle cells. In this study, we report the case of a 30-year-old man who presented with upper gastrointestinal bleeding and obstructive symptoms due to a giant Brunner's gland hamartoma in the duodenal bulb. The hamartoma was successfully removed by endoscopic resection. No significant complications were observed. Microscopically, the lesion was found to be entirely composed of variable Brunner's glands and adipocytes.

Childhood colon cancer in a patient with ataxia telangiectasia.

BACKGROUND: Ataxia-telangiectasia (AT) is a rare autosomal recessive disease characterized by progressive neurologic impairment and cerebellar ataxia. In addition, patients with this disease are known to have an inherent increased susceptibility to the development of cancer, predominantly hematologic malignancies. METHODS: We report the case of a young boy with AT from Russia, who had abdominal pain. Laboratory tests and radiologic examinations were performed to him. RESULTS: After abdominal computed tomography (CT), colonoscopy and surgical interventions, the young boy was diagnosed with colon cancer that had signet ring cell features. CONCLUSIONS: It is known that the patient with AT appeared to be predisposed to various tumors, including leukemia or lymphoma, which are more common in childhood. Even if the patient with AT could have solid tumor such as stomach cancer or breast cancer, it is less likely to have colon cancer, especially signet ring cell type. Actually, no case of colon cancer has ever been reported, especially in young patient and hence, we have focused on this point and are hereby reporting this unique case.

The Prevalence of Colonic Neoplasm in Cryptogenic Pyogenic Liver Abscess: A Prospectively Enrolled Cross-sectional Study.

BACKGROUND/AIMS: Several studies suggest that pyogenic liver abscess (PLA) is associated with colon neoplasm. A colonoscopic exam for cryptogenic PLA might detect a hidden colon neoplasm, through which intestinal flora can be transmitted into the liver. However, there are no prospectively enrolled cross-sectional data for colonic neoplasm in cryptogenic PLA. METHODS: Patients with PLA were prospectively enrolled from two university hospitals. Among them, all the patients with cryptogenic PLA were recommended for colonoscopic exam to check for colonic neoplasm. RESULTS: One hundred eighty-three patients with PLA were enrolled in the study for 22 months. One hundred and one (55.2%) patients did not have a definite cause of liver abscess at initial evaluation. The median diameter of the largest lesion was 5.7 cm (1.0-14.0 cm), and 74.3% of the patients were treated by percutaneous abscess drainage. Ninety-one percent of the patients who had an identified pathogen yielded Klebsiella. Sixty-two patients underwent colonoscopic exams, and no one had a colonic cancer, one had an adenomatous polyp with high grade dysplasia (1.6%), and 27 had adenomatous polyps with low grade dysplasia (43.5%; 41.0% in male and 43.5% in female). Of fifty patients who underwent an esophagogastroduodenoscopic exam, nine had gastric ulcers, one had an esophageal ulcer, and one had hemorrhagic gastritis. CONCLUSIONS: The prevalence of colonic neoplasm among the patients with cryptogenic PLA was not as high as that in previous studies. Further well-designed, large-scale studies are required to assess the association of the colon neoplasm and cryptogenic PLA.

Membrane-reinforced three-dimensional electrospun silk fibroin scaffolds for bone tissue engineering.

Electrospun silk fibroin (SF) scaffolds have drawn much attention because of their resemblance to natural tissue architecture such as extracellular matrix, and the biocompatibility of SF as a candidate material to replace collagen. However, electrospun scaffolds lack the physical integrity of bone tissue scaffolds, which require resistance to mechanical loadings. In this work, we propose membrane-reinforced electrospun SF scaffolds by a serial process of electrospinning and freeze-drying of SF solutions in two different solvents: formic acid and water, respectively. After wet electrospinning followed by replacement of methanol with water, SF nanofibers dispersed in water were mixed with aqueous SF solution. Freeze-drying of the mixed solution resulted in 3D membrane-connected SF nanofibrous scaffolds (SF scaffolds) with a thickness of a few centimeters. We demonstrated that the SF concentration of aqueous SF solution controlled the degree of membrane reinforcement between nanofibers. It was also shown that both increase in degree of membrane reinforcement and inclusion of hydroxyapatite (HAP) nanoparticles resulted in higher resistance to compressive loadings of the SF scaffolds. Culture of human osteoblasts on collagen, SF, and SF-HAP scaffolds showed that both SF and SF-HAP scaffolds had biocompatibility and cell proliferation superior to that of the collagen scaffolds. SF-HAP scaffolds with and without BMP-2 were used for in vivo studies for 4 and 8 weeks, and they showed enhanced bone tissue formation in rat calvarial defect models.

Benign Mature Teratoma in Anterior Mediastinum.

Teratoma of mediastinum is rare germ cell tumor. Anterior mediastinum is the most common extragonadal site. Benign mediastinal teratoma accounts for 60% of all mediastinal germ cell tumors. Benign mature teratoma has excellent prognosis after surgical excision. We present a case of 20-year-old woman diagnosed as benign mature teratoma which compressed main pulmonary trunk. The patient underwent surgical excision.

TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.

Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.

[A prospective study on rabeprazole-based triple therapy for Helicobacter pylori eradication in patients with peptic ulcer].

BACKGROUND/AIMS: Rabeprazole sodium is a potent proton pump inhibitor. We assessed the efficacy, safety and compliance of one-week triple therapy including rabeprazole with amoxicillin and clarithromycin for eradication of Helicobacter pylori (H. pylori). METHODS: Eighty-eight H. pylori-positive patients with peptic ulcer disease were received rabeprazole 10 mg bid, amoxicillin 1,000 mg bid and clarithromycin 500 mg bid for a week. Endoscopic examination with five biopsies (two specimens from the antrum, two from the gastric body, and one from the gastric angle) was performed. The status of H. pylori infection was assessed by histology (immunohistochemistry) of the biopsy specimens, 13C urea breath test, and CLO test at the beginning and 13C urea breath test 4 weeks after the completion of treatment. RESULTS: H. pylori eradication rates were 74.71% by intention-to-treat analysis and 87.84% by per-protocol analysis. The percentage of side effects was 12.5% and these side effects were not serious. CONCLUSIONS: One-week rabeprzole based triple therapy is an effective and safe regimen for H. pylori eradication in patients with peptic ulcer.

Peripheral blood gene expression of B7 and CD28 family members associated with tumor progression and microscopic lymphovascular invasion in colon cancer patients.

PURPOSE: To associate the global gene expression of B7/CD28 family transcripts with pathologic features of colon cancer, we determined the B7/CD28 family transcripts in peripheral blood mononuclear cells (PBMCs) from normal subjects and patients with adenomatous polyps and colon cancer, and correlated the results with pathologic features of colon cancer. METHODS: PBMCs from age-matched normal subjects and patients with adenomatous polyps and colon cancer were analyzed for peripheral blood transcripts (PBTs) of B7/CD28 family using real-time PCR. Differences in expression levels of B7/CD28 PBTs across all cancer stages and between colon cancer patients with or without microscopic lymphovascular invasion (LVI) were analyzed. RESULTS: The results showed a significant upregulation of PBTs of co-inhibitory molecules such as B7-H3 and PD-1 and a significant PBT downregulation of co-stimulatory molecules including CD28 and ICOS in colon cancer patients. Furthermore, the increase of B7-H3 PBT was strongly associated with tumor invasion (P = 0.025) and advanced TNM stages (P = 0.019), whereas the decline of co-stimulatory ligand B7-H2 PBT was related to regional lymph node metastasis (P = 0.028) and aggressive tumor invasion (P = 0.031). In addition, the ratios of PBT expression of CD28 family to B7 family such as CTLA-4 to B7-H2 and PD-1 to B7-H2 were significantly higher in colon cancer patients with microscopic LVI than in those without LVI (P = 0.001 and P = 0.016, respectively). CONCLUSIONS: Our results suggest that B7/CD28 family PBTs may serve as valuable markers reflecting the pathological features of colon cancer.