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1.  Cooperativity of E-cadherin and Smad4 Loss to Promote Diffuse-type Gastric Adenocarcinoma and Metastasis 
Molecular cancer research : MCR  2014;12(8):1088-1099.
Loss of E-cadherin (CDH1), Smad4 and p53 have all been shown to play an integral role in gastric, intestinal and breast cancer formation. Compound conditional knockout mice for Smad4, p53, and E-cadherin were generated to define and compare the roles of these genes in gastric, intestinal and breast cancer development by crossing with Pdx-1-Cre, Villin-Cre and MMTV-Cre transgenic mice. Interestingly, gastric adenocarcinoma was significantly more frequent in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice than in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1+/+ mice, demonstrating that Cdh1 heterozygosity accelerates the development and progression of gastric adenocarcinoma, in combination with loss of Smad4 and p53. Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice developed gastric adenocarcinomas without E-cadherin expression. However, intestinal and mammary adenocarcinomas with the same genetic background retained E-cadherin expression and were phenotypically similar to mice with both wild-type Cdh1 alleles. Lung metastases were identified in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, but not in the other genotypes. Nuclear β-catenin accumulation was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the inhibition of β-catenin signaling by E-cadherin or Smad4 down-regulates signaling pathways involved in metastases in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. Knockdown of β-catenin significantly inhibited migratory activity of Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ cell lines. Thus, loss of E-cadherin and Smad4 cooperate with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human gastric adenocarcinoma.
This study demonstrates that inhibition of β-catenin is a converging node for the anti-metastatic signaling pathways driven by E-cadherin and Smad4 in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, providing novel insights into mechanisms for gastric cancer metastasis.
PMCID: PMC4230498  PMID: 24784840
E-cadherin; Smad4; p53; β-catenin; metastasis
2.  Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model 
Exogenous administration of growth factors has potential benefits in wound healing; however, limited percutaneous absorption, inconsistent efficacy, and the need for high doses have hampered successful clinical use. To overcome these restrictions, we focused on the development of a topical formulation composed of highly skin-permeable multimeric nanocomplex of growth factors. In the present study, we fused low-molecular-weight protamine (LMWP) with epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-I), and platelet-derived growth factor A ligand (PDGF-A) (producing recombinant [r]LMWP-EGF, rLMWP-IGF-I, and rLMWP-PDGF-A, respectively) via genetic modification. Then, we used in vitro cell proliferation studies to assess the biological activity and the benefits of the combination. The LMWP-conjugated growth factors were complexed with low-molecular-weight heparin (LMWH) and formulated with Poloxamer 188 as a delivery vehicle. After confirming the enhanced skin permeability, in vivo studies were performed to assess whether the LMWP-conjugated growth factor nanocomplex formulations accelerated the healing of full-thickness wounds in mice. The LMWP-conjugated growth factors were biologically equivalent to their native forms, and their combination induced greater fibroblast proliferation. rLMWP-EGF showed significantly enhanced permeability and cumulative permeation, and the rates for rLMWP-IGF-I and rLMWP-PDGF-A, across excised mouse skin, were 124% and 164% higher, respectively, than for the native forms. The LMWP-fused growth factors resulted in formation of nanocomplexes (23.51±1.12 nm in diameter) in combination with LMWH. Topical delivery of growth factors fused with LMWP accelerated wound re-epithelialization significantly, accompanied by the formation of healthy granulation tissue within 9 days compared with a free–growth factor complex or vehicle. Thus, the LMWP-conjugated growth factor nanocomplex can induce rapid, comprehensive healing and may be a candidate wound-healing therapeutic.
PMCID: PMC4184407  PMID: 25288883
epidermal growth factor; insulin-like growth factor; platelet-derived growth factor
3.  Clinical Outcomes of Local Excision Following Preoperative Chemoradiotherapy for Locally Advanced Rectal Cancer 
To evaluate the treatment outcomes of local excision following preoperative chemoradiotherapy in patients with locally advanced rectal cancer who have not undergone radical surgery for any reason.
Materials and Methods
The data of 27 patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy followed by local excision were analyzed retrospectively. The primary endpoint was the 5-year relapse-free survival rate, and the secondary endpoint was the pattern of recurrence.
The median follow-up time was 81.8 months (range, 28.6 to 138.5 months). The 5-year local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), relapse-free survival (RFS), and overall survival (OS) were 88.9%, 81.1%, 77.8%, and 85.0%, respectively. Six (22%) patients developed treatment failure; one (4%) patient had local recurrence only, three (11%) patients had distant recurrence only, and two (7%) patients had both. The 5-year LRFS, DMFS, RFS, and OS for patients with ypT0-1 compared with ypT2-3 were 94.1% vs. 77.8% (p=0.244), 94.1% vs. 55.6% (p=0.016), 88.2% vs. 55.6% (p=0.051), and 94.1% vs. 66.7% (p=0.073), respectively.
Local excision following preoperative chemoradiotherapy may be an alternative treatment for highly selected patients with locally advanced rectal cancer who have achieved ypT0-1 after preoperative chemoradiotherapy.
PMCID: PMC4022824  PMID: 24851107
Rectal neoplasms; Local excision; Preoperative chemoradiotherapy; Survival
4.  Preclinical Efficacy Testing for Stomach and Liver Cancers 
Hollow fiber assays offer an early in vivo method of anticancer drug screening. The assays have been optimized for human cancers originating from the lung, breast, colon, ovary, and brain, but not from the stomach and liver. The current study focused on optimization of hollow fiber assays for gastric and hepatocellular carcinoma cell lines.
Materials and Methods
Gastric (SNU-16, SNU-484, SNU-668) and hepatocellular (HepG2, SK-Hep-1, Hep3B) carcinoma cell lines in hollow fibers were transplanted subcutaneously and intraperitoneally into mice, which were subsequently treated with a standard anticancer agent, paclitaxel. The hollow fiber activity of paclitaxel in each cell line was compared with the xenograft activity.
Using optimized inoculation densities and schedules, treatment with paclitaxel was effective in gastric carcinoma cell lines, SNU-16 and SNU-484, but not in SNU-668. In the hollow fiber assays, paclitaxel was effective in hepatocellular carcinoma cell lines, HepG2 and SK-Hep-1, but not in Hep3B. Consistent with the results of the hollow fiber assay, SNU-16 and SNU-484, but not SNU-668, showed tumor regression, and HepG2 and SK-Hep-1, but not Hep3B, showed effective tumor responses following treatment with paclitaxel in xenograft models. When EW7197, a novel compound, and flavopiridol were tested in SNU-16 cells under optimized conditions, the hollow fiber activity showed good correlation with the xenograft activity of each compound.
Our protocols may be useful for screening candidate small molecules that may exhibit activity against stomach and liver cancers, both of which are common in Korea.
PMCID: PMC4022828  PMID: 24851111
Hollow fiber assay; Xenograft model antitumor assay; Stomach neoplasms; Liver neoplasms
5.  Long-term survival without surgery following a complete response to pre-operative chemoradiotherapy for rectal cancer: A case series 
Oncology Letters  2013;6(6):1573-1576.
Pre-operative chemoradiotherapy (CRT) for rectal cancer yields a complete tumor response in 10–30% of patients. There is an argument for omitting surgery in these patients, but this remains highly controversial and the supporting evidence based on long-term follow-up is lacking. The present study analyzed the long-term outcomes of five patients with cT3 or cT4 rectal cancer who showed a clinical complete response (ycCR) following pre-operative CRT and underwent no surgery. The ycCR status was determined 7–12 weeks after the completion of CRT using clinical, endoscopic and radiological studies, including magnetic resonance imaging and biopsy. The follow-up period was 54–101 months. Three patients had no tumor recurrence and were alive with no evidence of disease at 101, 100 and 93 months, respectively. One patient developed local recurrence at 59 months and another developed lung metastasis at 32 months. The two patients with tumor recurrence remained disease-free 42 and 22 months after salvage pelvic and thoracic surgery, respectively. Despite being a small series, the long-term survival outcomes of the present study indicate that a non-operative approach may be feasible for a proportion of rectal cancer patients who reveal a ycCR following pre-operative CRT.
PMCID: PMC3834548  PMID: 24260048
rectal cancer; pre-operative chemoradiotherapy; clinical complete response; wait-and-see
6.  Trends in the eradication rates of Helicobacter pylori infection for eleven years 
AIM: To evaluate the trends in the eradication rate of Helicobacter pylori (H. pylori) over the past 11 years in a single center.
METHODS: This retrospective study covered the period from January 2000 to December 2010. We evaluated 5746 patients diagnosed with gastric ulcers (GU), duodenal ulcers (DU), GU + DU, or nonpeptic ulcers associated with an H. pylori infection. We treated them annually with the 2 wk standard first-line triple regimen, proton pump inhibitor (PPI) + amoxicilin + clarithromycin (PAC; PPI, clarithromycin 500 mg, and amoxicillin 1 g, all twice a day). The follow-up test was performed at least 4 wk after the completion of the 2 wk standard H. pylori eradication using the PAC regimen. We also assessed the eradication rates of 1 wk second-line therapy with a quadruple standard regimen (PPI b.i.d., tripotassium dicitrate bismuthate 300 mg q.i.d., metronidazole 500 mg t.i.d., and tetracycline 500 mg q.i.d.) after the failure of the first-line therapy. Statistical analysis was performed with 95%CI for the differences in the annual eradication rates.
RESULTS: A total of 5746 patients [2333 males (58.8%), 1636 females (41.2%); mean age of males vs females 51.31 ± 13.1 years vs 52.76 ± 13.6 years, P < 0.05, total mean age 51.9 ± 13.3 years (mean ± SD)] were investigated. Among these patients, 1674 patients were excluded: 35 patients refused treatment; 18 patients ceased H. pylori eradication due to side effects; 1211 patients had inappropriate indications for H. pylori eradication, having undergone stomach cancer operation or chemotherapy; and 410 patients did not undergo the follow-up. We also excluded 103 patients who wanted to stop eradication treatment after only 1 wk due to poor compliance or the side effects mentioned above. Finally, we evaluated the annual eradication success rates in a total of 3969 patients who received 2 wk first-line PAC therapy. The endoscopic and clinical findings in patients who received the 2 wk PAC were as follows: gastric ulcer in 855 (21.5%); duodenal ulcer in 878 (22.1%); gastric and duodenal ulcer in 124 (3.1%), erosive, atrophic gastritis and functional dyspepsia in 2055 (51.8%); and other findings (e.g., MALToma, patients who wanted to receive the therapy even though they had no abnormal endoscopic finding) in 57 (0.5%). The overall eradication rate of the 2 wk standard first-line triple regimen was 86.5%. The annual eradication rates from 2000 to 2010 were 86.7%, 85.4%, 86.5%, 83.3%, 89.9%, 90.5%, 88.4%, 84.5%, 89.1%, 85.8%, and 88.3%, sequentially (P = 0.06). No definite evidence of a significant change in the eradication rate was seen during the past eleven years. The eradication rates of second-line therapy were 88.9%, 82.4%, 85%, 83.9%, 77.3%, 85.7%, 84.4%, 87.3%, 83.3%, 88.9%, and 84% (P = 0.77). The overall eradication rate of 1 wk quadruple second-line therapy was 84.7%. There was no significant difference in the eradication rate according to the H. pylori associated diseases.
CONCLUSION: This study showed that there was no trend change in the H. pylori eradication rate over the most recent 11 years in our institution.
PMCID: PMC3516214  PMID: 23236238
Helicobacter pylori; Eradication; Proton pump inhibitor; Therapy; Clarithromycin
7.  An Update on Preoperative Radiotherapy for Locally Advanced Rectal Cancer 
Even in patients undergoing an optimal surgical technique (e.g., total mesorectal excision), radiotherapy provides a significant benefit in the local control of rectal cancer. Compared with postoperative treatment, chemoradiotherapy given preoperatively has been shown to decrease local recurrence rates and toxicity. Additionally, preoperative chemoradiotherapy permits the early identification of tumor responses to this cytotoxic treatment by surgical pathology. Pathological parameters reflecting the tumor response to chemoradiotherapy have been shown to be surrogate markers for long-term clinical outcomes. Post-chemoradiotherapy downstaging from cStage II-III to ypStage 0-I indicates a favorable prognosis, with no difference between ypStage 0 and ypStage I. Research is ongoing to develop useful tools (clinical, molecular, and radiological) for clinical determination of the pathologic chemoradiotherapeutic response before surgery, and possibly even before preoperative treatment. In the future, risk-adapted strategies, including intensification of preoperative therapy, conservative surgery, or the selective administration of postoperative chemotherapy, will be realized for locally-advanced rectal cancer patients based on their response to preoperative chemoradiotherapy.
PMCID: PMC3440486  PMID: 22993703
Rectal neoplasms; Radiotherapy; Chemoradiotherapy; Neoadjuvant
8.  Analysis of microsatellite instability in stool DNA of patients with colorectal cancer using denaturing high performance liquid chromatography 
AIM: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) for analyzing microsatellite instability (MSI) status in stool DNA of patients with colorectal cancer.
METHODS: A total of 80 cancer tissues from patients with primary sporadic colorectal tumor (proximal cancer: 27, distal cancer: 53) and matched stool (which were employed for comparison with the tissues) were analyzed for MSI status in BAT 26. DNA samples extracted from stool were evaluated by nested polymerase chain reaction (PCR) and DHPLC for MSI analysis.
RESULTS: Six cases (7.5%) of MSI were identified in BAT 26 from 80 cancer tissues. All the stool DNA samples from patients whose cancer tissue showed MSI also displayed MSI in BAT 26.
CONCLUSION: As MSI is one of the established fecal DNA markers to screen colorectal cancer, we propose to use DHPLC for the MSI analysis in fecal DNA.
PMCID: PMC4125677  PMID: 17075985
Colorectal cancer; Denaturing high performance liquid chromatography; Fecal DNA; Microsatellite instability; Stool
9.  Phase I Dose-Escalation Study of Proton Beam Therapy for Inoperable Hepatocellular Carcinoma 
The purpose of this study is to determine the optimal dose of proton beam therapy (PBT) in hepatocellular carcinoma (HCC) patients.
Materials and Methods
Inoperable HCC patients who had naïve, recurrent, or residual tumor to treatment were considered eligible for PBT. Patients received PBT with 60 GyE in 20 fractions (dose level 1; equivalent dose in 2 Gy fractions [EQD2], 65 GyE10); 66 GyE in 22 fractions (dose level 2; EQD2, 71.5 GyE10); or 72 GyE in 24 fractions (dose level 3; EQD2, 78 GyE10). Dose-limiting toxicity was determined by grade ≥ 3 acute toxicity.
Twenty-seven patients were enrolled; eight, seven, and 12 patients were treated with dose levels 1, 2, and 3, respectively. Overall, treatment was well tolerated, with no dose-limiting toxicities. The complete response (CR) rates of primary tumors after PBT for dose levels 1, 2, and 3 were 62.5% (5/8), 57.1% (4/7), and 100% (12/12), respectively (p=0.039). The 3-and 5-year local progression-free survival (LPFS) rates among 26 patients, excluding one patient who underwent liver transplantation after PBT due to its probable significant effect on disease control, were 79.9% and 63.9%, respectively, and the 3-and 5-year overall survival rates were 56.4% and 42.3%, respectively. The 3-year LPFS rate was significantly higher in patients who achieved CR than in those who did not (90% vs. 40%, p=0.003).
PBT is safe and effective and an EQD2 ≥ 78 GyE10 should be delivered for achievement of local tumor control.
PMCID: PMC4296848  PMID: 25381830
Hepatocellular carcinoma; Proton therapy; Radiotherapy
10.  Is elective inguinal radiotherapy necessary for locally advanced rectal adenocarcinoma invading anal canal? 
We investigated whether routine elective irradiation of a clinically negative inguinal node (IGN) is necessary for patients with locally advanced distal rectal cancer and anal canal invasion (ACI).
We reviewed retrospectively 1,246 patients with locally advanced rectal adenocarcinoma managed using preoperative or postoperative chemoradiotherapy and radical surgery between 2001 and 2011. The patients’ IGN was clinically negative at presentation and IGN irradiation was not performed. ACI was defined as the lower edge of the tumor being within 3 cm of the anal verge. Patients were divided into two groups, those with ACI (n = 189, 15.2%) and without ACI (n = 1,057, 84.8%).
The follow-up period was a median of 66 months (range, 3–142 months). Among the 1,246 patients, 10 developed IGN recurrence; 7 with ACI and 3 without ACI. The actuarial IGN recurrence rate at 5 years was 0.7%; 3.5% and 0.2% in patients with and without ACI, respectively (p < 0.001). Isolated IGN recurrence occurred in three patients, all of whom had ACI tumors. These three patients received curative intent local treatments, and one was alive with no evidence of disease 10 years after IGN recurrence. Salvage treatments in the other two patients controlled successfully the IGN recurrence for >5 years, but they developed second malignancy or pelvic and distant recurrences. Seven patients with non-isolated IGN recurrence died of disease at 5–22 months after IGN recurrence.
The low IGN recurrence rate even with ACI and the feasibility of salvage of isolated IGN recurrence indicated that routine elective IGN irradiation is not necessary for rectal cancer with ACI.
PMCID: PMC4299686  PMID: 25533887
Rectal cancer; Radiotherapy; Inguinal lymph node; Anal canal invasion
11.  Use of laparoscopy for diagnosing experimentally induced acute pancreatitis in dogs 
Journal of Veterinary Science  2014;15(4):551-556.
Diagnosis of acute pancreatitis in dogs remains a significant challenge despite the development of advanced diagnostic methodologies. Visual inspection and pancreas biopsy using laparoscopy are generally considered to be procedures free of complications when conducted on healthy animals. However, the usefulness of laparoscopy for diagnosing acute pancreatitis has not been assessed. In the present study, the efficacy of laparoscopy for diagnosing acute pancreatitis in dogs was evaluated in animals with experimentally induced acute pancreatitis. Gross appearance of the pancreatic area was examined by laparoscopy to survey for the presence of edema, adhesions, effusion, pseudocysts, hemorrhage, and fat necrosis. Laparoscopic biopsy was performed and the histopathologic results were compared to those of pancreatic samples obtained during necropsy. The correlation between laparoscopy and histopathologic findings of the pancreas was evaluated. The presence of adhesions, effusion, and hemorrhage in the pancreatic area observed by laparoscopy significantly correlated with the histopathologic results (p < 0.05). There was no significant relationship between the histopathologic and laparoscopic biopsy findings. Results of this study suggested that laparoscopic evaluation of gross lesions has clinical significance although the laparoscopic biopsy technique has some limitations. This method combined with additional diagnostic tools can be effective for diagnosing acute pancreatitis in dogs.
PMCID: PMC4269598  PMID: 24962411
acute pancreatitis; biopsy; dog; laparoscopy
12.  Low-mass-ion discriminant equation: A new concept for colorectal cancer screening 
Blood metabolites can be detected as low-mass ions (LMIs) by mass spectrometry (MS). These LMIs may reflect the pathological changes in metabolism that occur as part of a disease state, such as cancer. We constructed a LMI discriminant equation (LOME) to investigate whether systematic LMI profiling might be applied to cancer screening. LMI information including m/z and mass peak intensity was obtained by five independent MALDI-MS analyses, using 1,127 sera collected from healthy individuals and cancer patients with colorectal cancer (CRC), breast cancer (BRC), gastric cancer (GC) and other types of cancer. Using a two-stage principal component analysis to determine weighting factors for individual LMIs and a two-stage LMI selection procedure, we selected a total of 104 and 23 major LMIs by the LOME algorithms for separating CRC from control and rest of cancer samples, respectively. CRC LOME demonstrated excellent discriminating power in a validation set (sensitivity/specificity: 93.21%/96.47%). Furthermore, in a fecal occult blood test (FOBT) of available validation samples, the discriminating power of CRC LOME was much stronger (sensitivity/specificity: 94.79%/97.96%) than that of the FOBT (sensitivity/specificity: 50.00%/100.0%), which is the standard CRC screening tool. The robust discriminating power of the LOME scheme was reconfirmed in screens for BRC (sensitivity/specificity: 92.45%/96.57%) and GC (sensitivity/specificity: 93.18%/98.85%). Our study demonstrates that LOMEs might be powerful noninvasive diagnostic tools with high sensitivity/specificity in cancer screening. The use of LOMEs could potentially enable screening for multiple diseases (including different types of cancer) from a single sampling of LMI information.
PMCID: PMC4233965  PMID: 24096867
serum profiling; MALDI-TOF mass spectrometry; pattern recognition
13.  The antihypertension drug doxazosin suppresses JAK/STATs phosphorylation and enhances the effects of IFN-α/γ-induced apoptosis 
Genes & Cancer  2014;5(11-12):470-479.
Doxazosin, a commonly prescribed treatment for patients with benign prostatic hyperplasia, serves as an α1-blocker of the adrenergic receptors. In this study, we calculated its effect on the ovarian carcinoma cells. Doxazosin induces dose-dependent growth suppression and is additively activated through IFN-α or IFN-γ stimulation. They both enhanced G1 phase arrest, as well as the activity of caspase-3, and the reduction of cyclin D1 and CDK4 protein levels. Doxazosin growth suppression was abolished either by the Janus family of tyrosine kinase (JAK) or the signal transducer and activator of transcription (STAT) inhibitor treatment. The activity of JAK/STAT was dependent on the level of doxazosin, suggesting a requirement of doxazosin for the activation of JAK/STAT. Furthermore, doxazosin plus IFN-α or doxazosin plus IFN-γ additively suppressed the activation of the JAK/STAT signals through phosphorylation of JAK and STAT, thus affecting the activation of subsequent downstream signaling components PI3K, mTOR, 70S6K, and PKCδ. In vivo study demonstrated that doxazosin significantly suppressed tumor growth in an ovarian cancer cell xenograft mouse model, inducing apoptotic cell death by up-regulating the expression of p53, whereas c-Myc expression was markedly reduced. Our data indicate that doxazosin can modulate the apoptotic effects of IFN-α- and IFN-γ through the JAK/STAT signaling pathways. Collectively, we indicate that this action may be a potent chemotherapeutic property against ovarian carcinoma.
PMCID: PMC4279443  PMID: 25568671
doxazosin; interferon-α/γ; apoptotic cell death; JAK/STAT activation; cell cycle progression
14.  Antioxidative Activity of Blueberry Leaf Extract Prevents High-fat Diet-induced Obesity in C57BL/6 Mice 
Journal of Cancer Prevention  2014;19(3):209-215.
Health beneficial effects of blueberry have been well documented. Obesity is health hazard that is associated with metabolic abnormalities. We investigated the effect of blueberry leaf extract (BBLE) on high-fat diet (HFD)-induced obesity in C57BL/6J mice.
C57BL/6 mice were fed HFD with or without BBLE for 10 weeks. Body weight, serum parameter, and adipose tissues morphology were assessed. The expression of mRNA associated with adipogenesis was measured using real-time polymerase chain reaction (RT-PCR) analysis.
Administration of BBLE to mice challenged with HFD significantly decreased the body weight gain, the levels of plasma triglyceride (TG) and liver lipid peroxidation, and reduced the adipocyte size and improved hepatic status compared with the group treated with HFD only. BBLE treatment significantly improved glucose control compared with the HFD group. Moreover, BBLE showed an inhibitory effect on adipocyte differentiation in obese mice together with significant decrease in the lipid accumulation by downregulating gene expression of adipocyte-specific transcription factors, such as peroxisome proliferation-activity receptor and acetyl coenzyme A carboxylase and upregulating the mRNA expression of adiponectin, which are critical for adipogenesis.
BBLE suppressed the body weight gain in the HFD-fed C57BL/6 mice. Intake of BBLE reduced body weight in HFD-fed mice by 20%. Furthermore, BBLE supplementation significantly decreased the TG level in the liver and inhibited leptin secretion. BBLE supplementation also improved insulin resistance. Therefore, BBLE is a possible agent to prevent obesity.
PMCID: PMC4189509  PMID: 25337590
Blueberry leaf extracts; High-fat diet-induced obesity; Adipocytes
15.  Long-Term Efficacy of Endoscopic Submucosal Dissection Compared with Surgery for Early Gastric Cancer: A Retrospective Cohort Study 
Gut and Liver  2014;8(5):519-525.
This study aimed to compare the outcomes of endoscopic submucosal dissection (ESD) and gastrectomy based on the two sets of indications for ESD, namely guideline criteria (GC) and expanded criteria (EC).
Between January 2004 and July 2007, 213 early gastric cancer (EGC) patients were enrolled in this study. Of these patients, 142 underwent ESD, and 71 underwent gastrectomy. We evaluated the clinical outcomes of these patients according to the criteria.
The complication rates in the ESD and gastrectomy groups were 8.5% and 28.2%, respectively. The duration of hospital stay was significantly shorter in the ESD group than the gastrectomy group according to the GC and EC (p<0.001 and p<0.001, respectively). There was no recurrence in the ESD and gastrectomy groups according to the GC, and the recurrence rates in the ESD and gastrectomy groups were 4.7% and 0.0% according to the EC, respectively (p=0.279). The occurrence rates of metachronous cancer in the ESD and gastrectomy groups were 5.7% and 5.0% according to the GC (p=1.000) and 7.5% and 0.0% according to the EC (p=0.055), respectively.
Based on safety, duration of hospital stay, and long-term outcomes, ESD may be an effective and safe first-line treatment for EGC according to the EC and GC.
PMCID: PMC4164255  PMID: 25228976
Endoscopic submucosal dissection; Gastrectomy; Long-term outcome; Indication
16.  The antihypertension drug doxazosin inhibits tumor growth and angiogenesis by decreasing VEGFR-2/Akt/mTOR signaling and VEGF and HIF-1α expression 
Oncotarget  2014;5(13):4935-4944.
Doxazosin is an α1 adrenergic receptor blocker that also exerts antitumor effects. However, the underlying mechanisms by which it modulates PI3K/Akt intracellular signaling are poorly understood. In this study, we reveal that doxazosin functions as a novel antiangiogenic agent by inhibiting vascular endothelial growth factor (VEGF)-induced cell migration and proliferation. It also inhibited VEGF-induced capillary-like structure tube formation in vitro. Doxazosin inhibited the phosphorylation of VEGF receptor-2 (VEGFR-2) and downstream signaling, including PI3K, Akt, 3-phosphoinositide-dependent protein kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and hypoxia-inducible factor 1 (HIF-1α). However, it had no effect on VEGF-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Furthermore, doxazosin reduced tumor growth and suppressed tumor vascularization in a xenograft human ovarian cancer model. These results provide evidence that doxazosin functions in the endothelial cell system to modulate angiogenesis by inhibiting Akt and mTOR phosphorylation and interacting with VEGFR-2.
PMCID: PMC4148112  PMID: 24952732
doxazosin; anti-angiogenic activity; VEGFR-2; Akt/mTOR phosphorylation; endothelial cell
17.  Expression of phosphoenolpyruvate carboxykinase linked to chemoradiation susceptibility of human colon cancer cells 
BMC Cancer  2014;14:160.
Resistance to 5-fluorouracil (5-FU) in patients with colorectal cancer prevents effective treatment and leads to unnecessary and burdensome chemotherapy. Therefore, prediction of 5-FU resistance is imperative.
To identify the proteins linked to 5-FU resistance, two-dimensional gel electrophoresis-based proteomics was performed using the human colon cancer cell line SNU-C4R with induced 5-FU resistance. Proteins showing altered expression in SNU-C4R were identified by matrix-associated laser desorption/ionization–time-of-flight analysis, and their roles in susceptibility to 5-FU or radiation were evaluated in various cell lines by transfection of specific siRNA or creation of overexpression constructs. Changes in cellular signaling and expression of mitochondrial apoptotic factors were investigated by Western Blot analysis. A mitochondrial membrane potential probe (JC-1 dye) and a flow cytometry system were employed to determine the mitochondrial membrane potential. Finally, protein levels were determined by Western Blot analysis in tissues from 122 patients with rectal cancer to clarify whether each identified protein is a useful predictor of a chemoradiation response.
We identified mitochondrial phosphoenolpyruvate carboxykinase (mPEPCK) as a candidate predictor of 5-FU resistance. PEPCK was downregulated in SNU-C4R compared with its parent cell line SNU-C4. Overexpression of mPEPCK did not significantly alter the susceptibility to either 5-FU or radiation. Suppression of mPEPCK led to a decrease in both the cellular level of phosphoenolpyruvate and the susceptibility to 5-FU and radiation. Furthermore, the cellular levels of phosphoenolpyruvate (an end product of PEPCK and a substrate of pyruvate kinase), phosphorylated AKT, and phosphorylated 4EBP1 were decreased significantly secondary to the mPEPCK suppression in SNU-C4. However, mPEPCK siRNA transfection induced changes in neither the mitochondrial membrane potential nor the expression levels of mitochondrial apoptotic factors such as Bax, Bcl-2, and Bad. Downregulation of total PEPCK was observed in tissues from patients with rectal cancer who displayed poor responses to preoperative 5-FU-based radiation therapy.
Our overall results demonstrate that mPEPCK is a useful predictor of a response to chemoradiotherapy in patients with rectal cancer.
PMCID: PMC4016284  PMID: 24602180
mPEPCK; 5-FU resistance; Colon cancer; Chemoradiotherapy; Prediction
18.  Comparison of two preoperative chemoradiotherapy regimens for locally advanced rectal cancer: capecitabine alone versus capecitabine plus irinotecan 
To compare the short-term tumor response and long-term clinical outcome of two preoperative chemoradiotherapy (CRT) regimens for locally advanced rectal cancer.
This study included 231 patients scheduled for preoperative CRT using two chemotherapeutic protocols from April 2003–August 2006. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with capecitabine (n = 148) or capecitabine/irinotecan (n = 83). Surgery was performed 4–8 weeks after CRT completion. Tumor responses to CRT were assessed using both radiologic and pathologic measurements. Radiologic responses were evaluated by magnetic resonance volumetry, which was performed at the initial work-up and after completion of preoperative CRT just before surgery. Pathologic responses were assessed with downstaging (ypStage 0-1) and grading tumor regression. Clinical outcomes were evaluated in terms of local control, relapse-free survival, and overall survival rates.
Radiologic examination demonstrated that tumor volume decreased by 65.6% in the capecitabine group and 66.8% capecitabine/irinotecan group (p = 0.731). Postoperative pathologic stage determination showed that tumor downstaging occurred in 44.1% of the capecitabine group and 48.6% of the capecitabine/irinotecan group (p = 0.538). The sum of tumor regression grade 3 (near complete response) and 4 (complete response) after CRT were 28.6% in the capecitabine group and 37.5% in the capecitabine/irinotecan group (p = 0.247). There were no significant differences between the two groups in 5-year local control (91.7% vs. 92.5%; p = 0.875), relapse-free survival (80.8% vs. 77.2%; p = 0.685), and overall survival (88.4% vs. 90.4%; p = 0.723).
This study revealed no differences in the short-term tumor response and long-term clinical outcome between preoperative capecitabine and capecitabine/irinotecan CRT regimens for locally advanced rectal cancer.
PMCID: PMC3827873  PMID: 24188746
Rectal cancer; Preoperative chemoradiotherapy; Capecitabine; Irinotecan
19.  Dipeptidyl Peptidase 10, a Novel Prognostic Marker in Colorectal Cancer 
Yonsei Medical Journal  2013;54(6):1362-1369.
The dipeptidyl peptidase IV (DPPIV) gene family exhibits multiple functions and is involved in the pathogenesis of various diseases. It has attracted pharmaceutical interest in the areas of metabolic disorders as well as cancer. However, clinicopathologic significance of DPPIV family in colorectal cancer is not fully understood.
Materials and Methods
The clinical relevance of DPPIV and DPP10 expression was determined by immunohistochemical staining, and by assessing its clinicopathologic correlation in 383 colorectal cancer patients with known clinical outcomes.
DPPIV was not expressed in normal colon mucosa, but it showed luminal expression in 52 of the 383 colorectal cancers (13.5%). DPPIV expression in tumors was associated with right-sided location of the colon (p=0.010) and more advanced tumor stage (p=0.045). DPP10 was expressed in normal colonic mucosa, but its expression varied in primary colorectal cancer tissues. Loss of DPP10 expression was found in 11 colorectal cancers (CRCs) (2.9%), and multivariate analysis showed that loss of DPP10 expression was an independent factor for poor patient prognosis (p=0.008).
DPP10 may play a role in disease progression of colorectal cancer and loss of DPP10 expression in primary CRC is significantly associated with poor survival outcomes.
PMCID: PMC3809881  PMID: 24142639
Colorectal cancer; dipeptidyl peptidase 10; progression; prognosis
20.  GC/MS analysis of high-performance liquid chromatography fractions from Sophora flavescens and Torilis japonica extracts and their in vitro anti-neosporal effects on Neospora caninum 
Journal of Veterinary Science  2013;14(3):241-248.
We analyzed alcoholic extracts of herbs possessing anti-neosporal activity against Neospora (N.) caninum. To identify the chemical components of Sophora (S.) flavescens and Torilis (T.) japonica associated with anti-neosporal activity, specific fractions were isolated by high-performance liquid chromatography (HPLC). In vitro activity of the fractions against N. caninum was then assessed. Gas chromatography/mass spectrometry (GC/MS) was used to identify and quantify specific anti-neosporal molecules in the herbal extracts. Almost all HPLC fractions of S. flavescens and T. japonica had higher levels of anti-neosporal activity compared to the not treated control. Active constituents of the extracts were sophoridane, furosardonin A, and tetraisopropylidene-cyclobutane in S. flavescens; 5,17-β-dihydroxy-de-A-estra-5,7,9,14-tetraene, furanodiene, and 9,12-octadecadienoic acid (Z,Z)-(CAS,1) in T. japonica.
PMCID: PMC3788148  PMID: 23820198
GC/MS; HPLC; Neospora caninum; Sophora flavescens; Torilis japonica
21.  Vitamin D3 up-regulated protein 1 controls the priming phase of liver regeneration 
Journal of Veterinary Science  2013;14(3):257-262.
Vitamin D3 up-regulated protein 1 (VDUP1) is a potent growth suppressor that inhibits tumor cell proliferation and cell cycle progression when overexpressed. In a previous study, we showed that VDUP1 knockout (KO) mice exhibited accelerated liver regeneration because such animals could effectively control the expression of cell cycle regulators that drive the G1-to-S phase progression. In the present study, we further investigated the role played by VDUP1 in initial priming of liver regeneration. To accomplish this, VDUP1 KO and wild-type (WT) mice were subjected to 70% partial hepatectomy (PH) and sacrificed at different times after surgery. The hepatic levels of TNF-α and IL-6 increased after PH, but there were no significant differences between VDUP1 KO and WT mice. Nuclear factor-κB (NF-κB), c-Jun-N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT-3) were activated much earlier and to a greater extent in VDUP1 KO mice after PH. A single injection of TNF-α or IL-6 caused rapid activation of JNK and STAT-3 expression in both mice, but the responses were stronger and more sustained in VDUP1 KO mice. In conclusion, our findings provide evidence that VDUP1 plays a role in initiation of liver regeneration.
PMCID: PMC3788150  PMID: 23820201
c-Jun-N-terminal kinase; NF-κB; partial hepatectomy; signal transducer and activator of transcription 3; Vitamin D3 up-regulated protein 1
22.  Comparison of capecitabine and 5-fluorouracil in chemoradiotherapy for locally advanced pancreatic cancer 
Although capecitabine has theoretical advantages in the pharmacokinetics, such as higher intratumoral and lower systemic concentration, relative to bolus 5-fluorouracil (5-FU), outcomes of chemoradiotherapy (CRT) with capecitabine or bolus 5-FU have not been directly compared in patients with locally advanced pancreatic cancer. Therefore, we retrospectively compared the outcomes, including toxicity, tumor response, and overall survival, of oral capecitabine plus radiotherapy (RT) with bolus 5-FU plus RT, in patients with locally advanced pancreatic cancer.
Between August 2006 and January 2012, 98 patients with locally advanced pancreatic cancer received CRT, with 52 receiving concurrent oral capecitabine and 46 receiving bolus injection of 5-FU. Primary tumor and overall response after CRT were evaluated radiologically, and toxicity, tumor response, and overall survival (OS) were compared in the two groups.
Baseline clinical parameters of the two groups were similar. The rates of ≥ Grade 3 hematologic (0% vs. 8.7%, p = 0.045) and non-hematologic (0% vs. 8.7%, p = 0.045) toxicities were significantly lower in the capecitabine group than in the 5-FU group. Primary tumor (30.7% vs. 28.2%, p = 0.658) and overall (13.7% vs. 15.2%, p = 0.273) response rates and median OS time (12.5 months vs. 11.6 months, p = 0.655) were similar in the two groups.
Capecitabine plus RT may be a safe and feasible regimen for patients with locally advanced pancreatic cancer, with similar efficacy and low rates of toxicities compared with bolus 5-FU plus RT.
PMCID: PMC3702484  PMID: 23822606
Pancreatic cancer; Chemoradiotherapy; 5-Fluorouracil; Capecitabine
23.  Patterns of failure in patients with locally advanced rectal cancer receiving pre-operative or post-operative chemoradiotherapy 
We investigated patterns of failure in patients with locally advanced rectal cancer (LARC) according to chemoradiotherapy (CRT) timing: pre-operative versus post-operative. Also, patterns of failure, particularly distant metastasis (DM), were analyzed according to tumor location within the rectum.
In total, 872 patients with LARC who had undergone concurrent CRT and radical surgery between 2001 and 2007 were analyzed retrospectively. Concurrent CRT was administered pre-operatively (cT3–4) or post-operatively (pT3–4 or pN+) in 550 (63.1%) and 322 (36.9%) patients, respectively. Median follow-up period was 86 (range, 12–133) months for 673 living patients. Local recurrence (LR) was defined as any disease recurrence within the pelvis, and any failure outside the pelvis was classified as a DM. Only the first site of recurrence was scored.
In total, 226 (25.9%) patients developed disease recurrence. In the pre-operative CRT group, the incidences of isolated LR, combined LR and DM, and isolated DM were 17, 21, and 89 patients, respectively. In the post-operative CRT group, these incidences were 8, 15, and 76 patients, respectively. LR within 2 years constituted 44.7% and 60.9% of all LRs in the pre-operative and post-operative CRT groups, respectively. Late (> 5 years) LR comprised 13.2% and 4.3% of all LRs in the pre-operative and post-operative CRT groups, respectively. The lung was the most common DM site (108/249, 43.4%). Lung or para-aortic lymph node metastasis developed more commonly from low-to-mid rectal tumors while liver metastasis developed more commonly from upper rectal tumors. Lung metastasis occurred later than liver metastasis (n = 54; 22.6 ± 15.6 vs. 17.4 ± 12.1 months; P = 0.035).
This study showed that LARC patients receiving pre-operative CRT tended to develop late LR more often than those receiving post-operative CRT. Further extended follow-up than is conventional may be necessary in LARC patients who are managed with optimized multimodal treatments, and the follow-up strategy may need to be individualized according to tumor location within the rectum.
PMCID: PMC3653733  PMID: 23647920
Rectal cancer; Pattern of failure; Preoperative; Postoperative; Chemoradiotherapy
24.  Efficacy of Transradial Cerebral Angiography in the Elderly 
Transradial angiography has become popular among many cardiologists as a diagnostic and therapeutic tool. However, transradial cerebral angiography is not utilized to the same extent. The purpose of this study is to present our experience regarding the usefulness of transradial cerebral angiography, especially in elderly patients.
Between May 2011 and February 2012, a total of 126 cerebral angiographies were performed via a transradial approach in a single center. Of them, only 47 patients were over 60 years old. In our institution, we shifted the initial access from the right femoral artery to the right radial artery in all patients requiring cerebral angiography in 2011. We did not attempt radial access in 40 cases for variable reasons.
The procedural success rate was 92.2%. We have four failures of transradial angiography; two because of loop formations of the radial and brachial artery and two due to multiple puncture failures. All supra-aortic vessels were successfully catheterized. However, the selective catheterization rates of the left side distal vessels were lower, as success rates were 89.7% for the right internal carotid artery and 75% for the left internal carotid artery. Procedure-related vascular complications, such as puncture site hematoma, hand ischemia, pseudoaneurysm, arteriovenous fistula and arterial dissection were not observed in our series. However, intraprocedural thrombosis developed in one patient, which was resolved completely by intraarterial thrombolytic agents.
With advancing patient's age, we believe that transradial cerebral angiography is a useful tool to decrease patient's discomfort and more effectively manage the vessel tortuosity.
PMCID: PMC3698230  PMID: 23826476
Angiography; Cerebral angiography; Radial artery; Transradial
25.  Association between CASR Polymorphisms, Calcium Intake, and Colorectal Cancer Risk 
PLoS ONE  2013;8(3):e59628.
The current study aimed to assess the effect of dietary calcium intake and possible interactions with calcium-sensing receptor (CASR) gene polymorphisms on colorectal cancer risk.
A total of 420 colorectal cancer cases and 815 controls were included in the analysis. Calcium intake was investigated using a 103 item semi-quantitative food frequency questionnaire, and four single nucleotide polymorphisms (SNPs) within the CASR, rs10934578, rs12485716, rs2270916, and rs4678174, were evaluated.
No SNPs were associated with colorectal cancer risk after adjusting for covariates. Overall, no significant effect modification by CASR polymorphisms on the association between calcium intake and colorectal cancer risk were detected. However, all 4 of the polymorphisms within the CASR showed significantly higher odds ratios for association with colorectal cancer risk in the low-calcium-intake group compared to the high-calcium-intake group. In the case of rs2270916, individuals with the CC genotype and low calcium intake showed an increased colorectal cancer risk compared to their counterparts with the TT genotype and high calcium intake (OR = 2.11, 95% CI = 1.27–3.51).
Subjects with lower calcium intake exhibited a higher colorectal cancer risk compared with subjects with the same genotype who had higher calcium intake. Our results suggest that individuals who have low dietary calcium intake should be aware of their increased colorectal cancer risk and prevention strategies.
PMCID: PMC3610701  PMID: 23555732

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