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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  The Prevalence of Erosive Esophagitis Is Not Significantly Increased in a Healthy Korean Population - Could It Be Explained?: A Multi-center Prospective Study 
Researches on the potential risk factors for the development of erosive esophagitis have been conducted extensively, however, the results are conflicting. The aim of this multicenter study was to identify the prevalence rate and risk factors of erosive esophagitis and their interactions with residency status.
A total of 4,023 eligible subjects at 8 tertiary health care centers were evaluated using questionnaires, laboratory tests and endoscopy. Univariate and multivariate analyses were conducted to identify independent risk factors for erosive esophagitis.
The prevalence rate of reflux esophagitis was 8.8%. Los Angeles grade A was common type of erosive esophagitis. Residence in a large urban areas was negatively associated with the development of erosive esophagitis (OR, 0.60; 95% CI, 0.40-0.90). The high body mass index (≥ 25 kg/m2) was more frequent in residents of small and medium-sized cities than those in big cities (38.8% and 26.9%, respectively; P < 0.001). Seronegativity of Helicobacter pylori was associated with increased erosive esophagitis (OR, 1.91; 95% CI, 1.48-2.46). Triglyceride ≥ 150 mg/dL (OR, 1.65; 95% CI, 1.08-2.07), fasting glucose level ≥ 126 mg/dL (OR, 1.73; 95% CI, 1.06-2.81), and hiatal hernia (OR, 3.11; 95% CI, 1.87-5.16) were also associated with erosive esophagitis.
The prevalence rate of erosive esophagitis and its risk factors in this study were similar to the result of 8.0% of nationwide study in 2006. Residency and obesity are more important independent risk factors than H. pylori infection status for development of erosive esophagitis in Korea. These results suggest that the prevalence rate of erosive esophagitis in Korea might not increase as in the Western countries.
PMCID: PMC3548130  PMID: 23350050
Esophagitis; Helicobacter pylori; Risk factors
11.  Up-regulated expression of l-caldesmon associated with malignancy of colorectal cancer 
BMC Cancer  2012;12:601.
Caldesmon (CaD), a major actin-associated protein, is found in smooth muscle and non-muscle cells. Smooth muscle caldesmon, h-CaD, is a multifunctional protein, and non-muscle cell caldesmon, l-CaD, plays a role in cytoskeletal architecture and dynamics. h-CaD is thought to be an useful marker for smooth muscle tumors, but the role(s) of l-CaD has not been examined in tumors.
Primary colon cancer and liver metastasis tissues were obtained from colon cancer patients. Prior to chemoradiotherapy (CRT), normal and cancerous tissues were obtained from rectal cancer patients. Whole-tissue protein extracts were analyzed by 2-DE-based proteomics. Expression and phosphorylation level of main cellular signaling proteins were determined by western blot analysis. Cell proliferation after CaD siRNA transfection was monitored by MTT assay.
The expression level of l-CaD was significantly increased in primary colon cancer and liver metastasis tissues compared to the level in the corresponding normal tissues. In cancerous tissues obtained from the patients showing poor response to CRT (Dworak grade 4), the expression of l-CaD was increased compared to that of good response group (Dworak grade 1). In line with, l-CaD positive human colon cancer cell lines were more resistant to 5-fluorouracil (5-FU) and radiation treatment compared to l-CaD negative cell lines. Artificial suppression of l-CaD increased susceptibility of colon cancer cells to 5-FU, and caused an increase of p21 and c-PARP, and a decrease of NF-kB and p-mTOR expression.
Up-regulated expression of l-CaD may have a role for increasing metastatic property and decreasing CRT susceptibility in colorectal cancer cells.
PMCID: PMC3572427  PMID: 23241148
12.  Clinical outcomes of balloon-occluded retrograde transvenous obliteration for the treatment of gastric variceal hemorrhage in Korean patients with liver cirrhosis: a retrospective multicenter study 
Clinical and molecular hepatology  2012;18(4):368-374.
This study evaluated the clinical outcomes of balloon-occluded retrograde transvenous obliteration (BRTO) for the treatment of hemorrhage from gastric varices (GV) in Korean patients with liver cirrhosis (LC).
We retrospectively analyzed data from 183 LC patients who underwent BRTO for GV bleeding in 6 university-based hospitals between January 2001 and December 2010.
Of the 183 enrolled patients, 49 patients had Child-Pugh (CP) class A LC, 105 had CP class B, and 30 had CP class C at the time of BRTO. BRTO was successfully performed in 177 patients (96.7%). Procedure-related complications (e.g., pulmonary thromboembolism and renal infarction) occurred in eight patients (4.4%). Among 151 patients who underwent follow-up examinations of GV, 79 patients (52.3%) achieved eradication of GV, and 110 patients (72.8%) exhibited marked shrinkage of the treated GV to grade 0 or I. Meanwhile, new-appearance or aggravation of esophageal varices (EV) occurred in 54 out of 136 patients who underwent follow-up endoscopy (41.2%). During the 36.0±29.2 months (mean±SD) of follow-up, 39 patients rebled (hemorrhage from GV in 7, EV in 18, nonvariceal origin in 4, and unknown in 10 patients). The estimated 3-year rebleeding-free rate was 74.8%, and multivariate analysis showed that CP class C was associated with rebleeding (odds ratio, 2.404; 95% confidence-interval, 1.013-5.704; P=0.047).
BRTO can be performed safely and effectively for the treatment of GV bleeding. However, aggravation of EV or bleeding from EV is not uncommon after BRTO; thus, periodic endoscopy to follow-up of EV with or without prophylactic treatment might be necessary in LC patients undergoing BRTO.
PMCID: PMC3540373  PMID: 23323252
Balloon-occluded retrograde transvenous obliteration; Esophageal varices; Gastric varices; Liver cirrhosis; Variceal hemorrhage
13.  Increasing Trend of Colorectal Cancer Incidence in Korea, 1999-2009 
This study was conducted in order to demonstrate changing trends in colorectal cancer incidence according to sex, age group, and anatomical location in the Korean population.
Materials and Methods
Data from the Korea Central Cancer Registry between 1999 and 2009 were analyzed. Annual percent changes (APCs) of sex- and age-specific incidence rates for cancer of the proximal colon (International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD-10] code C18.0-18.5), distal colon (C18.6-18.7), and rectum (C19-20), and male-to-female incidence rate ratios (IRR) were calculated.
The age-standardized incidence rate (ASR) of colorectal cancer was 27 (per 100,000) in 1999 and increased to 50.2 in 2009 among men (APC, 6.6%). The ASR for women was 17.2 in 1999 and 26.9 in 2009 (APC, 5.1%). The rectum was the most common site of cancer among both men and women during 1999 and 2009. However, the distal colon had the highest APC (10.8% among men and 8.4% among women), followed by the proximal colon (7.9% among men and 6.6% among women), and rectum (5.2% among men and 2.4% among women). The proportion of rectal cancer decreased from 51.5% in 1999 to 47.1% in 2009 among men, and from 50.5% to 42.8% among women. An increase in the male-to-female IRR was observed for distal colon cancer and rectal cancer, whereas the IRR for proximal colon cancer was stable.
The rapid increase in colorectal cancer incidence is mainly attributed to the increase in colon cancer, especially distal colon cancer, and may be explained by a transition of risk factors for subsites or by the effect of colorectal cancer screening.
PMCID: PMC3546268  PMID: 23341785
Colorectal neoplasms; Incidence; Korea; Trends
14.  SRY-positive 78, XY ovotesticular disorder of sex development in a wolf cloned by nuclear transfer 
Journal of Veterinary Science  2012;13(2):211-213.
Recently, we reported the three wolves cloning with normal karyotype from somatic cells of endangered male gray wolves (Canis lupus), but one wolf had female external genitalia. In this study, we conducted further clinical, histological, and genetic analyses. This cloned wolf had a normal uterus but developed ovotestis. Through molecular analysis of the SRY gene, a mutation in the coding sequence of SRY gene could be excluded as a cause of intersexuality. This is the first report of a cloned wolf with a 78, XY ovotesticular disorder affecting sexual development characterized by bilateral ovotestes.
PMCID: PMC3386349  PMID: 22705746
hermaphrodite; intersexuality; wolf
15.  Ginkgo biloba extract (GbE) enhances the anti-atherogenic effect of cilostazol by inhibiting ROS generation 
Experimental & Molecular Medicine  2012;44(5):311-318.
In this study, the synergistic effect of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H)-quinolinone (cilostazol) and Ginkgo biloba extract (GbE) was examined in apolipoprotein E (ApoE) null mice. Co-treatment with GbE and cilostazol synergistically decreased reactive oxygen species (ROS) production in ApoE null mice fed a high-fat diet. Co-treatment resulted in a significantly decreased atherosclerotic lesion area compared to untreated ApoE mice. The inflammatory cytokines and adhesion molecules such as monocyte chemoattractant-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and VCAM-1 which can initiate atherosclerosis were significantly reduced by the co-treatment of cilostazol with GbE. Further, the infiltration of macrophages into the intima was decreased by co-treatment. These results suggest that co-treatment of GbE with cilostazol has a more potent anti-atherosclerotic effect than treatment with cilostazol alone in hyperlipidemic ApoE null mice and could be a valuable therapeutic strategy for the treatment of atherosclerosis.
PMCID: PMC3366324  PMID: 22282402
atherosclerosis; cilostazol; cytokines; disease models, animal; Ginkgo biloba; inflammation; macrophages; reactive oxygen species
16.  The Usefulness of Procalcitonin and C-Reactive Protein as Early Diagnostic Markers of Bacteremia in Cancer Patients with Febrile Neutropenia 
Procalcitonin (PCT) and C-reactive protein (CRP) are well known inflammatory markers. This study was designed to determine whether PCT and CRP are useful as early diagnostic markers for bacteremia in cancer patients with febrile neutropenia (FN) in the emergency department (ED).
Materials and Methods
In this retrospective study, 286 episodes of FN in the ED were consecutively included between June 2009 and August 2010. From medical records, clinical characteristics including PCT and CRP were extracted and analyzed.
Bacteremia was identified in 38 (13.3%) of the 286 episodes. The median values of PCT (2.8 ng/mL vs. 0.0 ng/mL, p=0.000) and CRP (15.9 mg/dL vs. 5.6 mg/dL, p=0.002) were significantly higher in the group with bacteremia compared to the group without bacteremia. In univariate analysis, elevated PCT (>0.5 ng/mL) and CRP (>10 mg/dL) as well as older age, hypotension, tachycardia, tachypnea, and high body temperature were significantly associated with bacteremia. On multivariate analysis, elevated PCT (>0.5 ng/mL) (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.4 to 9.2; p<0.01) and tachypnea (OR, 3.4; 95% CI, 1.4 to 8.5; p<0.01) were independent early diagnostic markers for bacteremia in FN patients. The area under the curve of PCT was 74.8% (95% CI, 65.1 to 84.6%) and that of CRP was 65.5% (95% CI, 54.8 to 76.1%). With a PCT cut-off value of 0.5 ng/mL, sensitivity and specificity were 60.5% and 82.3%, respectively, while the sensitivity and specificity were 57.6% and 67.3%, respectively, with a CRP cutoff of 10 mg/dL.
These findings suggest that PCT is a useful early diagnostic marker for the detection of bacteremia in FN at the ED and has better diagnostic value than CRP.
PMCID: PMC3192879  PMID: 22022295
Procalcitonin; C-reactive protein; Neutropenia; Biomarkers; Bacteremia
17.  Synergistically enhanced osteogenic differentiation of human mesenchymal stem cells by culture on nanostructured surfaces with induction media 
Biomacromolecules  2010;11(7):1856-1862.
We have examined the effects of surface nanotopography on in vitro osteogenesis of human mesenchymal stem cells (hMSCs). UV-assisted capillary force lithography was employed to fabricate a scalable (4 cm × 5 cm), well-defined nanostructured substrate of a UV curable polyurethane polymer with dots (150-, 400-, 600-nm diameter) and lines (150-, 400-, 600-nm width). The influence of osteogenic differentiation of hMSCs was characterized at day 8 by alkaline phosphatase (ALP) assay, RT-PCR, and real time PCR analysis. We found that hMSCs cultured on the nanostructured surfaces in osteogenic induction media showed significantly higher ALP activity compared to unpatterned PUA surface (control group). In particular, the hMSCs on the 400-nm dot pattern showed the highest level of ALP activity. Further investigation with real-time quantitative RT-PCR analysis demonstrated significantly higher expression of core binding factor 1 (Cbfa1), osteopontin (OP), and osteocalcin (OC) levels in hMSCs cultured on the 400-nm dot pattern in osteogenic induction media. These findings suggest that surface nanotopography can enhance osteogenic differentiation synergistically with biochemical induction substance.
PMCID: PMC2921863  PMID: 20568737
18.  Clinical outcomes of chemoradiotherapy for locally recurrent rectal cancer 
To assess the clinical outcome of chemoradiotherapy with or without surgery for locally recurrent rectal cancer (LRRC) and to find useful and significant prognostic factors for a clinical situation.
Between January 2001 and February 2009, 67 LRRC patients, who entered into concurrent chemoradiotherapy with or without surgery, were reviewed retrospectively. Of the 67 patients, 45 were treated with chemoradiotherapy plus surgery, and the remaining 22 were treated with chemoradiotherapy alone. The mean radiation doses (biologically equivalent dose in 2-Gy fractions) were 54.6 Gy and 66.5 Gy for the chemoradiotherapy with and without surgery groups, respectively.
The median survival duration of all patients was 59 months. Five-year overall (OS), relapse-free (RFS), locoregional relapse-free (LRFS), and distant metastasis-free survival (DMFS) were 48.9%, 31.6%, 66.4%, and 40.6%, respectively. A multivariate analysis demonstrated that the presence of symptoms was an independent prognostic factor influencing OS, RFS, LRFS, and DMFS. No statistically significant difference was found in OS (p = 0.181), RFS (p = 0.113), LRFS (p = 0.379), or DMFS (p = 0.335) when comparing clinical outcomes between the chemoradiotherapy with and without surgery groups.
Chemoradiotherapy with or without surgery could be a potential option for an LRRC cure, and the symptoms related to LRRC were a significant prognostic factor predicting poor clinical outcome. The chemoradiotherapy scheme for LRRC patients should be adjusted to the possibility of resectability and risk of local failure to focus on local control.
PMCID: PMC3118124  PMID: 21595980
19.  Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells 
Respiratory Research  2011;12(1):49.
Many studies have found that smoking reduces lung function, but the relationship between cigarette smoke and allergic asthma has not been clearly elucidated, particularly the role of mast cells. This study aimed to investigate the effects of smoke exposure on allergic asthma and its association with mast cells.
BALB/c mice were sensitized and challenged by OVA to induce asthma, and bone marrow-derived mast cells (BMMCs) were stimulated with antigen/antibody reaction. Mice or BMMCs were exposed to cigarette smoke or CSE solution for 1 mo or 6 h, respectively. The recruitment of inflammatory cells into BAL fluid or lung tissues was determined by Diff-Quik or H&E staining, collagen deposition by Sircol assay, penh values by a whole-body plethysmography, co-localization of tryptase and Smad3 by immunohistochemistry, IgE and TGF-β level by ELISA, expressions of Smads proteins, activities of signaling molecules, or TGF-β mRNA by immunoblotting and RT-PCR.
Cigarette smoke enhanced OVA-specific IgE levels, penh values, recruitment of inflammatory cells including mast cells, expressions of smad family, TGF-β mRNA and proteins, and cytokines, phosphorylations of Smad2 and 3, and MAP kinases, co-localization of tryptase and Smad3, and collagen deposition more than those of BAL cells and lung tissues of OVA-induced allergic mice. CSE solution pretreatment enhanced expressions of TGF-β, Smad3, activities of MAP kinases, NF-κB/AP-1 or PAI-1 more than those of activated-BMMCs.
The data suggest that smoke exposure enhances antigen-induced mast cell activation via TGF-β/Smad signaling pathways in mouse allergic asthma, and that it exacerbates airway inflammation and remodeling.
PMCID: PMC3098800  PMID: 21496353
20.  Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L 
Astrocytes, which play an active role in chronic inflammatory diseases like multiple sclerosis, exist close to mast cells with which they share perivascular localization. We previously demonstrated the possibility that astrocytes and mast cells interact in vitro and in vivo. This study aimed to investigate the signaling pathways and the role for astrocytes in the interaction of astrocytes and mast cells.
We co-cultured human U87 glioblastoma (U87) and human mast cell-1 (HMC-1) cell lines, and mouse cerebral cortices-derived astrocytes and mouse bone marrow-derived mast cells (BMMCs). Intracellular Ca2+ ([Ca2+]i) was measured by confocal microscopy; CD40 siRNA by Silencer Express Kit; small GTPases by GTP-pull down assay; PKCs, MAPKs, CD40, CD40L, Jak1/2, STAT1, TNF receptor 1 (TNFR1) by Western blot; NF-κB and AP-1 by EMSA; cytokines by RT-PCR. An experimental allergic encephalomyelitis (EAE) model was induced using myelin oligodendrocyte glycoprotein (MOG) peptide and pertussis toxin in mice. Co-localization of TNFR1 and astrocytes in EAE brain tissues was determined by immunohistochemistry.
Each astrocyte co-culture had increases in [Ca2+]i levels, release of cytokines and chemokines; activities of Rho-family GTPases, NF-κB/AP-1/STAT1727, and Jack1/2, STAT1701. These effects were inhibited by anti-CD40 antibody or CD40 siRNA, and signaling pathways for Jak1/2 were inhibited by anti-TNFR1 antibody. EAE score, expression of TNFR1, and co-localization of TNFR1 and astrocytes were enhanced in brain of the EAE model. Anti-CD40 antibody or 8-oxo-dG pretreatment reduced these effects in EAE model.
These data suggest that astrocytes activated by the CD40-CD40L interaction in co-culture induce inflammatory cytokine production via small GTPases, and the secreted cytokines re-activate astrocytes via Jak/STAT1701 pathways, and then release more cytokines that contribute to exacerbating the development of EAE. These findings imply that the pro-inflammatory mediators produced by cell-to-cell cross-talk via interaction of CD40-CD40L may be as a promising therapeutic target for neurodegenerative diseases like MS.
PMCID: PMC3068960  PMID: 21410936
21.  Epidemiological characteristics of pulmonary pneumocystosis and concurrent infections in pigs in Jeju Island, Korea 
Journal of Veterinary Science  2011;12(1):15-19.
Epidemiological characteristics of swine pulmonary Pneumocystis (P.) carinii and concurrent infections were surveyed on Jeju Island, Korea, within a designated period in 172 pigs submitted from 54 farms to the Department of Veterinary Medicine, Jeju National University. The submitted cases were evaluated by histopathology, immunohistochemistry, PCR/RT-PCR, and bacteriology. P. carinii infection was confirmed in 39 (22.7%) of the 172 pigs. Histopathologically, the lungs had moderate to severe lymphohistioctyic interstitial pneumonia with variable numbers of fungal organisms within lesions. Furthermore, porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV-2) co-infection was a common phenomenon (12.8%, 20.5%, and 48.7% were positive for PRRS, PCV-2, or both, respectively, as determined by PCR/RT-PCR). Infection was much more concentrated during winter (December to March) and 53.8% of the infected pigs were 7- to 8-weeks old. In addition, three pigs showed co-infection with bacteria such as Pasteurella multocida and Streptococcus suis. The results of the present study suggest that the secondary P. carinii infection is common following primary viral infection in swine in Korea. They further suggest that co-infection of P. carinii might be enhanced by the virulence of primary pathogens or might have synergistic effects in the pigs with chronic wasting diseases.
PMCID: PMC3053462  PMID: 21368558
concurrent infection; P. carinii; PCV-2; pig; PRRSV
22.  Whole-liver radiotherapy for end-stage colorectal cancer patients with massive liver metastases and advanced hepatic dysfunction 
To investigate whether whole-liver radiotherapy (RT) is beneficial in end-stage colorectal cancer with massive liver metastases and severe hepatic dysfunction.
Between June 2004 and July 2008, 10 colorectal cancer patients, who exhibited a replacement of over three quarters of their normal liver by metastatic tumors and were of Child-Pugh class B or C in liver function with progressive disease after undergoing chemotherapy, underwent whole-liver RT. RT was administered using computed tomography-based three-dimensional planning and the median dose was 21 Gy (range, 21-30) in seven fractions. Improvement in liver function tests, defined as a decrease in the levels within 1 month after RT, symptom palliation, toxicity, and overall survival were analyzed retrospectively.
Levels of alkaline phosphatase, total bilirubin, aspartate transaminase, and alanine transaminase improved in 8, 6, 9, and all 10 patients, respectively, and the median reduction rates were 42%, 68%, 50%, and 57%, respectively. Serum carcinoembryonic antigen level decreased after RT in three of four assessable patients. For all patients, pain levels decreased and acute toxicity consisted of nausea/vomiting of grade ≤ 2. Further chemotherapy became possible in four of 10 patients. Mean survival after RT was 80 ± 80 days (range, 20-289); mean survival for four patients who received post-RT chemotherapy was 143 ± 100 days (range, 65-289), versus 38 ± 16 days (range, 20-64) for the six patients who did not receive post-RT chemotherapy (p = 0.127).
Although limited by small case number, this study demonstrated a possible role of whole-liver RT in improving hepatic dysfunction and delaying mortality from hepatic failure for end-stage colorectal cancer patients with massive liver metastases. Further studies should be followed to confirm these findings.
PMCID: PMC2987942  PMID: 20977728
23.  Histopathological risk factors for lymph node metastasis in submucosal invasive colorectal carcinoma of pedunculated or semipedunculated type 
Journal of Clinical Pathology  2006;60(8):912-915.
To evaluate the histopathological risk factors for lymph node metastasis in cases of pedunculated or semipedunculated submucosal invasive colorectal carcinoma (SICC).
A total of 48 patients with non‐sessile SICC who underwent systematic lymph node dissection were included. Tumour size, histological grade, angiolymphatic invasion, tumour budding, dedifferentiation, objective submucosal invasion depth from the identified muscularis mucosa, relative invasion depth of the submucosal layer, and depth of stalk invasion were investigated histopathologically.
Lymph node metastasis was observed in seven cases (14.6%). Univariate analysis showed angiolymphatic invasion and tumour budding to be significantly associated with lymph node metastasis. Multivariate analysis showed that tumour budding was the only independent factor associated with lymph node metastasis in cases of non‐sessile SICC.
Results indicate that tumour budding is a useful risk factor for predicting lymph node metastasis in cases of pedunculated or semipedunculated SICC.
PMCID: PMC1994481  PMID: 16997919
colorectal carcinoma; pedunculated; lymph node metastasis; risk factors; tumour budding
24.  Porcine abortion outbreak associated with Toxoplasma gondii in Jeju Island, Korea 
Journal of Veterinary Science  2009;10(2):147-151.
This report deals with the acute onset of an abortion outbreak and high sow mortality in one pig herd consisted of 1,200 pigs and 120 sows on Jeju Island, Korea. Affected pregnant sows showed clinical signs, including high fever, gradual anorexia, vomiting, depression, recumbency, prostration, abortion, and a few deaths. Four dead sows, five aborted fetuses from the same litter, and 17 sera collected from sows infected or normal were submitted to the Pathology Division of the National Veterinary Research and Quarantine Service for diagnostic investigation. Grossly, hepatomegaly and splenomegaly were observed in sows. Multiple necrotic foci were scattered in the lungs, liver, spleen, and lymph nodes. Microscopically, multifocal necrotizing lesions and protozoan tachyzoites were present in the lesions. Tachyzoites of Toxoplasma (T.) gondii were detected immunohistochemically. Latex agglutination showed that the sera of 7 of 17 (41.2%) sows were positive for antibody to T. gondii. The disease outbreak in this herd was diagnosed as epizootic toxoplasmosis. To our knowledge, this is the first report of porcine toxoplasmosis with a high abortion rate and sow mortality in Korea.
PMCID: PMC2801119  PMID: 19461210
abortion; pig; sow mortality; tachyzoite; Toxoplasma gondii
25.  Cerebellar vermian hypoplasia in a Cocker Spaniel 
Journal of Veterinary Science  2008;9(2):215-217.
An eight-week-old female Cocker Spaniel was presented with ataxia, dysmetria and intention tremor. At 16 weeks, the clinical signs did not progress. Investigation including imaging studies of the skull and cerebrospinal fluid analysis were performed. The computed tomography revealed a cyst-like dilation at the level of the fourth ventricle associated with vermal defect in the cerebellum. After euthanasia, a cerebellar hypoplasia with vermal defect was identified on necropsy. A polymerase chain reaction amplification of cerebellar tissue revealed the absence of an in utero parvoviral infection. Therefore, the cerebellar hypoplasia in this puppy was consistent with diagnosis of primary cerebellar malformation comparable to Dandy-Walker syndrome in humans.
PMCID: PMC2839102  PMID: 18487946
cerebellar hypoplasia; dog; vermian defect

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