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1.  Nomogram to predict ypN status after chemoradiation in patients with locally advanced rectal cancer 
British Journal of Cancer  2014;111(2):249-254.
Pelvic lymph node (LN) status after preoperative chemoradiotherapy (CRT) is an important indicator of oncologic outcome in patients with locally advanced rectal cancer. The purpose of this study was to develop a nomogram to predict LN status after preoperative CRT in locally advanced rectal cancer patients.
The nomogram was developed in a training cohort (n=891) using logistic regression analyses and validated in a validation cohort (n=258) from a prospectively registered tumour registry at Asan Medical Center. The model was internally and externally validated for discrimination and calibration using bootstrap resampling. Model performance was evaluated by the concordance index (c-index) and calibration curve.
Pretreatment ypT stage, patient age, preCRT tumour differentiation, cN stage, lymphovascular invasion, and perineural invasion were reliable predictors of LN metastasis after preoperative CRT. The nomogram developed using these parameters had c-indices of 0.81 (training) and 0.77 (validation). The calibration plot suggested good agreement between actual and nomogram-predicted LN status after preoperative CRT.
This nomogram improves prediction of LN status after preoperative CRT in patients with locally advanced rectal cancer. It will be useful for counselling patients as well as for the design and stratification of patients in clinical trials.
PMCID: PMC4102937  PMID: 24967873
rectal cancer; preoperative chemoradiotherapy; nomogram; lymph node
2.  Daily physical activity and physical function in adult maintenance hemodialysis patients 
Maintenance hemodialysis (MHD) patients reportedly display reduced daily physical activity (DPA) and physical performance. Low daily physical activity and decreased physical performance are each associated with worse outcomes in chronic kidney disease patients. Although daily physical activity and physical performance might be expected to be related, few studies have examined such relationships in MHD patients, and methods for examining daily physical activity often utilized questionnaires rather than activity monitors. We hypothesized that daily physical activity and physical performance are reduced and correlated with each other even in relatively healthier MHD patients.
Daily physical activity, 6-min walk distance (6-MWT), sit-to-stand, and stair-climbing tests were measured in 72 MHD patients (32 % diabetics) with limited comorbidities and 39 normal adults of similar age and gender mix. Daily physical activity was examined by a physical activity monitor. The human activity profile was also employed.
Daily physical activity with the activity monitor, time-averaged over 7 days, and all three physical performance tests were impaired in MHD patients, to about 60–70 % of normal values (p < 0.0001 for each measurement). Human activity profile scores were also impaired (p < 0.0001). MHD patients spent more time sleeping or in marked physical inactivity (p < 0.0001) and less time in ≥ moderate activity (p < 0.0001). These findings persisted when comparisons to normals were restricted to men or women separately. After adjustment, daily physical activity correlated with 6-MWT but not the two other physical performance tests. Human activity profile scores correlated more closely with all three performance tests than did DPA.
Even in relatively healthy MHD patients, daily physical activity and physical performance are substantially impaired and correlated. Whether training that increases daily physical activity or physical performance will improve clinical outcome in MHD patients needs to be examined.
PMCID: PMC4159490  PMID: 24777474
Chronic kidney disease; Kidney failure; Physical performance; Exercise; Exercise capacity
Biology of Sport  2014;31(1):73-79.
The study investigated the effect of high- and low-intensity exercise training on inflammatory reaction of blood and skeletal muscle in streptozotocin (STZ)-induced diabetic male Sprague-Dawley rats (243 ± 7 g, 8 weeks). The rats completed treadmill running in either high-intensity exercise (6 weeks of exercise training, acute bouts of exercise) or low-intensity exercise (6 weeks of exercise training). Non-running, sedentary rats served as controls. To induce diabetes mellitus, rats received a peritoneal injection of STZ (50 mg · kg−1). Rats were sacrificed immediately after an acute bout of exercise and 6 weeks of exercise training. Inflammatory factors were analyzed by ELISA and by immune blotting from the soleus and extensor digitorum longus muscles. In the serum, inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-4) and reactive oxygen species (ROS) (nitric oxide and malondialdehyde) increased in diabetic rats. However, all exercise training groups displayed reduced inflammatory cytokines and reactive oxygen species. In skeletal muscles, low-intensity exercise training, but not high intensity exercise, reduced the levels of COX-2, iNOS, and MMP-2, which were otherwise markedly elevated in the presence of STZ. Moreover, the levels of GLUT-4 and MyoD were effectively increased by different exercise intensity and exercise duration. Low-intensity exercise training appeared most effective to reduce diabetes-related inflammation. However, high-intensity training also reduced inflammatory factors in tissue-specific muscles. The data implicate regular exercise in protecting against chronic inflammatory diseases, such as diabetes.
PMCID: PMC3994589  PMID: 25187675
diabetes mellitus; intensity exercise training; inflammation; ROS; GLUT-4; MyoD
4.  Feasibility of proposed single-nucleotide polymorphisms as predictive markers for targeted regimens in metastatic colorectal cancer 
British Journal of Cancer  2013;108(9):1862-1869.
Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy.
A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway.
For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively.
LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.
PMCID: PMC3658526  PMID: 23579219
colorectal cancer; targeted chemotherapy; marker; LIFR rs3729740; ANXA11 rs1049550
5.  Ret finger protein inhibits muscle differentiation by modulating serum response factor and enhancer of polycomb1 
Cell Death and Differentiation  2011;19(1):121-131.
Skeletal myogenesis is precisely regulated by multiple transcription factors. Previously, we demonstrated that enhancer of polycomb 1 (Epc1) induces skeletal muscle differentiation by potentiating serum response factor (SRF)-dependent muscle gene activation. Here, we report that an interacting partner of Epc1, ret finger protein (RFP), blocks skeletal muscle differentiation. Our findings show that RFP was highly expressed in skeletal muscles and was downregulated during myoblast differentiation. Forced expression of RFP delayed myoblast differentiation, whereas knockdown enhanced it. Epc1-induced enhancements of SRF-dependent multinucleation, transactivation of the skeletal α-actin promoter, binding of SRF to the serum response element, and muscle-specific gene induction were blocked by RFP. RFP interfered with the physical interaction between Epc1 and SRF. Muscles from rfp knockout mice (Rfp−/−) mice were bigger than those from wild-type mice, and the expression of SRF-dependent muscle-specific genes was upregulated. Myotube formation and myoblast differentiation were enhanced in Rfp−/− mice. Taken together, our findings highlight RFP as a novel regulator of muscle differentiation that acts by modulating the expression of SRF-dependent skeletal muscle-specific genes.
PMCID: PMC3252832  PMID: 21637294
ret finger protein; muscle differentiation; serum response factor; enhancer of polycomb1
6.  Efficacy and safety of solifenacin succinate in Korean patients with overactive bladder: a randomised, prospective, double-blind, multicentre study 
We assessed the efficacy and safety of solifenacin compared with tolterodine for treatment of overactive bladder (OAB) in Korean patients.
Materials and methods:
The study was randomised, double-blind, tolterodine-controlled trial in Korea. Patients had average frequency of ≥ 8 voids per 24 h and episodes of urgency or urgency incontinence ≥ 3 during 3-day voiding diary period. Patients were randomised to 12-week double-blind treatment with either tolterodine immediate release (IR) 2 mg twice daily (TOL4) or solifenacin 5 mg (SOL5) or 10 mg (SOL10) once daily. The outcome measure was mean change in daily micturition frequency, volume, daily frequency of urgency incontinence, urgency and nocturia from baseline to week 12. Quality of life was assessed using the King’s Health Questionnaire.
A total of 357 were randomised and 329 were evaluated for efficacy. All voiding parameters recorded in micturition diary improved after treatment in all three groups. Mean changes in volume voided were 19.30 ml (26.69%) in TOL4, 30.37 ml (25.89%) in SOL5 and 37.12 ml (33.36%) in SOL10 group (p = 0.03). Speed of onset of SOL10 efficacy on urgency incontinence was faster than that of SOL5 and TOL4. Quality of life improved in all three groups. Dry mouth was the most common adverse event; its incidence was the lowest in SOL5 group (7.63%, compared with 19.49% and 18.64% in SOL10 and TOL4 groups respectively).
Solifenacin succinate 5 and 10 mg once daily improve OAB symptoms with acceptable tolerability levels compared with tolterodine IR 4 mg. Solifenacin 5 mg is a recommended starting dose in Korean patients with OAB.
PMCID: PMC2680337  PMID: 19143854
7.  Phase II study of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck 
British Journal of Cancer  2005;93(10):1117-1121.
We aimed to evaluate the efficacy and safety of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In total, 37 patients with stage III or IV SCCHN were enrolled on the study. The chemotherapy consisted of two cycles of intravenous cisplatin of 80 mg m−2 on day 1 and oral capecitabine 825 mg m−2 twice daily from day 1 to day 14 at 3-week intervals. The radiotherapy (1.8–2.0 Gy 1 fraction day−1 to a total dose of 70–70.2 Gy) was delivered to the primary tumour site and neck. The primary tumour sites were as follows: oral cavity (n=6), oropharynx (n=11), hypopharynx (n=8), larynx (n=3), nasopharynx (n=6), and paranasal sinus (n=3). After the chemoradiotherapy, 29 complete responses (78.4%) and 6 partial responses (16.2%) were confirmed. Grade 3 or 4 neutropenia occurred only in two patients, plus grade 3 febrile neutropenia was observed only in one patient. At a median follow-up duration of 19.8 months, the estimated overall survival and progression-free survival rate at 2-year was 76.8 and 57.9%, respectively. Concurrent chemoradiotherapy with capecitabine and cisplatin was found to be well tolerated and effective in patients with locally advanced SCCHN.
PMCID: PMC2361495  PMID: 16251869
capecitabine; chemoradiotherapy; cisplatin; head and neck cancer
8.  Virus activation by vitamin A and NO2 gas exposures in hamsters. 
Hamsters exposed to 10 ppm NO2 for 5 hr once a week for 4 weeks while undergoing acute vitamin A deficiency showed much reduced epithelial cell regeneration in the terminal bronchioles. Quantitative analysis done by autoradiography and scintillation counting from lung tissues indicates much reduced cell kinetics occurring in terminal bronchiolar alveolar region. Alveolar necrosis was often observed and no type II cell reversion occurred. Virus particles were found within the alveolar epithelial plasma membrane.
PMCID: PMC1637426  PMID: 908309
9.  Natural occurrence of Fusarium mycotoxins (trichothecenes and zearalenone) in barley and corn in Korea. 
Applied and Environmental Microbiology  1993;59(11):3798-3802.
Barley is produced in four provinces, Chonbuk, Chonnam, Kyungbuk, and Kyungnam, and corn is mainly produced in the Kangwon province in Korea. The natural occurrence of Fusarium mycotoxins was surveyed in 39 barley and 46 corn samples from different areas. Five 8-ketotrichothecenes, namely deoxynivalenol (DON), nivalenol (NIV), 4-acetylnivalenol (4-ANIV), 3-acetyldeoxynivalenol (3-ADON), and 4,15-diacetylnivalenol (4,15-DANIV), and zearalenone (ZEA) were detected in barley. DON, NIV, and ZEA were the major contaminants in barley, with mean levels of 170, 1,011, and 287 ng/g, respectively. On the other hand, DON, 15-acetyldeoxynivalenol (15-ADON), NIV, 4-ANIV, 4,15-DANIV, and ZEA were detected in corn samples. DON and 15-ADON were the major contaminants in corn, with mean levels of 310 and 297 ng/g, respectively. The survey indicated that the natural occurrence of monoacetyl-DON and the ratios of NIV to DON in two cereals were different. In addition, this is the first report of the natural occurrence of 4,15-DANIV in cereals.
PMCID: PMC182534  PMID: 8285686
10.  A case of disseminated Trichosporon beigelii infection in a patient with myelodysplastic syndrome after chemotherapy. 
Journal of Korean Medical Science  2001;16(4):505-508.
Trichosporonosis is a potentially life-threatening infection with Trichosporon beigelii, the causative agent of white piedra. The systemic infection by this fungus has been most frequently described in immunocompromised hosts with neutropenia. Here, we report the first patient with disseminated infection by T. beigelii in Korea, acquired during a period of severe neutropenia after chemo-therapy for myelodysplastic syndrome. The patient recovered from the infection after an early-intensified treatment with amphotericin B and a rapid neutrophil recovery. The disseminated infection by T. beigelii is still rare, however, is an emerging fatal mycosis in immunocompromised patients with severe neutropenia.
PMCID: PMC3054774  PMID: 11511798
11.  Germline mutations of the STK11 gene in Korean Peutz–Jeghers syndrome patients 
British Journal of Cancer  2000;82(8):1403-1406.
Peutz–Jeghers syndrome (PJS) is an autosomal dominantly inherited disease characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation, with an increased risk for various neoplasms, including gastrointestinal cancer. Recently, the PJS gene encoding the serine/threonine kinase STK11 (also named LKB1) was mapped to chromosome 19p13.3, and germline mutations were identified in PJS patients. We screened a total of ten Korean PJS patients (nine sporadic cases and one familial case including two patients) to investigate the germline mutations of the STK11 gene. By polymerase chain reaction–single-strand conformation polymorphism and DNA sequencing analysis, three kinds of mis-sense mutation and a frame-shift mutation were identified: codon 232 (TCC to CCC) in exon 5, codon 256 (GAA to GCA) in exon 6, codon 324 (CCG to CTG) in exon 8, and a guanine insertion at codon 342 resulting in a premature stop codon in exon 8. These mis-sense variants were not detected in 100 control DNA samples. Furthermore, we found an intronic mutation at the dinucleotide sequence of a splice-acceptor site: a one base substitution from AG to CG in intron 1, which may cause aberrant splicing. Most reported germline mutations of the STK11 gene in PJS patients were frame-shift or non-sense mutations resulting in truncated proteins. Together, these findings indicate that germline mis-sense mutations of the STK11 gene are found in PJS patients in addition to truncating mutations. The effects of these mutations on protein function require further examination. In summary, we found germline mutations of the STK11 gene in five out of ten Korean PJS patients. © 2000 Cancer Research Campaign
PMCID: PMC2363369  PMID: 10780518
Peutz–Jeghers syndrome; STK11; germline mutation
12.  Combination of oxaliplatin, fluorouracil, and leucovorin in the treatment of fluoropyrimidine-pretreated patients with metastatic colorectal cancer. 
There has been no standard therapy for patients with metastatic colorectal cancer who have failed to first-line fluorouracil-based treatment. The present study was designed to assess the efficacy and toxicities of a combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin in fluoropyrimidine-pretreated patients with metastatic colorectal cancer. Chemotherapy consisted of oxaliplatin 85 mg/m2 on day 1, followed by leucovorin 20 mg/m2 and 5-FU 1,200 mg/m2 on days 1 and 2. Treatment courses were repeated every two weeks. Thirty-nine patients were enrolled in this study. All patients previously received fluoropyrimidine-based chemotherapy. Thirty-one patients were assessable for response and 33 for treatment toxicity. Six patients required dose reduction of 5-FU due to grade III/IV cytopenia. Nausea/vomiting and peripheral neuropathy were common non-hematologic toxicities. Overall response rate was 42.0% including 3 complete response and 10 partial response. The median response duration was 91 days (range, 28-224+). The median duration of progression-free survival was 132 days (range, 40-308). A combination of oxaliplatin, 5-FU, and leucovorin showed high response rate in fluoropyrimidine-pretreated patients with metastatic colorectal cancer, but the duration of response was relatively short. It may be worthwhile to explore its therapeutic potential in the first-line treatment setting.
PMCID: PMC3054558  PMID: 11289404
13.  Isolated splenic metastasis from colorectal carcinoma: a case report. 
Journal of Korean Medical Science  2000;15(3):355-358.
Isolated splenic metastasis arising from colorectal carcinoma is very rare and there has been only 6 cases reported in the English literature. A new case is presented, and its possible pathogenesis was considered with previously reported cases. A 65-year-old male patient had received a right hemicolectomy for ascending colon cancer 36 months earlier. He was followed up regularly with serial measurement of serum carcinoembryonic antigen (CEA). Rising serum CEA was discovered from 33 months postoperatively and CT revealed an isolated splenic metastasis. He therefore underwent splenectomy, which was proven to be a metastatic adenocarcinoma with similar histological feature to the original tumor. As all reported cases showed elevated serum CEA at the time of metastasis, isolated splenic metastasis might be associated with CEA in regard to its biological functions of immunosuppression and adhesion.
PMCID: PMC3054643  PMID: 10895982
14.  Extramammary Paget's disease with aggressive behavior: a report of two cases. 
Journal of Korean Medical Science  1999;14(2):223-226.
Extramammary Paget's disease (EMPD) is an intraepithelial neoplastic disorder which is included as a rare malignant condition. However, it sometimes shows aggressive behavior of local recurrence and coexisting malignancy. We had experienced nine cases of EMPD involving the scrotum for seven years. Two cases of them presented metastasis. The first case presented extensive inguinal lymph node metastasis with underlying adnexal adenocarcinoma one year after wide local excision. The second case initially presented multiple metastasis to the liver and in the lymph node. The latter, showing fulminant progression with liver metastasis, may be only the second case reported in English literature. EMPD is considered as a malignant neoplasm with aggressive behavior from initial presentation. Because wide local excision of the lesion alone may be occasionally insufficient, a careful follow-up must be done to detect recurrence or internal malignancy.
PMCID: PMC3054357  PMID: 10331574
15.  Vitamin A and the susceptibility of respiratory tract tissues to carcinogenic insult. 
The influence of vitamin A on the development of chemically induced lung carcinomas in rats was investigated. Rats were maintained on low, "normal" and excess levels of retinyl acetate (RA). Respiratory tract-squamous carcinomas were induced by intratracheal injections of 3-methylcholanthrene (3-MCA). The carcinogen doses used ranged from 1.25 to 10.0 mg of 3-MCA. Serial sacrifices conducted during the first 20 weeks following carcinogen exposure showed that metaplastic lung nodules, presumed to be precursors of later appearing carcinomas, occurred earlier and at higher incidence in rats maintained on low levels of RA than in rats maintained on moderate or high levels of RA. The development of invasive pulmonary carcinomas was enhanced at all four carcinogen doses in rats receiving low levels of RA as compared to rats receiving moderate or high levels of RA. No consistent difference in lung cancer incidence existed between the groups receiving normal and high levels of RA. The data clearly show an increased susceptibility of vitamin A-deficient rats to develop chemically induced lung cancers. Possible mechanisms underlying this effect are discussed.
PMCID: PMC1637367  PMID: 510247
17.  Extensive colonic stricture due to pelvic actinomycosis. 
Journal of Korean Medical Science  1995;10(2):142-146.
A 36-year-old woman presented with a palpable tender mass at the left lower quadrant of the abdomen. She had suffered from constipation for five years and had a previous history of intrauterine device-use for one year. Preoperative barium enema and abdominopelvic CT showed a compatible finding of rectosigmoid colon cancer or left ovary cancer. She underwent segmental resection of the sigmoid colon along with the removal of left distal ureter, left ovary and salpinx. Pathologic examination revealed actinomycotic abscesses containing sulfur granules. Thereafter, she took parenteral ampicillin (50mg/kg/day) for one month and oral amoxicillin (250mg, tid) for 2 months consecutively. The patient has no specific problems for 6 months after surgical resection and long-term antibiotic therapy. This report may be the first of intrauterine device-associated pelvic actinomycosis involving both sigmoid colon and rectum extensively.
PMCID: PMC3054142  PMID: 7576294
18.  Sambutoxin, a new mycotoxin produced by toxic Fusarium isolates obtained from rotted potato tubers. 
Applied and Environmental Microbiology  1994;60(12):4380-4386.
Ninety-nine isolates of Fusarium species were obtained from rotted potato tubers from various parts of Korea. Of these isolates, 80 were identified as Fusarium oxysporum, F. solani, or F. sambucinum. The isolates of these species were grown on autoclaved wheat grains and examined for toxicity in a rat-feeding test. A total of 8 of 57 F. oxysporum isolates, 3 of 14 F. solani isolates, and 5 of 9 F. sambucinum isolates caused the death of the rats. Of the 16 toxic isolates, 1 isolate of F. oxysporum produced a substantial amount of moniliformin, which could account for its toxicity. None of the other 15 isolates produced trichothecenes, moniliformin, fusarochromanone, fumonisin B1, or wortmannin. F. sambucinum PZF-4 produced an unknown toxin in wheat culture. This new toxin, given the trivial name sambutoxin, caused toxic effects in rats, including body weight loss, feed refusal, hemorrhage in the stomach and intestines, and, finally, death when rats were fed diets supplemented with 0.05 and 0.1% sambutoxin. The toxin was also toxic to chicken embryos, and the 50% lethal concentration was 29.6 micrograms per egg. Sambutoxin formed as white crystals that turned purple when combined with reagents such as sulfuric acid and p-anisaldehyde. It exhibited a green color immediately after treatment with potassium ferricyanide-ferric chloride. Its UV spectrum had absorption maxima at 213, 233, and 254 nm, and its infrared spectrum showed an amide group at 1,650 and 1,560 cm-1 and a hydroxy group at 3,185 cm-1. Mass spectrometry showed that the molecular weight of the toxin was 453 and the molecular formula was C28H39NO4.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC201996  PMID: 7811078

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