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1.  Gentamicin-Loaded Wound Dressing With Polyvinyl Alcohol/Dextran Hydrogel: Gel Characterization and In Vivo Healing Evaluation 
AAPS PharmSciTech  2010;11(3):1092-1103.
To develop a gentamicin-loaded wound dressing, cross-linked hydrogel films were prepared with polyvinyl alcohol (PVA) and dextran using the freezing–thawing method. Their gel properties such as gel fraction, swelling, water vapor transmission test, morphology, tensile strength, and thermal property were investigated. In vitro protein adsorption test, in vivo wound healing test, and histopathology were performed. Dextran decreased the gel fraction, maximum strength, and thermal stability of hydrogels. However, it increased the swelling ability, water vapor transmission rate, elasticity, porosity, and protein adsorption. The drug gave a little positive effect on the gel properties of hydrogels. The gentamicin-loaded wound dressing composed of 2.5% PVA, 1.13% dextran, and 0.1% drug was more swellable, flexible, and elastic than that with only PVA because of its cross-linking interaction with PVA. In particular, it could provide an adequate level of moisture and build up the exudates on the wound area. From the in vivo wound healing and histological results, this gentamicin-loaded wound dressing enhanced the healing effect more compared to conventional product because of the potential healing effect of gentamicin. Thus, this gentamicin-loaded wound dressing would be used as a potential wound dressing with excellent forming and improved healing effect in wound care.
doi:10.1208/s12249-010-9474-0
PMCID: PMC2974132  PMID: 20607628
dextran; gentamicin; histological examination; wound dressing; wound healing effect
2.  Intracranial Extraskeletal Myxoid Chondrosarcoma : Case Report and Literature Review 
Intracranial extraskeletal myxoid chondrosarcoma is extremely rare, with only seven patients previously reported. We present a case report of a 21-year-old woman admitted for weakness in her right extremities and symptoms of increased intracranial pressure. Magnetic resonance imaging (MRI) revealed hydrocephalus and a well-enhanced large mass around her left thalamus. A left parietal craniotomy and a cortisectomy at the superior parietal lobule were performed. Total surgical resection was also performed, and pathology results confirmed an extraskeletal myxoid chondrosarcoma. Postoperative MRI showed no residual tumor, and the patient underwent radiotherapy. After six months of radiotherapy, the patient's headache and weakness had improved to grade IV. This malignant tumor showed high rates of recurrence in previous reports. We here report another occurrence of this highly malignant and rare tumor in a patient treated using total surgical excision and adjuvant radiotherapy.
doi:10.3340/jkns.2012.52.3.246
PMCID: PMC3483328  PMID: 23115670
Brain neoplasms; Chondrosarcoma; Choroid plexus
3.  Blockade of ERK Phosphorylation in the Nucleus Accumbens Inhibits the Expression of Cocaine-induced Behavioral Sensitization in Rats 
Repeated administration of psychostimulants such as cocaine leads to the development of behavioral sensitization. Extracellular signal-Regulated Kinase (ERK), an enzyme important for long-term neuronal plasticity, has been implicated in such effects of these drugs. Although the nucleus accumbens (NAcc) is the site mediating the expression of behavioral sensitization by drugs of abuse, the precise role of ERK activation in this site has not been determined. In this study we demonstrate that blockade of ERK phosphorylation in the NAcc by a single bilateral microinjections of PD98059 (0.5 or 2.0µ g/side), or U0126 (0.1 or 1.0µg/side), into this site dose-dependently inhibited the expression of cocaine-induced behavioral sensitization when measured at day 7 following 6 consecutive daily cocaine injections (15 mg/kg, i.p.). Acute microinjection of either vehicle or PD98059 alone produced no different locomotor activity compared to saline control. Further, microinjection of PD98059 (2.0µ g/side) in the NAcc specifically lowered cocaine-induced increase of ERK phosphorylation levels in this site, while unaffecting p-38 protein levels. These results indicate that ERK activation in the NAcc is necessary for the expression of cocaine-induced behavioral sensitization, and further suggest that repeated cocaine evokes neuronal plasticity involving ERK pathway in this site leading to long-lasting behavioral changes.
doi:10.4196/kjpp.2011.15.6.389
PMCID: PMC3282227  PMID: 22359477
Cocaine; Behavioral sensitization; PD98059; U0126; Nucleus accumbens
4.  Experience and analysis of level VII cervical lymph node metastases in patients with papillary thyroid carcinoma 
Purpose
Papillary thyroid cancer with level VII (anterior superior mediastinal lymph nodes) lymph node metastasis belongs to Stage IV a according to the Americal Joint Committee on Cancer cancer staging. The aim of our study was to identify clinicopathologic factors that are related to level VII cervical lymph node metastasis and to suggest recommendations for level VII dissection.
Methods
We reviewed 195 patients with papillary thyroid carcinoma who had their initial operation containing level VII dissection from April 2006 to June 2007. Level VII dissection involved lymph nodes in the anterior superior mediastinum and tracheoesophageal grooves, extending from the suprasternal notch to the innominate artery. Clinicophathologic factors, such as gender, age and lateral neck metastasis, related to Level VII metastasis were analyzed by tumor size, multifocality of tumor, extrathyroidal extension and lymphovascular invasion.
Results
Nine (4.6%) of 195 patients with papillary thyroid carcinoma had level VII metastasis. Clinicopathologic factors that were related to level VII metastasis included lateral neck metastasis (P < 0.01), tumor size (P < 0.01) and lymphovascular invasion (P < 0.05).
Conclusion
If preoperatively, the tumor size is over 1.5 cm, or there is lateral neck metastasis, level VII dissection must be considered. If there is lymphovascular invasion pathologic findings postoperatively, special attention should be paid for detection of level VII recurrence.
doi:10.4174/jkss.2011.80.5.307
PMCID: PMC3204699  PMID: 22066053
Level VII dissection; Papillary thyroid carcinoma
5.  Case of an Ectopic Thyroid Gland at the Lateral Neck Masquerading as a Metastatic Papillary Thyroid Carcinoma 
Journal of Korean Medical Science  2008;23(3):548-550.
Ectopic thyroid glands generally occur in the midline as a result of abnormal median migration, and their presence lateral to the midline is rare. We present one case of an ectopic thyroid gland masquerading as a lateral neck metastasis of a papillary thyroid carcinoma (PTC). In this case of a 54-yr-old woman with left PTC, we suspected left lateral neck metastasis on preoperative neck computed tomography. The patient underwent total thyroidectomy, central compartment neck dissection, and left modified radical neck dissection (MRND). The patient was diagnosed as having an accessory thyroid gland on the lateral neck on the final pathologic report. Surgeons should be aware of the existence of an ectopic thyroid gland in unusual locations.
doi:10.3346/jkms.2008.23.3.548
PMCID: PMC2526509  PMID: 18583899
Ectopic Thyroid; Carcinoma, Papillary
6.  SUMOylation of ZFP282 potentiates its positive effect on estrogen signaling in breast tumorigenesis 
Oncogene  2012;32(35):10.1038/onc.2012.420.
Estrogen receptor α (ERα) plays critical roles in development and progression of breast cancer, and the coiled-coil co-activator (CoCoA) is an important ERα co-activator for estrogen-induced gene expression. The small ubiquitin-like modifier (SUMO) pathway is hyperactivated in breast cancer, but the mechanism by which SUMOylation regulates ERα-mediated transcription remains poorly understood. Here, we identified ZFP282 as a CoCoA binding protein. ZFP282 associates directly with ERα and cooperates synergistically with CoCoA to enhance ERα function. ZFP282 is required for estrogen-induced expression of ERα target genes and estrogen-dependent breast cancer cell growth and tumorigenesis. In addition, we found that ZFP282 is SUMOylated and that SUMOylation positively regulates the co-activator activity of ZFP282 by increasing its binding affinity to ERα and CoCoA and consequently increasing recruitment of ZFP282-CoCoA complex to the promoter of ERα target genes. These findings reveal essential roles for ZFP282 and its SUMOylation in estrogen signaling and breast tumorigenesis.
doi:10.1038/onc.2012.420
PMCID: PMC3874449  PMID: 22986521
breast cancer; co-activator; CoCoA; SUMOylation; ZFP282
7.  Temozolomide Salvage Chemotherapy for Recurrent Anaplastic Oligodendroglioma and Oligo-Astrocytoma 
Objective
To evaluate the efficacy of temozolomide (TMZ) chemotherapy for recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA).
Methods
A multi-center retrospective trial enrolled seventy-two patients with histologically proven AO/AOA who underwent TMZ chemotherapy for their recurrent tumors from 2006 to 2010. TMZ was administered orally (150 to 200 mg/m2/day) for 5 days per 28 days until unacceptable toxicity occurred or tumor progression was observed.
Results
TMZ chemotherapy cycles administered was median 5.3 (range, 1-41). The objective response rate was 24% including 8 cases (11%) of complete response and another 23 patients (32%) were remained as stable disease. Severe side effects (≥grade 3) occurred only in 9 patients (13%). Progression-free survival (PFS) of all patients was a median 8.0 months (95% confidence interval, 6.0-10.0). The time to recurrence of a year or after was a favorable prognostic factor for PFS (p<0.05). Overall survival (OS) was apparently differed by the patient's histology, as AOA patients survived a median OS of 18.0 months while AO patients did not reach median OS at median follow-up of 11.5 months (range 2.7-65 months). Good performance status of Eastern Cooperative Oncology Group 0 and 1 showed prolonged OS (p<0.01).
Conclusion
For recurrent AO/AOA after surgery followed by radiation therapy, TMZ could be recommended as a salvage therapy at the estimated efficacy equal to procarbazine, lomustine, and vincristine (PCV) chemotherapy at first relapse. For patients previously treated with PCV, TMZ is a favorable therapeutic option as 2nd line salvage chemotherapy with an acceptable toxicity rate.
doi:10.3340/jkns.2013.54.6.489
PMCID: PMC3921276  PMID: 24527191
Anaplastic oligodendroglioma; Anaplastic oligoastrocytoma; Chemotherapy; Recurrence; Temozolomide
8.  Validation of the Korean version of the European Organization for Research and Treatment of Cancer brain cancer module (EORTC QLQ-BN20) in patients with brain tumors 
Background
The European Organization for Research and Treatment of Cancer Quality of Life Brain Cancer Module has been translated into Korean, but to date, its reliability and validity have been evaluated in a pilot study alone. The European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire is, overall, a valid instrument to assess the health-related quality of life in Korean cancer patients, although its reliability and validity have not yet been evaluated in patients with brain tumors. This study aimed at evaluating the psychometric properties of these instruments in patients with brain tumors.
Findings
The 2 instruments were used for 307 Korean patients with brain tumors. Multi-trait scaling confirmed the scale structure of the instruments with good item convergent and discriminant validity. The reliability was acceptable for all scales except for cognitive functioning and nausea and vomiting. The instruments could be used to distinguish between clinically distinct groups of patients.
Conclusions
The study findings indicate that the instruments are valid and suitable for the assessment of the health-related quality of life in patients with brain tumors as well as in those with primary brain cancer.
doi:10.1186/1477-7525-11-145
PMCID: PMC3766694  PMID: 23981813
Brain tumor; Health-related quality of life; QLQ-BN20; QLQ-C30; Validation; Korea
9.  CCAR1 promotes chromatin loading of androgen receptor (AR) transcription complex by stabilizing the association between AR and GATA2 
Nucleic Acids Research  2013;41(18):8526-8536.
Androgen receptor (AR), a ligand-dependent transcription factor, plays a critical role in prostate cancer onset and progression, and its transcriptional function is mediated largely by distinct nuclear receptor co-regulators. Here, we show that cell cycle and apoptosis regulator 1 (CCAR1) functions as an AR co-activator. CCAR1 interacted with and enhanced the transcriptional activity of AR. Depletion of CCAR1 caused reduction in androgen-dependent expression of a subset of AR target genes. We further showed that CCAR1 is required for recruitment of AR, MED1 and RNA polymerase II to the enhancers of AR target genes and for androgen-induced long-range prostate specific antigen enhancer–promoter interaction. The molecular mechanism underlying CCAR1 function in AR-mediated transcription involves CCAR1-mediated enhanced recruitment of GATA2, a pioneer factor for AR, to AR-binding sites. CCAR1 stabilized the interaction between AR and GATA2 by interacting directly with both proteins, thereby facilitating AR and GATA2 occupancy on the enhancers. Furthermore, CCAR1 depletion inhibited the growth, migration, invasion of prostate cancer cells and reduced the tumorigenicity of prostate cancer cells in vivo. Our results firmly established CCAR1 as an AR co-activator that plays a key role in AR transcription complex assembly and has an important physiological role in androgen signaling and prostate tumorigenesis.
doi:10.1093/nar/gkt644
PMCID: PMC3794601  PMID: 23887938
10.  Prognostic Factors and Therapeutic Outcomes in 22 Patients with Pleomorphic Xanthoastrocytoma 
Objective
Pleomorphic xanthoastrocytoma (PXA) is a rare primary low-grade astrocytic tumor classified as WHO II. It is generally benign, but disease progression and malignant transformation have been reported. Prognostic factors for PXA and optimal therapies are not well known.
Methods
The study period was January 2000 to March 2012. Data on MR findings, histology, surgical extents and adjuvant therapies were reviewed in twenty-two patients diagnosed with PXA.
Results
The frequent symptoms of PXA included seizures, headaches and neurologic deficits. Tumors were most common in the temporal lobe followed by frontal, parietal and occipital lobes. One patient who died from immediate post-operative complications was excluded from the statistical analysis. Of the remaining 21 patients, 3 (14%) died and 7 (33%) showed disease progression. Atypical tumor location (p<0.001), peritumoral edema (p=0.022) and large tumor size (p=0.048) were correlated with disease progression, however, Ki-67 index and necrosis were not statistically significant. Disease progression occurred in three (21%) of 14 patients who underwent GTR, compared with 4 (57%) of 7 patients who did not undergo GTR, however, it was not statistically significant. Ten patients received adjuvant radiotherapy and the tumors were controlled in 5 of these patients.
Conclusion
The prognosis for PXA is good; in our patients overall survival was 84%, and event-free survival was 59% at 3 years. Atypical tumor location, peritumoral edema and large tumor size are significantly correlated with disease progression. GTR may provide prolonged disease control, and adjuvant radiotherapy may be beneficial, but further study is needed.
doi:10.3340/jkns.2013.53.5.281
PMCID: PMC3730029  PMID: 23908701
Pleomorphic xanthoastrocytoma; Prognosis; outcome; Radiotherapy
11.  Vertebral Distraction during Anterior Cervical Discectomy and Fusion Causes Postoperative Neck Pain 
Objective
Vertebral distraction is routinely performed during anterior cervical discectomy and fusion (ACDF). Overdistraction can injure the facet joints and may cause postoperative neck pain consequently. The purpose of this study was to investigate the clinical relevance of distraction force during ACDF.
Methods
This study included 24 consecutive patients with single level cervical disc disease undergoing single level ACDF. We measure the maximum torque just before the the arm of the Caspar retractor was suspended by the rachet mechanism by turning the lever on the movable arm using a torque meter. In order to turn the lever using the torque driver, we made a linear groove on the top of the lever. We compared the neck disability index (NDI) and visual analogue scale (VAS) scores between the high torque group (distraction force>6 kgf·cm) and the low torque group (distraction force≤6 kgf·cm) at routine postoperative intervals of 1, 3, 5 days and 1, 3, 6 months.
Results
The VAS scores for posterior neck pain had a linear correlation with torque at postoperative 1st and 3rd days (y=0.99×-1.1, r2=0.82; y=0.77×-0.63, r2=0.73, respectively). VAS scores for posterior neck pain were lower in the low torque group than in the high torque group on both 1 and 3 days postoperatively (3.1±1.3, 2.6±1.0 compared with 6.0±0.6, 4.9±0.8, p<0.01). However, the difference in NDI scores was not statistically significant in all postoperative periods.
Conclusion
Vertebral distraction may cause posterior neck pain in the immediate postoperative days. We recommend not to distract the intervertebral disc space excessively with a force of more than 6.0 kgf·cm.
doi:10.3340/jkns.2013.53.5.288
PMCID: PMC3730030  PMID: 23908702
Postoperative pain; Zygapophyseal joint; Spinal fusion; Cervical spine
12.  A Case of Medullary Thyroid Carcinoma with de novo V804M RET Germline Mutation 
Journal of Korean Medical Science  2013;28(1):156-159.
Many cases of RET proto-oncogene mutations of hereditary medullary thyroid carcinoma (MTC) have been reported in Korea. However, MTC with V804M RET proto-oncogene germline mutations have not been reported in Korea. A 33-yr-old man was diagnosed with a 0.7-cm sized thyroid nodule. Laboratory testing revealed serum calcitonin was elevated. The patient underwent total thyroidectomy with central compartment neck dissection for the thyroid tumor. RET gene analysis was performed in both the index patient and his family. There were no V804M RET mutation and abnormal laboratory findings within his family except the index patient. Therefore, this patient was a de novo V804M RET germline mutation.
doi:10.3346/jkms.2013.28.1.156
PMCID: PMC3546095  PMID: 23341727
Medullary Thyroid Carcinoma; RET Proto-oncogene; V804M RET Germline Mutation
13.  Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice 
Little is known about the transcriptional regulation of tumor angiogenesis, and tumor ECs (tECs) remain poorly characterized. Here, we studied the expression pattern of the transcription factor Sox17 in the vasculature of murine and human tumors and investigated the function of Sox17 during tumor angiogenesis using Sox17 genetic mouse models. Sox17 was specifically expressed in tECs in a heterogeneous pattern; in particular, strong Sox17 expression distinguished tECs with high VEGFR2 expression. Whereas overexpression of Sox17 in tECs promoted tumor angiogenesis and vascular abnormalities, Sox17 deletion in tECs reduced tumor angiogenesis and normalized tumor vessels, inhibiting tumor growth. Tumor vessel normalization by Sox17 deletion was long lasting, improved anticancer drug delivery into tumors, and inhibited tumor metastasis. Sox17 promoted endothelial sprouting behavior and upregulated VEGFR2 expression in a cell-intrinsic manner. Moreover, Sox17 increased the percentage of tumor-associated CD11b+Gr-1+ myeloid cells within tumors. The vascular effects of Sox17 persisted throughout tumor growth. Interestingly, Sox17 expression specific to tECs was also observed in highly vascularized human glioblastoma samples. Our findings establish Sox17 as a key regulator of tumor angiogenesis and tumor progression.
doi:10.1172/JCI64547
PMCID: PMC3533291  PMID: 23241958
14.  A Case of Primary Cardiac Lymphoma Mimicking Acute Coronary and Aortic Syndrome 
Korean Circulation Journal  2012;42(11):776-780.
Primary cardiac lymphoma (PCL) is a rare disorder, but the incidence is increasing and its clinical manifestations are various. We report a case of PCL, which mimics an acute coronary and aortic syndrome. A 51 year-old female was presented with chest pain radiating to the back. Her initial electrocardiogram revealed T wave inversion in the leads of V 5-6, II, III and aVF. Additionally, cardiac troponin-T was slightly elevated. Chest radiography showed marked mediastinal widening. Computed tomography scan showed a huge pericardial mass. The histopathologic findings of the mass were compatible with diffuse large B cell lymphoma. She died of refractory ventricular tachycardia, probably, due to an extensive infiltration of PCL to the myocardium.
doi:10.4070/kcj.2012.42.11.776
PMCID: PMC3518713  PMID: 23236331
Cardiac tumor; Chest pain; Acute coronary syndrome
15.  Experience and analysis of Delphian lymph node metastasis in patients with papillary thyroid carcinoma 
Background
Recently, lymph node metastasis (LNM) has been regarded as an important factor influencing loco-regional recurrence and survival rate in papillary thyroid cancer (PTC) patients. The aims of this study were to investigate the detection rate and metastasis rate of the Delphian lymph node (DLN) and clinical patterns related to regional LNM, and to examine how DLN metastasis affects PTC treatment.
Methods
We reviewed the medical records of 413 patients with pathologically confirmed PTC from among 452 patients who underwent thyroid surgery between January 2010 and October 2010 in the Department of Endocrine Surgery at Kosin University Gospel Hospital in Busan, South Korea.
Results
Multivariate analyses revealed a significantly higher proportion of cases with lymphovascular invasion (56.6% vs. 12.5%, P <0.001), central neck node metastasis (88.6% vs. 34.5%, P <0.001) and lateral neck node metastasis (47.2% vs. 10.2%, P <0.005) among cases with DLN metastasis compared to those without. The negative predictive value (NPV) of DLN metastasis with regard to the presence of contralateral central LNM for cases with a tumor size 1 cm or smaller than 1 cm was found to be 93.3% (127/136).
Conclusion
When DLN metastasis is not detected in papillary thyroid microcarcinomas (PTMC), thyroid lobectomy on the affected side and ipsilateral central neck lymph node dissection should be sufficient. In addition, even in cases where lateral neck LNM is not detected on preoperative examination, if DLN metastasis is detected postoperatively, more careful attention should be paid to the lateral neck nodes during follow-up.
doi:10.1186/1477-7819-10-226
PMCID: PMC3542107  PMID: 23110552
Delphian lymph node; Papillary thyroid cancer; Central neck lymph node
16.  Temozolomide during and after Radiotherapy for Newly Diagnosed Glioblastomas : A Prospective Multicenter Study of Korean Patients 
Objective
This study was performed to determine the safety and outcome of concurrent chemoradiotherapy (CCRT) and adjuvant chemotherapy with temozolomide for Korean patients with a newly diagnosed glioblastoma.
Methods
Patients were recruited from four institutions between 2004 and 2007. The patients received fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks and daily temozolomide, followed by 6 cycles of adjuvant temozolomide. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response, and safety.
Results
A total of 103 patients were enrolled in this study. Ninety-six patients (93%) completed the CCRT and 54 patients (52%) received 6 cycles of adjuvant temozolomide. The response rate was 73% (53/73) and the tumor control rate was 92% (67/73). Of the 96 patients who completed the CCRT, the median OS was 18.0 months and the 1- and 2-year OS rates were 74 and 38%, respectively. The median PFS was 10.0 months and the 1- and 2-year PFS rates were 33 and 16%, respectively. The only significant prognostic factor of survival was the extent of surgical resection (p<0.05). CCRT resulted in grade 3 or 4 hematologic toxic effects in 8% of patients. No opportunistic infections were noted.
Conclusion
This study is the first prospective multi-institutional report of CCRT and adjuvant chemotherapy with temozolomide for patients with a newly diagnosed glioblastoma in Korea. The current protocol may prolong the survival of Korean patients with a glioblastoma and may be tolerable in terms of toxicity.
doi:10.3340/jkns.2012.52.2.92
PMCID: PMC3467382  PMID: 23091665
Temozolomide; Chemoradiotherapy; Glioblastoma; Korea
17.  Neurofibromatosis type 1 associated with papillary thyroid carcinoma incidentally detected by thyroid ultrasonography: a case report 
Introduction
Neurofibromatosis type 1 is a common heritable neurocutaneous disorder. Neurofibromatosis type 1 may be associated with tumors of the central nervous system and pheochromocytoma. However, papillary thyroid carcinoma associated with neurofibromatosis type 1 is very rare. We present what is, to the best of our knowledge, the first case of papillary thyroid carcinoma to be detected incidentally by ultrasonography in a patient with neurofibromatosis type 1.
Case presentation
A 63-year-old South Korean man with neurofibromatosis type 1 presented to our study hospital because of thyroid nodules detected incidentally by ultrasonography. Papillary thyroid carcinoma was diagnosed by ultrasonography-guided fine-needle aspiration, and then a total thyroidectomy with central compartment neck dissection was performed. The B isoform of the RafV600E mutation was identified by multiplex real-time polymerase chain reaction assay.
Conclusions
Papillary thyroid carcinoma associated with neurofibromatosis type 1 is very rare. However, it is speculated that papillary thyroid carcinoma is more likely to be detected in patients with neurofibromatosis type 1 if screening by ultrasonography is performed for them.
doi:10.1186/1752-1947-6-179
PMCID: PMC3427039  PMID: 22747746
18.  A coactivator role of CARM1 in the dysregulation of β-catenin activity in colorectal cancer cell growth and gene expression 
Molecular cancer research : MCR  2011;9(5):660-670.
Aberrant activation of Wnt/β-catenin signaling, resulting in the expression of Wnt regulated oncogenes, is recognized as a critical factor in the etiology of colorectal cancer. Occupancy of β-catenin at promoters of Wnt target genes drives transcription, but the mechanism of β-catenin action remains poorly understood. Here, we show that CARM1 (coactivator associated protein arginine methyltransferase 1) interacts with β-catenin and positively modulates β-catenin-mediated gene expression. In colorectal cancer cells with constitutively high Wnt/β-catenin activity, depletion of CARM1 inhibits expression of endogenous Wnt/β-catenin target genes and suppresses clonal survival and anchorage-independent growth. We also identified a colorectal cancer cell line (RKO) with a low basal level of β-catenin, which is dramatically elevated by treatment with Wnt3a. Wnt3a also increased expression of a subset of endogenous Wnt target genes, and CARM1 was required for the Wnt-induced expression of these target genes and the accompanying dimethylation of arginine 17 of histone H3. Depletion of β-catenin from RKO cells diminished the Wnt-induced occupancy of CARM1 on a Wnt target gene, indicating that CARM1 is recruited to Wnt target genes through its interaction with β-catenin and contributes to transcriptional activation by mediating events (including histone H3 methylation) which are downstream from the actions of β-catenin. Therefore, CARM1 is an important positive modulator of Wnt/β-catenin transcription and neoplastic transformation, and may thereby represent a novel target for therapeutic intervention in cancers involving aberrantly activated Wnt/β-catenin signaling.
doi:10.1158/1541-7786.MCR-10-0223
PMCID: PMC3096696  PMID: 21478268
CARM1; Wnt/β-catenin; coactivators; transcriptional regulation; colorectal cancers
19.  Relapse pattern and prognostic factors for patients with primary central nervous system lymphoma 
Background
Primary central nervous system lymphoma (PCNSL) rarely relapses in extracranial sites, and no specialized guidelines for follow-up evaluation have been proposed.
Methods
We analyzed 65 patients with newly diagnosed PNCSL to evaluate the pattern of relapse and prognostic factors.
Results
Of the 65 patients analyzed, 55 had only parenchymal brain disease, and 10 had both intracranial and extracranial lesions. As a first-line treatment, 29 patients received chemotherapy only (CTx), 13 received chemotherapy followed by whole brain radiotherapy (CTx-WBRT), 18 received chemotherapy followed by autologous stem cell transplantation (CTx-ASCT), 2 received palliative WBRT, and 3 received best supportive care. The overall response rate to the initial treatment was 75.8%, with specific response rates of 62.1% to CTx, 84.6% to CTx-WBRT, and 100% to CTx-ASCT. The complete response (CR) rate was higher with CTx-ASCT than in the absence of ASCT (77.8% vs. 43.2%; P=0.025). After a median follow-up of 18.8 months, the median failure-free survival (FFS) and overall survival (OS) were 13.0 and 36.1 months, respectively. No systemic relapse without a CNS lesion was noted. Multivariate analysis showed that ASCT was predictive of better FFS but not of OS. Age and the Memorial-Sloan Kettering Cancer Center prognostic score were predictive of survival.
Conclusion
We observed no systemic relapse without a CNS lesion, suggesting that regular systematic evaluation of extracranial sites may not always be necessary. Age was prognostic of survival irrespective of treatment scheme. ASCT may improve CR rate and FFS.
doi:10.5045/kjh.2012.47.1.60
PMCID: PMC3317473  PMID: 22479279
Primary CNS lymphoma; Relapse; Prognostic factor
20.  Amphetamine-induced ERM Proteins Phosphorylation Is through PKCβ Activation in PC12 Cells 
Amphetamine, a synthetic psychostimulant, is transported by the dopamine transporter (DAT) to the cytosol and increases the exchange of extracellular amphetamine by intracellular dopamine. Recently, we reported that the phosphorylation levels of ezrin-radixin-moesin (ERM) proteins are regulated by psychostimulant drugs in the nucleus accumbens, a brain area important for drug addiction. However, the significance of ERM proteins phosphorylation in response to drugs of abuse has not been fully investigated. In this study, using PC12 cells as an in vitro cell model, we showed that amphetamine increases ERM proteins phosphorylation and protein kinase C (PKC) β inhibitor, but not extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinases (PI3K) inhibitors, abolished this effect. Further, we observed that DAT inhibitor suppressed amphetamine-induced ERM proteins phosphorylation in PC12 cells. These results suggest that PKCβ-induced DAT regulation may be involved in amphetmaine-induced ERM proteins phosphorylation.
doi:10.4196/kjpp.2011.15.4.245
PMCID: PMC3186925  PMID: 21994482
Amphetamine; ERM proteins (ezrin, radixin, moesin); PKCβ; PC12 cells; Dopamine transporter
21.  Reciprocal roles of DBC1 and SIRT1 in regulating estrogen receptor α activity and co-activator synergy 
Nucleic Acids Research  2011;39(16):6932-6943.
Estrogen receptor α (ERα) plays critical roles in development and progression of breast cancer. Because ERα activity is strictly dependent upon the interaction with coregulators, coregulators are also believed to contribute to breast tumorigenesis. Cell Cycle and Apoptosis Regulator 1 (CCAR1) is an important co-activator for estrogen-induced gene expression and estrogen-dependent growth of breast cancer cells. Here, we identified Deleted in Breast Cancer 1 (DBC1) as a CCAR1 binding protein. DBC1 was recently shown to function as a negative regulator of the NAD-dependent protein deacetylase SIRT1. DBC1 associates directly with ERα and cooperates synergistically with CCAR1 to enhance ERα function. DBC1 is required for estrogen-induced expression of a subset of ERα target genes as well as breast cancer cell proliferation and for estrogen-induced recruitment of ERα to the target promoters in a gene-specific manner. The mechanism of DBC1 action involves inhibition of SIRT1 interaction with ERα and of SIRT1-mediated deacetylation of ERα. SIRT1 also represses the co-activator synergy between DBC1 and CCAR1 by binding to DBC1 and disrupting its interaction with CCAR1. Our results indicate that DBC1 and SIRT1 play reciprocal roles as major regulators of ERα activity, by regulating DNA binding by ERα and by regulating co-activator synergy.
doi:10.1093/nar/gkr347
PMCID: PMC3167635  PMID: 21596782
22.  Effect of Aspiration Thrombectomy on Microvascular Dysfunction in ST-Segment Elevation Myocardial Infarction With an Elevated Neutrophil Count 
Korean Circulation Journal  2011;41(2):68-75.
Background and Objectives
Aspiration thrombectomy (AT) during primary percutaneous coronary intervention (PCI) is an effective adjunctive therapy for ST-segment elevation myocardial infarction (STEMI). An elevated neutrophil count in STEMI is associated with microvascular dysfunction and adverse outcomes. We evaluated whether AT can improve microvascular dysfunction in patients with STEMI and an elevated neutrophil count.
Subjects and Methods
Seventy patients with STEMI undergoing primary PCI from August 2007 to February 2009 in our institution were classified by tertiles of neutrophil count on admission (<5,300/mm3, 5,300-7,600/mm3, and >7,600/mm3). The angiographic outcome was post-procedural thrombolysis in myocardial infarction (TIMI) flow grade. Microvascular dysfunction was assessed by TIMI myocardial perfusion (TMP) grade and ST-segment resolution on electrocardiography 90 minutes after PCI. The clinical outcome was major adverse cardiac event (MACE), defined as cardiac death, re-infarction, and target lesion revascularization at 9 months.
Results
There were no significant differences in the clinical characteristics and pre- and post-procedural TIMI flow grades between the neutrophil tertiles. As the neutrophil count increased, a lower tendency toward TMP grade 3 (83% vs. 52% vs. 54%, p=0.06) and more persistent residual ST-segment elevation (>4 mm: 13% vs. 26% vs. 58%, p=0.005) was observed. The 9-month MACE rate was similar between the groups. On subgroup analysis of AT patients (n=52) classified by neutrophil tertiles, the same tendency toward less frequent TMP grade 3 (77% vs. 56% vs. 47%, p=0.06) and persistent residual ST-segment elevation (>4 mm: 12% vs. 28% vs. 53%, p=0.05) was observed as neutrophil count increased.
Conclusion
A higher neutrophil count at presentation in STEMI is associated with more severe microvascular dysfunction after primary PCI, which is not improved with AT.
doi:10.4070/kcj.2011.41.2.68
PMCID: PMC3053563  PMID: 21430991
Myocardial infarction; Neutrophils
23.  Primary Cardiac Lymphoma Presenting With Atrioventricular Block 
Korean Circulation Journal  2010;40(2):94-98.
Primary cardiac lymphomas (PCL) are extremely rare. Clinical manifestations may be variable and are attributed to location. Here, we report on a case of PCL presenting with atrioventricular (AV) block. A 55 year-old male had experienced chest discomfort with unexplained dyspnea and night sweating. His initial electrocardiogram (ECG) revealed a first degree AV block. Along with worsening chest discomfort and dyspnea, his ECG changed to show second degree AV block (Mobitz type I). Computed tomography (CT) scan showed a cardiac mass (about 7 cm) and biopsy was performed. Pathologic finding confirmed diffuse large B-cell lymphoma. The patient was treated with multi-drug combination chemotherapy (R-CHOP: Rituximab, cyclophoshamide, anthracycline, vincristine, and prednisone). After treatment, ECG changed to show normal sinus rhythm with complete remission on follow-up CT scan.
doi:10.4070/kcj.2010.40.2.94
PMCID: PMC2827810  PMID: 20182596
Lymphoma, Large B-cell, Diffuse; Cardiac tumor; Atrioventricular block
24.  Primary Cardiac Angiosarcoma Presenting With Cardiac Tamponade 
Korean Circulation Journal  2010;40(2):86-89.
Primary cardiac angiosarcoma is a very rare disease with a poor prognosis. We report a case of a patient with a primary cardiac angiosarcoma who presented with cardiac tamponade; the angiosarcoma was successfully resected surgically.
doi:10.4070/kcj.2010.40.2.86
PMCID: PMC2827808  PMID: 20182594
Cardiac tumor; Angiosarcoma; Hemopericardium
25.  Involvement of Vts1, a structure-specific RNA-binding protein, in Okazaki fragment processing in yeast 
Nucleic Acids Research  2009;38(5):1583-1595.
The non-essential VTS1 gene of Saccharomyces cerevisiae is highly conserved in eukaryotes and encodes a sequence- and structure-specific RNA-binding protein. The Vts1 protein has been implicated in post-transcriptional regulation of a specific set of mRNAs that contains its-binding site at their 3′-untranslated region. In this study, we identified VTS1 as a multi-copy suppressor of dna2-K1080E, a lethal mutant allele of DNA2 that lacks DNA helicase activity. The suppression was allele-specific, since overexpression of Vts1 did not suppress the temperature-dependent growth defects of dna2Δ405N devoid of the N-terminal 405-amino-acid residues. Purified recombinant Vts1 stimulated the endonuclease activity of wild-type Dna2, but not the endonuclease activity of Dna2Δ405N, indicating that the activation requires the N-terminal domain of Dna2. Stimulation of Dna2 endonuclease activity by Vts1 appeared to be the direct cause of suppression, since the multi-copy expression of Dna2-K1080E suppressed the lethality observed with its single-copy expression. We found that vts1Δ dna2Δ405N and vts1Δdna2-7 double mutant cells displayed synergistic growth defects, in support of a functional interaction between two genes. Our results provide both in vivo and in vitro evidence that Vts1 is involved in lagging strand synthesis by modulating the Dna2 endonuclease activity that plays an essential role in Okazaki fragment processing.
doi:10.1093/nar/gkp1135
PMCID: PMC2836565  PMID: 20007605

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