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Young-Joo Jin,
Jin-Woo Lee,
Jung-Il Lee,
Sang Hoon Park,
Choong Kee Park,
Young Seok Kim,
Sook-Hyang Jeong,
Yun Soo Kim,
Ju Hyun Kim,
Seong Gyu Hwang, [......],
Hyung Joon Yim,
Jae Youn Cheong, Sung Won Cho,
June Sung Lee,
Young Min Park,
Jeong Won Jang,
Chun Kyon Lee,
Joo Hyun Sohn,
Jin Mo Yang,
Seungbong Han
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ABSTRACT: BACKGROUND: Two recent Italian studies suggested that Pegylated-interferon (PEG-IFN) alfa-2a achieves a higher sustained virological response (SVR) rate than PEG-IFN alfa-2b. We intended to compare the efficacy and safety of PEG-IFN alfa-2a with those of PEG-IFN alfa-2b in Korean patients with chronic hepatitis C virus (HCV). METHODS: This retrospective, multi-center trial was conducted on 661 treatment-naive chronic HCV patients. Patients received PEG-IFN alfa-2a (180mug/week; n=402) or PEG-IFN alfa-2b (1.5mug/kg/week; n=259) with ribavirin (800--1200 mg/day) for 24 or 48 weeks according to HCV genotypes. RESULTS: Early virologic response and sustained virologic response (SVR) rates were not significantly different between two PEG-IFN groups both in patients with HCV genotype 1 (all P-values>0.05) and 2/3 (all P-values>0.05). SVR rates were not different between two groups in each categorized baseline characteristics: age (years) (<=50 and >50), HCV viral load (IU/mL) (<=7x105 and >7x105), and hepatic fibrosis (F0-2 and F3-4) (all P-values >0.05). In additional analysis for 480 patients who sufficiently complied with treatment doses and duration (80/80/80 rule) and propensity-score matched analysis, SVR rates were not different between two groups both in patients with HCV genotype 1 and 2/3 (all P-values >0.05). Adverse event rates were similar between two groups. CONCLUSIONS: Unlike the Western data, efficacy and safety of PEG-IFN alfa-2a were similar to those of PEG-IFN alfa-2b in chronically HCV-infected Korean patients regardless of age, HCV viral load, and hepatic fibrosis.
BMC Gastroenterology 04/2013; 13(1):74. · 2.42 Impact Factor
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ABSTRACT: Endochondral bone formation begins with the development of a cartilage intermediate that is subsequently replaced by calcified bone. The mechanisms occurring during early chondrogenesis that control both mesenchymal cell differentiation into chondrocytes and cell proliferation are not clearly understood in vertebrates. Indian hedgehog (Ihh), one of the hedgehog signaling molecules, is known to control both the hypertrophy of chondrocytes and bone replacement; these processes are particularly important in postnatal endochondral bone formation rather than in early chondrogenesis. In this study, we utilized the maternal transfer of 5E1 to E12.5 in mouse embryos, a process that leads to an attenuation of Ihh activity. As a result, mouse limb bud chondrogenesis was inhibited, and an exogenous recombinant IHH protein enhanced the proliferation and differentiation of mesenchymal cells. Analysis of the genetic relationships in the limb buds suggested a more extensive role for Ihh and Runx genes in early chondrogenesis. The transfer of 5E1 decreased the expression of Runx2 and Runx3, whereas an exogenous recombinant IHH protein increased Runx2 and Runx3 expression. Moreover, a transcription factor Gli1 in hedgehog pathway enhances the direct induction of both Runx2 and Runx3 transcription. These findings suggested that Ihh signaling plays an important role in chondrocyte proliferation and differentiation via interactions with Runx2 and Runx3.
PLoS ONE 01/2013; 8(2):e55296. · 4.09 Impact Factor
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Gyung-Min Park,
Duk-Woo Park,
Yong-Giun Kim, Sung Won Cho,
Byung-Joo Sun,
Ki Won Hwang,
Yoo Ri Kim,
Jung-Min Ahn,
Hae-Geun Song,
Won-Jang Kim,
Jong-Young Lee,
Soo-Jin Kang,
Seung-Whan Lee,
Young-Hak Kim,
Cheol Whan Lee,
Seong-Wook Park,
Seung-Jung Park
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ABSTRACT: OBJECTIVE: To evaluate long-term patterns of luminal changes after implantation of different types of drug-eluting stents (DES), we analyzed the serial angiographic outcomes of patients implanted with zotarolimus-eluting stents (ZES), sirolimus-eluting stents (SES), or paclitaxel-eluting stents (PES). BACKGROUND: Little is known regarding long-term luminal changes after DES implantation. METHODS: As a subgroup analysis of the ZEST trial, we performed complete angiographic evaluation immediately after the procedure and at 9 months and 2 years in 111 patients with 165 lesions (36 patients with ZES, 40 with SES, and 35 with PES). RESULTS: Baseline clinical, angiographic, and procedural characteristics were similar among the three groups. Quantitative angiographic analysis revealed significant decreases in minimal luminal diameter 9 months after stent implantation in the ZES (from 2.71 ± 0.49 to 2.21 ± 0.42 mm, P < 0.001), SES (from 2.79 ± 0.49 to 2.58 ± 0.57 mm, P < 0.001), and PES (from 2.66 ± 0.45 to 2.19 ± 0.52 mm, P < 0.001) groups. However, significant late improvements with different degree in luminal diameter were observed between 9 months and 2 years in the ZES (from 2.21 ± 0.42 to 2.39 ± 0.58 mm, P = 0.001), SES (from 2.58 ± 0.57 to 2.66 ± 0.60 mm, P = 0.039), and PES (from 2.19 ± 0.52 to 2.43 ± 0.52 mm, P < 0.001) groups. CONCLUSION: Serial angiographic follow-up study revealed a biphasic luminal response after DES implantation, characterized by an early progression phase for the first 9 months and a late regression phase from 9 months to 2 years. © 2012 Wiley Periodicals, Inc.
Catheterization and Cardiovascular Interventions 03/2012; · 2.29 Impact Factor
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Yong-Giun Kim,
Duk-Woo Park,
Woo Seok Lee,
Gyung-Min Park,
Byung Joo Sun,
Chang Hoon Lee,
Ki Won Hwang, Sung Won Cho,
Yoo Ri Kim,
Hae Geun Song, [......],
Seung-Whan Lee,
Young-Hak Kim,
Cheol Whan Lee,
Seong-Wook Park,
Seungbong Han,
Sung-Ho Jung,
Suk Jung Choo,
Cheol Hyun Chung,
Jae-Won Lee,
Seung-Jung Park
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ABSTRACT: Diabetes mellitus is a major risk factor for coronary artery disease (CAD) and for diffuse and progressive atherosclerosis. We evaluated the outcomes of drug-eluting stent (DES) placement and coronary artery bypass grafting (CABG) in 891 diabetic patients (489 for DES implantation and 402 for CABG) and 2,151 nondiabetic patients (1,058 for DES implantation and 1,093 for CABG) with multivessel CAD treated from January 2003 through December 2005 and followed up for a median 5.6 years. Outcomes of interest included death; the composite outcome of death, myocardial infarction (MI), or stroke; and repeat revascularization. In diabetic patients, after adjusting for baseline covariates, 5-year risk of death (hazard ratio 1.01, 95% confidence interval 0.77 to 1.33, p = 0.96) and the composite of death, MI, or stroke (hazard ratio 1.03, 95% confidence interval 0.80 to 1.31, p = 0.91) were similar in patients undergoing DES or CABG. However, rate of repeat revascularization was significantly higher in the DES group (hazard ratio 3.69, 95% confidence interval 2.64 to 5.17, p <0.001). These trends were consistent in nondiabetic patients (hazard ratio 0.80, 95% confidence interval 0.55 to 1.16, p = 0.23 for death; hazard ratio 0.77, 95% confidence interval 0.56 to 1.05, p = 0.10 for composite of death, MI, or stroke; hazard ratio 2.77, 95% CI 1.95 to 3.91, p <0.001 for repeat revascularization). There was no significant interaction between diabetic status and treatment strategy on clinical outcomes (p for interaction = 0.36 for death; 0.20 for the composite of death, MI, or stroke; and 0.40 for repeat revascularization). In conclusion, there was no significant prognostic influence of diabetes on long-term treatment with DES or CABG in patients with multivessel CAD.
The American journal of cardiology 03/2012; 109(11):1548-57. · 3.58 Impact Factor
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ABSTRACT: Laparoscopic-assisted gastrectomy (LAG) is a minimal invasive surgery for stomach cancer. The endoscopic approach for postoperative complications could reduce re-operation. The aim of our study is to investigate the efficacy of endoscopic procedures and postoperative complications of LAG.
A total of 393 patients who underwent LAG for early gastric cancer were included retrospectively. Technical and clinical success of endoscopic procedures and the relationship between postoperative complications and the types of resection and anastomosis were evaluated.
The mean age of patients was 58 years old and the number of men was 250 (63.8%). Forty five complications occurred in 37 patients (11.5%). Early (within 1 month) and late (after 1 month) postoperative complications occurred in 30 (7.7%) and 6 (1.5%) patients, respectively. Endoscopic procedures were performed for intraluminal bleeding, anastomotic leakage and anastomotic stenosis. Clinical and technical success of endoscopic procedures was 100% (16/16) and 93.8% (15/16) respectively. The occurrence of anastomotic leakage and anastomotic stenosis were significantly high in LATG and Roux-en-Y group than LADG and Billroth-I, and LADG and Billroth-II groups.
Our study showed that endoscopic procedures could effectively control postoperative anastomotic complications. Anastomotic leakage and stenosis occurred more frequently in patients who underwent LATG with Roux-en-Y anastomosis.
Hepato-gastroenterology 03/2012; 59(116):1308-12. · 0.66 Impact Factor
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Jun Hwan Yoo,
Sung Jae Shin,
Kee Myung Lee,
Jae Myoung Choi,
Jeong Ook Wi,
Dong Hoon Kim,
Sun Gyo Lim,
Jae Chul Hwang,
Jae Youn Cheong,
Byung Moo Yoo,
Kwang Jae Lee,
Jin Hong Kim, Sung Won Cho
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ABSTRACT: Endoscopic submucosal dissection (ESD) enables en bloc resection of larger gastric neoplasms. However, the procedure is associated with a high incidence of perforation. Perforations during ESD are divided into macro- and microperforations. Although both types of perforations could cause widespread tissue injury and secondary sepsis, very little is known concerning the risk factors for perforations according to the type of perforation. Thus, this study was performed to evaluate the risk factors for macro-, micro-, and all perforations (both) during ESD.
823 gastric lesions (gastric adenoma or early gastric cancer) in 729 patients treated by ESD were enrolled, and their records were reviewed retrospectively. Risk factors were evaluated, focusing on age, sex, gastric neoplasm-related factors (12 locations, resected size, gross type of lesions, presence of ulceration, presence of fibrosis, pathologic diagnosis, and depth of invasion), and ESD procedure-related factors (type of knife, immediate bleeding during ESD, en bloc resection, procedure time, and the number of ESD cases experienced by the endoscopist).
Of the 823 gastric lesions, the rates of all perforation, macroperforation, and microperforation were 9.6%, 7.5%, and 2.1%, respectively. Risk factors for all perforations on multivariate analysis were location of tumor in upper portion, presence of fibrosis, and long procedure time (>2 h). Risk factors for macroperforations were the same as all perforations. Risk factors for microperforations on multivariate analysis were old age (≥81 years), depth of invasion (muscularis mucosa), and long procedure time (>2 h).
The risk factors for perforations during ESD could differ according to the type of perforation. Therefore, although macroperforation did not develop during ESD, it would be necessary to consider the possibility of microperforation in case of old age, long procedure time, and (deep) depth of invasion.
Surgical Endoscopy 03/2012; 26(9):2456-64. · 4.01 Impact Factor
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ABSTRACT: Retinoic acid receptors (RARs), which are involved in retinoic acid signal transduction, are essential for maintaining the differentiated state of epithelial tissues. Mammary glands are skin appendages whose development is initiated through continuous cell-cell interactions between the ectoderm and the adjacent mesenchyme. Considerable progress has been made in elucidating the molecular basis of these interactions in mammary gland formation in mouse embryos, including the network of initiating signals comprising Fgfs, Wnts and Bmps involved in gland positioning and the transcription factors, Tbx3 and Lef1, essential for mammary gland development. Here, we provide evidence that retinoic acid signaling may also be involved in mammary gland development. We documented the expression of gene-encoding enzymes that produce retinoic acid (Raldh2) and enzymes that degrade it (Cyp26a1, Cyp26b1). We also analyzed the expression of RAR-β, a direct transcriptional target of retinoic acid signaling. Raldh2 and RAR-β were expressed in E10-E10.5 mouse embryos in somites adjacent to the flank region where mammary buds 2, 3 and 4 develop. These expression patterns overlapped with that of Fgf10, which is known to be required for mammary gland formation. RAR-β was also expressed in the mammary mesenchyme in E12 mouse embryos; RAR-β protein was expressed in the mammary epithelium and developing fat pad. Retinoic acid levels in organ cultures of E10.5 mouse embryo flanks were manipulated by adding either retinoic acid or citral, a retinoic acid synthesis inhibitor. Reduced retinoic acid synthesis altered the expression of genes involved in retinoic acid homeostasis and also demonstrated that retinoic acid signaling is required for Tbx3 expression, whereas high levels of retinoic acid signaling inhibited Bmp4 expression and repressed Wnt signaling. The results of the experiments using RNAi against Tbx3 and Wnt10b suggested feedback interactions that regulate retinoic acid homeostasis in mammary gland-forming regions. We produced a molecular model for mammary gland initiation that incorporated retinoic acid signaling.
Developmental Biology 02/2012; 365(1):259-66. · 4.07 Impact Factor
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ABSTRACT: Tooth morphogenesis is regulated by sequential and reciprocal interaction between oral epithelium and neural-crest-derived ectomesenchyme. The interaction is controlled by various signal molecules such as bone morphogenetic protein (BMP), Hedgehog, fibroblast growth factor (FGF), and Wnt. Zeb family is known as a transcription factor, which is essential for neural development and neural-crest-derived tissues, whereas the role of the Zeb family in tooth development remains unclear. Therefore, this study aimed to investigate the expression profiles of Zeb1 and Zeb2 during craniofacial development focusing on mesenchyme of palate, hair follicle, and tooth germ from E12.5 to E16.5. In addition, we examined the interaction between Zeb family and BMP4 during tooth development. Both Zeb1 and Zeb2 were expressed at mesenchyme of the palate, hair follicle, and tooth germ throughout the stages. In the case of tooth germ at the cap stage, the expression of Zeb1 and Zeb2 was lost in epithelium-separated dental mesenchyme. However, the expression of Zeb1 and Zeb2 in the dental mesenchyme was recovered by Bmp4 signaling via BMP4-soaked bead and tissue recombination. Our results suggest that Zeb1 and Zeb2, which were mediated by BMP4, play an important role in neural-crest-derived craniofacial organ morphogenesis, such as tooth development.
Histochemie 02/2012; 137(6):791-800. · 2.59 Impact Factor
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ABSTRACT: The root apex of the tooth elongates until the completion of root development. Although the signaling molecules inducing root elongation have been studied, the characteristic of the cells having the ability to maintain the root elongation remains unclear. This study aimed to investigate the characteristics of the cells involved in the root elongation. Octamer-binding factor 3/4 (Oct3/4) is known as one of the key regulators in maintaining the pluripotency and self-renewal properties of embryonic stem cells. Bmi1, the polycomb-group transcriptional repressor, has emerged as a key regulator in several cellular processes including stem cell self-renewal and cancer cell proliferation. At the beginning of root formation, ameloblasts expressed Oct3/4 in the nucleus, except in the apex of the cervical loop, in which Bmi1and cyclinD were expressed. At PN6, the expression of Oct3/4 in the ameloblasts shifted from the nucleus to the cytoplasm, whereas ameloblastin-negative Hertwig's epithelial root sheath (HERS) cells expressed Bmi1 and cyclinD. By PN10, the cells in the apex of HERS began to express Oct3/4 in their nucleus, whereas Bmi1 and cyclinD began to decrease in their expressions. The odontoblasts consistently expressed Oct3/4 in their cytoplasm. Our results suggest that (1) Oct3/4 creates the border between the ameloblasts from the proliferative region of HERS, (2) Bmi1-positive cells would be one of the candidates resulting in root elongation and (3) the Oct3/4 expression in the cytoplasm of odontoblasts may be related to maintain the odontoblastic characteristics.
Cell and Tissue Research 01/2012; 347(2):479-84. · 3.11 Impact Factor
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ABSTRACT: Palate development requires coordinating proper cellular and molecular events in palatogenesis, including the epithelial-mesenchymal transition (EMT), apoptosis, cell proliferation, and cell migration. Zeb1 and Zeb2 regulate epithelial cadherin (E-cadherin) and EMT during organogenesis. While microRNA 200b (miR-200b) is known to be a negative regulator of Zeb1 and Zeb2 in cancer progression, its regulatory effects on Zeb1 and Zeb2 in palatogenesis have not yet been clarified. The aim of this study is to investigate the relationship between the regulators of palatal development, specifically, miR-200b and the Zeb family. Expression of both Zeb1 and Zeb2 was detected in the mesenchyme of the mouse palate, while miR-200b was expressed in the medial edge epithelium. After contact with the palatal shelves, miR-200b was expressed in the palatal epithelial lining and epithelial island around the fusion region but not in the palatal mesenchyme. The function of miR-200b was examined by overexpression via a lentiviral vector in the palatal shelves. Ectopic expression of miR-200b resulted in suppression of the Zeb family, upregulation of E-cadherin, and changes in cell migration and palatal fusion. These results suggest that miR-200b plays crucial roles in cell migration and palatal fusion by regulating Zeb1 and Zeb2 as a noncoding RNA during palate development.
Histochemie 01/2012; 137(4):459-70. · 2.59 Impact Factor
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Sang Hoon Park,
Choong Kee Park,
Jin Woo Lee,
Young Seok Kim,
Sook-Hyang Jeong,
Yun Soo Kim,
Ju Hyun Kim,
Seong Gyu Hwang,
Kyu Sung Rim,
Hyung Joon Yim,
Jae Youn Cheong, Sung Won Cho,
June Sung Lee,
Young Min Park,
Jeong Won Jang,
Chun Kyon Lee,
Joo Hyun Shon,
Jin Mo Yang,
Young Soo Ju
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ABSTRACT: We aimed to evaluate the efficacy and safety of peginterferon plus ribavirin for chronic hepatitis C (CHC) patients under real life setting in Korea.
We retrospectively analyzed the medical records of 758 CHC patients treated with peginterferon plus ribavirin between 2000 and 2008 from 14 university hospitals in the Gyeonggi-Incheon area in Korea.
Hepatitis C virus (HCV) genotype 1 was detected in 61.2% of patients, while genotype 2 was detected in 35.5%. Baseline HCV RNA level was ≥6×10(5) IU/mL in 51.6% of patients. The sustained virological response (SVR) rate was 59.6% regardless of genotype; 53.6% in genotype 1 and 71.4% in genotype 2/3. On multivariate analysis, male gender (p=0.011), early virological response (p<0.001), genotype 2/3 (p<0.001), HCV RNA <6×10(5) IU/mL (p=0.005) and adherence to the drug >80% of the planned dose (p<0.001) were associated with SVR. The rate of premature discontinuation was 35.7%. The main reason for withdrawal was intolerance to the drug due to common adverse events or cytopenia (48.2%).
Our data suggest that the efficacy of peginterferon and ribavirin therapy in Koreans is better in Koreans than in Caucasians for the treatment of CHC, corroborating previous studies that have shown the superior therapeutic efficacy of this regimen in Asians.
Gut and liver 01/2012; 6(1):98-106. · 0.83 Impact Factor
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ABSTRACT: Octamer-binding factor 3/4 (Oct3/4) is one of the key regulators maintaining the pluripotency and self-renewal in embryonic stem cells and is involved in the developmental events. However, the functional significance of Oct3/4 remains to be clarified during tooth morphogenesis. This study aimed to examine the functional role of Oct3/4 in mouse. During tooth morphogenesis (E11-E16.5), Oct3/4-positive cells, detected by nuclear immunoreaction, increased in number, and subsequently, their immunoreaction shifted from the nucleus to the cytoplasm at the stage of cell differentiation (E18.5). Quantitative real-time PCR clearly demonstrated the relationship between isoforms of Oct3/4 and the in vivo cellular localization of Oct3/4, suggesting that the Oct3/4 expressed in nucleus was Oct3/4A, whereas that expressed in the cytoplasm was Oct3/4B. RNAi knockdown of Oct3/4 induced apoptosis and arrested tooth morphogenesis. Our results suggest that (1) the increased number of Oct3/4-positive cells with nuclear immunoreaction correlate with active cell proliferation during tooth morphogenesis and (2) the shift of Oct3/4 from the nucleus to the cytoplasm plays a crucial role in cell differentiation.
Histochemie 12/2011; 137(3):367-76. · 2.59 Impact Factor
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ABSTRACT: Palatal ridges, or rugae palatinae, are corrugated structures observed in the hard palate region. They are found in most mammalian species, but their number and arrangement are species-specific. Nine palatal rugae are found in the mouse secondary palate. Previous studies have shown that epithelial Shh signaling in the palatal ridge plays an important role during rugae development. Moreover, Wnt family members, including LEF1, play a functional role in orofacial morphogenesis. To explore the function of Shh during rugae development, we utilized the maternal transfer of 5E1 (anti-Shh antibody) to mouse embryos. 5E1 induced abnormal rugae patterning characterized by a spotted shape of palatal ridge rather than a stripe. The expression patterns of Shh and Shh-related genes, Sostdc1, Lef1 and Ptch1, were disrupted following 5E1 injection. Moreover, rugae-specific cell proliferation and inter-rugae-specific apoptosis were affected by inhibition of Shh signaling. We hypothesize that the altered gene expression patterns and the change in molecular events caused by the inhibition of Shh signaling may have induced abnormal rugae patterning. Furthermore, we propose a reaction-diffusion model generated by Wnt, Shh and Sostdc1 signaling. In this study, we show that Sostdc1, a secreted inhibitor of the Wnt pathway, is a downstream target of Shh and hypothesize that the interaction of Wnt, Shh and Sostdc1 is a pivotal mechanism controlling the spatial patterning of palatal rugae.
Histochemie 12/2011; 136(6):663-75. · 2.59 Impact Factor
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ABSTRACT: Various cellular and molecular events are involved in palatogenesis, including apoptosis, epithelial-mesenchymal transition (EMT), cell proliferation, and cell migration. Smad2 and Snail, which are well-known key mediators of the transforming growth factor beta (Tgf-β) pathway, play a crucial role in the regulation of palate development. Regulatory effects of microRNA 200b (miR-200b) on Smad2 and Snail in palatogenesis have not yet been elucidated. The aim of this study is to determine the relationship between palate development regulators miR-200b and Tgf-β-mediated genes. Expression of miR-200b, E-cadherin, Smad2, and Snail was detected in the mesenchyme of the mouse palate, while miR-200b was expressed in the medial edge epithelium (MEE) and palatal mesenchyme. After the contact of palatal shelves, miR-200b was no longer expressed in the mesenchyme around the fusion region. The binding activity of miR-200b to both Smad2 and Snail was examined using a luciferase assay. MiR-200b directly targeted Smad2 and Snail at both cellular and molecular levels. The function of miR-200b was determined by overexpression via a lentiviral vector in the palatal shelves. Ectopic expression of miR-200b resulted in suppression of these Tgf-β-mediated regulators and changes of apoptosis and cell proliferation in the palatal fusion region. These results suggest that miR-200b plays a crucial role in regulating the Smad2, Snail, and in apoptosis during palatogenesis by acting as a direct non-coding, influencing factor. Furthermore, the molecular interactions between miR-200b and Tgf-β signaling are important for proper palatogenesis and especially for palate fusion. Elucidating the mechanism of palatogenesis may aid the design of effective gene-based therapies for the treatment of congenital cleft palate.
Histochemie 11/2011; 137(1):67-78. · 2.59 Impact Factor
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ABSTRACT: We have previously demonstrated that tooth size is determined by dental mesenchymal factors. Exogenous bone morphogenetic protein (BMP)4, Noggin, fibroblast growth factor (FGF)3 and FGF10 have no effect on tooth size, despite the expressions of Bmp2, Bmp4, Fgf3, Fgf10 and Lef1 in the dental mesenchyme. Among the wingless (Wnt) genes that are differentially expressed during tooth development, only Wnt5a is expressed in the dental mesenchyme. The aims of the present study were to clarify the expression pattern of Wnt5a in developing tooth germs and the role of Wnt5a in the regulation of tooth size by treatment with exogenous WNT5A with/without an apoptosis inhibitor on in vitro tooth germs combined with transplantation into kidney capsules. Wnt5a was intensely expressed in both the dental epithelium and mesenchyme during embryonic days 14-17, overlapping partly with the expressions of both Shh and Bmp4. Moreover, WNT5A retarded the development of tooth germs by markedly inducing cell death in the non-dental epithelium and mesenchyme but not widely in the dental region, where the epithelial-mesenchymal gene interactions among Wnt5a, Fgf10, Bmp4 and Shh might partly rescue the cells from death in the WNT5A-treated tooth germ. Together, these results indicate that WNT5A-induced cell death inhibited the overall development of the tooth germ, resulting in smaller teeth with blunter cusps after tooth-germ transplantation. Thus, it is suggested that Wnt5a is involved in regulating cell death in non-dental regions, while in the dental region it acts as a regulator of other genes that rescue tooth germs from cell death.
Cell and Tissue Research 09/2011; 345(3):367-77. · 3.11 Impact Factor
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ABSTRACT: The retinoic acid (RA) signaling pathway is known to play important roles during craniofacial development and skeletogenesis. However, the specific mechanism involving RA in cranial base development has not yet been clearly described. This study investigated how RA modulates endochondral bone development of the cranial base by monitoring the RA receptor RARγ, BMP4, and markers of proliferation, programmed cell death, chondrogenesis, and osteogenesis. We first examined the dynamic morphological and molecular changes in the sphenooccipital synchondrosis-forming region in the mouse embryo cranial bases at E12-E16. In vitro organ cultures employing beads soaked in RA and retinoid-signaling inhibitor citral were compared. In the RA study, the sphenooccipital synchondrosis showed reduced cartilage matrix and lower BMP4 expression while hypertrophic chondrocytes were replaced with proliferating chondrocytes. Retardation of chondrocyte hypertrophy was exhibited in citral-treated specimens, while BMP4 expression was slightly increased and programmed cell death was induced within the sphenooccipital synchondrosis. Our results demonstrate that RA modulates chondrocytes to proliferate, differentiate, or undergo programmed cell death during endochondral bone formation in the developing cranial base.
Journal of Experimental Zoology Part B Molecular and Developmental Evolution 08/2011; 316(8):574-83. · 2.42 Impact Factor
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Sung-Won Cho,
Sungwook Kwak,
Thomas E Woolley,
Min-Jung Lee,
Eun-Jung Kim,
Ruth E Baker,
Hee-Jin Kim,
Jeon-Soo Shin,
Cheryll Tickle,
Philip K Maini,
Han-Sung Jung
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ABSTRACT: Each vertebrate species displays specific tooth patterns in each quadrant of the jaw: the mouse has one incisor and three molars, which develop at precise locations and at different times. The reason why multiple teeth form in the jaw of vertebrates and the way in which they develop separately from each other have been extensively studied, but the genetic mechanism governing the spatial patterning of teeth still remains to be elucidated. Sonic hedgehog (Shh) is one of the key signaling molecules involved in the spatial patterning of teeth and other ectodermal organs such as hair, vibrissae and feathers. Sostdc1, a secreted inhibitor of the Wnt and Bmp pathways, also regulates the spatial patterning of teeth and hair. Here, by utilizing maternal transfer of 5E1 (an anti-Shh antibody) to mouse embryos through the placenta, we show that Sostdc1 is downstream of Shh signaling and suggest a Wnt-Shh-Sostdc1 negative feedback loop as a pivotal mechanism controlling the spatial patterning of teeth. Furthermore, we propose a new reaction-diffusion model in which Wnt, Shh and Sostdc1 act as the activator, mediator and inhibitor, respectively, and confirm that such interactions can generate the tooth pattern of a wild-type mouse and can explain the various tooth patterns produced experimentally.
Development 03/2011; 138(9):1807-16. · 6.60 Impact Factor
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ABSTRACT: The runt-domain transcription factor Runx3 plays crucial roles during development such as regulating gene expression. It has been shown that Runx3 is involved in neurogenesis, thymopoiesis and functions like a tumor suppressor. Runx3 null mouse die soon after birth as a result of multiple organ defects. Runx3 null mouse lung shows an abnormal phenotype and loss of Runx3 induced remodeling in the lung. Interestingly, lung adenocarcinoma is observed in Runx3 heterozygous mice at 18 months of age. During lung development various cellular and molecular events occur such as cell proliferation, cell death, differentiation and epithelial-mesenchymal transition (EMT). To understand the specific lethal events in Runx3 null mice, we examined cellular and molecular networks involved in EMT, and EMT inducers were quantified by RT-qPCR during lung development. Excessive EMT was observed in lungs at PN1 day in Runx3 null mice and PN18 months in Runx3 heterozygous mice. Pharmacologic inhibition of EMT was used to curb tumor progression. In this study, U0126 was injected to pregnant mouse for inhibition of pERK signaling. After U0126 treatment, life spans of newborn mice were increased and lung hyperplasia was partially rescued by down-regulated cell proliferation and EMT. Our data suggest that Runx3 is involved in crucial regulation of alveolar differentiation and tumor suppression in developing mouse lung.
Differentiation 02/2011; 81(4):261-8. · 2.81 Impact Factor
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ABSTRACT: Recent studies have demonstrated the existence of dental stem cells in the continuously growing tooth. However, much remains to be learned about the complex mechanism involving stem cells during tooth development. We determined the expression patterns of four stem cell markers ABCG2, Bmi-1, Oct-3/4, and Yap in the developing mouse incisors between embryonic day (E) 11 and postnatal day (PN) 20. ABCG2 was localized strongly in the perivascular region of the incisor mesenchyme from E11 to PN20, and in the odontoblasts from E18 to PN20. Bmi-1 was expressed in both the dental epithelium and mesenchyme from E11 to E14. The expression of Bmi-1 was noticeably reduced at E16, and was restricted to the apical bud from E16 to PN20. Oct-3/4 was localized in the nucleus of the cells in the superficial layer and stellate reticulum within the dental epithelium from E11 to E14 and in the apical bud from E16 to PN20. Meanwhile, once the ameloblasts and odontoblasts began to appear at E16, they expressed Oct-3/4 in the cytoplasm. Yap was expressed in most of the basal cells of the incisor dental epithelium from E11 to E14, but was expressed mainly in the transit-amplifying (TA) cells within the basal cell layer from E16 to PN20. The unique and overlapping expression patterns of ABCG2, Bmi-1, Oct-3/4, and Yap suggest the independent and interactive functions of the four stem cell markers in the developing mouse incisor.
Gene Expression Patterns 11/2010; 11(3-4):163-70. · 2.02 Impact Factor
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ABSTRACT: Although tridermic species have two junctional regions of ectoderm and endoderm between their epidermis and digestive tract, we actually know little about these particular boundaries. Cytokeratins are the major intermediate filaments of epithelial cells and show a high degree of tissue specificity. Therefore, to characterize the epithelial cells in the junctional region of ectoderm and endoderm, we immunohistochemically examined the localization of cytokeratins 5, 7/17, 14, 18, Sox17, and alpha-fetoprotein (AFP) in the oropharyngeal and anorectal regions during the mouse gastrulation process. At embryonic day (E) 9.5, cytokeratins 5, 7/17, 14, and 18 were detected in all epithelial cells of the oropharyngeal region. At E12.5, cytokeratin 5-positive cells were not observed in the middle area of the oral cavity; however, the immunoreactivity was strong in the anterior and posterior areas. The immunoreaction of cytokeratins 18 was seen only in the middle and posterior areas of the oral mucosa. Cytokeratins 7/17 and 14 were localized in all areas of the oropharyngeal region. Sox17 and AFP, which are endodermal markers, were detected in the middle and posterior areas of the oral mucosa, but not in the anterior area. Moreover, this same localization pattern of cytokeratins also existed in the anorectal region of the E12.5 embryo, suggesting that the localization of cytokeratins and endodermal markers might give an implication for the boundary between ectoderm and endoderm. These results also suggest that these cytokeratins are useful molecules for monitoring the epithelial cell differentiation in the junctional region of the germ layers.
The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 11/2010; 293(11):1864-72. · 1.47 Impact Factor
