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1.  Supratentorial Hemangioblastoma with Unusual Features 
Korean Journal of Pathology  2014;48(6):462-465.
PMCID: PMC4284497  PMID: 25588642
2.  Patterns of Neutropenia and Risk Factors for Febrile Neutropenia of Diffuse Large B-Cell Lymphoma Patients Treated with Rituximab-CHOP 
Journal of Korean Medical Science  2014;29(11):1493-1500.
Febrile neutropenia (FN) is the major toxicity of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen in the treatment of diffuse large B-cell lymphoma (DLBCL). The prediction of neutropenia and FN is mandatory to continue the planned R-CHOP therapy resulting in successful anti-cancer treatment. The clinical features and patterns of neutropenia and FN from 181 DLBCL patients treated with R-CHOP were analyzed retrospectively. Sixty percent (60.2%) of patients experienced at least one episode of grade 4 neutropenia. Among them, 42.2% of episodes progressed to FN. Forty-eight percent (48.8%) of patients with FN was experienced their first FN during the first cycle of R-CHOP. All those patients never experienced FN again during the rest cycles of R-CHOP. Female, higher stage, international prognostic index (IPI), age ≥65 yr, comorbidities, bone marrow involvement, and baseline serum albumin ≤3.5 mg/dL were significant risk factors for FN by univariate analysis. Among these variables, comorbidities (P=0.009), bone marrow involvement (P=0.006), and female gender (P=0.024) were independent risk factors for FN based on multivariate analysis. On observing the patterns of neutropenia and FN, primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) and antibiotics should be considered particularly in female patients, patients with comorbidities, or when there is bone marrow involvement of disease.
Graphical Abstract
PMCID: PMC4234916  PMID: 25408580
Febrile Neutropenia; Lymphoma; Large B-Cell; Diffuse; R-CHOP Chemotherapy
3.  High Expression of Aldo-Keto Reductase 1B10 Is an Independent Predictor of Favorable Prognosis in Patients with Hepatocellular Carcinoma 
Gut and Liver  2014;8(6):648-654.
Upregulation of aldo-keto reductase 1B10 (AKR1B10) through the mitogenic activator protein-1 signaling pathway might promote hepatocarcinogenesis and tumor progression. The goal of this study was to evaluate the prognostic significance of AKR1B10 protein expression in patients with hepatocellular carcinoma after surgery.
A tissue microarray was used to detect the expression level of AKR1B10 protein in tumors from 255 patients with hepatocellular carcinoma who underwent curative hepatectomy. The impact of AKR1B10 expression on the survival of patients was analyzed. The median follow-up period was 119.8 months.
High AKR1B10 protein expression was observed in 125 of the 255 patients with hepatocellular carcinoma (49.0%). High AKR1B10 expression was significantly associated with a lack of invasion of the major portal vein (p=0.022), a lack of intrahepatic metastasis (p=0.010), lower the American Joint Committee on Cancer T stage (p=0.016), lower the Barcelona Clinic Liver Cancer stage (p=0.006), and lower α-fetoprotein levels (p=0.020). High AKR1B10 expression was also correlated with a lack of early recurrence (p=0.022). Multivariate analyses of survival revealed that intrahepatic metastases and lower albumin levels were independent predictors of both shorter recurrence-free survival and shorter disease-specific survival. High AKR1B10 expression was an independent predictor of both longer recurrence-free survival (p=0.024) and longer disease-specific survival (p=0.046).
High AKR1B10 protein expression might be useful as a marker of a favorable prognosis in patients with hepatocellular carcinoma after curative hepatectomy.
PMCID: PMC4215452  PMID: 25287169
AKR1B10; Carcinoma; hepatocellular; Survival
4.  High Expression of Ribonucleotide Reductase Subunit M2 Correlates with Poor Prognosis of Hepatocellular Carcinoma 
Gut and Liver  2014;8(6):662-668.
Ribonucleotide reductase subunit M2 (RRM2) catalyzes the production of deoxynucleotide triphosphates, which are necessary for DNA synthesis. RRM2 has been reported to play an active role in tumor progression, and elevated RRM2 levels have been correlated with poor prognosis for colorectal cancer patients. This study aimed to elucidate the prognostic significance of RRM2 protein expression in hepatocellular carcinoma after surgery.
RRM2 protein expression was evaluated using immunohistochemistry in tumor tissues from 259 hepatocellular carcinoma patients who underwent curative hepatectomy.
High RRM2 expression was observed in 210 of 259 patients (81.1%) with hepatocellular carcinomas. High RRM2 expression was significantly associated with viral etiology (p=0.035) and liver cirrhosis (p=0.036). High RRM2 expression was correlated with early recurrence (p=0.004) but not with late recurrence (p=0.144). Logistic regression analysis revealed that high RRM2 expression (p=0.040) and intrahepatic metastasis (p<0.001) were independent predictors of early recurrence. High RRM2 expression unfavorably influenced both shorter recurrence-free survival (p=0.011) and shorter disease-specific survival (p=0.002) and was an independent predictor of shorter disease-specific survival (p=0.008).
High RRM2 protein expression might be a useful marker for predicting early recurrence and may be a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy.
PMCID: PMC4215454  PMID: 25368754
Ribonucleotide reductase subunit M2; Hepatocellular carcinoma; Survival
5.  Polarized and Stage-Dependent Distribution of Immunoreactivity for Novel PDZ-Binding Protein Preso1 in Adult Neurogenic Regions 
Endocrinology and Metabolism  2014;29(3):349-355.
Adult neural stem cells have the potential for self-renewal and differentiation into multiple cell lineages via symmetric or asymmetric cell division. Preso1 is a recently identified protein involved in the formation of dendritic spines and the promotion of axonal growth in developing neurons. Preso1 can also bind to cell polarity proteins, suggesting a potential role for Preso1 in asymmetric cell division.
To investigate the distribution of Preso1, we performed immunohistochemistry with adult mouse brain slice. Also, polarized distribution of Preso1 was assessed by immunocytochemistry in cultured neural stem cells.
Immunoreactivity for Preso1 (Preso1-IR) was strong in the rostral migratory stream and subventricular zone, where proliferating transit-amplifying cells and neuroblasts are prevalent. In cultured neural stem cells, Preso1-IR was unequally distributed in the cell cytosol. We also observed the distribution of Preso1 in the subgranular zone of the hippocampal dentate gyrus, another neurogenic region in the adult brain. Interestingly, Preso1-IR was transiently observed in the nuclei of doublecortin-expressing neuroblasts immediately after asymmetric cell division.
Our study demonstrated that Preso1 is asymmetrically distributed in the cytosol and nuclei of neural stem/progenitor cells in the adult brain, and may play a significant role in cell differentiation via association with cell polarity machinery.
PMCID: PMC4192811  PMID: 25309794
Preso1; Frmpd4; Cell polarity; Subventricular zone; Dentate gyrus; Adult neural stem cells
6.  ABA Renewal Involves Enhancements in Both GluA2-Lacking AMPA Receptor Activity and GluA1 Phosphorylation in the Lateral Amygdala 
PLoS ONE  2014;9(6):e100108.
Fear renewal, the context-specific relapse of fear following fear extinction, is a leading animal model of post-traumatic stress disorders (PTSD) and fear-related disorders. Although fear extinction can diminish fear responses, this effect is restricted to the context where the extinction is carried out, and the extinguished fear strongly relapses when assessed in the original acquisition context (ABA renewal) or in a context distinct from the conditioning and extinction contexts (ABC renewal). We have previously identified Ser831 phosphorylation of GluA1 subunit in the lateral amygdala (LA) as a key molecular mechanism for ABC renewal. However, molecular mechanisms underlying ABA renewal remain to be elucidated. Here, we found that both the excitatory synaptic efficacy and GluA2-lacking AMPAR activity at thalamic input synapses onto the LA (T-LA synapses) were enhanced upon ABA renewal. GluA2-lacking AMPAR activity was also increased during low-threshold potentiation, a potential cellular substrate of renewal, at T-LA synapses. The microinjection of 1-naphtylacetyl-spermine (NASPM), a selective blocker of GluA2-lacking AMPARs, into the LA attenuated ABA renewal, suggesting a critical role of GluA2-lacking AMPARs in ABA renewal. We also found that Ser831 phosphorylation of GluA1 in the LA was increased upon ABA renewal. We developed a short peptide mimicking the Ser831-containing C-tail region of GluA1, which can be phosphorylated upon renewal (GluA1S); thus, the phosphorylated GluA1S may compete with Ser831-phosphorylated GluA1. This GluA1S peptide blocked the low-threshold potentiation when dialyzed into a recorded neuron. The microinjection of a cell-permeable form of GluA1S peptide into the LA attenuated ABA renewal. In support of the GluA1S experiments, a GluA1D peptide (in which the serine at 831 is replaced with a phosphomimetic amino acid, aspartate) attenuated ABA renewal when microinjected into the LA. These findings suggest that enhancements in both the GluA2-lacking AMPAR activity and GluA1 phosphorylation at Ser831 are required for ABA renewal.
PMCID: PMC4055738  PMID: 24925360
7.  Up-regulation of neogenin-1 increases cell proliferation and motility in gastric cancer 
Oncotarget  2014;5(10):3386-3398.
Although elevated expression of neogenin-1 has been detected in human gastric cancer tissue, its role in gastric tumorigenesis remains unclear due to the lack of neogenin-1 studies in cancer. Therefore, we demonstrated here the function and regulatory mechanism of neogenin-1 in gastric cancer. Neogenin-1 ablation decreased proliferation and migration of gastric cancer cells, whereas its over-expression reversed these effects. Xenografted analyses using gastric cancer cells displayed statistically significant inhibition of tumor growth by neogenin-1 depletion. Interestingly, galectin-3 interacted with HSF-1 directly, which facilitated nuclear-localization and binding on neogenin-1 promoter to drive its transcription and gastric cancer cell motility. The galectin-3-increased gastric cancer cell motility was down-regulated by HSF-1 depletion. Moreover, the parallel expression patterns of galectin-3 and neogenin-1, as well as those of HSF-1 and neogenin-1, were detected in the malignant tissues of gastric cancer patients. Taken together, high-expression of neogenin-1 promotes gastric cancer proliferation and motility and its expression is regulated by HSF-1 and galectin-3 interaction. In addition, we propose further studies for neogenin-1 and its associated pathways to provide them as a proper target for gastric cancer therapy.
PMCID: PMC4102817  PMID: 24930499
Neogenin-1; Galectin-3; Heat shock factor (HSF)-1; Cancer metastasis; Gastric cancer
8.  Angular and temperature dependence of current induced spin-orbit effective fields in Ta/CoFeB/MgO nanowires 
Scientific Reports  2014;4:4491.
Current induced spin-orbit effective magnetic fields in metal/ferromagnet/oxide trilayers provide a new way to manipulate the magnetization, which is an alternative to the conventional current induced spin transfer torque arising from noncollinear magnetization. Ta/CoFeB/MgO structures are expected to be useful for non-volatile memories and logic devices due to its perpendicular anisotropy and large current induced spin-orbit effective fields. However many aspects such as the angular and temperature dependent phenomena of the effective fields are little understood. Here, we evaluate the angular and temperature dependence of the current-induced spin-orbit effective fields considering contributions from both the anomalous and planar Hall effects. The longitudinal and transverse components of effective fields are found to have strong angular dependence on the magnetization direction at 300 K. The transverse field decreases significantly with decreasing temperature, whereas the longitudinal field shows weaker temperature dependence. Our results reveal important features and provide an opportunity for a more comprehensive understanding of current induced spin-orbit effective fields.
PMCID: PMC3967151  PMID: 24670317
9.  Eagle's syndrome: a case report 
Eagle's syndrome is a disease caused by an elongated styloid process or calcified stylohyoid ligament. Eagle defined the disorder in 1937 by describing clinical findings related to an elongated styloid process, which is one of the numerous causes of pain in the craniofacial and cervical region. The prevalence of individuals with this anatomic abnormality in the adult population is estimated to be 4% with 0.16% of these individuals reported to be symptomatic. Eagle's syndrome is usually characterized by neck, throat, or ear pain; pharyngeal foreign body sensation; dysphagia; pain upon head movement; and headache. The diagnosis of Eagle's syndrome must be made in association with data from the clinical history, physical examination, and imaging studies. Patients with increased symptom severity require surgical excision of the styloid process, which can be performed through an intraoral or an extraoral approach. Here, we report a rare case of stylohyoid ligament bilaterally elongated to more than 60 mm in a 51-year-old female. We did a surgery by extraoral approach and patient's symptom was improved.
PMCID: PMC3949492  PMID: 24627843
Eagle syndrome; Elongated styloid process
10.  Retrospective clinical study of mandible fractures 
The purpose of this article is to analyze the incidence, demographic distribution, type, and etiology of mandible fractures that were treated by the Department of Oral and Maxillofacial Surgery in Kyung Hee University Dental Hospital from January 2002 to December 2012.
Materials and Methods
This was a descriptive and analytic retrospective study that evaluated 735 patients that were treated for mandible fracture.
This study included 1,172 fractures in 735 patients. The ratio of male to female patients was 5.45 : 1; the maximum value was in patients between 20 and 29 years (38.1%) and the minimum in patients over 70 years old. The monthly distribution of facial fractures peaked in the fall and was lower during winter. No specific correlation was identified based on the annual fracture distribution. Among the 735 fracture patients, 1.59 fracture lines were observed per patient. The most frequent site was the symphysis, which accounted for a total of 431 fractures, followed by the angle (348), condyle (279), and body (95). The symphysis with angle was the most common site identified in combination with fracture and accounted for 22.4%, followed by symphysis with condyle (19.8%). The angle was the most frequent site of single fractures (20.8%). The major cause of injury was accidental trauma (43.4%), which was followed by other causes such as violence (33.9%), sports-related accidents (10.5%), and traffic accidents (10.1%). Fracture incidents correlated with alcohol consumption were reported between 10.0%-26.9% annually.
Although mandible fracture pattern is similar to the previous researches, there is some changes in the etiologic factors.
PMCID: PMC3949494  PMID: 24627839
Mandible; Jaw fractures; Mandibular fractures; Alcohol drinking; Trauma
11.  Impaired Extinction of Learned Contextual Fear Memory in Early Growth Response 1 Knockout Mice 
Molecules and Cells  2014;37(1):24-30.
Inductive expression of early growth response 1 (Egr-1) in neurons is associated with many forms of neuronal activity. However, only a few Egr-1 target genes are known in the brain. The results of this study demonstrate that Egr-1 knockout (KO) mice display impaired contextual extinction learning and normal fear acquisition relative to wild-type (WT) control animals. Genome-wide microarray experiments revealed 368 differentially expressed genes in the hippocampus of Egr-1 WT exposed to different phases of a fear conditioning paradigm compared to gene expression profiles in the hippocampus of KO mice. Some of genes, such as serotonin receptor 2C (Htr2c), neuropeptide B (Npb), neuronal PAS domain protein 4 (Npas4), NPY receptor Y1 (Npy1r), fatty acid binding protein 7 (Fabp7), and neuropeptide Y (Npy) are known to regulate processing of fearful memories, and promoter analyses demonstrated that several of these genes contained Egr-1 binding sites. This study provides a useful list of potential Egr-1 target genes which may be regulated during fear memory processing.
PMCID: PMC3907009  PMID: 24552706
contextual fear conditioning; Egr-1; extinction; hippocampus; microarray
12.  Traumatic Intradural Lumbar Disc Herniation without Bone Injury 
Korean Journal of Spine  2013;10(3):181-184.
Intradural lumbar disc herniation is a rare disease. According to the reports of intradural lumbar disc herniations, most cases have developed as a chronic degenerative disc diseases. Traumatic intradural lumbar disc herniations are even rarer. A 52-year-old man visited our emergency center with numbness in his left calf and ankle after falling accident. Initial impression by radiologic findings was a spinal subdural hematoma at the L1 level. A follow up image two weeks later, however, did not demonstrate any interval change. The patient was decided to have an operation. In operative findings, a ruptured disc particle penetrating the ventral and dorsal dura was indentified after laminectomy. It was assumed to be a traumatic outcome not a degenerative change.
PMCID: PMC3941752  PMID: 24757484
Intradural disc herniation; Subdural hematoma; Lumbar spine
13.  Measurement of Critical Structures around Paraclinoidal Area : A Cadaveric Morphometric Study 
Although removal of the anterior clinoid process (ACP) is essential surgical technique, studies about quantitative measurements of the space broadening by the anterior clinoidectomy are rare. The purposes of this study are to investigate the dimension of the ACP, to quantify the improved exposure of the parasellar space after extradural anterior clinoidectomy and to measure the correlation of each structure around the paraclinoidal area.
Eleven formalin-fixed Korean adult cadaveric heads were used and frontotemporal craniotomies were done bilaterally. The length of C6 segment of the internal carotid artery on its lateral and medial side and optic nerve length were checked before and after anterior clinoidectomy. The basal width and height of the ACP were measured. The relationships among the paraclinoidal structures were assessed. The origin and projection of the ophthalmic artery (OA) were investigated.
The mean values of intradural basal width and height of the ACP were 10.82 mm and 7.61 mm respectively. The mean length of the C6 lateral and medial side increased 49%. The mean length of optic nerve increased 97%. At the parasellar area, the lengths from the optic strut to the falciform liament, distal dural ring, origin of OA were 6.69 mm, 9.36 mm and 5.99 mm, respectively. The distance between CN III and IV was 11.06 mm.
With the removal of ACP, exposure of the C6 segments and optic nerve can expand 49% and 97%, respectively. This technique should be among a surgeon's essential skills for treating lesions around the parasellar area.
PMCID: PMC3772280  PMID: 24044074
Anterior clinoid process; Extradural anterior clinoidectomy; Optic strut; Ophthalmic segment
14.  High-efficiency tooth bleaching using non-thermal atmospheric pressure plasma with low concentration of hydrogen peroxide 
Journal of Applied Oral Science  2013;21(3):265-270.
Light-activated tooth bleaching with a high hydrogen peroxide (HP; H2O2) concentration has risks and the actual role of the light source is doubtful. The use of conventional light might result in an increase in the temperature and cause thermal damage to the health of the tooth tissue.
This study investigated the efficacy of tooth bleaching using non-thermal atmospheric pressure plasma (NAPP) with 15% carbamide peroxide (CP; CH6N2O3) including 5.4% HP, as compared with conventional light sources.
Material and Methods:
Forty human teeth were randomly divided into four groups: Group I (CP+NAPP), Group II (CP+plasma arc lamp; PAC), Group III (CP+diode laser), and Group IV (CP alone). Color changes (ΔE ) of the tooth and tooth surface temperatures were measured. Data were evaluated by one-way analysis of variance (ANOVA) and post-hoc Tukey's tests.
Group I showed the highest bleaching efficacy, with a ΔE value of 1.92-, 2.61 and 2.97-fold greater than those of Groups II, III and IV, respectively (P<0.05). The tooth surface temperature was maintained around 37ºC in Group I, but it reached 43ºC in Groups II and III.
The NAPP has a greater capability for effective tooth bleaching than conventional light sources with a low concentration of HP without causing thermal damage. Tooth bleaching using NAPP can become a major technique for in-office bleaching in the near future.
PMCID: PMC3881910  PMID: 23857658
Tooth bleaching; Plasma gases; Hydrogen peroxide; Temperature
15.  Patterns of Brain Atrophy in Clinical Variants of Frontotemporal Lobar Degeneration 
The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups.
Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects.
Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology.
The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.
PMCID: PMC3609420  PMID: 23306166
Frontotemporal dementia; Primary progressive aphasia; Longitudinal study; Magnetic resonance imaging; Tensor-based morphometry; White matter
16.  Current routine practice and clinico-pathological characteristics associated with acute promyelocytic leukemia in Korea 
Blood research  2013;48(1):31-34.
Acute promyelocytic leukemia (APL) can be life threatening, necessitating emergency therapy with prompt diagnosis by morphologic findings, immunophenotyping, cytogenetic analysis, or molecular studies. This study aimed to assess the current routine practices in APL and the clinico-pathologic features of APL.
We reviewed the medical records of 48 Korean patients (25 men, 23 women; median age, 51 (20-80) years) diagnosed with APL in 5 university hospitals between March 2007 and February 2012.
The WBC count at diagnosis and platelet count varied from 0.4 to 81.0 (median 2.0)×109/L and 2.7 to 124.0 (median 54.5)×109/L, respectively. The median values for prothrombin time and activated partial thromboplastin time were 14.7 (11.3-44.1) s and 29 (24-62) s, respectively. All but 2 patients (96%) showed a fibrin/fibrinogen degradation product value of >20 µg/mL. The D-dimer median value was 5,000 (686-55,630) ng/mL. The t(15;17)(q22;q12 and PML-RARA fusion was found in all patients by chromosome analysis and/or multiplex reverse transcriptase-polymerase chain reaction (RT-PCR), with turnaround times of 8 (2-19) d and 7 (2-13) d, respectively. All patients received induction chemotherapy: all-trans retinoic acid (ATRA) alone (N=11, 26%), ATRA+idarubicin (N=25, 58%), ATRA+cytarabine (N=3, 7%), ATRA+idarubicin+cytarabine (N=4, 9%).
Since APL is a medical emergency and an accurate diagnosis is a prerequisite for prompt treatment, laboratory support to implement faster diagnostic tools to confirm the presence of PML-RARA is required.
PMCID: PMC3625006  PMID: 23589792
Acute promyelocytic leukemia; PML-RARA; Immunophenotyping; Cytogenetic analysis; All-trans retinoic acid
17.  Galectin-3 increases the motility of mouse melanoma cells by regulating matrix metalloproteinase-1 expression 
Experimental & Molecular Medicine  2012;44(6):387-393.
Although mounting evidence indicates the involvement of galectin-3 in cancer progression and metastasis, the underlying molecular mechanisms remain largely unknown. In this study, we investigated the effect and possible mechanism of galectin-3 on the migration and invasion of B16F10, a metastatic melanoma cell line, in which galectin-3 and matrix metalloproteinase-1 (MMP-1) were both found to be highly expressed. Knockdown of galectin-3 with specific siRNA reduced migration and invasion, which was associated with reduced expression of MMP-1. To further investigate the underlying mechanism, we examined the effect of galectin-3 knockdown on the activity of AP-1, a transcriptional factor regulating MMP-1 expression. We found that galectin-3 directly interacted with AP-1 and facilitated the binding of this complex to the MMP-1 promoter that drives MMP-1 transcription. Moreover, silencing of galectin-3 inhibited binding of fra-1 and c-Jun to promoter sites of MMP-1 gene. Consistent with these in vitro findings, our in vivo study demonstrated that galectin-3 shRNA treatment significantly reduced the total number of mouse lung metastatic nodules. Taken together, galectin-3 facilitates cell migration and invasion in melanoma in vitro and can induce metastasis in vivo, in part through, regulating the transcription activity of AP-1 and thereby up-regulating MMP-1 expression.
PMCID: PMC3389077  PMID: 22437631
galectin 3; matrix metalloproteinase 1; melanoma; neoplasm metastasis; RNA, small interfering; transcription factor AP-1
18.  Reversible Plasticity of Fear Memory-Encoding Amygdala Synaptic Circuits Even after Fear Memory Consolidation 
PLoS ONE  2011;6(9):e24260.
It is generally believed that after memory consolidation, memory-encoding synaptic circuits are persistently modified and become less plastic. This, however, may hinder the remaining capacity of information storage in a given neural circuit. Here we consider the hypothesis that memory-encoding synaptic circuits still retain reversible plasticity even after memory consolidation. To test this, we employed a protocol of auditory fear conditioning which recruited the vast majority of the thalamic input synaptic circuit to the lateral amygdala (T-LA synaptic circuit; a storage site for fear memory) with fear conditioning-induced synaptic plasticity. Subsequently the fear memory-encoding synaptic circuits were challenged with fear extinction and re-conditioning to determine whether these circuits exhibit reversible plasticity. We found that fear memory-encoding T-LA synaptic circuit exhibited dynamic efficacy changes in tight correlation with fear memory strength even after fear memory consolidation. Initial conditioning or re-conditioning brought T-LA synaptic circuit near the ceiling of their modification range (occluding LTP and enhancing depotentiation in brain slices prepared from conditioned or re-conditioned rats), while extinction reversed this change (reinstating LTP and occluding depotentiation in brain slices prepared from extinguished rats). Consistently, fear conditioning-induced synaptic potentiation at T-LA synapses was functionally reversed by extinction and reinstated by subsequent re-conditioning. These results suggest reversible plasticity of fear memory-encoding circuits even after fear memory consolidation. This reversible plasticity of memory-encoding synapses may be involved in updating the contents of original memory even after memory consolidation.
PMCID: PMC3176280  PMID: 21949700
19.  Identification of a shared F8 mutation in the Korean patients with acquired hemophilia A 
Although uncommon, acquired hemophilia A (HA) is associated with a high rate of mortality due to severe bleeding. In spite of many hypotheses regarding the cause of acquired HA, there is as yet no established theory. In this study, we investigated the possibility that mutation(s) in the F8 gene may be correlated with the development of inhibitory autoantibodies. Direct sequencing analysis was performed on all 26 exons of the F8 gene of 2 patients exhibiting acquired HA. Both patients were found to share a common point mutation (c.8899G>A) in the 3'-untranslated region (3'-UTR) of exon 26. This is the first report on the genotyping of F8 in the context of acquired HA.
PMCID: PMC3065628  PMID: 21461305
Haemophilia A; Mutation profiling; Sequence variation; Acquired haemophilia A
20.  Spontaneous Contractions Augmented by Cholinergic and Adrenergic Systems in the Human Ureter 
Interstitial cells of Cajal (ICC) evoke pacemaker activities in many tissues. The purpose of this study was to investigate the relationship between interstitial cell and pacemaker activity in the human ureter through the recording of spontaneous contractions. Spontaneous contractions of eight circular and longitudinal smooth muscle strips of the human ureter to acetylcholine (ACh) and/or norepinephrine (NE) were observed. Human ureteral strips were divided into proximal and distal groups, and each group was subdivided into circular and longitudinal groups. The proximal group showed spontaneous activities of 3~4 times within 5 minutes in the longitudinal group. ACh (10-4 M) augmented the frequency of the spontaneous contractions. The cumulative application of NE also augmented the frequency in a dose-dependent manner. The effects of NE application were inhibited by concomitant application of 10-5 M glibenclamide. Receptor tyrosine kinase (c-kit) staining revealed abundant ICCs only in proximal tissues. Therefore, spontaneous contractions of the human ureter might be modulated by ICC in the proximal region, and the actions might be related with the activation of cholinergic and/or adrenergic system mediated by a glibenclamide-sensitive pathway.
PMCID: PMC3062082  PMID: 21461239
Interstitial cell of Cajal; Pacemaker activity; Spontaneous contraction; Human ureter
21.  Molecular Characterization of the Tumor Suppressor Candidate 5 Gene: Regulation by PPARγ and Identification of TUSC5 Coding Variants in Lean and Obese Humans 
PPAR Research  2010;2009:867678.
Tumor suppressor candidate 5 (TUSC5) is a gene expressed abundantly in white adipose tissue (WAT), brown adipose tissue (BAT), and peripheral afferent neurons. Strong adipocyte expression and increased expression following peroxisome proliferator activated receptor γ (PPARγ) agonist treatment of 3T3-L1 adipocytes suggested a role for Tusc5 in fat cell proliferation and/or metabolism. However, the regulation of Tusc5 in WAT and its potential association with obesity phenotypes remain unclear. We tested the hypothesis that the TUSC5 gene is a bona fide PPARγ target and evaluated whether its WAT expression or single-nucleotide polymorphisms (SNPs) in the TUSC5 coding region are associated with human obesity. Induction of Tusc5 mRNA levels in 3T3-L1 adipocytes by troglitazone and GW1929 followed a dose-response consistent with these agents' binding affinities for PPARγ. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPARγ protein binds a ∼ −1.1 kb promotor sequence of murine TUSC5 transiently during 3T3-L1 adipogenesis, concurrent with histone H3 acetylation. No change in Tusc5 mRNA or protein levels was evident in type 2 diabetic patients treated with pioglitazone. Tusc5 expression was not induced appreciably in liver preparations overexpressing PPARs, suggesting that tissue-specific factors regulate PPARγ responsiveness of the TUSC5 gene. Finally, we observed no differences in Tusc5 WAT expression or prevalence of coding region SNPs in lean versus obese human subjects. These studies firmly establish the murine TUSC5 gene locus as a PPARγ target, but the significance of Tusc5 in obesity phenotypes or in the pharmacologic actions of PPARγ agonists in humans remains equivocal.
PMCID: PMC2830574  PMID: 20204174
22.  A case of donor-derived granulocytic sarcoma after allogeneic hematopoietic stem cell transplantation 
The occurrence of granulocytic sarcoma as a pattern of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare. In this paper, we report a rare case of acute myeloid leukemia (AML) relapsed as a granulocytic sarcoma of the donor type. The patient was diagnosed as having AML and underwent an allo-HSCT from his matched sibling donor. Fifty-seven months after allo-HSCT, he developed granulocytic sarcomas of duodenum, jejunum, and left sterno-cleido-mastoid muscle. The bone marrow was normal with 100% donor chimerism. A Y chromosome PCR was performed on the patient's duodenum specimen as well as bone marrow aspirate in order to check the patient-origin cells. The duodenal specimen was found to contain 41.2% SRY-positive cells (from the donor). Repeat endoscopy on day 2 of chemotherapy showed that the granulocytic sarcoma had shrunk dramatically. The patient died of sepsis during the nadir state 35 days after starting salvage chemotherapy.
PMCID: PMC2982999  PMID: 21120167
Granulocytic sarcoma; AML; Allo-HSCT; Donor type
23.  Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD 
PLoS Biology  2009;7(9):e1000187.
A two step mechanism was identified that regulates receptor endocytosis during the development of long-term depression (LTD), a long-lasting decrease in synaptic transmission.
Long-term depression (LTD) is a long-lasting activity-dependent decrease in synaptic strength. NMDA receptor (NMDAR)–dependent LTD, an extensively studied form of LTD, involves the endocytosis of AMPA receptors (AMPARs) via protein dephosphorylation, but the underlying mechanism has remained unclear. We show here that a regulated interaction of the endocytic adaptor RalBP1 with two synaptic proteins, the small GTPase RalA and the postsynaptic scaffolding protein PSD-95, controls NMDAR-dependent AMPAR endocytosis during LTD. NMDAR activation stimulates RalA, which binds and translocates widespread RalBP1 to synapses. In addition, NMDAR activation dephosphorylates RalBP1, promoting the interaction of RalBP1 with PSD-95. These two regulated interactions are required for NMDAR-dependent AMPAR endocytosis and LTD and are sufficient to induce AMPAR endocytosis in the absence of NMDAR activation. RalA in the basal state, however, maintains surface AMPARs. We propose that NMDAR activation brings RalBP1 close to PSD-95 to promote the interaction of RalBP1-associated endocytic proteins with PSD-95-associated AMPARs. This suggests that scaffolding proteins at specialized cellular junctions can switch their function from maintenance to endocytosis of interacting membrane proteins in a regulated manner.
Author Summary
Neurons adapt over time in order to dampen their response to prolonged or particularly strong stimuli. This process, termed long-term depression (LTD), results in a long-lasting decrease in the efficiency of synaptic transmission. One extensively studied form of LTD requires the activation of a specific class of receptors known as NMDA glutamate receptors (NMDARs). A key molecular event initiated by NMDA receptor activation is the stimulation of protein phosphatases. Another key event is internalization via endocytosis of synaptic AMPA glutamate receptors (AMPARs). However, the mechanism by which protein dephosphorylation is coupled to AMPAR endocytosis has remained unclear. Here, we help to define this mechanism. We show that endocytic proteins, including RalBP1, are widely distributed in neurons under normal conditions. Upon NMDAR activation, the small GTPase RalA becomes activated and binds to RalBP1, resulting in the translocation of RalBP1 and RalBP1-associated endocytic proteins to synapses. At the same time, RalBP1 becomes dephosphorylated, which promotes its binding to the postsynaptic scaffold protein PSD-95, a protein that itself associates with AMPARs. This concerted recruitment of endocytic proteins to the vicinity of AMPARs results in AMPAR endocytosis. On the basis of our data, we propose a model in which dual binding of RalBP1 to both RalA and PSD-95 following RalBP1 dephosphorylation is essential for NMDAR-dependent AMPAR endocytosis during LTD.
PMCID: PMC2730530  PMID: 19823667
24.  Low Expression of Bax Predicts Poor Prognosis in Resected Non-small Cell Lung Cancer Patients with Non-squamous Histology† 
The present study evaluated the prognostic significance of apoptosis-related proteins p53, Bax and galectin-3 in patients with non-small cell lung cancer (NSCLC) treated with surgical resection.
We investigated the expression of these proteins and their association with clinicopathologic characteristics including disease-free survival (DFS) and overall survival (OS) in 205 NSCLC patients who underwent surgical resection (Stage I, 97; II, 46; IIIA, 45; IIIB, 17) using immunohistochemistry. Eighty-eight patients (43%) received adjuvant treatment (chemotherapy: 8, radiotherapy: 24, both: 56).
High expressions of Bax, p53 and galectin-3 were observed in 48 (23%), 81 (40%) and 105 (51%) patients, respectively. Low expression of Bax was significantly associated with male gender, squamous cell histology and low expression of galectin-3. Five-year DFS and OS of total patients were 37 and 46%, respectively. High expressions of p53 and galectin-3 were not associated with poor DFS or OS, and no significant correlation existed between low expression of Bax and outcome of patients. However, in patients with non-squamous histology (108 patients), low expression of Bax was a significant independent predictor of poor DFS (P = 0.017) and OS (P = 0.037). In addition, in patients with Stage II or III disease, low expression of Bax significantly correlated with poor DFS (P = 0.004). It was also the most significant independent poor prognostic factor second only to a large primary tumor size in Stage II or III patients with non-squamous histology.
Low expression of Bax was significantly associated with poor prognosis in resected NSCLC patients with non-squamous histology.
PMCID: PMC2565351  PMID: 18772168
non-small cell lung cancer; Bax; prognosis
25.  Spontaneous Ligamentum Flavum Hematoma in the Rigid Thoracic Spine : A Case Report and Review of the Literature 
Ligamentum flavum hematoma is a rare condition. Twenty cases including present case have been reported in English-language literature. Among them, only one case reported in pure thoracic spine. A 72-year-old man presented with thoracic myelopathy without precedent cause. Magnetic resonance images revealed a posterior semicircular mass which was located in T7 and T8 level compressing the spinal cord dorsally. T7-8 total laminectomy and extirpation of the mass was performed. One month later following surgery, the patient fully recovered to normal state. Pathologic result was confirmed as ligamentum flavum hematoma. Ligamentum flavum hematoma of rigid thoracic spine is a very rare disease entity. Most reported cases were confined to mobile cervical and lumbar spine. Surgeons should be aware that there seems to be another different pathogenesis other than previously reported cases of mobile cervical and lumbar spine.
PMCID: PMC2588285  PMID: 19096657
Ligamentum flavum; Hematoma; Thoracic spine; Myelopathy

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