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1.  Improvement of diabetes and hypertension after gastrectomy: A nationwide cohort study 
AIM: To evaluate the effect of gastrectomy on diabetes mellitus (DM) and hypertension (HTN) in non-obese gastric cancer patients.
METHODS: A total of 100000 patients, diagnosed with either type 2 DM or HTN, were randomly selected from the 2004 Korean National Health Insurance System claims. Among them, 360 diabetes and 351 hypertensive patients with gastric cancer who had been regularly treated without chemotherapy from January 2005 to December 2010 were selected. They were divided into three groups according to their treatment methods: total gastrectomy (TG), subtotal gastrectomy (STG) and endoscopic resection (ER).
RESULTS: The drug discontinuation rate of anti-diabetic and anti-hypertensive agents after gastric cancer treatment was 9.7% and 11.1% respectively. DM appeared to be improved more frequently (22.8%) and earlier (mean ± SE 28.6 ± 1.8 mo) in TG group than in the two other groups [improved in 9.5% of ER group (37.4 ± 1.1 mo) and 6.4% of STG group (47.0 ± 0.8 mo)]. The proportion of patients treated with multiple drugs decreased more notably in TG group compared to others (P = 0.001 in DM, and P = 0.035 in HTN). In TG group, adjusted hazard ratio for the improvement of DM was 2.87 (95%CI: 1.15-7.17) in a multi-variate analysis and better control of DM was observed with survival analysis (P < 0.001).
CONCLUSION: TG was found to decrease the need for anti-diabetic medications which can be reflective of improved glycemic control, to a greater extent than either ER or STG in non-obese diabetic patients.
PMCID: PMC4306161  PMID: 25632190
Diabetes; Hypertension; Gastrectomy; Gastric cancer; National cohort
3.  Expression of Myeloid Antigen in Neoplastic Plasma Cells Is Related to Adverse Prognosis in Patients with Multiple Myeloma 
BioMed Research International  2014;2014:893243.
We evaluated the association between the expression of myeloid antigens on neoplastic plasma cells and patient prognosis. The expression status of CD13, CD19, CD20, CD33, CD38, CD56, and CD117 was analyzed on myeloma cells from 55 newly diagnosed patients, including 36 men (65%), of median age 61 years (range: 38–78). Analyzed clinical characteristics and laboratory parameters were as follows: serum β2-microglobulin, lactate dehydrogenase, calcium, albumin, hemoglobin, serum creatinine concentrations, bone marrow histology, and cytogenetic findings. CD13+ and CD33+ were detected in 53% and 18%, respectively. Serum calcium (P = 0.049) and LDH (P = 0.018) concentrations were significantly higher and morphologic subtype of immature or plasmablastic was more frequent in CD33+ than in CD33− patients (P = 0.022). CD33 and CD13 expression demonstrate a potential prognostic impact and were associated with lower overall survival (OS; P = 0.001 and P = 0.025) in Kaplan-Meier analysis. Multivariate analysis showed that CD33 was independently prognostic of shorter progression free survival (PFS; P = 0.037) and OS (P = 0.001) with correction of clinical prognostic factors. This study showed that CD13 and CD33 expression associated with poor prognosis in patients with MM implicating the need of analysis of these markers in MM diagnosis.
PMCID: PMC4065753  PMID: 24991573
4.  An Aminopropyl Carbazole Derivative Induces Neurogenesis by Increasing Final Cell Division in Neural Stem Cells 
Biomolecules & Therapeutics  2015;23(4):313-319.
P7C3 and its derivatives, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol (1) and N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-methylbenzenesulfonamide (2), were previously reported to increase neurogenesis in rat neural stem cells (NSCs). Although P7C3 is known to increase neurogenesis by protecting newborn neurons, it is not known whether its derivatives also have protective effects to increase neurogenesis. In the current study, we examined how 1 induces neurogenesis. The treatment of 1 in NSCs increased numbers of cells in the absence of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), while not affecting those in the presence of growth factors. Compound 1 did not induce astrocytogenesis during NSC differentiation. 5-Bromo-2′-deoxyuridine (BrdU) pulsing experiments showed that 1 significantly enhanced BrdU-positive neurons. Taken together, our data suggest that 1 promotes neurogenesis by the induction of final cell division during NSC differentiation.
PMCID: PMC4489824  PMID: 26157546
Neurodegenerative diseases; Neural stem cells; Neurogenesis; Final cell division; Aminopropyl carbazoles
5.  Dual inhibition of canonical and non-canonical NF-κB pathways demonstrates significant anti-tumor activities in multiple myeloma 
NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma (MM) in the context of the bone marrow (BM) microenvironment. Both canonical and non-canonical pathways contribute to total NF-κB activity. Recent studies have demonstrated a critical role for the non-canonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the non-canonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity.
Experimental design
MM cell lines, primary patient cells, and the human MM xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and non-canonical NF-κB pathways.
We show that PBS-1086 induces potent cytotoxicity in MM cells, but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and anti-apoptotic effects of the BM milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant MM cell lines and patient MM cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANKL-induced NF-κB activation. Finally, in a xenograft model of human MM in the BM milieu, PBS-1086 shows significant in vivo anti-MM activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells.
Our data demonstrate that PBS-1086 is a promising dual inhibitor of the canonical and non-canonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of MM and related bone lesions.
PMCID: PMC4456190  PMID: 22806876
multiple myeloma; NF-κB; Rel inhibitors; canonical and non-canonical pathways
6.  Kuwanon V Inhibits Proliferation, Promotes Cell Survival and Increases Neurogenesis of Neural Stem Cells 
PLoS ONE  2015;10(2):e0118188.
Neural stem cells (NSCs) have the ability to proliferate and differentiate into neurons and glia. Regulation of NSC fate by small molecules is important for the generation of a certain type of cell. The identification of small molecules that can induce new neurons from NSCs could facilitate regenerative medicine and drug development for neurodegenerative diseases. In this study, we screened natural compounds to identify molecules that are effective on NSC cell fate determination. We found that Kuwanon V (KWV), which was isolated from the mulberry tree (Morus bombycis) root, increased neurogenesis in rat NSCs. In addition, during NSC differentiation, KWV increased cell survival and inhibited cell proliferation as shown by 5-bromo-2-deoxyuridine pulse experiments, Ki67 immunostaining and neurosphere forming assays. Interestingly, KWV enhanced neuronal differentiation and decreased NSC proliferation even in the presence of mitogens such as epidermal growth factor and fibroblast growth factor 2. KWV treatment of NSCs reduced the phosphorylation of extracellular signal-regulated kinase 1/2, increased mRNA expression levels of the cyclin-dependent kinase inhibitor p21, down-regulated Notch/Hairy expression levels and up-regulated microRNA miR-9, miR-29a and miR-181a. Taken together, our data suggest that KWV modulates NSC fate to induce neurogenesis, and it may be considered as a new drug candidate that can regenerate or protect neurons in neurodegenerative diseases.
PMCID: PMC4338147  PMID: 25706719
7.  Biomarkers of thyroid function and autoimmunity for predicting high-risk groups of thyroid cancer: a nested case–control study 
BMC Cancer  2014;14:873.
A remarkable increase in the number of thyroid cancer cases has been reported in recent years; however, the markers to predict high-risk groups have not been fully established.
We conducted a case–control study (257 cases and 257 controls) that was nested in the Cancer Screenee Cohort Study between August 2002 and December 2010; the mean follow-up time for this study was 3.1 ± 2.2 years. The levels of total triiodothyronine (TT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroglobulin (Tg), anti-thyroperoxidase antibody (TPOAb), and anti-thyroglobulin antibody (TgAb) were measured using samples with pre-diagnostic status. Logistic regression models were used to examine the association between thyroid function/autoimmunity and thyroid cancer risk.
When the markers were categorized by the tertile distributions of the control group, the highest tertile of FT4 (OR = 1.73, 95% CI = 1.11 - 2.69) and the middle tertile of TSH (OR = 1.77, 95% CI = 1.14 - 2.74) were associated with an increased risk of thyroid cancer by multivariate analyses. In addition, an elevated risk for thyroid cancer was found in subjects with TPOAb levels above 30 IU/mL (OR = 8.47, 95% CI = 5.39 - 13.33 for 30–60 IU/mL and OR = 4.48, 95% CI = 2.59 - 7.76 for ≥60 IU/mL). Stratified analyses indicated that some of these associations differed by sex, BMI, smoking status, and the duration of follow-up.
This study demonstrated that the levels of biomarkers of thyroid function/autoimmunity, particularly the presence of TPOAb, might be used as diagnostic markers for predicting thyroid cancer risk. Our findings suggest that careful monitoring of thyroid biomarkers may be helpful for identifying Korean populations at high-risk for thyroid cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-873) contains supplementary material, which is available to authorized users.
PMCID: PMC4289269  PMID: 25421041
Thyroid cancer; Biomarkers; Thyroid function; Autoimmunity; TPOAb
8.  Elevated Red Blood Cell Distribution Width as a Simple Prognostic Factor in Patients with Symptomatic Multiple Myeloma 
BioMed Research International  2014;2014:145619.
Red blood cell distribution width (RDW) is a parameter reported in complete blood cell count tests, and has been reported as an inflammatory biomarker. Multiple myeloma (MM) is known to be associated with inflammatory microenvironments. However, the importance of RDW has been seldom studied in MM. For this study, 146 symptomatic myeloma patients with available RDW at diagnosis were retrospectively reviewed, and their characteristics were compared between two groups, those with high (>14.5%) and normal (≤14.5%) RDW. RDW was correlated to hemoglobin, MM stage, β2-microglobulin, M-protein, bone marrow plasma cells, and cellularity (P < 0.001). During induction, overall response rates of the two groups were similar (P = 0.195); however, complete response rate was higher in the normal-RDW group than it was in the high-RDW group (P = 0.005). With a median follow-up of 47 months, the normal-RDW group showed better progression-free survival (PFS) (24.2 versus 17.0 months, P = 0.029) compared to the high-RDW group. Overall survival was not different according to the RDW level (P = 0.236). In multivariate analysis, elevated RDW at diagnosis was a poor prognostic factor for PFS (HR 3.21, 95% CI 1.24–8.32) after adjustment with other myeloma-related prognostic factors. RDW would be a simple and immediately available biomarker of symptomatic MM, reflecting the systemic inflammation.
PMCID: PMC4055253  PMID: 24963470
9.  Overexpression, crystallization and preliminary X-ray crystallographic analysis of the variable lymphocyte receptor 2913 ectodomain fused with internalin B 
The VLR2913 ectodomain fused with internalin B was crystallized and diffraction data were collected to a maximum resolution of 2.04 Å.
In jawless vertebrates, variable lymphocyte receptors (VLRs) play a crucial role in the recognition of antigens as part of the adaptive immune system. Leucine-rich repeat (LRR) modules and the highly variable insert (HVI) of VLRs contribute to the specificity and diversity of antigen recognition. VLR2913, the antigen of which is not known, contains the same HVI amino-acid sequence as that of VLR RBC36, which recognizes the H-trisaccharide from human blood type O erythrocytes. Since the HVI sequence is rarely identical among all known VLRs, identification of the antigen for VLR2913 and the main contributing factors for antigen recognition based on a comparison of VLR2913 and VLR RBC36 has been attempted. To initiate and facilitate this structural approach, the ectodomain of VLR2913 was fused with the N-terminal domain of internalin B (InlB-VLR2913-ECD). Three amino-acid residues on the concave surface of the LRR modules of InlB-VLR2913-ECD were mutated, considering important residues for hydrogen bonds in the recognition of H-trisaccharide by VLR RBC36. InlB-VLR2913-ECD was overexpressed in Escherichia coli and was crystallized at 295 K using the sitting-drop vapour-diffusion method. X-ray diffraction data were collected to 2.04 Å resolution and could be indexed in the tetragonal space group P41212 (or P43212), with unit-cell parameters a = 91.12, b = 91.12, c = 62.87 Å. Assuming that one monomer molecule was present in the crystallographic asymmetric unit, the calculated Matthews coefficient (V M) was 2.75 Å3 Da−1 and the solvent content was 55.2%. Structural determination of InlB-VLR2913-ECD by molecular replacement is in progress.
PMCID: PMC3539700  PMID: 23295483
variable lymphocyte receptor; VLR; adaptive immunity; antigen recognition
10.  Comparison of Ectopic Gene Expression Methods in Rat Neural Stem Cells 
Neural stem cells (NSCs) have the ability to proliferate and differentiate into various types of cells that compose the nervous system. To study functions of genes in stem cell biology, genes or siRNAs need to be transfected. However, it is difficult to transfect ectopic genes into NSCs. Thus to identify the suitable method to achieve high transfection efficiency, we compared lipid transfection, electroporation, nucleofection and retroviral transduction. Among the methods that we tested, we found that nucleofection and retroviral transduction showed significantly increased transfection efficiency. In addition, with retroviral transduction of Ngn2 that is known to induce neurogenesis in various types of cells, we observed facilitated final cell division in rat NSCs. These data suggest that nucleofection and retroviral transduction provide high efficiency of gene delivery system to study functions of genes in rat NSCs.
PMCID: PMC3579101  PMID: 23439859
Electroporation; Lipid-Mediated transfection; Neural stem cells; Nucleofection; Retrovirus
11.  A Case of Locally Advanced Breast Cancer Complicated by Pulmonary Tumor Thrombotic Microangiopathy 
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare, malignancy-related complication that causes marked pulmonary hypertension, right heart failure, and death. We report on a patient with locally advanced breast cancer whose course was complicated by fatal PTTM based on clinical and laboratory findings.
PMCID: PMC3546274  PMID: 23341791
Breast neoplasms; Pulmonary hypertension; Pulmonary tumor thrombotic microangiopathy
12.  Blockade of the MEK/ERK signaling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo 
British journal of haematology  2010;149(4):537-549.
We investigate cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026, more potently (9-10 fold) than AZD6244, inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation. Inhibition of proliferation induced by AS703026 was mediated by G0-G1 cell cycle arrest and was accompanied by reduction of c-maf oncogene expression. AS703026 further induced apoptosis via caspase 3 and PARP cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti-MM therapies. Significant tumor growth reduction in AS703026- vs. vehicle-treated mice bearing H929 MM xenograft tumors correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nM) was cytotoxic against the majority of tumor cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC-induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti-MM agents, to improve patient outcome.
PMCID: PMC3418597  PMID: 20331454
multiple myeloma (MM); MEK1/2 inhibitor; bone marrow stromal cells (BMSCs); novel kinase inhibitor therapy
13.  Altered Cellular Kinetics in the Growth Plate of the Femoral Head of Spontaneously Hypertensive Rats 
Yonsei Medical Journal  2012;53(3):625-633.
Pathologic changes in the growth plate remain unknown in Legg-Calvé-Perthes (LCP) disease. Spontaneously hypertensive rats have proven to be a good model for studying LCP disease. This study investigated the histopathologic changes and the expression of vascular endothelial growth factor in the growth plate of spontaneously hypertensive rats (SHR).
Materials and Methods
Sixty SHR rats were divided into two groups: those showing osteonecrosis (SHR+n group: 32), and those showing normal ossification (SHR-n group: 28). Thirty Wister Kyoto rats served as a control. For histomorphological measurement, the length of each zone of the growth plate was measured. Cell kinetics was measured by 5-bromo-2'-deoxyuridin (BrdU) immunohistochemistry and transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assays. Vascular endothelial growth factor (VEGF) immunohistochemistry was used to identify of expression of VEGF.
The lengths of growth plates of the SHR+n group were significantly shorter in the initial growth period than those of the other groups. The lowest proliferative rate and the highest apoptosis rate were observed in the SHR+n group at the initial growth period. The expression of VEGF in the growth plate of the SHR group was lower than the control group, and it was lower in the SHR+n group than in the SHR-n group.
The growth plate of the SHR+n group was found to be affected by disease process of ischemic necrosis of the femoral head, and this might explain the relative overgrowth of the greater trochanter in the later stages of LCP disease.
PMCID: PMC3343426  PMID: 22477009
Spontaneous hypertensive rats; growth plate; avascular necrosis; apoptosis; vascular endothelial growth factor
14.  Altered Cellular Kinetics in Growth Plate according to Alterations in Weight Bearing 
Yonsei Medical Journal  2012;53(3):618-624.
To examine the effects of change in weight bearing on the growth plate metabolism, a simulated animal model of weightlessness was introduced and the chondrocytes' cellular kinetics was evaluated.
Materials and Methods
Unloading condition on the hind-limb of Sprague-Dawley rats was created by fixing a tail and lifting the hind-limb. Six rats aged 6 weeks old were assigned to each group of unloading, reloading, and control groups of unloading or reloading. Unloading was maintained for three weeks, and then reloading was applied for another one week thereafter. Histomorphometry for the assessment of vertical length of the growth plate, 5-bromo-2'-deoxyuridin immunohistochemistry for cellular kinetics, and biotin nick end labeling transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay for chondrocytes apoptosis in the growth plate were performed.
The vertical length of the growth plate and the proliferative potential of chondrocytes were decreased in the unloading group compared to those of control groups. Inter-group differences were more significant in the proliferative and hypertrophic zones. Reloading increased the length of growth plate and proliferative potential of chondrocytes. However, apoptotic changes in the growth plate were not affected by the alterations of weight bearing.
Alterations in the weight bearing induced changes in the chondrocytic proliferative potential of the growth plate, however, had no effects on the apoptosis. This may explain why non-weight bearing in various clinical situations hampers normal longitudinal bone growth. Further studies on the factors for reversibility of chondrocytic proliferation upon variable mechanical stresses are needed.
PMCID: PMC3343419  PMID: 22477008
Cellular kinetics; growth plate; changes in weight bearing
15.  Epidermal growth factor receptor status in anaplastic thyroid carcinoma 
Journal of Clinical Pathology  2006;60(8):881-884.
The epidermal growth factor receptor (EGFR) has been reported to be overexpressed in anaplastic thyroid carcinoma (ATC). In vitro studies have shown that EGFR tyrosine kinase inhibitors (TKIs) greatly inhibit cellular growth and induced apoptosis in the ATC cell lines, while somatic mutations in the tyrosine kinase domain or an increased gene copy number are associated with increased sensitivity to TKIs in non‐small cell lung cancer.
To investigate the prevalence of EGFR overexpression, gene amplification and activating mutation in the tyrosine kinase domain in patients with ATC.
The EGFR gene status and protein expression were investigated by direct DNA sequencing of the hot‐spot regions in exons 18, 19 and 21, fluorescence in situ hybridisation (FISH), and immunohistochemistry in tumour tissues from 23 patients with ATC.
On mutational analysis and FISH, neither mutations in the hot‐spots nor gene amplification was observed. However, high polysomy was identified in 14/23 (60.9%) patients with ATC. All cases with immunohistochemistry (IHC) positivity (n = 6) had high polysomy, whereas 8/17 (47.1%) cases with IHC negativity had high polysomy (p = 0.048). High polysomy was observed in all 10 cases with giant cell subtype, but in only 4/11 (36.3%) with squamoid and 0/2 with spindle cell sarcomatoid subtype. There was no statistically significant correlation between FISH positivity of ATC tumour and presence of well‐differentiated component.
Despite the low incidence of somatic EGFR gene mutation and amplification in the study samples, in view of the fact that high polysomy was often identified by FISH, as well as the current lack of therapeutic options, EGFR TKIs are worth investigating for treating the patients with ATC who have at least giant cell subtype.
PMCID: PMC1994497  PMID: 17079354
anaplastic thyroid carcinoma; EGFR; high polysomy
16.  Breast Cancer Diagnosis Using a Microfluidic Multiplexed Immunohistochemistry Platform 
PLoS ONE  2010;5(5):e10441.
Biomarkers play a key role in risk assessment, assessing treatment response, and detecting recurrence and the investigation of multiple biomarkers may also prove useful in accurate prediction and prognosis of cancers. Immunohistochemistry (IHC) has been a major diagnostic tool to identify therapeutic biomarkers and to subclassify breast cancer patients. However, there is no suitable IHC platform for multiplex assay toward personalized cancer therapy. Here, we report a microfluidics-based multiplexed IHC (MMIHC) platform that significantly improves IHC performance in reduction of time and tissue consumption, quantification, consistency, sensitivity, specificity and cost-effectiveness.
Methodology/Principal Findings
By creating a simple and robust interface between the device and human breast tissue samples, we not only applied conventional thin-section tissues into on-chip without any additional modification process, but also attained perfect fluid control for various solutions, without any leakage, bubble formation, or cross-contamination. Four biomarkers, estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR) and Ki-67, were examined simultaneously on breast cancer cells and human breast cancer tissues. The MMIHC method improved immunoreaction, reducing time and reagent consumption. Moreover, it showed the availability of semi-quantitative analysis by comparing Western blot. Concordance study proved strong consensus between conventional whole-section analysis and MMIHC (n = 105, lowest Kendall's coefficient of concordance, 0.90). To demonstrate the suitability of MMIHC for scarce samples, it was also applied successfully to tissues from needle biopsies.
The microfluidic system, for the first time, was successfully applied to human clinical tissue samples and histopathological diagnosis was realized for breast cancers. Our results showing substantial agreement indicate that several cancer-related proteins can be simultaneously investigated on a single tumor section, giving clear advantages and technical advances over standard immunohistochemical method. This novel concept will enable histopathological diagnosis using numerous specific biomarkers at a time even for small-sized specimens, thus facilitating the individualization of cancer therapy.
PMCID: PMC2862720  PMID: 20454672
17.  Normalization of Red Cell Enolase Level Following Allogeneic Bone Marrow Transplantation in a Child with Diamond-Blackfan Anemia 
Journal of Korean Medical Science  2010;25(4):626-629.
We describe a girl with Diamond-Blackfan anemia with accompanying red cell enolase deficiency. At the age of 9 yr old, the patient received allogeneic bone marrow transplantation from her HLA-identical sister who had normal red cell enolase activity. While the post transplant DNA analysis with short tandem repeat has continuously demonstrated a stable mixed chimerism on follow-up, the patient remains transfusion independent and continues to show a steady increase in red cell enolase activity for over two and a half years following bone marrow transplantation.
PMCID: PMC2844588  PMID: 20358009
Anemia, Diamond-Blackfan; Erythrocyte Enzyme Deficiency; Red Cell Enolase Deficiency; Bone Marrow Transplantation
18.  Identification of hypoxanthine as a urine marker for non-Hodgkin lymphoma by low-mass-ion profiling 
BMC Cancer  2010;10:55.
Non-Hodgkin lymphoma (NHL) is a hematologic malignancy for which good diagnostic markers are lacking. Despite continued improvement in our understanding of NHL, efforts to identify diagnostic markers have yielded dismal results. Here, we translated low-mass-ion information in urine samples from patients with NHL into a diagnostic marker.
To minimize experimental error, we tested variable parameters before MALDI-TOF analysis of low-mass ions in urine. Urine from 30 controls and 30 NHL patients was analyzed as a training set for NHL prediction. All individual peak areas were normalized to total area up to 1000 m/z. The training set analysis was repeated four times. Low-mass peaks that were not affected by changes in experimental conditions were collected using MarkerView™ software. Human Metabolome Database (HMDB) searches and ESI LC-MS/MS analyses were used to identify low-mass ions that exhibited differential patterns in control and NHL urines. Identified low-mass ions were validated in a blinded fashion in 95 controls and 66 NHL urines to determine their ability to discriminate NHL patients from controls.
The 30 highest-ranking low-mass-ion peaks were selected from the 60-urine training set, and three low-mass-ion peaks with high intensity were selected for identification. Of these, a 137.08-m/z ion showed lower mass-peak intensity in urines of NHL patients, a result that was validated in a 161-urine blind validation set (95 controls and 66 NHL urines). The 130.08-m/z ion was identified from HMDB searches and ESI LC-MS/MS analyses as hypoxanthine (HX). The HX concentration in urines of NHL patients was significantly decreased (P < 0.001) and was correlated with the mass-peak area of the 137.08-m/z ion. At an HX concentration cutoff of 17.4 μM, sensitivity and specificity were 79.2% and 78.4%, respectively.
The present study represents a good example of low-mass-ion profiling in the setting of disease screening using urine. This technique can be a powerful non-invasive diagnostic tool with high sensitivity and specificity for NHL screening. Furthermore, HX identified in the study may be a useful single urine marker for NHL screening.
PMCID: PMC2841663  PMID: 20175931
19.  Epstein-Barr virus-transformation of B-cell lines in ovarian cancer patients: feasibility of genomic storage for unlimited use 
Journal of Gynecologic Oncology  2009;20(4):243-245.
The aim of the current study is to test whether immortalized B-lymphocyte cell line via Ebstein-Barr virus (EBV) transformation is feasible and can be an unlimited source of genome wide study.
We obtained peripheral whole blood from 5 ovarian cancer patients and immortalized the B-cell lines using EBV transformation. The success rate was analyzed and the bio-identity of the genome was performed using human leukocyte antigen (HLA) identity test.
EBV transformation was successful in all 5 cases (95% confidence interval, 46.3% to 100%). After cryopreservation of EBV-transformed B-cell lines and subsequent thawing, we observed that all cell lines were viable and proliferative. To check bio-identity, HLA-A, B, and DR were tested between the genome of the original samples and the transformed samples. The HLA typing revealed that all observed HLA-A, B, and DR type was identical in 5 cases before and after EBV-transformation.
The current results suggest that EBV-transformation of peripheral blood is an efficient tool in genome banking. The EBV-transformed B-cell lines may be a valuable resource of genome in multi-center translational research by the Korean Gynecologic Oncology Group.
PMCID: PMC2799024  PMID: 20041102
Genomics; Epidemiology; DNA storage; EBV transformation; Cryopreservation
20.  Neonatal Hair Nicotine Levels and Fetal Exposure to Paternal Smoking at Home 
American Journal of Epidemiology  2008;168(10):1140-1144.
Exposure to environmental tobacco smoke (ETS) is a major risk to human health, and the home is the greatest single source of ETS for children. The authors investigated fetal exposure to paternal smoking at home during pregnancy. Korean families were included as trios of fathers, mothers, and neonates identified in 2005–2007. Sixty-three trios were finally enrolled in this study after exclusion of those in which the mother was a smoker or was regularly exposed to ETS at places other than the home. Nicotine and cotinine concentrations in hair were measured by using liquid chromatography–tandem mass spectrometry to determine long-term exposure to ETS. The difference between neonatal nicotine concentrations in the smoker and nonsmoker groups was not statistically significant. However, in the indoor-smoker group, neonatal nicotine concentrations were significantly higher than in the outdoor and nonsmoker groups (P < 0.05). Furthermore, neonatal nicotine concentrations in the outdoor-smoker group were not different from those in the nonsmoker group. These findings indicate that paternal smoking inside the home leads to significant fetal and maternal exposure to ETS and may subsequently affect fetal health. Conversely, findings show that paternal smoking outside the home prevents the mother and her fetus from being exposed to ETS.
PMCID: PMC2727244  PMID: 18801888
fetus; hair; nicotine; smoking; tobacco smoke pollution
21.  Allogeneic Blood Transfusion Given Before Radiotherapy Is Associated with the Poor Clinical Outcome in Patients with Cervical Cancer 
Yonsei Medical Journal  2008;49(6):993-1003.
To analyze the effect of allogeneic blood transfusion on clinical outcome in 119 patients with stage IIB cervical cancer who were treated with radiotherapy ± chemotherapy.
Patients and Methods
Medical records were examined for hemoglobin levels before and during radiotherapy, history of allogeneic blood transfusions and the time point when transfusions were given. These factors were retrospectively analyzed along with other clinical risk factors for influences on the patients' clinical outcomes.
Thirty-two patients (26.9%) received packed red blood cell transfusion (mean, 3.4 units; range, 1 - 12 units) before or during radiotherapy. Median follow-up period was 39.3 months (range, 7.6 - 58.4 months). Patients with history of transfusion showed poorer metastasis-free survival and a trend toward poorer overall survival than non-transfused patients. When patients who received transfusions were sub-divided by the time of transfusion, those who received transfusions before radiotherapy had significantly poorer clinical outcome than those who received transfusions during radiotherapy. In a multivariable analysis, patients with pretreatment transfusion showed a higher risk of distant metastasis (HR = 3.75, 95% CI: 1.28 - 12.15, p = 0.017) and decreased overall survival rates (HR = 4.62, 95% CI: 1.15-18.54, p = 0.031) compared with those of other patients.
Our results suggest that allogeneic blood transfusions given before radiotherapy may be associated with higher incidence of distant metastases and decreased survival in patients with stage IIB cervical cancer.
PMCID: PMC2628023  PMID: 19108024
Anemia; blood transfusion; cervical cancer; metastasis; radiotherapy
22.  Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability 
BMC Cancer  2008;8:286.
Elucidating the molecular mechanisms by which tumors become resistant to Herceptin is critical for the treatment of Her2-overexpressed metastatic breast cancer.
To further understand Herceptin resistance mechanisms at the molecular level, we used comparative proteome approaches to analyze two human breast cancer cell lines; Her2-positive SK-BR-3 cells and its Herceptin-resistant SK-BR-3 (SK-BR-3 HR) cells.
Heat-shock protein 27 (HSP27) expression was shown to be upregulated in SK-BR-3 HR cells. Suppression of HSP27 by specific siRNA transfection increased the susceptibility of SK-BR-3 HR cells to Herceptin. In the presence of Herceptin, Her2 was downregulated in both cell lines. However, Her2 expression was reduced by a greater amount in SK-BR-3 parent cells than in SK-BR-3 HR cells. Interestingly, co-immunoprecipitation analysis showed that HSP27 can bind to Her2. In the absence of Herceptin, HSP27 expression is suppressed and Her2 expression is reduced, indicating that downregulation of Her2 by Herceptin can be obstructed by the formation of a Her2-HSP27 complex.
Our present study demonstrates that upregulated HSP27 in human breast cancer cells can reduce Herceptin susceptibility by increasing Her2 protein stability.
PMCID: PMC2567332  PMID: 18834540
23.  Serum HER2 as a Response Indicator to Various Chemotherapeutic Agents in Tissue HER2 Positive Metastatic Breast Cancer 
The aim of study was to evaluate the usefulness of serum HER2 as a therapeutic response indicator in patients with HER2 positive metastatic breast cancer (MBC).
Materials and Methods
The levels of serum HER2 and CA15.3 were assayed in 148 serial serum samples from 50 HER2 positive MBC patients at both the baseline and follow-ups. The changes in the levels of serum HER2 and CA15.3 in relation to the tumor responses to the various chemotherapy regimens were monitored.
The levels of serum HER2 and CA15.3 were elevated in 82% and 62% of tissue HER2 positive patients, respectively, prior to therapies, with the changes in both tumor markers showing statistical significance in relation to the tumor responses (p<0.01) in patients with elevated baseline serum markers.
The level of serum HER2 could be a valuable response indicator, not only for trastuzumab containing therapy, but also for other common MBC chemotherapeutic agents. Also, as it is more frequently elevated, the serum level of HER2 may also be a more useful tumor marker than CA15.3 in HER2 positive MBC.
PMCID: PMC2741656  PMID: 19771257
Serum HER2; CA15.3; Metastatic breast cancer; Response; Trastuzumab; Monitoring
24.  De novo CD5 Positive Diffuse Large B-cell Lymphomas with Bone Marrow Involvement in Korean 
Journal of Korean Medical Science  2004;19(6):815-819.
In CD5 positive (CD5+) mature B-cell lymphomas, newly recognized CD5+ diffuse large B-cell lymphoma (DLBCL) has been characterized by aggressive features. We studied twenty-five cases with CD5+ lymphomas involving bone marrow. Eleven cases were diagnosed as chronic lymphocytic leukemia, six cases were diagnosed as mantle cell lymphoma (MCL), and three cases with morphologic characteristics of MCL and without both the cyclin D1 expression and IGH/CCND1 rearrangement were unclassifiable. The remaining five cases, showing large to medium-sized lym-phoid cells with prominent nucleoli and a moderate amount of cytoplasm, were diagnosed as DLBCL. Five DLBCL cases were positive for CD5, CD20, surface immuno-globulin, but negative for CD23. Patients with CD5+ DLBCL showed a high age of onset (median, 68 yr) and two patients expired one month after the diagnosis. Since CD5+ DLBCL forms a distinct subgroup of DLBCL, a study of CD5 expression in DLBCL would be helpful to predict prognosis and to determine future therapeutic strategy. To the best of our knowledge, this is the first report on de novo CD5+ DLBCL in Koreans.
PMCID: PMC2816303  PMID: 15608391
Antigens, CD5; Leukemia, Lymphocytic, Chronic; Lymphoma, Mantle-Cell; Lymphoma, Large-Cell, Diffuse
25.  Marker chromosomes in Korean patients: incidence, identification and diagnostic approach. 
Journal of Korean Medical Science  2003;18(6):773-778.
The identification of marker chromosomes is important for genetic counseling. However, the origin or composition can rarely be defined with conventional cytogenetic technique alone. In this study, we investigated the incidences and types of marker chromosomes in Korean patients and attempted to establish a cost-effective diagnostic approach for marker chromosomes. We reviewed the karyotypes of 2,984 patients that were requested for the cytogenetic analysis between 1997 and 2003 at the Samsung Medical Center. Ten marker chromosomes were found and identified using fluorescent in situ hybridization (FISH). Among the ten marker chromosomes, six were supernumerary marker chromosomes (SMCs) and the rest were marker chromosomes in Turner syndrome (TS). The incidence of SMCs was 2.01/1,000, slightly higher than that previously reported. Five of six SMCs were satellited marker chromosomes. Three bisatellited marker chromosomes originated from chromosome 15 and two from chromosome 22. The origin of one SMC could not be identified. All marker chromosomes in TS originated from X- or Y chromosome. The application of FISH is indispensable to identify marker chromosomes, and the appropriate selection of probes is necessary for cost-effective analysis. For analyzing satellited marker chromosomes, application of probes for chromosome 15 followed by those for chromosome 22 is recommended and in cases of TS, probes for sex chromosomes should take precedence.
PMCID: PMC3055124  PMID: 14676430

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