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1.  Proposal for a Standardized Pathology Report of Gastroenteropancreatic Neuroendocrine Tumors: Prognostic Significance of Pathological Parameters 
Korean Journal of Pathology  2013;47(3):227-237.
Background
There is confusion in the diagnosis and biological behaviors of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), because of independently proposed nomenclatures and classifications. A standardized form of pathology report is required for the proper management of patients.
Methods
We discussed the proper pathological evaluation of GEP-NET at the consensus conference of the subcommittee meeting for the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. We then verified the prognostic significance of pathological parameters from our previous nationwide collection of pathological data from 28 hospitals in Korea to determine the essential data set for a pathology report.
Results
Histological classification, grading (mitosis and/or Ki-67 labeling index), T staging (extent, size), lymph node metastasis, and lymphovascular and perineural invasion were significant prognostic factors and essential for the pathology report of GEP-NET, while immunostaining such as synaptophysin and chromogranin may be optional. Furthermore, the staging system, either that of the 2010 American Joint Cancer Committee (AJCC) or the European Neuroendocrine Tumor Society (ENETS), should be specified, especially for pancreatic neuroendocrine neoplasms.
Conclusions
A standardized pathology report is crucial for the proper management and prediction of prognosis of patients with GEP-NET.
doi:10.4132/KoreanJPathol.2013.47.3.227
PMCID: PMC3701818  PMID: 23837015
Neuroendocrine tumors; Digestive system; Pathology; Staging; Grading; Prognosis
2.  Current Trends of the Incidence and Pathological Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Korea 2000-2009: Multicenter Study 
Purpose
As a result of various independently proposed nomenclatures and classifications, there is confusion in the diagnosis and prediction of biological behavior of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A comprehensive nationwide study is needed in order to understand the biological characteristics of GEP-NETs in Korea.
Materials and Methods
We collected 4,951 pathology reports from 29 hospitals in Korea between 2000 and 2009. Kaplan-Meier survival analysis was used to determine the prognostic significance of clinicopathological parameters.
Results
Although the GEP-NET is a relatively rare tumor in Korea, its incidence has increased during the last decade, with the most significant increase found in the rectum. The 10-year survival rate for well-differentiated endocrine tumor was 92.89%, in contrast to 85.74% in well differentiated neuroendocrine carcinoma and 34.59% in poorly differentiated neuroendocrine carcinoma. Disease related death was most common in the biliary tract (62.2%) and very rare in the rectum (5.2%). In Kaplan-Meier survival analysis, tumor location, histological classification, extent, size, mitosis, Ki-67 labeling index, synaptophysin expression, lymphovascular invasion, perineural invasion, and lymph node metastasis showed prognostic significance (p<0.05), however, chromogranin expression did not (p=0.148). The 2000 and 2010 World Health Organization (WHO) classification proposals were useful for prediction of the prognosis of GEP-NET.
Conclusion
The incidence of GEP-NET in Korea has shown a remarkable increase during the last decade, however, the distribution of tumors in the digestive system differs from that of western reports. Assessment of pathological parameters, including immunostaining, is crucial in understanding biological behavior of the tumor as well as predicting prognosis of patients with GEP-NET.
doi:10.4143/crt.2012.44.3.157
PMCID: PMC3467418  PMID: 23091441
Gastro-enteropancreatic neuroendocrine tumor; Incidence; Prognosis; Pathology
3.  Gastric angiodysplasia in a hereditary hemorrhagic telangiectasia type 2 patient 
Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominantly inherited disease that occurs in approximately one in 5000 to 8000 people. Clinical diagnosis of HHT is made when a person presents three of the following four criteria: family history, recurrent nosebleeds, mucocutaneous telangiectasis, and arteriovenous malformations (AVM) in the brain, lung, liver and gastrointestinal (GI) tract. Although epistaxis is the most common presenting symptom, AVMs affecting the lungs, brain and GI tract provoke a more serious outcome. Heterozygous mutations in endoglin, activin receptor-like kinase 1 (ACVRL1; ALK1), and SMAD4, the genes involved in the transforming growth factor-β family signaling cascade, cause HHT. We report here the case of a 63 year-old male patient who presented melena and GI bleeding episodes, proven to be caused by bleeding from multiple gastric angiodysplasia. Esophagogastroduodenoscopy revealed multiple angiodysplasia throughout the stomach. Endoscopic argon plasma coagulation was performed to control bleeding from a gastric angiodysplasia. The patient has been admitted several times with episodes of hemoptysis and hematochezia. One year ago, the patient was hospitalized due to right-sided weakness, which was caused by left basal ganglia hemorrhage as the part of HHT presentation. In family history, the patient’s mother and elder sister had died, due to intracranial hemorrhage, and his eldest son has been suffered from recurrent epistaxis for 20 years. A genetic study revealed a mutation in exon 3 of ALK1 (c.199C > T; p.Arg67Trp) in the proband and his eldest son presenting epistaxis.
doi:10.3748/wjg.v18.i15.1840
PMCID: PMC3332300  PMID: 22553411
Hereditary hemorrhagic telangiectasia; Angiodysplasia; Intracranial hemorrhage; Epistaxis; Activin receptor-like kinase 1
4.  The significance of ectopic crypt formation in the differential diagnosis of colorectal polyps 
Diagnostic Pathology  2014;9(1):212.
Background
Ectopic crypts, defined as abnormally positioned crypts that have lost their orientation toward the muscularis mucosae, have been suggested to be the best defining histologic feature of traditional serrated adenoma (TSA). However, the significance of ectopic crypt formation (ECF) in the distinction between TSA and conventional adenoma (CA) has rarely been studied.
Methods
We designed this study to determine if ECF can be found in CA and its presence is exclusive to TSA. We studied 107 TSAs and 191 CAs including 106 tubular adenomas (TAs), 66 tubulovillous adenomas (TVAs), and 19 villous adenomas (VAs).
Results
ECF was identified in most (79.4%) but not all TSAs. Additionally, ECF was not infrequent in CA (62 of 191, 32.5%), and its presence correlated with the presence of a villous component and larger tumor size (each p <0.001).
Conclusions
Based on its strong association with the presence of a villous component and larger tumor size, ECF appears to be involved in the protuberant growth of colorectal CA. Because ECF can be found in CA, particularly in cases with a villous component, the possibility of CA should be considered before making a diagnosis of TSA when encountering colorectal polyps with ECF.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_212
doi:10.1186/s13000-014-0212-x
PMCID: PMC4247761  PMID: 25421018
Traditional serrated adenoma; Conventional adenoma; Colon; Ectopic crypt formation; BRAF; KRAS
5.  Chondrosarcoma: With Updates on Molecular Genetics 
Sarcoma  2011;2011:405437.
Chondrosarcoma (CHS) is a malignant cartilage-forming tumor and usually occurs within the medullary canal of long bones and pelvic bones. Based on the morphologic feature alone, a correct diangosis of CHS may be difficult, Therefore, correlation of radiological and clinicopathological features is mandatory in the diagnosis of CHS. The prognosis of CHS is closely related to histologic grading, however, histologic grading may be subjective with high inter-observer variability. In this paper, we present histologic grading system and clinicopathological and radiological findings of conventional CHS. Subtypes of CHSs, such as dedifferentiated, mesenchymal, and clear cell CHSs are also presented. In addition, we introduce updated cytogenetic and molecular genetic findings to expand our understanding of CHS biology. New markers of cell differentiation, proliferation, and cell signaling might offer important therapeutic and prognostic information in near future.
doi:10.1155/2011/405437
PMCID: PMC3042668  PMID: 21403832
6.  A multicenter phase II study of everolimus in patients with progressive unresectable adenoid cystic carcinoma 
BMC Cancer  2014;14(1):795.
Background
The aim of this study was to examine the efficacy and safety of everolimus in patients with progressive unresectable adenoid cystic carcinoma (ACC).
Methods
Histologically confirmed ACC patients with documented disease progression within 12 months prior to the study entry were eligible. Everolimus was given at a dose of 10 mg daily until progression or occurrence of unacceptable toxicities. The primary endpoint was a 4-month progression-free survival (PFS).
Results
A total of 34 patients were enrolled. The 4-month PFS probability was 65.5% (95% one-sided confidence interval [CI], 47.7 to infinity). Median PFS duration was 11.2 months (95% CI, 3.6 to 15.8). Complete or partial response was not achieved. Twenty-seven (79.4%, 95% CI, 63.2 to 89.6) patients showed stable disease (SD). Tumor shrinkage within SD criteria was observed in 15 patients (44.1%) and SD lasting 6 months was observed in 13 patients (38.2%). Four patients had disease progression. Among the 18 patients with both pre- and post-treatment (at 8 weeks) FDG-PET scans available, 8 patients (44.4%) showed a partial metabolic response, defined as a ≥25% reduction in maximum standardized uptake values (SUVmax). The most common adverse events were stomatitis, anemia, asthenia, and leukopenia. No unexpected everolimus related toxicities were reported.
Conclusions
Everolimus showed promising efficacy and good tolerability in progressive unresectable ACC.
Trial registration
ClinicalTrials.gov identifier, NCT01152840
doi:10.1186/1471-2407-14-795
PMCID: PMC4228069  PMID: 25362970
Adenoid cystic carcinoma; Everolimus; RAD001; Clinical trial
7.  Next generation sequencing unravels the biosynthetic ability of Spearmint (Mentha spicata) peltate glandular trichomes through comparative transcriptomics 
BMC Plant Biology  2014;14(1):292.
Background
Plant glandular trichomes are chemical factories with specialized metabolic capabilities to produce diverse compounds. Aromatic mint plants produce valuable essential oil in specialised glandular trichomes known as peltate glandular trichomes (PGT). Here, we performed next generation transcriptome sequencing of different tissues of Mentha spicata (spearmint) to identify differentially expressed transcripts specific to PGT. Our results provide a comprehensive overview of PGT’s dynamic metabolic activities which will help towards pathway engineering.
Results
Spearmint RNAs from 3 different tissues: PGT, leaf and leaf stripped of PGTs (leaf-PGT) were sequenced by Illumina paired end sequencing. The sequences were assembled de novo into 40,587 non-redundant unigenes; spanning a total of 101 Mb. Functions could be assigned to 27,025 (67%) unigenes and among these 3,919 unigenes were differentially expressed in PGT relative to leaf - PGT. Lack of photosynthetic transcripts in PGT transcriptome indicated the high levels of purity of isolated PGT, as mint PGT are non-photosynthetic. A significant number of these unigenes remained unannotated or encoded hypothetical proteins. We found 16 terpene synthases (TPS), 18 cytochrome P450s, 5 lipid transfer proteins and several transcription factors that were preferentially expressed in PGT. Among the 16 TPSs, two were characterized biochemically and found to be sesquiterpene synthases.
Conclusions
The extensive transcriptome data set renders a complete description of genes differentially expressed in spearmint PGT. This will facilitate the metabolic engineering of mint terpene pathway to increase yield and also enable the development of strategies for sustainable production of novel or altered valuable compounds in mint.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0292-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-014-0292-5
PMCID: PMC4232691  PMID: 25367433
Spearmint; Next generation sequencing; Transcriptome; Glandular trichomes; Terpenes; Carvone; Terpene synthases
8.  Survival outcomes and toxicity of intraoperative intraperitoneal chemotherapy in advanced epithelial ovarian cancer 
Obstetrics & Gynecology Science  2014;57(6):484-491.
Objective
To assess the effect of single-dose cisplatin intraperitoneally administered during cytoreductive surgery in advanced epithelial ovarian cancer.
Methods
Data from patients who underwent surgical management followed by intravenous (IV) chemotherapy for stage III epithelial ovarian cancer from 2003 to 2012 were retrospectively reviewed. Subjects were divided into intraperitoneal (IP) and no-intraperitoneal (NIP) groups according to the administration of IP cisplatin 100 mg during the staging surgery. Clinical results such as survival outcomes and chemotherapeutic toxicity were compared between the two groups.
Results
Thirty-seven patients in the IP group and 26 in the NIP group were identified. There were no significant differences between the two groups in basic characteristics such as age, histology, and surgical procedures. After the surgery with or without IP chemotherapy, there was no difference in the rate of either hematologic or gastrointestinal toxicity or in the rate of incompletion of following IV chemotherapy. Tumor recurrence occurred in 67.6% (25 patients) of IP group and 57.7% (15 patients) of NIP group (P=0.423) during the mean follow-up period of 37 months. The 3-year disease free-survival rate was 39.9% in the IP group and 35.8% in the NIP group, and the relative risk of recurrence was 0.864 (95% confidence interval, 0.447-1.673; P=0.665) in the IP group as compared with the NIP group.
Conclusion
IP chemotherapy with single-dose cisplatin during cytoreductive surgery is safe and feasible with little chemotherapeutic toxicity in advanced epithelial ovarian cancer, but no distinct improvement in survival could be demonstrated in the present study.
doi:10.5468/ogs.2014.57.6.484
PMCID: PMC4245342  PMID: 25469337
Intraperitoneal chemotherapy; Ovarian neoplasms; Survival outcome; Toxicity
9.  Nutritional Status of Vitamin D and the Effect of Vitamin D Supplementation in Korean Breast-fed Infants 
We investigated the vitamin D status and the effect of vitamin D supplementation in Korean breast-fed infants. The healthy term newborns were divided into 3 groups; A, formula-fed; B, breast-fed only; S, breast-fed with vitamin D supplementation. We measured serum concentrations of vitamin D (25OHD3), calcium (Ca), phosphorus (P), alkaline phosphatase (AP), intact parathyroid hormone (iPTH) and bone mineral density (BMD) at 6 and 12 months of age. Using questionnaires, average duration of sun-light exposure and dietary intake of vitamin D, Ca and P were obtained. At 6 and 12 months of age, 25OHD3 was significantly higher in group S than in group B (P<0.001). iPTH was significantly lower in group S than in group B at 6 months (P=0.001), but did not differ at 12 months. Regardless of vitamin D supplementation, BMD was lower in group B and S than in group A (P<0.05). Total intake of vitamin D differed among 3 groups (P<0.001, A>S>B), but total intake of Ca and P were higher in group A than in group B and S (P<0.001). In conclusion, breast-fed infants show lower vitamin D status and bone mineralization than formula-fed infants. Vitamin D supplementation (200 IU/day) in breast-fed infants increases serum 25-OH vitamin D3, but not bone mineral density.
doi:10.3346/jkms.2010.25.1.83
PMCID: PMC2800022  PMID: 20052352
Vitamin D; Nutritional Status; Bone Density; Vitamin D Deficiency; Dietary Supplements; Breast feeding; Infant
10.  Regulatory Effect of 25-hydroxyvitamin D3 on Nitric Oxide Production in Activated Microglia 
Microglia are activated by inflammatory and pathophysiological stimuli in neurodegenerative diseases, and activated microglia induce neuronal damage by releasing cytotoxic factors like nitric oxide (NO). Activated microglia synthesize a significant amount of vitamin D3 in the rat brain, and vitamin D3 has an inhibitory effect on activated microglia. To investigate the possible role of vitamin D3 as a negative regulator of activated microglia, we examined the effect of 25-hydroxyvitamin D3 on NO production of lipopolysaccharide (LPS)-stimulated microglia. Treatment with LPS increased the production of NO in primary cultured and BV2 microglial cells. Treatment with 25-hydroxyvitamin D3 inhibited the generation of NO in LPS-activated primary microglia and BV2 cells. In addition to NO production, expression of 1-α-hydroxylase and the vitamin D receptor (VDR) was also upregulated in LPS-stimulated primary and BV2 microglia. When BV2 cells were transfected with 1-α-hydroxylase siRNA or VDR siRNA, the inhibitory effect of 25-hydroxyvitamin D3 on activated BV2 cells was suppressed. 25-Hydroxyvitamin D3 also inhibited the increased phosphorylation of p38 seen in LPS-activated BV2 cells, and this inhibition was blocked by VDR siRNA. The present study shows that 25-hydroxyvitamin D3 inhibits NO production in LPS-activated microglia through the mediation of LPS-induced 1-α-hydroxylase. This study also shows that the inhibitory effect of 25-hydroxyvitamin D3 on NO production might be exerted by inhibiting LPS-induced phosphorylation of p38 through the mediation of VDR signaling. These results suggest that vitamin D3 might have an important role in the negative regulation of microglial activation.
doi:10.4196/kjpp.2014.18.5.397
PMCID: PMC4211123  PMID: 25352759
25-Hydroxyvitamin D3; 1-α-Hydroxylase; Microglia activation; Vitamin D receptor
11.  Correlations Between Electrically Quantified Pain Degree, Subjectively Assessed Visual Analogue Scale, and the McGill Pain Questionnaire: A Pilot Study 
Annals of Rehabilitation Medicine  2014;38(5):665-672.
Objective
To evaluate the clinical utility of the electrically calculated quantitative pain degree (QPD) and to correlate it with subjective assessments of pain degree including a visual analogue scale (VAS) and the McGill Pain Questionnaire (MPQ).
Methods
We recruited 25 patients with low back pain. Of them, 21 patients suffered from low back pain for more than 3 months. The QPD was calculated using the PainVision (PV, PS-2100; Nipro Co., Osaka, Japan). We applied electrodes to the medial forearm of the subjects and the electrical stimulus was amplified sequentially. Minimum perceived current (MPC) and pain equivalent current (PEC) were defined as minimum electrical stimulation that could be sensed by the subject and electrical stimulation that could trigger actual pain itself. To eliminate individual differences, we defined QPD as the following: QPD=PEC-MPC/MPC. We scored pre-treatment QPD three times at admission and post-treatment QPD once at discharge. The VAS, MPQ, and QPD were evaluated and correlations between the scales were analyzed.
Results
Result showed significant test-retest reliability (ICC=0.967, p<0.001) and the correlation between QDP and MPQ was significant (at admission SRCC=0.619 and p=0.001; at discharge SRCC=0.628, p=0.001). However, the correlation between QPD and VAS was not significant (at admission SRCC=0.240, p=0.248; at discharge SRCC=0.289, p=0.161).
Conclusion
Numerical values measured with PV showed consistent results with repeated calculations. Electrically measured QPD showed an excellent correlation with MPQ but not with VAS. These results demonstrate that PV is a significantly reliable device for quantifying the intensity of low back pain.
doi:10.5535/arm.2014.38.5.665
PMCID: PMC4221395  PMID: 25379496
Low back pain; Pain measurement; Pain threshold
12.  Age-related Deterioration of Hematopoietic Stem Cells 
Aging is the process of system deterioration over time in the whole body. Stem cells are self-renewing and therefore have been considered exempt from the aging process. Earlier studies by Hayflick showed that there is an intrinsic limit to the number of divisions that mammalian somatic cells can undergo, and cycling kinetics and ontogeny-related studies strongly suggest that even the most primitive stem cell functions exhibit a certain degree of aging. Despite these findings, studies on the effects of aging on stem cell functions are inconclusive. Here we review the age-related properties of hematopoietic stem cells in terms of intrinsic and extrinsic alterations, proliferative potential, signaling molecules, telomere and telomerase, senescence and cancer issues, regenerative potential and other indications of stem cell aging are discussed in detail.
PMCID: PMC4021776  PMID: 24855509
Hematopoietic stem cells; Aging; Phenotype shift; Proliferative potential
13.  SMAD1-deficiency in either endothelial or smooth muscle cells can predispose mice to pulmonary hypertension 
Hypertension  2013;61(5):1044-1052.
A deficiency in bone morphogenetic protein receptor type 2 (BMPR2) signaling is a central contributor in the pathogenesis of pulmonary arterial hypertension (PAH). We have recently shown that endothelial-specific Bmpr2-deletion by a novel L1Cre line resulted in pulmonary hypertension. SMAD1 is one of the canonical signal transducers of the BMPR2 pathway, and its reduced activity has been shown to be associated with PAH. In order to determine whether SMAD1 is an important downstream mediator of BMPR2 signaling in the pathogenesis of PAH, we analyzed pulmonary hypertension phenotypes in Smad1-conditional knockout mice by deleting the Smad1 gene either in endothelial cells or in smooth muscle cells using L1Cre or Tagln-Cre mouse lines, respectively. A significant number of the L1Cre(+); Smad1 (14/35) and Tagln-Cre(+);Smad1 (4/33) mutant mice showed elevated pulmonary pressure, right ventricular hypertrophy and a thickening of pulmonary arterioles. A pulmonary EC line in which the Bmpr2 gene deletion can be induced by 4-hydroxy tamoxifen was established. SMAD1 phosphorylation in Bmpr2-deficient cells was markedly reduced by BMP4 but unaffected by BMP7. The sensitivity of SMAD2 phosphorylation by TGF-β1 was enhanced in the Bmpr2-deficient cells, and the inhibitory effect of TGF-β1-mediated SMAD2 phosphorylation by BMP4 was impaired in the Bmpr2-deficient cells. Furthermore, transcript levels of several known TGF-β downstream genes implicated in pulmonary hypertension were elevated in the Bmpr2-deficient cells. Taken together, these data suggest that SMAD1 is a critical mediator of BMPR2 signaling pertinent to PAH, and that an impaired balance between BMP4 and TGF-β1 may account for the pathogenesis of PAH.
doi:10.1161/HYPERTENSIONAHA.111.199158
PMCID: PMC3740527  PMID: 23478097
pulmonary arterial hypertension; BMPR2; SMAD1; pulmonary endothelial cells; conditional knock-out mice
14.  FAIRY: a randomized controlled patient-blind phase III study to compare the efficacy and safety of intravenous ferric carboxymaltose (Ferinject®) to placebo in patients with acute isovolemic anemia after gastrectomy - study protocol for a randomized controlled trial 
Trials  2014;15:111.
Background
Isovolemic anemia (decrease in hemoglobin concentration with normal or even increased blood volume) after gastric cancer surgery may negatively influence short- and long-term outcomes. Therefore correction of isovolemic postoperative anemia is supposed to be beneficial. This prospective randomized placebo-controlled multicenter trial is designed to evaluate the efficacy of ferric carboxymaltose administration with the primary end point of successful hemoglobin level increase by 2 g/dl at 12 weeks after randomization.
Methods and design
Gastric cancer patients after oncologic resection and postoperative hemoglobin level ≥ 7 g/dl to <10 g/dl at postoperative days 5 to 7 will be eligible for trial inclusion. After randomization, 450 patients (225 per group) are going to be subjected either to administration of ferric carboxymaltose (treatment group) or normal (0.9%) saline (placebo group). Patients will be blinded to the intervention. Patients will undergo evaluation for hemoglobin level, hematology and quality of life assessment 3 and 12 weeks after randomization.
Discussion
Correction of isovolemic postoperative anemia in gastric cancer patients after oncologic resection is considered to be beneficial. Administration of ferric carboxymaltose is considered to be superior to placebo for anemia correction without the possible risks of red blood cell transfusion. Further, improved quality of life for patients with quick recovery of hemoglobin levels is expected.
Trial registration
NCT01725789 (international: http://www.clinicaltrials.gov) and NCCCTS-12-644 (NCC, Korea).
doi:10.1186/1745-6215-15-111
PMCID: PMC3992134  PMID: 24708660
Ferric carboxymaltose; Isovolemic postoperative anemia; Gastric cancer; Randomized controlled trial
15.  Gene silencing of Sugar-dependent 1 (JcSDP1), encoding a patatin-domain triacylglycerol lipase, enhances seed oil accumulation in Jatropha curcas 
Background
Triacylglycerols (TAGs) are the most abundant form of storage oil in plants. They consist of three fatty acid chains (usually C16 or C18) covalently linked to glycerol. SDP1 is a specific lipase for the first step of TAG catabolism in Arabidopsis seeds. Arabidopsis mutants deficient in SDP1 accumulate high levels of oils, probably due to blockage in TAG degradation. We applied this knowledge from the model plant, Arabidopsis thaliana, to engineer increased seed oil content in the biodiesel plant Jatropha curcas using RNA interference (RNAi) technology.
Results
As Jatropha is a biodiesel crop, any significant increase in its seed oil content would be an important agronomic trait. Using A. thaliana as a model plant, we found that a deficiency of SDP1 led to higher TAG accumulation and a larger number of oil bodies in seeds compared with wild type (Columbia-0; Col-0). We cloned Jatropha JcSDP1, and verified its function by complementation of the Arabidopsis sdp1-5 mutant. Taking advantage of the observation with Arabidopsis, we used RNAi technology to generate JcSDP1 deficiency in transgenic Jatropha. We found that Jatropha JcSDP1-RNAi plants accumulated 13 to 30% higher total seed storage lipid, along with a 7% compensatory decrease in protein content, compared with control (CK; 35S:GFP) plants. Free fatty acid (FFA) content in seeds was reduced from 27% in control plants to 8.5% in JcSDP1-RNAi plants.
Conclusion
Here, we showed that SDP1 deficiency enhances seed oil accumulation in Arabidopsis. Based on this result, we generated SDP1-deficient transgenic Jatropha plants using by RNAi technology with a native JcSDP1 promoter to silence endogenous JcSDP1 expression. Seeds of Jatropha JcSDP1-RNAi plants accumulated up to 30% higher total lipid and had reduced FFA content compared with control (CK; 35S:GFP) plants. Our strategy of improving an important agronomic trait of Jatropha can be extended to other oil crops to yield higher seed oil.
doi:10.1186/1754-6834-7-36
PMCID: PMC4016141  PMID: 24606605
Inducible maker-free JcSDP1-RNAi; Jatropha; sdp1-5; Triacylglycerols (TAGs)
16.  Effect of Dose Escalation with Single Opioid, Fentanyl Matrix in Patients Not Controlling Cancer Pain: A Multicenter, Prospective, Observational Study in Korea 
Purpose
End-of-dose failure (EOD) is a clinically common observation and many cancer patients increase the frequency of opioid administration. Fentanyl matrix use is known to be effective in patients with chronic cancer pain. To measure the effectiveness of increase in a single dose of fentanyl matrix in patients whose pain was not controlled sufficiently, we perform this study.
Materials and Methods
A multi-center, open-label, prospective, observational study was conducted in 30 hospitals in Korea, between August and December 2008.
Results
A total of 452 patients were enrolled; 404 patients completed the study. The mean pain intensity decreased from 5.27 at the first visit to 3.37 at the end of the trial. There was a significant difference in pain intensity (p < 0.001) between the first and last visits. The percentage of pain intensity difference was 30.1%. The prevalence of EOD at the first visit was 73% from the 452 enrolled patients. After the use of fentanyl patch, EOD decreased from 73% to 56%. Pain intensity of patients experiencing EOD was 5.64 at the baseline compared to 4.27 in patients without EOD. On final visit, pain intensity in patients with and without EOD was 4.02 and 2.54, respectively. The observed adverse events were mainly nausea, asthenia, constipation and diarrhea.
Conclusion
This study demonstrated that increasing dose of fentanyl patch decreased pain intensity and decreased the rate of patients experiencing EOD. Thus, fentanyl patch may be an effective modality in cancer patients whose pain was previously not controlled sufficiently; the side effects were as could be expected with an opioid.
doi:10.4143/crt.2013.45.4.263
PMCID: PMC3893323  PMID: 24453998
Fentanyl; Neoplasms; Pain
17.  Generalized Joint Hypermobility in Healthy Female Koreans: Prevalence and Age-Related Differences 
Annals of Rehabilitation Medicine  2013;37(6):832-838.
Objective
Objective To evaluate the prevalence of generalized joint hypermobility (GJH) in healthy female Koreans and to determine whether the degree of GJH differs between children and adults.
Methods
Two groups of females were enrolled, a group of girls from an elementary school (n=404) and women from a call center (n=266). GJH was diagnosed using the Beighton score, which is composed of an evaluation of bilateral knees, elbows, thumbs, and fifth fingers as well as thoracolumbar joint. The GJH and localized hypermobility of each joint was compared between the two groups, and the pattern of hypermobility according to age and dominant hand was investigated.
Results
Total prevalence of GJH was 50.0% (335/750), and it was more frequently observed in the group of girls (58.9%, 238/404) than women (36.5%, 97/266). The degree of GJH expressed in terms of Beighton score was inversely correlated with age (p<0.05). Significant differences in localized hypermobility of the thumb and fifth finger were found between the two groups and were postulated as the cause for the decline in GJH with age. The pattern of decreased mobility proportional to aging differed between the two joints. Decreased mobility occurred equally on both sides of the thumb but was biased toward the fifth finger of the dominant side (mostly the right).
Conclusion
The female Koreans appeared to have a high prevalence of GJH. The incidence of GJH decreased as age increased as a result of decreased mobility of the fifth finger on the dominant side.
doi:10.5535/arm.2013.37.6.832
PMCID: PMC3895523  PMID: 24466518
Joint hypermobility; Beighton score; Dominant hand; Stiff joint
18.  Disparity in the Fear of Falling Between Urban and Rural Residents in Relation With Socio-economic Variables, Health Issues, and Functional Independency 
Annals of Rehabilitation Medicine  2013;37(6):848-861.
Objective
To investigate disparities in the fear of falling between urban and rural communities in relation to socio-demographics, health status, and functional level.
Methods
A total of 974 subjects aged 40 years or older participated in this study (335 urban residents and 639 rural). They completed a questionnaire about socio-demographics, health-related variables, and experience with falls. We employed both direct questioning and the Korean version of Falls Efficacy Scale-International (KFES-I) to investigate fear of falling in terms of perceptive fear and higher level of concern over falling during daily activities. The Korean version of Instrumental Activities of Daily Living was used to assess functional independency.
Results
Aging, female gender, fall history, and the presence of chronic medical problems were independently associated with higher prevalence for the fear of falling. Both perceptive fear of falling and a higher level of concern over falling were more prevalent in the rural senior population compared with those in the urban population when they had the following characteristics: lower income or educational background, physical laborer or unemployed, no chronic medical morbidity, or functional independency in daily activities.
Conclusion
The disparity in the fear of falling between the two areas is thought to be related to age structure, and it may also exist in healthy or functionally independent senior populations under the influence of socio-environmental factors. A senior population with lower socio-economic status residing in a rural area might be related with a greater vulnerability to the fear of falling. We should consider regional characteristics when we design fall-related studies or develop fall-prevention programs at the community level.
doi:10.5535/arm.2013.37.6.848
PMCID: PMC3895525  PMID: 24466520
Accidental falls; Geriatric assessment; Activities of daily living
19.  Addition of Exogenous NAD+ Prevents Mefloquine-Induced Neuroaxonal and Hair Cell Degeneration through Reduction of Caspase-3-Mediated Apoptosis in Cochlear Organotypic Cultures 
PLoS ONE  2013;8(11):e79817.
Background
Mefloquine is widely used for the treatment of malaria. However, this drug is known to induce neurological side effects including depression, anxiety, balance disorder, and sensorineural hearing loss. Yet, there is currently no treatment for these side effects.
Principal Findings
In this study, we show that the coenzyme NAD+, known to play a critical role in maintaining the appropriate cellular redox environment, protects cochlear axons and sensory hair cells from mefloquine-induced degeneration in cultured rat cochleae. Mefloquine alone destroyed hair cells and nerve fiber axons in rat cochlear organotypics cultures in a dose-dependent manner, while treatment with NAD+ protected axons and hair cells from mefloquine-induced degeneration. Furthermore, cochlear organs treated with mefloquine showed increased oxidative stress marker levels, including superoxide and protein carbonyl, and increased apoptosis marker levels, including TUNEL-positive nuclei and caspases-3. Treatment with NAD+ reduced the levels of these oxidative stress and apoptosis markers.
Conclusions/Significance
Taken together, our findings suggest that that mefloquine disrupts the cellular redox environment and induces oxidative stress in cochlear hair cells and nerve fibers leading to caspases-3-mediated apoptosis of these structures. Exogenous NAD+ suppresses mefloquine-induced oxidative stress and prevents the degeneration of cochlear axons and sensory hair cells caused by mefloquine treatment.
doi:10.1371/journal.pone.0079817
PMCID: PMC3819247  PMID: 24223197
20.  Interaction of Human PD-L1 and B7-1 
Molecular immunology  2008;45(13):3567-3572.
Numerous studies have pointed to the role of Programmed Death-1 Ligand 1 (PD-L1) in regulating tolerance, chronic infection, and tumor immunity. Recently, we have identified murine B7-1 as a new binding partner for murine PD-L1. Human and mouse B7-1 share only 46% identity, leading us to question whether human B7-1 and PD-L1 can participate in a similar interaction. Here we show that human B7-1 can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. We characterize a series of anti-human PD-L1 monoclonal antibodies and identify antibodies that can block interactions of PD-L1 with B7-1, PD-1, or both. Since PD-L1 and CD28 on T cells may compete for B7-1 as a binding partner and CD8 T cells may express high or low levels of CD28, we examined when PD-L1 and CD28 are co-expressed on CD8 T cells. We compared the time-course and extent of PD-L1 induction on CD8 CD28high versus CD28low T cells following stimulation with anti-CD3. We show that PD-L1 is induced to a higher level on CD28high T cells than on CD28low T cells upon activation. These results suggest that PD-L1 may play an important and undervalued role on human T cells.
doi:10.1016/j.molimm.2008.05.014
PMCID: PMC3764616  PMID: 18585785
CD80; CD274; surface plasmon resonance; adhesion; antibody
21.  Expression and Activity of the Na-K ATPase in Ischemic Injury of Primary Cultured Astrocytes 
Astrocytes are reported to have critical functions in ischemic brain injury including protective effects against ischemia-induced neuronal dysfunction. Na-K ATPase maintains ionic gradients in astrocytes and is suggested as an indicator of ischemic injury in glial cells. Here, we examined the role of the Na-K ATPase in the pathologic process of ischemic injury of primary cultured astrocytes. Chemical ischemia was induced by sodium azide and glucose deprivation. Lactate dehydrogenase assays showed that the cytotoxic effect of chemical ischemia on astrocytes began to appear at 2 h of ischemia. The expression of Na-K ATPase α1 subunit protein was increased at 2 h of chemical ischemia and was decreased at 6 h of ischemia, whereas the expression of α1 subunit mRNA was not changed by chemical ischemia. Na-K ATPase activity was time-dependently decreased at 1, 3, and 6 h of chemical ischemia, whereas the enzyme activity was temporarily recovered to the control value at 2 h of chemical ischemia. Cytotoxicity at 2 h of chemical ischemia was significantly blocked by reoxygenation for 24 h following ischemia. Reoxygenation following chemical ischemia for 1 h significantly increased the activity of the Na-K ATPase, while reoxygenation following ischemia for 2 h slightly decreased the enzyme activity. These results suggest that the critical time for ischemia-induced cytotoxicity of astrocytes might be 2 h after the initiation of ischemic insult and that the increase in the expression and activity of the Na-K ATPase might play a protective role during ischemic injury of astrocytes.
doi:10.4196/kjpp.2013.17.4.275
PMCID: PMC3741483  PMID: 23946686
Chemical ischemia; Na-K ATPase; Primary cultured astrocytes
22.  Solitary myofibroma of the sigmoid colon: case report and review of the literature 
Diagnostic Pathology  2013;8:90.
A 58-year-old woman presented with a solitary myofibroma that arose in the sigmoid colon. Computed tomography revealed a highly enhanced intramural mass (1.3-cm maximum diameter) in the proximal sigmoid colon. Histologically, the tumor exhibited a biphasic growth pattern, which comprised haphazardly arranged, interwoven fascicles of plump, myoid-appearing spindle cells with elongated nuclei and abundant eosinophilic cytoplasm, and more cellular areas of primitive-appearing polygonal cells that were arranged in a hemangiopericytomatous pattern. The tumor cells were positive for smooth muscle actin (SMA), and negative for desmin, h-caldesmon, CD34, cytokeratin, S100 protein, and CD117. The Ki-67 labeling index was not high (up to 7%). Based on these histologic and immunohistochemical features, our patient was diagnosed with a myofibroma of the sigmoid colon. The presence of solitary myofibroma in the intestine of an adult requires attention to avoid misdiagnosis as a more aggressive mesenchymal tumor.
Virtual Slides
The virtual silde(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2096403796957687
doi:10.1186/1746-1596-8-90
PMCID: PMC3711989  PMID: 23742153
Myofibroma; Solitary; Sigmoid colon; Adult
23.  Causes of Hand Tingling in Visual Display Terminal Workers 
Annals of Rehabilitation Medicine  2013;37(2):221-228.
Objective
To offer the basic data about the causes and distribution of hand tingling, symptoms and physical findings, and pressure pain threshold in desk workers.
Methods
Five physiatrists participated in the screening test composed of history and physical examination. A total of 876 desk workers were evaluated and of them 37 subjects with hand tingling were selected. For further analyzing, detailed history taking and meticulous physical examination were taken. Pressure pain threshold (PPT) at the infraspinatus, upper trapezius, flexor carpi radialis, rhomboideus, and flexor pollicis longus were examined. PPT measurements were repeated three times with two minute intervals by a pressure algometer. Electrodiagnostic study was done to detect potential neurologic abnormalities.
Results
The causes of hand tingling in order of frequency were: myofascial pain syndrome, 68%; cervical radiculopathy, 27%; rotator cuff syndrome, 11%; tenosynovitis, 8%; and carpal tunnel syndrome, 5%. The location of trigger points in the myofascial pain syndrome, which were proven to evoke a tingling sensation to the hand in order of frequency were: infraspinatus, 65.4%; upper trapezius, 57.7%; flexor carpi radialis, 38.5%; rhomboideus 15.4%; and flexor pollicis longus 11.5%. The PPT of the affected side was significantly lower than that of the unaffected side in myofascial pain syndrome (p<0.05).
Conclusion
The most common cause of hand tingling in desk workers was myofascial pain syndrome rather than carpal tunnel syndrome. Common trigger points to evoke hand tingling were in the infraspinatus and upper trapezius.
doi:10.5535/arm.2013.37.2.221
PMCID: PMC3660483  PMID: 23705117
Hand tingling; Myofascial pain syndromes; VDT workers; Pressure pain threshold
24.  Human Platelet Antigen Genotyping and Expression of CD109 (Human Platelet Antigen 15) mRNA in Various Human Cell Types 
BioMed Research International  2013;2013:946403.
CD109 gene encodes a glycosylphosphatidylinositol-linked glycoprotein found in a subset of platelets and endothelial cell, and human platelet antigen (HPA) 15 is found on CD109. We evaluated the HPA genotype and/or the CD109 mRNA expression on two peripheral blood stem cells (PBSC), two peripheral bloods (PB), 12 granulocyte products, natural killer (NK)-92, B-lymphocyte (CO88BV59-1), K-562 leukemia cell line, human embryonic stem cell (hESC), and human fibroblasts (HF). HPA genotyping was performed by SNaPshot assay and CD109 mRNA expression was evaluated by real-time PCR with SYBR green and melting curve analysis. Genotype HPA-15a/-15a was found in PBSC#1 and two granulocyte products, and HPA-15a/-15b was found in PBSC#2, eight granulocyte products, NK-92, K-562, hESC, and HF, and HPA-15b/-15b was found in two granulocyte products. CD109 mRNA expression was highly increased in HF and increased in CD34+ and CD34− PBSCs and some granulocyte products, compared to the PB. However, the increase of expression level varied among the PBSC and granulocyte products. The CD109 mRNA expression of NK-92, K-562, hESC, and CO 88BV59-1 was not detected. HPA genotype was evaluated in various cells and the expression of CD109, which contains HPA 15, was different among cell lines and high in HF and PBSCs.
doi:10.1155/2013/946403
PMCID: PMC3583088  PMID: 23509816
25.  Decreased Metabolism in the Cerebral Cortex in Early-Stage Huntington's Disease: A Possible Biomarker of Disease Progression? 
Background and Purpose
Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder. Genetic analysis of abnormal CAG expansion in the IT15 gene allows disease confirmation even in the preclinical stage. However, because there is no treatment to cure or delay the progression of this disease, monitoring of biological markers that predict progression is warranted.
Methods
FDG-PET was applied to 13 patients with genetically confirmed HD in the early stage of the disease. We recorded the initial and follow-up statuses of patients using the Independence Scale (IS) of the Unified Huntington's Disease Rating Scale. The progression rate (PR) was calculated as the annual change in the IS. The patients were divided into two groups with faster and slower progression, using the median value of the PR as the cut-off. FDG-PET data were analyzed using regions of interest, and compared among the two patient groups and 11 age- and sex-matched controls.
Results
The mean CAG repeat size in patients was 44.7. The CAG repeat length was inversely correlated with the age at onset as reported previously, but was not correlated with the clinical PR. Compared with normal controls, hypometabolism was observed even at very early stages of the disease in the bilateral frontal, temporal, and parietal cortices on FDG-PET. The decreases in metabolism in the bilateral frontal, parietal, and right temporal cortices were much greater in the faster-progression group than in the slower-progression group.
Conclusions
A decrease in cortical glucose metabolism is suggested as a predictor for identifying a more rapid form of progression in patients with early-stage HD.
doi:10.3988/jcn.2013.9.1.21
PMCID: PMC3543905  PMID: 23346156
Huntington's disease; biomarker; FDG-PET; progression; cortical metabolism

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