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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.  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
5.  Review of the Registration in the Clinical Research Information Service 
Clinical research registration is required in many countries to improve transparency of clinical research and to ensure subject safety. Developed in February 2010, the Clinical Research Information Service (CRIS) is an online registration system for clinical studies in Korea and one of the primary registries of the World Health Organization (WHO) International Clinical Trials Registry Platform. The present analysis investigated the characteristics of studies registered in the CRIS between February 2010 and December 2014. Data for the analysis were extracted from the CRIS database. As of December 31, 2014, 1,323 clinical studies were registered. Of these, 938 (70.9%) were interventional studies and 385 (29.1%) were observational studies. A total of 248 (18.7%) studies were funded by government sources, 1,051 (79.4%) by non-government sources, and 24 (1.8%) by both. The most frequently studied disease category based on the ICD-10 classification was the digestive system (13.1%), followed by the nervous system (9.4%) and musculoskeletal system (9.1%). Only 17.8% of the studies were registered prior to enrollment of the first subject. Comparing the number of registered or approved clinical studies between the CRIS, the Ministry of Food and Drug Safety, and ClinicalTrials.gov suggests that a considerable number of clinical studies are not registered with the CRIS; therefore, we would suggest that such registration should be the mandatory legal requirement.
Graphical Abstract
doi:10.3346/jkms.2016.31.1.1
PMCID: PMC4712566  PMID: 26770030
Clinical Trials as Topic; Databases, Factual; Information Dissemination; Internet; Registries; Republic of Korea
6.  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
7.  Slip-Related Changes in Plantar Pressure Distribution, and Parameters for Early Detection of Slip Events 
Annals of Rehabilitation Medicine  2015;39(6):897-904.
Objective
To investigate differences in plantar pressure distribution between a normal gait and unpredictable slip events to predict the initiation of the slipping process.
Methods
Eleven male participants were enrolled. Subjects walked onto a wooden tile, and two layers of oily vinyl sheet were placed on the expected spot of the 4th step to induce a slip. An insole pressure-measuring system was used to monitor plantar pressure distribution. This system measured plantar pressure in four regions (the toes, metatarsal head, arch, and heel) for three events: the step during normal gait; the recovered step, when the subject recovered from a slip; and the uncorrected, harmful slipped step. Four variables were analyzed: peak pressure (PP), contact time (CT), the pressure-time integral (PTI), and the instant of peak pressure (IPP).
Results
The plantar pressure pattern in the heel was unique, as compared with other parts of the sole. In the heel, PP, CT, and PTI values were high in slipped and recovered steps compared with normal steps. The IPP differed markedly among the three steps. The IPPs in the heel for the three events were, in descending order (from latest to earliest), slipped, recovered, and normal steps, whereas in the other regions the order was normal, recovered, and slipped steps. Finally, the metatarsal head-to-heel IPP ratios for the normal, recovered, and slipped steps were 6.1±2.9, 3.1±3.0, and 2.2±2.5, respectively.
Conclusion
A distinctive plantar pressure pattern in the heel might be useful for early detection of a slip event to prevent slip-related injuries.
doi:10.5535/arm.2015.39.6.897
PMCID: PMC4720765  PMID: 26798603
Accidental falls; Accident prevention; Gait; Foot; Pressure
8.  Relief of Chronic Posterior Neck Pain Depending on the Type of Forest Therapy: Comparison of the Therapeutic Effect of Forest Bathing Alone Versus Forest Bathing With Exercise 
Annals of Rehabilitation Medicine  2015;39(6):957-963.
Objective
To compare the pain-reducing effect of forest bathing alone versus forest bathing in combination with stretching and strengthening exercises in patients with chronic posterior neck pain.
Methods
Sixty-four subjects with posterior neck pain that had lasted more than 3 months were enrolled. They were randomly divided into a forest bathing alone (FBA) group and a forest bathing with exercise (FBE) group; each group included 32 subjects. All subjects from both groups walked every morning in the forest for about 2 hours for 5 days. In the afternoon, the FBE group did a stretching and strengthening exercise for about 4 hours; the FBA group had free time in the woods. Visual analog scale (VAS) on one day, VAS over the previous week, neck disability index (NDI), EuroQol 5D-3L VAS (EQ VAS) and index (EQ index), McGill pain questionnaire (MPQ), the number of trigger points in the posterior neck region (TRPs), and the range of motion of the cervical spine were evaluated on the first and last day of the program and compared between the two groups.
Results
The number of TRPs were significantly reduced in the FBE group compared with the FBA group (p=0.013). However, the other scales showed no significant difference between the two groups.
Conclusion
When patients with chronic posterior neck pain underwent a short-term forest bathing (less than 7 days) program, FBE was more effective in the reduction of the number of TRPs than FBA. However, all other pain measurement scales we evaluated showed no statistically significant difference between the two protocols.
doi:10.5535/arm.2015.39.6.957
PMCID: PMC4720772  PMID: 26798610
Neck pain; Exercise therapy; Chronic pain; Musculoskeletal pain; Complementary therapies
9.  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
10.  Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors 
Purpose
OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors.
Materials and Methods
Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively.
Results
Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression.
Conclusion
This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity.
doi:10.4143/crt.2014.249
PMCID: PMC4614199  PMID: 25715763
OPB-31121; STAT3; STAT3 inhibitor; Solid tumor; Phase I
11.  Change in Musculoskeletal Pain in Patients With Work-Related Musculoskeletal Disorder After Tailored Rehabilitation Education: A One-Year Follow-Up Survey 
Annals of Rehabilitation Medicine  2015;39(5):726-734.
Objective
To apply tailored rehabilitation education to video display terminal (VDT) workers with musculoskeletal pain and to assess changes in musculoskeletal pain after rehabilitation education.
Methods
A total of 8,828 VDT workers were screened for musculoskeletal disorders using a self-report questionnaire. Six hundred twenty-six VDT workers selected based on their questionnaires were enrolled in musculoskeletal rehabilitation education, which consisted of education on VDT syndrome and confirmed diseases, exercise therapy including self-stretching and strengthening, and posture correction. One year later, a follow-up screening survey was performed on 316 VDT workers, and the results were compared with the previous data.
Results
Compared with the initial survey, pain intensity was significantly decreased in the neck area; pain duration and frequency were significantly decreased in the low back area; and pain duration, intensity, and frequency were significantly decreased in the shoulder and wrist after tailored rehabilitation education. In addition, pain duration, intensity, and frequency showed a greater significant decrease after tailored rehabilitation education in the mild pain group than in the severe pain group.
Conclusions
This study found that work-related musculoskeletal pain was reduced after tailored rehabilitation education, especially in the shoulder, wrist, and low back.
doi:10.5535/arm.2015.39.5.726
PMCID: PMC4654079  PMID: 26605170
Video display terminal worker; Work-related musculoskeletal pain; Tailored rehabilitation education
12.  Glutamine Deprivation Causes Hydrogen Peroxide-induced Interleukin-8 Expression via Jak1/Stat3 Activation in Gastric Epithelial AGS Cells 
Journal of Cancer Prevention  2015;20(3):179-184.
Background:
The Janus kinase (Jak)/Signal transducers of activated transcription (Stat) pathway is an upstream signaling pathway for NF-κB activation in Helicobacter pylori-induced interleukin (IL)-8 production in gastric epithelial AGS cells. H. pylori activates NADPH oxidase and produces hydrogen peroxide, which activates Jak1/Stat3 in AGS cells. Therefore, hydrogen peroxide may be critical for IL-8 production via Jak/Stat activation in gastric epithelial cells. Glutamine is depleted during severe injury and stress and contributes to the formation of glutathione (GSH), which is involved in conversion of hydrogen peroxide into water as a cofactor for GSH peroxidase.
Methods:
We investigated whether glutamine deprivation induces hydrogen peroxide-mediated IL-8 production and whether hydrogen peroxide activates Jak1/Stat3 to induce IL-8 in AGS cells. Cells were cultured in the presence or absence of glutamine or hydrogen peroxide, with or without GSH or a the Jak/Stat specific inhibitor AG490.
Results:
Glutamine deprivation decreased GSH levels, but increased levels of hydrogen peroxide and IL-8, an effect that was inhibited by treatment with GSH. Hydrogen peroxide induced the activation of Jak1/Stat3 time-dependently. AG490 suppressed hydrogen peroxide- induced activation of Jak1/Stat3 and IL-8 expression in AGS cells, but did not affect levels of reactive oxygen species in AGS cells.
Conclusions:
In gastric epithelial AGS cells, glutamine deprivation increases hydrogen peroxide levels and IL-8 expression, which may be mediated by Jak1/Stat3 activation. Glutamine supplementation may be beneficial for preventing gastric inflammation by suppressing hydrogen peroxide-mediated Jak1/Stat3 activation and therefore, reducing IL-8 production. Scavenging hydrogen peroxide or targeting Jak1/Stat3 may also prevent oxidant-mediated gastric inflammation.
doi:10.15430/JCP.2015.20.3.179
PMCID: PMC4597806  PMID: 26473156
Glutamine; Hydrogen peroxide; Janus kinase; Interleukin-8; Signal transducers of activated transcription
13.  Glutamatergic Effects of Divalproex in Manic Adolescents: A Proton Magnetic Resonance Spectroscopy Study 
Objectives
This study used proton magnetic resonance spectroscopy (1H MRS) to evaluate the in vivo effects of extended-release divalproex sodium on the glutamatergic system in adolescents with bipolar disorder and to identify baseline neurochemical predictors of clinical remission.
Method
Adolescents with bipolar disorder who were experiencing a manic or mixed episode (n=25) were treated with open-label, extended-release divalproex (serum levels 85–125 mcg/mL) and underwent 1H MRS scans at baseline (prior to treatment) and on days 7 and 28. Healthy comparison subjects (n=15) also underwent 1H MRS scans at the same time points. Glutamate (Glu) and Glutamate+glutamine (Glx) concentrations were measured in three voxels: anterior cingulate cortex (ACC) and left and right ventrolateral prefrontal cortex (LVLPFC and RVLPFC) and were compared between bipolar and healthy subjects. Within the bipolar subjects, Glu and Glx concentrations at baseline and each time point were also compared between remitters and non-remitters following divalproex treatment.
Results
At baseline, no differences in Glu or Glx concentrations between bipolar and healthy subjects were observed. Group (HC vs BP) by time effects revealed an interaction for Glu in the ACC and change over time effects for Glx were noted in the ACC in patients with bipolar disorder (increase from day 0 to day 7 and then a decrease from day 7 to day 28) but not in HC. Remitters had significantly lower baseline Glx concentrations in LVLPFC and in remitters, change in LVLPFC Glu correlated with the change in YMRS score.
Conclusions
Successful treatment of mania with divalproex may be predicted by lower baseline concentrations of Glx in the LVLPFC and, in remitters, the degree of symptomatic improvement is related to the change in Glu concentrations in this region, suggesting that divalproex may work via modulation of the prefrontal glutamatergic system in youth with bipolar disorder.
doi:10.1016/j.jaac.2012.03.009
PMCID: PMC4499458  PMID: 22632623
bipolar disorder; mania; Glx; glutamate; glutamine
14.  Sessile serrated adenoma/polyps with a depressed surface: a rare form of sessile serrated adenoma/polyp 
Diagnostic Pathology  2015;10:75.
Sessile serrated adenoma/polyps (SSA/Ps) usually appear flat to sessile with a smooth-appearing surface. However, macroscopic appearances of SSA/P can vary from flat-elevated to nodular and can even show a pedunculated configuration as we previously reported. The aim of the current study was to evaluate the clinicopathologic features of another under-recognized form of SSA/P which shows a depressed surface. Among 634 cases of sessile serrated adenoma/polyp, a total of seven sessile serrated adenoma/polyps showing a depressed surface were identified in 6 patients during the review of endoscopic images between January 2013 and November 2013. One of these was found during the review of previous endoscopic images of the same patient. Patients were more often middle-aged to elderly men (83.3 %) and had synchronous conventional adenomas and/or SSA/Ps except for one man. The polyps usually occurred in the proximal colon (71.4 %) and the mean size of polyps was 9.3 mm (range; 6-13 mm). Most cases (71.4 %) were of a flat-elevated type, and the remaining polyps (28.6 %) were sessile. The majority of polyps (85.7 %) showed a mucus cap. All but one of the cases (85.7 %) showed BRAF-V600E mutations. Our findings are that SSA/Ps can show a central depression although such cases are rare. The endoscopic and clinicopathologic features of SSA/Ps showing a depressed surface appear to be similar to usual SSA/Ps except for the presence of a depressed surface and marked male preponderance.
Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1562070886167874.
doi:10.1186/s13000-015-0325-x
PMCID: PMC4474440  PMID: 26088907
Sessile serrated adenoma; Colon; Endoscopy; Serrated polyp
15.  Anticancer Effect of Lycopene in Gastric Carcinogenesis 
Journal of Cancer Prevention  2015;20(2):92-96.
Gastric cancer ranks as the most common cancer and the second leading cause of cancer-related death in the world. Risk factors of gastric carcinogenesis include oxidative stress, DNA damage, Helicobacter pylori infection, bad eating habits, and smoking. Since oxidative stress is related to DNA damage, smoking, and H. pylori infection, scavenging of reactive oxygen species may be beneficial for prevention of gastric carcinogenesis. Lycopene, one of the naturally occurring carotenoids, has unique structural and chemical features that contributes to a potent antioxidant activity. It shows a potential anticancer activity and reduces gastric cancer incidence. This review will summarize anticancer effect and mechanism of lycopene on gastric carcinogenesis based on the recent experimental and clinical studies.
doi:10.15430/JCP.2015.20.2.92
PMCID: PMC4492364  PMID: 26151041
Anticancer effect; Lycopene; Gastric carcinogenesis
16.  The floral transcriptome of ylang ylang (Cananga odorata var. fruticosa) uncovers biosynthetic pathways for volatile organic compounds and a multifunctional and novel sesquiterpene synthase 
Journal of Experimental Botany  2015;66(13):3959-3975.
Highlight
Combined RNA sequencing and chemical analysis led to the identification of biosynthetic pathway genes for volatile organic compounds and the discovery of novel terpene synthases in ylang ylang flowers.
The pleasant fragrance of ylang ylang varieties (Cananga odorata) is mainly due to volatile organic compounds (VOCs) produced by the flowers. Floral scents are a key factor in plant–insect interactions and are vital for successful pollination. C. odorata var. fruticosa, or dwarf ylang ylang, is a variety of ylang ylang that is popularly grown in Southeast Asia as a small shrub with aromatic flowers. Here, we describe the combined use of bioinformatics and chemical analysis to discover genes for the VOC biosynthesis pathways and related genes. The scented flowers of C. odorata var. fruticosa were analysed by gas chromatography/mass spectrometry and a total of 49 VOCs were identified at four different stages of flower development. The bulk of these VOCs were terpenes, mainly sesquiterpenes. To identify the various terpene synthases (TPSs) involved in the production of these essential oils, we performed RNA sequencing on mature flowers. From the RNA sequencing data, four full-length TPSs were functionally characterized. In vitro assays showed that two of these TPSs were mono-TPSs. CoTPS1 synthesized four products corresponding to β-thujene, sabinene, β-pinene, and α-terpinene from geranyl pyrophosphate and CoTPS4 produced geraniol from geranyl pyrophosphate. The other two TPSs were identified as sesqui-TPSs. CoTPS3 catalysed the conversion of farnesyl pyrophosphate to α-bergamotene, whereas CoTPS2 was found to be a multifunctional and novel TPS that could catalyse the synthesis of three sesquiterpenes, β-ylangene, β-copaene, and β-cubebene. Additionally, the activities of the two sesqui-TPSs were confirmed in planta by transient expression of these TPS genes in Nicotiana benthamiana leaves by Agrobacterium-mediated infiltration.
doi:10.1093/jxb/erv196
PMCID: PMC4473991  PMID: 25956881
β-Copaene; β-cubebene; β-ylangene; Cananga odorata var. fruticosa; floral scent; terpene synthase; terpenes; volatile organic compounds; ylang ylang.
17.  Neural Substrates of Motor and Non-Motor Symptoms in Parkinson’s Disease: A Resting fMRI Study 
PLoS ONE  2015;10(4):e0125455.
Background
Recently, non-motor symptoms of Parkinson’s disease (PD) have been considered crucial factors in determining a patient’s quality of life and have been proposed as the predominant features of the premotor phase. Researchers have investigated the relationship between non-motor symptoms and the motor laterality; however, this relationship remains disputed. This study investigated the neural connectivity correlates of non-motor and motor symptoms of PD with respect to motor laterality.
Methods
Eight-seven patients with PD were recruited and classified into left-more-affected PD (n = 44) and right-more affected PD (n = 37) based on their MDS-UPDRS (Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale) motor examination scores. The patients underwent MRI scanning, which included resting fMRI. Brain regions were labeled as ipsilateral and contralateral to the more-affected body side. Correlation analysis between the functional connectivity across brain regions and the scores of various symptoms was performed to identify the neural connectivity correlates of each symptom.
Results
The resting functional connectivity centered on the ipsilateral inferior orbito-frontal area was negatively correlated with the severity of non-motor symptoms, and the connectivity of the contralateral inferior parietal area was positively correlated with the severity of motor symptoms (p < 0.001, |r| > 0.3).
Conclusions
These results suggest that the inferior orbito-frontal area may play a crucial role in non-motor dysfunctions, and that the connectivity information may be utilized as a neuroimaging biomarker for the early diagnosis of PD.
doi:10.1371/journal.pone.0125455
PMCID: PMC4409348  PMID: 25909812
18.  Screening of Immune-Active Lactic Acid Bacteria 
The purpose of this study was to investigate the effect of lactic acid bacteria (LAB) cell wall extract on the proliferation and cytokine production of immune cells to select suitable probiotics for space food. Ten strains of LAB (Lactobacillus bulgaricus, L. paracasei, L. casei, L. acidophilus, L. plantarum, L. delbruekii, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, and Pedicoccus pentosaceus) were sub-cultured and further cultured for 3 d to reach 7-10 Log colony-forming units (CFU)/mL prior to cell wall extractions. All LAB cell wall extracts failed to inhibit the proliferation of BALB/c mouse splenocytes or mesenteric lymphocytes. Most LAB cell wall extracts except those of L. plantarum and L. delbrueckii induced the proliferation of both immune cells at tested concentrations. In addition, the production of TH1 cytokine (IFN-γ) rather than that of TH2 cytokine (IL-4) was enhanced by LAB cell wall extracts. Of ten LAB extracts, four (from L. acidophilus, L. bulgaricus, L. casei, and S. thermophiles) promoted both cell proliferating and TH1 cytokine production. These results suggested that these LAB could be used as probiotics to maintain immunity and homeostasis for astronauts in extreme space environment and for general people in normal life.
doi:10.5851/kosfa.2015.35.4.541
PMCID: PMC4662138  PMID: 26761877
lactic acid bacteria; cell wall extracts; proliferation; TH1 cytokine IFN-γ; TH2 cytokine IL-4
19.  The significance of ectopic crypt formation in the differential diagnosis of colorectal polyps 
Diagnostic Pathology  2014;9:212.
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
20.  A multicenter phase II study of everolimus in patients with progressive unresectable adenoid cystic carcinoma 
BMC Cancer  2014;14:795.
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
21.  Next generation sequencing unravels the biosynthetic ability of Spearmint (Mentha spicata) peltate glandular trichomes through comparative transcriptomics 
BMC Plant Biology  2014;14:292.
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
22.  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
23.  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
24.  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
25.  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

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