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1.  Quantitative proteomic analysis shows differentially expressed HSPB1 in glioblastoma as a discriminating short from long survival factor and NOVA1 as a differentiation factor between low-grade astrocytoma and oligodendroglioma 
BMC Cancer  2015;15:481.
Background
Gliomas account for more than 60 % of all primary central nervous system neoplasms. Low-grade gliomas display a tendency to progress to more malignant phenotypes and the most frequent and malignant gliomas are glioblastomas (GBM). Another type of glioma, oligodendroglioma originates from oligodendrocytes and glial precursor cells and represents 2–5 % of gliomas. The discrimination between these two types of glioma is actually controversial, thus, a molecular distinction is necessary for better diagnosis.
Methods
iTRAQ-based quantitative proteomic analysis was performed on non-neoplastic brain tissue, on astrocytoma grade II, glioblastoma with short and long survival and oligodendrogliomas.
Results
We found that expression of nucleophosmin (NPM1), glucose regulated protein 78 kDa (GRP78), nucleolin (NCL) and heat shock protein 90 kDa (HSP90B1) were increased, Raf kinase inhibitor protein (RKIP/PEBP1) was decreased in glioblastoma and they were associated with a network related to tumor progression. Expression level of heat shock protein 27 (HSPB1/HSP27) discriminated glioblastoma presenting short (6 ± 4 months, n = 4) and long survival (43 ± 15 months, n = 4) (p = 0.00045). Expression level of RNA binding protein nova 1 (NOVA1) differentiated low-grade oligodendroglioma and astrocytoma grade II (p = 0.0082). Validation were done by Western blot, qRT-PCR and immunohistochemistry in a larger casuistry.
Conclusion
Taken together, our quantitative proteomic analysis detected the molecular triad, NPM1, GRP78 and RKIP participating together with NCL and HSP27/HSPB1 in a network related to tumor progression. Additionally, two new important targets were uncovered: NOVA1 useful for diagnostic refinement differentiating astrocytoma from oligodendroglioma, and HSPB1/HSP27, as a predictive factor of poor prognosis for GBM.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1473-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1473-9
PMCID: PMC4502388  PMID: 26108672
Glioma; Network analysis; Isobaric tag; Cancer proteomics; Biomarkers
2.  High-fat diet feeding significantly attenuates anagliptin-induced regeneration of islets of Langerhans in streptozotocin-induced diabetic mice 
Background
DPP-4 inhibitors reportedly exert effects on both alpha and beta cells, and promote the proliferation and survival of beta cells. We investigated the effects of anagliptin on structurally-impaired islets of Langerhans in streptozotocin (STZ)-treated mice, fed either a normal or a high-fat diet. Pdx-1 expression in the pancreas and serum insulin/glucagon concentrations were also examined.
Findings
Anagliptin treatment significantly up-regulated pancreatic Pdx-1 expression, with elevated serum glucagon-like peptide-1 concentrations, regardless of whether the diet was normal or high-fat. However, interestingly, the beta cell regeneration, structural normalization of islets of Langerhans including alpha cell: beta cell area ratios, and serum insulin elevation, all observed with anagliptin administration in the animals fed a normal diet, were markedly suppressed in the high-fat fed group.
Conclusions
High-fat diet feeding clearly weakened the regenerative effects of anagliptin on the islets of Langerhans in STZ-treated mice. Our findings suggest the importance of normalizing lipid metabolism for full manifestation of DPP-4 inhibitor effects on the islets of Langerhans.
Electronic supplementary material
The online version of this article (doi:10.1186/s13098-015-0047-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13098-015-0047-y
PMCID: PMC4475295  PMID: 26097511
DPP-4 inhibitor; Anagliptin; Streptozotocin; High-fat diet; Islet of Langerhans
3.  Unnecessary Dieting Intention and Behavior among Female Students in Naha City, Japan 
Tropical Medicine and Health  2015;43(2):131-140.
Weight concerns and dieting are prevalent among female adolescents both in Western and Asian countries. They can result in negative psychological and physiological consequences. This study aimed to examine the relative importance of social and personal factors in the decision to diet among female adolescent students in Japan, applying the Theory of Planned Behavior. Data were collected from five junior high schools and three high schools in Naha City, Okinawa Prefecture, in 2010, through self-administered questionnaires. The data of 756 female students were assessed. The independent variables included social factor variables (norms) and personal factor variables (attitude to dieting, perceived behavior control, body esteem, body-figure discrepancy and past dieting). The dependent variables were dieting intention and behavior. Hierarchical multiple regression analyses were performed to examine three models: model 1 (age and obesity index), model 2 (social factor variables with age and obesity index) and model 3 (all variables). Although model 2 failed to explain a substantial proportion of the variance, model 3 explained approximately a half of the variance for intention (R2 = 0.507) and more than one third of the variance for behavior (R2 = 0.376). Past experience of dieting was the best predictor of both dieting intention and behavior. Body esteem was the second best predictor for dieting behavior. In conclusion, personal factors are more likely than social factors to drive the dieting decision. Diet education programs should consider targeting frequent dieters and those with poor body esteem.
doi:10.2149/tmh.2014-33
PMCID: PMC4491491  PMID: 26161031
Dieting; adolescents; body esteem; Japan
4.  Fibromyalgia, milnacipran and experimental pain modulation: study protocol for a double blind randomized controlled trial 
Trials  2015;16:134.
Background
The prevalence of fibromyalgia increases worldwide and is characterized by widespread and chronic pain. Treatment is difficult and includes both drug and non-drug approaches. Milnacipran, an antidepressant, is used for fibromyalgia, with a possible beneficial effect on central pain modulation. Our hypothesis is that the efficacy of milnacipran in fibromyalgia depends on the performance of pain inhibitory controls.
Methods/design
A randomized, double blind, clinical trial (NCT01747044) with two parallel groups, in 48 women with fibromyalgia, is planned in the Clinical Pharmacology Center, University Hospital, Clermont-Ferrand, France. Conditioned pain modulation (estimated with thermal stimuli using a numeric pain rating scale), the primary endpoint measure, is evaluated before and one month after treatment with milnacipran or placebo. Secondary outcome measures include the predictability of pain descending pathways performance for milnacipran efficacy, tolerance and cognitive function. Data analysis is performed using mixed models; the tests are two-sided, with a type I error set at alpha = 0.05. Not only will this trial allow estimation of the beneficial effect of milnacipran on pain and on descending pain pathways but it will also evaluate whether the performance of this modulatory system could be predictive of its efficacy in alleviating pain.
Discussion
This method would allow clinicians to take a pro-active attitude by performing a rapid psychophysical test before starting milnacipran treatment and would avoid unnecessary prescription while preventing therapeutic failure in patients who often face this recurrent problem.
Trial registration
ClinicalTrials.gov NCT01747044.
doi:10.1186/s13063-015-0659-4
PMCID: PMC4393595  PMID: 25873248
conditioned; diffuse noxious inhibitory controls; fibromyalgia; milnacipran; pain modulation; randomized clinical trial
5.  LOX Expression and Functional Analysis in Astrocytomas and Impact of IDH1 Mutation 
PLoS ONE  2015;10(3):e0119781.
Lysyl oxidase (LOX) is involved in vital biological processes such as cell motility, cell signaling and gene regulation. Deregulation of this protein can contribute to tumor formation and progression. Although it is known that LOX is involved in invasion, proliferation and tumor migration in other types of tumors, studies of LOX in astrocytomas of different grades are scarce. The purpose of our study was to characterize LOX, BMP1 and HIF1A expression by real-time PCR in astrocytomas with WHO grades I to IV compared to non-neoplastic brain tissue. IDH1 mutational status was determined by PCR and sequencing. LOX protein expression was also analyzed by immunohistochemistry. LOX functional analyses were performed using siRNA knockdown and the specific inhibitor BAPN in two glioblastoma cell lines. The expression levels of LOX, BMP1 and HIF1A were correlated and analyzed according to IDH1 mutation status and to the clinical end-point of overall survival of glioblastoma patients. The results demonstrate that increased expression and activity of LOX, BMP1 and HIF1A were positively correlated with the malignant grade of astrocytomas. LOX protein expression also increased according to the degree of malignancy, with localization in the cytoplasm and nucleus and staining observed in endothelial cells. Glioblastoma with a mutation in IDH1 expressed lower levels of LOX in the nucleus, and IDH1-mutated cases showed lower LOX expression levels when compared to wild-type IDH1 cases. LOX knockdown and inhibition by BAPN in U87MG and A172 cell lines affected migration, invasion and soft agar colony formation. Taken together, these results corroborate the role of LOX in the migration, invasion and angiogenesis of astrocytomas. Furthermore, LOX expression is influenced by IDH1 mutational status. This work provides new insights for researchers aiming to design targeted therapies to control astrocytomas.
doi:10.1371/journal.pone.0119781
PMCID: PMC4366168  PMID: 25790191
6.  Coronary plaque progression of non-culprit lesions after culprit percutaneous coronary intervention in patients with moderate to advanced chronic kidney disease: intravascular ultrasound and integrated backscatter intravascular ultrasound study 
Previous studies have suggested that the deterioration of renal function increases the risk of major adverse clinical events not only in culprit lesions but also in non-culprit lesions (NCLs) after percutaneous coronary intervention (PCI). This study evaluated serial coronary plaque change of NCL in patients with different stages of chronic kidney disease (CKD) using intravascular ultrasound (IVUS) and integrated backscatter IVUS (IB-IVUS). In 113 patients (113 NCLs) underwent both IVUS-guided PCI and follow-up IVUS, volumetric IVUS analyses were performed at proximal reference NCLs in de novo target vessels post PCI and at 8-month follow-up. NCLs were divided into 4 groups based on baseline CKD stage: CKD-1, n = 18; CKD-2, n = 42; CKD-3, n = 29; and CKD4–5, n = 24. We compared serial changes of plaque burden and composition among groups under statin treatment. Plaque progression occurred in CKD-3 (+4.6 mm3, p < 0.001) and CKD4–5 (+9.8 mm3, p < 0.001) despite anti-atherosclerotic treatment, whereas plaque regression occurred in CKD-1 (−5.4 mm3, p = 0.002) and CKD-2 (−3.2 mm3, p = 0.001) mainly due to initiate statin treatment after PCI. Plaque volume change was correlated with eGFR (p < 0.0001). Multivariate analysis showed CKD stage 3–5 was an independent predictor of plaque progression. Regarding IB-IVUS analyses, lipid plaque increased in CKD-3 (+4.6 mm3, p < 0.001) and CKD4–5 (+5.4 mm3, p < 0.001), but decreased in CKD-2 (−2.7 mm3, p < 0.05). Fibrotic plaque also increased in CKD4–5 (+3.4 mm3, p < 0.001). Moderate to advanced CKD was associated with coronary plaque progression characterized by greater lipid and fibrotic plaque volumes in NCL under statin treatment after culprit PCI.
doi:10.1007/s10554-015-0633-y
PMCID: PMC4446522  PMID: 25724567
Chronic kidney disease; Coronary atherosclerosis; Intravascular ultrasound; Plaque characteristics
7.  Apoptosis induction associated with the ER stress response through up-regulation of JNK in HeLa cells by gambogic acid 
Background
Gambogic acid (GA) was extracted from the dried yellow resin of gamboge (Garcinia hanburyi) which is traditionally used as a coloring material for painting and cloth dying. Gamboge has been also used as a folk medicine for an internal purgative and externally infected wound. We focused on the mechanisms of apoptosis induction by GA through the unfold protein response (ER stress) in HeLa cells.
Methods
The cytotoxic effect of GA against HeLa cells was determined by trypan blue exclusion assay. Markers of ER stress such as XBP-1, GRP78, CHOP, GADD34 and ERdj4 were analyzed by RT-PCR and Real-time RT-PCR. Cell morphological changes and apoptotic proteins were performed by Hoechst33342 staining and Western blotting technique.
Results
Our results indicated a time- and dose-dependent decrease of cell viability by GA. The ER stress induction is determined by the up-regulation of spliced XBP1 mRNA and activated GRP78, CHOP, GADD34 and ERdj4 expression. GA also induced cell morphological changes such as nuclear condensation, membrane blebbing and apoptotic body in Hela cells. Apoptosis cell death detected by increased DR5, caspase-8, −9, and −3 expression as well as increased cleaved-PARP, while decreased Bcl-2 upon GA treatment. In addition, phosphorylated JNK was up-regulated but phosphorylated ERK was down-regulated after exposure to GA.
Conclusions
These results suggest that GA induce apoptosis associated with the ER stress response through up-regulation of p-JNK and down-regulation of p-ERK in HeLa cells.
doi:10.1186/s12906-015-0544-4
PMCID: PMC4340837  PMID: 25887496
Gambogic acid; Anticancer; ER stress; Apoptosis; HeLa cells
8.  Long-Term Pancreatic Beta Cell Exposure to High Levels of Glucose but Not Palmitate Induces DNA Methylation within the Insulin Gene Promoter and Represses Transcriptional Activity 
PLoS ONE  2015;10(2):e0115350.
Recent studies have implicated epigenetics in the pathophysiology of diabetes. Furthermore, DNA methylation, which irreversibly deactivates gene transcription, of the insulin promoter, particularly the cAMP response element, is increased in diabetes patients. However, the underlying mechanism remains unclear. We aimed to investigate insulin promoter DNA methylation in an over-nutrition state. INS-1 cells, the rat pancreatic beta cell line, were cultured under normal-culture-glucose (11.2 mmol/l) or experimental-high-glucose (22.4 mmol/l) conditions for 14 days, with or without 0.4 mmol/l palmitate. DNA methylation of the rat insulin 1 gene (Ins1) promoter was investigated using bisulfite sequencing and pyrosequencing analysis. Experimental-high-glucose conditions significantly suppressed insulin mRNA and increased DNA methylation at all five CpG sites within the Ins1 promoter, including the cAMP response element, in a time-dependent and glucose concentration-dependent manner. DNA methylation under experimental-high-glucose conditions was unique to the Ins1 promoter; however, palmitate did not affect DNA methylation. Artificial methylation of Ins1 promoter significantly suppressed promoter-driven luciferase activity, and a DNA methylation inhibitor significantly improved insulin mRNA suppression by experimental-high-glucose conditions. Experimental-high-glucose conditions significantly increased DNA methyltransferase activity and decreased ten-eleven-translocation methylcytosine dioxygenase activity. Oxidative stress and endoplasmic reticulum stress did not affect DNA methylation of the Ins1 promoter. High glucose but not palmitate increased ectopic triacylglycerol accumulation parallel to DNA methylation. Metformin upregulated insulin gene expression and suppressed DNA methylation and ectopic triacylglycerol accumulation. Finally, DNA methylation of the Ins1 promoter increased in isolated islets from Zucker diabetic fatty rats. This study helps to clarify the effect of an over-nutrition state on DNA methylation of the Ins1 promoter in pancreatic beta cells. It provides new insights into the irreversible pathophysiology of diabetes.
doi:10.1371/journal.pone.0115350
PMCID: PMC4319953  PMID: 25658116
9.  Progressive Relapse of Ligamentum Flavum Ossification Following Decompressive Surgery 
Asian Spine Journal  2014;8(6):835-839.
Thoracic ossification of the ligamentum flavum (T-OLF) is a relatively rare spinal disorder that generally requires surgical intervention, due to its progressive nature and the poor response to conservative therapy. The prevalence of OLF has been reported at 3.8%-26%, which is similar to that of cervical ossification of the posterior longitudinal ligament (OPLL). The progression of OPLL after cervical laminoplasty for the treatment of OPLL is often shown in long-term follow-up. However, there have been no reports on the progression of OLF following surgery. We report a case of thoracic myelopathy secondary to the progressive relapse of OLF following laminectomy.
doi:10.4184/asj.2014.8.6.835
PMCID: PMC4278992  PMID: 25558329
Thoracic ossification of ligamentum flavum; Progressive relapse
10.  Comparing Biofouling Control Treatments for Use on Aquaculture Nets 
Test panels comprised of uncoated, copper coated and silicone coated 7/8'' (22 mm) mesh knitted nylon net were evaluated to compare their properties and the effectiveness to prevent biofouling. This paper describes test procedures that were developed to quantify the performance in terms of antifouling, cleanability, drag and cost. The copper treatment was the most effective at controlling fouling, however, the silicone treated nets were the easiest to clean. The drag forces on the net were a function of twine diameter, twine roughness and fouling. After immersion, the uncoated nets had the most drag followed by the silicone and copper treatments. The cost of applying silicone to nets is high; however, improved formulations may provide a non-toxic alternative to control fouling.
doi:10.3390/ijms151222142
PMCID: PMC4284699  PMID: 25474085
net fouling; net coatings; drag; biocides; fouling release; cleaning; test methods
11.  Hypoxia and fatty liver 
World Journal of Gastroenterology : WJG  2014;20(41):15087-15097.
The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.
doi:10.3748/wjg.v20.i41.15087
PMCID: PMC4223242  PMID: 25386057
Hypoxia; Fatty liver disease; Hypoxia-inducible factor; Lipid metabolism; Obstructive sleep apnea
12.  Long unidirectional barbed suturing technique with extracorporeal traction in laparoscopic myomectomy 
BMC Surgery  2014;14:84.
Background
Myomectomy is now often performed laparoscopically rather than by laparotomy to alleviate the risk of postoperative adhesions and reduce postoperative pain. However, intracorporeal knot-tying under direct laparoscopy is difficult and requires proficiency. We conducted a retrospective study comparing the results of a long unidirectional barbed suturing technique (with V-Loc180 suture) and the results of conventional suturing as applied to laparoscopic myomectomy.
Methods
In women who underwent laparoscopic myomectomy in our university hospital between January 2011 and April 2013, uninterrupted suturing of 2 or more layers was performed. These women were divided into 2 groups according to the method of suturing: those in whom standard absorbable sutures were used (group P, n =42) and those in whom our suturing technique was used (group V, n =41). Patient characteristics and surgical variables were compared between the 2 groups.
Results
No significant between-group difference was observed in age (p = .975), body mass index (p = .778), GnRHa administration (p = .059), intraoperative vasopressin dose (p = .364), intraoperative blood loss (73.8 ± 64.1 vs. 59.3 ± 54.0 mL, respectively; p = .199), myoma mass (212.6 ± 133.3 vs. 208.3 ± 198.4 g, respectively; p = .134), ΔHb (p = .517), or postoperative hospital stay (p = .314). Operation time (mean ± SD) was significantly shorter for group V (71.2 ± 22.9 minutes; range, 28.0–110.0 minutes; p < .001) than for group P (94.4 ± 27.2 minutes; range, 53.0–165.0 minutes). No patient required intraoperative transfusion or conversion to laparotomy.
Conclusions
Our suturing technique exploits the features of unidirectional barbed sutures and can be used in the same way as the conventional method when performing continuous suturing for laparoscopic myomectomy. Our data suggest that operation time can be reduced by as much as 25% with this new technique.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2482-14-84) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2482-14-84
PMCID: PMC4217315  PMID: 25345546
13.  Safety and possible effects of low-intensity resistance training associated with partial blood flow restriction in polymyositis and dermatomyositis 
Introduction
Our aim was to evaluate the safety and efficacy of a low-intensity resistance training program combined with partial blow flow restriction (BFR training) in a cohort of patients with polymyositis (PM) and dermatomyositis (DM).
Methods
In total, 13 patients with PM and DM completed a 12-week twice a week low-intensity (that is, 30% one-repetition-maximum (1RM)) resistance exercise training program combined with partial blood flow restriction (BFR). Assessments of muscle strength, physical function, quadriceps cross sectional (CSA) area, health-related quality of life, and clinical and laboratory parameters were assessed at baseline and after the intervention.
Results
The BFR training program was effective in increasing the maximal dynamic strength in both the leg-press (19.6%, P <0.001) and knee-extension exercises (25.2% P <0.001), as well as in the timed-stands (15.1%, P <0.001) and timed-up-and-go test (−4.5%, P =0.002). Quadriceps CSA was also significantly increased after the intervention (4.57%, P =0.01). Similarly, all of the components of the Short Form-36 Health Survey, the Health Assessment Questionnaire scores, and the patient- and physician reported Visual Analogue Scale were significantly improved after training (P <0.05). Importantly, no clinical evidence or any other self-reported adverse event were found. Laboratory parameters (creatine kinase and aldolase) were also unchanged (P >0.05) after the intervention.
Conclusions
We demonstrated that a 12-week supervised low-intensity resistance training program associated with partial blood flow restriction may be safe and effective in improving muscle strength and function as well as muscle mass and health-related quality of life in patients with PM and DM.
Trial registration
Clinicaltrials.gov NCT01501019. Registered November 29, 2011.
doi:10.1186/s13075-014-0473-5
PMCID: PMC4232679  PMID: 25344395
14.  Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies 
Science translational medicine  2014;6(224):224ra24.
The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
doi:10.1126/scitranslmed.3007094
PMCID: PMC4017867  PMID: 24553385
15.  Transient Helical Structure during PI3K and Fyn SH3 Domain Folding 
The journal of physical chemistry. B  2013;117(17):10.1021/jp400167s.
A growing list of proteins, including the β-sheet-rich SH3 domain, is known to transiently populate a compact α-helical intermediate before settling into the native structure. Examples have been discovered in cryogenic solvent as well as by pressure jumps. Earlier studies of lambda repressor mutants showed that transient states with excess helix are robust in an all-α protein. Here we extend a previous study of src SH3 domain to two new SH3 sequences, phosphatidylinositol 3-kinase (PI3K) and a Fyn mutant, to see how robust such helix-rich transients are to sequence variations in this β-sheet fold. We quantify helical structure by circular dichroism (CD), protein compactness by small angle X-ray scattering (SAXS), and transient helical populations by cryo-stopped flow CD. Our results show that transient compact helix-rich intermediates are easily accessible on the folding landscape of different SH3 domains. In molecular dynamics simulations, force field errors are often blamed for transient non-native structure. We suggest that experimental examples of very fast α-rich transient misfolding could become a more subtle test for further force field improvements than observation of the native state alone.
doi:10.1021/jp400167s
PMCID: PMC3841067  PMID: 23537292
circular dichroism; small angle X-ray scattering; cryosolvent; secondary structure; protein folding
16.  Identification of causative pregnancy of gestational trophoblastic neoplasia diagnosed during pregnancy by short tandem repeat analysis 
Highlights
•Gestational trophoblastic neoplasia can arise during the first trimester originating from trophoblasts of concurrent pregnancy.•Intraplacental choriocarcinoma can be developed from trophoblasts of a previous pregnancy.
doi:10.1016/j.gynor.2014.04.001
PMCID: PMC4059915  PMID: 24944881
DNA analysis; Intra-placental choriocarcinoma; Placental site trophoblastic tumor; Pregnancy; Short tandem repeat
17.  Incidence and Clinical Impact of Stent Fracture After the Nobori Biolimus‐Eluting Stent Implantation 
Background
Stent fracture (SF) after drug‐eluting stent implantation has become an important concern. The aim of this study was to assess the incidence, predictors, and clinical impact of SF after biolimus‐eluting stent.
Methods and Results
A total of 1026 patients with 1407 lesions undergoing the Nobori biolimus‐eluting stent implantation and follow‐up angiography within 9 months after index procedure were analyzed. SF was defined as complete or partial separation of the stent, as assessed by using plain fluoroscopy, intravascular ultrasound, or optical coherence tomography during the follow‐up. We assessed the rate of SF and the cumulative incidence of clinically driven target lesion revascularization and definite stent thrombosis within 9 months. SF was observed in 58 (4.1%) of 1407 lesions and 57 (5.5%) of 1026 patients. Lesions with hinge motion (OR 8.90, 95% CI 3.84 to 20.6, P<0.001), tortuosity (OR 4.16, 95% CI 1.75 to 9.88, P=0.001), and overlapping stents (OR 2.41, 95% CI 0.95 to 6.10, P=0.06) were predictors of SF. Cumulative incidence of clinically driven target lesion revascularization within 9 months was numerically higher in the SF group than that in the non‐SF group (12.0% versus 1.0%). Cumulative incidence of definite stent thrombosis within 9 months tended to be higher in the SF group than that in the non‐SF group (1.7% versus 0.5%).
Conclusions
SF after biolimus‐eluting stent occurs in 4.1% of lesions and appears to be associated with clinically driven target lesion revascularization.
doi:10.1161/JAHA.113.000703
PMCID: PMC4187487  PMID: 24650925
biolimus‐eluting stent; drug‐eluting stent fracture; in‐stent restenosis; percutaneous coronary intervention
18.  Structural study of hNck2 SH3 domain protein in solution by circular dichroism and X-ray solution scattering 
Biophysical chemistry  2013;0:39-46.
We have done conformational study of hNck2 SH3 domain by means of far-ultraviolet (far-UV) circular dichroism (CD) and X-ray solution scattering (XSS). The results indicated that the following: (1) hNck2 SH3 domain protein exhibited concentration dependent monomer–dimer transition at neutral pH, while the secondary structure of this protein was independent of the protein concentration. (2) The hNck2 SH3 domain also exhibited pH dependent monomer–dimer transition. This monomer–dimer transition was accompanied with helix-β transition of the secondary structural change. Moreover, the acid-induced conformation, which was previously studied by Liu and Song by CD and nuclear magnetic resonance (NMR), was found to be not compact, but the conformation of the protein at acidic pH was similar to the cold denatured state (C-state) reported by Yamada et al. for equine β-lactoglobulin. We calculated that a structure of the equilibrium helix-rich intermediate of the hNck2 SH3 domain by DAMMIF program.
doi:10.1016/j.bpc.2013.02.005
PMCID: PMC3925460  PMID: 23524290
Equilibrium helix-rich intermediate; Monomer–dimer transition; C-state
19.  RECURRENCE OF SOLITARY FIBROUS TUMOR OF THE CERVICAL SPINAL CORD 
Nagoya Journal of Medical Science  2014;76(1-2):217-223.
ABSTRACT
Solitary fibrous tumor (SFT) mostly originates from the pleura because of proliferation of fibroblast cells. It is extremely rare for the tumor to originate from the spinal cord. Here, we report a rare case of SFT in the spinal cord that recurred repeatedly and progressed from intramedullary to extramedullary. A 40-year-old man underwent C4-5 intramedullary and extramedullary tumor resection in another hospital. Eighteen years later, he experienced symptoms of myelopathy because of tumor recurrence; therefore, he consulted with our hospital and underwent tumor resection again. During surgery, we found that the tumor had an intramedullary and extramedullary location. Only partial resection was possible because of intraoperative deterioration in the compound motor action potential (CMAP). After resection, the pathological diagnosis was SFT. The postoperative course was good. However, two years later, a third tumor resection was required because of dysuria and tumor growth. In this surgery, total resection of the tumor was possible without intraoperative deterioration of the CMAP. The tumor has not subsequently recurred. However, SFT recurrence is relatively common and careful follow-up is required for early detection of recurrence, even after successful removal of the tumor.
PMCID: PMC4345722  PMID: 25130009
solitary fibrous tumor; intramedullary; extramedullary; cervical spinal cord; recurrence
20.  Unilateral instrumented fixation for cervical dumbbell tumors 
Purpose
The purpose of this study was to describe the radiological outcomes in patients with unilateral instrumented fixation for cervical dumbbell tumors.
Patients and methods
Fourteen consecutive individuals were included in the present study. We included Eden type II and III tumors in this cohort study and analyzed fixed segment fusion rates, screw failure with multiplanar reconstruction computed tomography (CT) scan radiographs and lateral radiographs with flexion-extension dynamic views, and immediate postoperative and last follow-up radiographs after surgery.
Results
The mean follow-up was 105.4 months. There were six men and eight women ranging in age from 32 to 70 years (mean age, 48 years). Twenty pedicle screws (PSs) and 11 lateral mass screws (LMSs) were used in total. There were seven patients with only PSs, four with only LMSs, and three with PSs at C2 and LMSs at C3. PS misplacement occurred in three screws of insertions including two screws with grade 1 misplacement and one screw with grade 2 misplacement, and no grade 3 misplacement occurred. All screws breached the lateral wall with no apparent superior or inferior misplacement. None of the LMSs were misplaced. Fortunately, no complication could be directly attributed to screw insertion. Radiological evidence showed that all patients achieved successful fusion with no screw loosening or breakage. However, two patients who received only LMS fixation had degenerative spondylolisthesis at the upper fusion segment at the last follow-up.
Conclusions
Grade 2 PS misplacement occurred in one screw of insertions. Unilateral pedicle screw fixation for cervical dumbbell tumors is a useful surgical method that can successfully fuse vertebrae with good postoperative alignment.
doi:10.1186/1749-799X-9-2
PMCID: PMC3898569  PMID: 24438086
Unilateral instrumented fixation; Cervical dumbbell tumors; Pedicle screw misplacement
21.  High expression of N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma 
British Journal of Cancer  2012;107(12):1969-1977.
Background:
Gestational trophoblastic diseases (GTDs) are related to trophoblasts, and human chorionic gonadotropin (hCG) is secreted by GTDs as well as normal placentas. However, the asparagine-linked sugar chains on hCG contain abnormal biantennary structures in invasive mole and choriocarcinoma, but not normal pregnancy or hydatidiform mole. N-acetylglucosaminyltransferase-IV (GnT-IV) catalyses β1,4-N-acetylglucosamine branching on asparagine-linked oligosaccharides, which are consistent with the abnormal sugar chain structures on hCG.
Methods:
We investigated GnT-IVa expression in GTDs and placentas by immunohistochemistry, western blot, and RT–PCR. We assessed the effects of GnT-IVa knockdown in choriocarcinoma cells in vitro and in vivo.
Results:
The GnT-IVa was highly expressed in trophoblasts of invasive mole and choriocarcinoma, and moderately in extravillous trophoblasts during the first trimester, but not in hydatidiform mole or other normal trophoblasts. The GnT-IVa knockdown in choriocarcinoma cells significantly reduced migration and invasive capacities, and suppressed cellular adhesion to extracellular matrix proteins. The extent of β1,4-N-acetylglucosamine branching on β1 integrin was greatly reduced by GnT-IVa knockdown, although the expression of β1 integrin was not changed. In vivo studies further demonstrated that GnT-IVa knockdown suppressed tumour engraftment and growth.
Conclusion:
These findings suggest that GnT-IVa is involved in regulating invasion of choriocarcinoma through modifications of the oligosaccharide chains of β1 integrin.
doi:10.1038/bjc.2012.496
PMCID: PMC3516685  PMID: 23169300
beta1 integrin; choriocarcinoma; human chorionic gonadotropin; invasion; N-acetylglucosaminyltransferase-IV
22.  Correction: Analysis of the Proteinaceous Components of the Organic Matrix of Calcitic Sclerites from the Soft Coral Sinularia sp. 
PLoS ONE  2013;8(11):10.1371/annotation/40505aa8-17cf-49c0-8d1d-1e28af8553cb.
doi:10.1371/annotation/40505aa8-17cf-49c0-8d1d-1e28af8553cb
PMCID: PMC3850287
23.  Features of the Onset of Takayasu's Arteritis According to Gender 
Arquivos Brasileiros de Cardiologia  2013;101(4):359-365.
Background
Although there are various published epidemiological studies regarding Takayasu's arteritis (TA), none have analyzed the influence of gender on the clinical and laboratory manifestations or vascular alterations at disease onset.
Objectives
To analyze the influence of gender on clinical and laboratory manifestations and variations in vascular imaging at TA onset.
Methods
A retrospective, unicentric cohort study that evaluated 55 consecutive TA patients between 1982 and 2012. All available clinical data and laboratory test results related to the onset of the disease were analyzed. We included only patients aged 12-35 years at diagnosis to exclude age-related factors.
Results
We analyzed 17 men and 38 women, mostly Caucasian, with a comparable mean age between genders. There was no gender difference regarding the clinical or laboratory characteristics, comorbidities, or smoking habit, except for abdominal pain, which was more common in men. Regarding vascular lesions, the presence of ascending aortic aneurysms was significantly more frequent in males. Male gender represented an independent risk factor for the occurrence of abdominal pain and ascending aortic aneurysms in TA patients.
Conclusion
Abdominal pain and ascending aortic aneurysms occurred more frequently in men with TA, suggesting a more severe disease profile in males.
doi:10.5935/abc.20130180
PMCID: PMC4062373  PMID: 23979780
Takayasu Arteritis / epidemiology; Male; Female; Cohort Studies; Aortic Aneurysm, Abdominal; Abdominal Pain
24.  Myositis-specific and myositis-associated autoantibody profiles and their clinical associations in a large series of patients with polymyositis and dermatomyositis 
Clinics  2013;68(7):909-914.
OBJECTIVE:
To analyze the prevalence of myositis-specific and myositis-associated autoantibodies and their clinical correlations in a large series of patients with dermatomyositis/polymyositis.
METHOD:
This cross-sectional study enrolled 127 dermatomyositis cases and 95 polymyositis cases. The disease-related autoantibody profiles were determined using a commercially available blood testing kit.
RESULTS:
The prevalence of myositis-specific autoantibodies in all 222 patients was 34.4%, whereas myositis-associated autoantibodies were found in 41.4% of the patients. The most frequently found autoantibody was anti-Ro-52 (36.9%), followed by anti-Jo-1 (18.9%), anti-Mi-2 (8.1%), anti-Ku (4.1%), anti-SRP (3.2%), anti-PL-7 (3.2%), anti-PL-12 (2.7%), anti-PM/Scl75 (2.7%), and anti-PM/Scl100 (2.7%). The distributions of these autoantibodies were comparable between polymyositis and dermatomyositis, except for a higher prevalence of anti-Jo-1 in polymyositis. Anti-Mi-2 was more prevalent in dermatomyositis. Notably, in the multivariate analysis, anti-Mi-2 and anti-Ro-52 were associated with photosensitivity and pulmonary disorders, respectively, in dermatomyositis. Anti-Jo-1 was significantly correlated with pulmonary disorders in polymyositis. Moreover, anti-Ro-52 was associated with anti-Jo-1 in both diseases. No significant correlation was observed between the remaining autoantibodies and the clinical and/or laboratory findings.
CONCLUSIONS:
Our data are consistent with those from other published studies involving other populations, although certain findings warrant consideration. Anti-Ro-52 and anti-Jo-1 were strongly associated with one another. Anti-Ro-52 was correlated with pulmonary disorders in dermatomyositis, whereas anti-Jo-1 was correlated with pulmonary alterations in polymyositis.
doi:10.6061/clinics/2013(07)04
PMCID: PMC3715024  PMID: 23917652
Dermatomyositis; Idiopathic Inflammatory Myopathies; Myositis-Associated Autoantibodies; Myositis-Specific Autoantibodies; Polymyositis
25.  Chloroquine diphosphate: a risk factor for herpes zoster in patients with dermatomyositis/polymyositis 
Clinics  2013;68(5):621-627.
OBJECTIVES:
Herpes zoster has been widely described in the context of different systemic autoimmune diseases but not dermatomyositis/polymyositis. Therefore, we analyzed the prevalence, risk factors and herpes zoster outcomes in this population.
METHOD:
A retrospective cohort study of herpes zoster infections in dermatomyositis/polymyositis patients was performed. The patients were followed at a tertiary center from 1991 to 2012. For the control group, each patient with herpes zoster was paired with two patients without herpes zoster. Patients were matched by gender and the type of myositis, age at myositis onset and disease duration.
RESULTS:
Of 230 patients, 24 (10.4%) had a histories of herpes zoster (19 with dermatomyositis and five with polymyositis, two-thirds female). The mean age of the patients with herpes zoster was 44.6±16.8 years. No difference between the groups was found regarding cumulative clinical manifestations. Disease activity, autoantibody, muscle and leukogram parameters were also comparable between the groups. No differences in immunosuppressive (alone or in association with other immunosuppressive therapies) or glucocorticoid (current use, medium dose and cumulative dose in the last two months) therapies were found between patients with and without herpes zoster. However, a higher proportion of patients in the herpes zoster group received chloroquine diphosphate compared to the control group. All of the patients received acyclovir; 58.3% of patients had postherpetic neuralgia and no cases of recurrence were reported. Furthermore, individuals who were taking high prednisone doses at the time of the herpes zoster diagnosis had reduced levels of postherpetic neuralgia.
CONCLUSIONS:
These data suggest that chloroquine diphosphate could predispose patients with dermatomyositis/polymyositis to developing herpes zoster, particularly women and dermatomyositis patients.
doi:10.6061/clinics/2013(05)07
PMCID: PMC3654292  PMID: 23778404
Antimalarial; Chloroquine Diphosphate; Dermatomyositis; Herpes Zoster; Inflammatory Myopathies; Polymyositis; Risk Factors

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