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1.  Association study of genetic variants on chromosome 7q31 with susceptibility to normal tension glaucoma in a Japanese population 
Eye  2013;27(8):979-983.
The caveolin 1 to caveolin 2 (CAV1–CAV2) gene region on chromosome 7q31 has been reported to be associated with susceptibility to primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) in previous studies. We investigated whether genetic variants in the CAV1–CAV2 region are associated with NTG in Japanese patients. Two hundred and ninety-two Japanese patients with NTG and 352 Japanese healthy controls were recruited. We genotyped three single-nucleotide polymorphisms; that is, rs1052990, rs4236601, and rs7795356, in the CAV1–CAV2 gene region and assessed the allelic diversity among cases and controls. The frequency of the minor allele (G) of rs1052990 was significantly decreased in NTG cases compared with controls (P=0.014, OR=0.71), whereas NTG or POAG cases had a significantly higher frequency of the allele than controls in previous studies. Conversely, rs7795356 did not show any significant association with NTG cases, and rs4236601 was monomorphic in the Japanese study population. Our findings did not correspond with previous positive results, suggesting that CAV1–CAV2 variants studied in the present study are not important risk factors for NTG susceptibility in all populations. Further studies are needed to elucidate the possible contribution of the CAV1–CAV2 region to the development of glaucoma.
doi:10.1038/eye.2013.123
PMCID: PMC3740316  PMID: 23743525
association study; CAV1; CAV2; normal tension glaucoma; single-nucleotide polymorphism
2.  Identification of leptospiral 3-hydroxyacyl-CoA dehydrogenase released in the urine of infected hamsters 
BMC Microbiology  2014;14:132.
Background
Leptospirosis is a global zoonosis caused by pathogenic Leptospira. The non-specific clinical signs and symptoms of leptospirosis lead to its misdiagnosis. To date, there is still no reliable rapid test kit that can accurately diagnose leptospirosis at bedside or in field. In this research, with the ultimate goal of formulating a rapid and accurate diagnostic tool for leptospirosis, we aimed to identify leptospiral proteins excreted in urine of infected hamsters, which are thought to mimic Weil’s disease.
Results
Hamsters were subcutaneously infected with leptospires, and the general attributes of urine as well as the proteins excreted in it were examined. Some leptospiral proteins were found to be excreted in the urine from the early phase of infection. The most important finding of this study was the detection of the lipid-metabolizing enzyme, 3-hydroxyacyl-CoA dehydrogenase (HADH), before the onset of illness, when leptospires were not yet detected in the urine of infected hamsters.
Conclusions
This is the first report on the detection of leptospiral HADH in the host urine, which may be a possible candidate leptospiral antigen that can be used in the early diagnosis of human and animal leptospirosis.
doi:10.1186/1471-2180-14-132
PMCID: PMC4036750  PMID: 24884439
Leptospirosis; 3-hydroxyacyl-CoA dehydrogenase; Urine; Hamster; Diagnosis
3.  Estrogen-Dependent Uterine Secretion of Osteopontin Activates Blastocyst Adhesion Competence 
PLoS ONE  2012;7(11):e48933.
Embryo implantation is a highly orchestrated process that involves blastocyst-uterine interactions. This process is confined to a defined interval during gestation referred to as the “window of embryo implantation receptivity”. In mice this receptive period is controlled by ovarian estrogen and involves a coordination of blastocyst adhesion competence and uterine receptivity. Mechanisms coordinating the acquisition of blastocyst adhesion competence and uterine receptivity are largely unknown. Here, we show that ovarian estrogen indirectly regulates blastocyst adhesion competence. Acquisition of blastocyst adhesion competence was attributed to integrin activation (e.g. formation of adhesion complexes) rather than de novo integrin synthesis. Osteopontin (OPN) was identified as an estrogen-dependent uterine endometrial gland secretory factor responsible for activating blastocyst adhesion competence. Increased adhesion complex assembly in OPN-treated blastocysts was mediated through focal adhesion kinase (FAK)- and phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways. These findings define for the first time specific regulatory components of an estrogen-dependent pathway coordinating blastocyst adhesion competence and uterine receptivity.
doi:10.1371/journal.pone.0048933
PMCID: PMC3494704  PMID: 23152823
4.  NRFL-1, the C. elegans NHERF Orthologue, Interacts with Amino Acid Transporter 6 (AAT-6) for Age-Dependent Maintenance of AAT-6 on the Membrane 
PLoS ONE  2012;7(8):e43050.
The NHERF (Na+/H+ exchanger regulatory factor) family has been proposed to play a key role in regulating transmembrane protein localization and retention at the plasma membrane. Due to the high homology between the family members, potential functional compensations have been a concern in sorting out the function of individual NHERF numbers. Here, we studied C. elegans NRFL-1 (C01F6.6) (nherf-like protein 1), the sole C. elegans orthologue of the NHERF family, which makes worm a model with low genetic redundancy of NHERF homologues. Integrating bioinformatic knowledge of C. elegans proteins into yeast two-hybrid scheme, we identified NRFL-1 as an interactor of AAT-6, a member of the C. elegans AAT (amino acid transporter) family. A combination of GST pull-down assay, localization study, and co-immunoprecipitation confirmed the binding and characterized the PDZ interaction. AAT-6 localizes to the luminal membrane even in the absence of NRFL-1 when the worm is up to four-day old. A fluorescence recovery after photobleaching (FRAP) analysis suggested that NRFL-1 immobilizes AAT-6 at the luminal membrane. When the nrfl-1 deficient worm is six-day or older, in contrast, the membranous localization of AAT-6 is not observed, whereas AAT-6 tightly localizes to the membrane in worms with NRFL-1. Sorting out the in vivo functions of the C. elegans NHERF protein, we found that NRFL-1, a PDZ-interactor of AAT-6, is responsible for the immobilization and the age-dependent maintenance of AAT-6 on the intestinal luminal membrane.
doi:10.1371/journal.pone.0043050
PMCID: PMC3419730  PMID: 22916205
5.  GPI-anchor synthesis is indispensable for the germline development of the nematode Caenorhabditis elegans 
Molecular Biology of the Cell  2012;23(6):982-995.
Twenty-four Caenorhabditis elegans genes are involved in GPI-anchor synthesis. Based on the isolation of a deletion allele of the PIGA gene mediating the first step of GPI-anchor synthesis, GPI-anchor synthesis in somatic gonads and/or in germline is shown to be indispensable for the normal development of oocytes and eggs.
Glycosylphosphatidylinositol (GPI)-anchor attachment is one of the most common posttranslational protein modifications. Using the nematode Caenorhabditis elegans, we determined that GPI-anchored proteins are present in germline cells and distal tip cells, which are essential for the maintenance of the germline stem cell niche. We identified 24 C. elegans genes involved in GPI-anchor synthesis. Inhibition of various steps of GPI-anchor synthesis by RNA interference or gene knockout resulted in abnormal development of oocytes and early embryos, and both lethal and sterile phenotypes were observed. The piga-1 gene (orthologue of human PIGA) codes for the catalytic subunit of the phosphatidylinositol N-acetylglucosaminyltransferase complex, which catalyzes the first step of GPI-anchor synthesis. We isolated piga-1–knockout worms and found that GPI-anchor synthesis is indispensable for the maintenance of mitotic germline cell number. The knockout worms displayed 100% lethality, with decreased mitotic germline cells and abnormal eggshell formation. Using cell-specific rescue of the null allele, we showed that expression of piga-1 in somatic gonads and/or in germline is sufficient for normal embryonic development and the maintenance of the germline mitotic cells. These results clearly demonstrate that GPI-anchor synthesis is indispensable for germline formation and for normal development of oocytes and eggs.
doi:10.1091/mbc.E10-10-0855
PMCID: PMC3302757  PMID: 22298425
6.  Use of protein array technology to investigate receptor tyrosine kinases activated in hepatocellular carcinoma 
Receptor tyrosine kinases (RTKs) play a role in various processes, including cell growth, differentiation, apoptosis and carcinogenesis. RTKs are activated in various types of cancers, including breast, stomach, colon, pancreas and liver cancer and hepatocellular carcinoma (HCC). In the present study, protein array technology was used to analyze the expression status of various RTKs activated in HCC. The expression of activated RTKs was examined in the HCC cell lines, Alex, HuH7, Li-7, Hep3B, HLE and HLF; in the human normal hepatocyte cell line, hNHeps; and in human HCC and adjacent non-cancerous tissues. Of the 42 different phospho-RTKs, 15 (ErbB2, ErbB3, ErbB4, FGFR2α, FGFR3, insulin R, Mer, PDGFRβ, c-Ret, ROR2, Tie, TrkA, VEGFR3, EphA1 and EphA4) were activated in some of the cancer cell lines studied. Among these, only ErbB2 was activated in all the HCC cell lines examined. Also, in vitro experiments were performed in subcutaneous HCC-bearing athymic nude mice to determine the therapeutic effects of inhibiting ErbB2 activation using the ErbB2-targeting drug trastuzumab. The results revealed that trastuzumab markedly suppressed the growth of HCC. These data suggest that ErbB2 is activated in HCC and that trastuzumab may play a role in the treatment of this disease. In addition, the use of protein array technology is proposed as a tool for detecting the expression of activated RTKs and identifying an effective RTK-based therapy.
doi:10.3892/etm.2011.215
PMCID: PMC3440766  PMID: 22977516
receptor tyrosine kinases; hepatocellular carcinoma
7.  Genotyping HLA-DRB1 and HLA-DQB1 alleles in Japanese patients with normal tension glaucoma 
Molecular Vision  2010;16:1874-1879.
Purpose
Normal tension glaucoma (NTG) is a subtype of glaucoma in which intraocular pressure is within the statistically normal range. NTG may be associated with an immune disorder. The aim of this study was to determine whether specific alleles in the human leukocyte antigen (HLA)-DRB1 and HLA-DQB1 genes correlated with NTG in Japanese patients.
Methods
We genotyped the HLA-DRB1 and HLA-DQB1 alleles in 113 Japanese patients with NTG and in 184 healthy Japanese control subjects using the polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) Luminex method. We assessed the allelic diversity in patients and controls.
Results
There were no statistically significant differences in the allele frequency of HLADRB1 and HLA-DQB1 between NTG patients and control subjects, and no HLA-DRB1-HLA-DQB1 haplotypes demonstrated any significant association with NTG.
Conclusions
Our findings suggest that HLA-DRB1 and HLA-DQB1 polymorphisms have no significant effect on the development of NTG in Japanese patients.
PMCID: PMC2956698  PMID: 21031025
8.  Correction: A Model of Postural Control in Quiet Standing: Robust Compensation of Delay-Induced Instability Using Intermittent Activation of Feedback Control 
PLoS ONE  2009;4(7):10.1371/annotation/96e08e7f-22f0-445d-8fb3-fe7b071d0a3a.
doi:10.1371/annotation/96e08e7f-22f0-445d-8fb3-fe7b071d0a3a
PMCID: PMC2727545
9.  A Model of Postural Control in Quiet Standing: Robust Compensation of Delay-Induced Instability Using Intermittent Activation of Feedback Control 
PLoS ONE  2009;4(7):e6169.
The main purpose of this study is to compare two different feedback controllers for the stabilization of quiet standing in humans, taking into account that the intrinsic ankle stiffness is insufficient and that there is a large delay inducing instability in the feedback loop: 1) a standard linear, continuous-time PD controller and 2) an intermittent PD controller characterized by a switching function defined in the phase plane, with or without a dead zone around the nominal equilibrium state. The stability analysis of the first controller is carried out by using the standard tools of linear control systems, whereas the analysis of the intermittent controllers is based on the use of Poincaré maps defined in the phase plane. When the PD-control is off, the dynamics of the system is characterized by a saddle-like equilibrium, with a stable and an unstable manifold. The switching function of the intermittent controller is implemented in such a way that PD-control is ‘off’ when the state vector is near the stable manifold of the saddle and is ‘on’ otherwise. A theoretical analysis and a related simulation study show that the intermittent control model is much more robust than the standard model because the size of the region in the parameter space of the feedback control gains (P vs. D) that characterizes stable behavior is much larger in the latter case than in the former one. Moreover, the intermittent controller can use feedback parameters that are much smaller than the standard model. Typical sway patterns generated by the intermittent controller are the result of an alternation between slow motion along the stable manifold of the saddle, when the PD-control is off, and spiral motion away from the upright equilibrium determined by the activation of the PD-control with low feedback gains. Remarkably, overall dynamic stability can be achieved by combining in a smart way two unstable regimes: a saddle and an unstable spiral. The intermittent controller exploits the stabilizing effect of one part of the saddle, letting the system evolve by alone when it slides on or near the stable manifold; when the state vector enters the strongly unstable part of the saddle it switches on a mild feedback which is not supposed to impose a strict stable regime but rather to mitigate the impending fall. The presence of a dead zone in the intermittent controller does not alter the stability properties but improves the similarity with biological sway patterns. The two types of controllers are also compared in the frequency domain by considering the power spectral density (PSD) of the sway sequences generated by the models with additive noise. Different from the standard continuous model, whose PSD function is similar to an over-damped second order system without a resonance, the intermittent control model is capable to exhibit the two power law scaling regimes that are typical of physiological sway movements in humans.
doi:10.1371/journal.pone.0006169
PMCID: PMC2704954  PMID: 19584944
10.  Recognition of a common rDNA target site in archaea and eukarya by analogous LAGLIDADG and His–Cys box homing endonucleases 
Nucleic Acids Research  2008;36(22):6988-6998.
The presence of a homing endonuclease gene (HEG) within a microbial intron or intein empowers the entire element with the ability to invade genomic targets. The persistence of a homing endonuclease lineage depends in part on conservation of its DNA target site. One such rDNA sequence has been invaded both in archaea and in eukarya, by LAGLIDADG and His–Cys box homing endonucleases, respectively. The bases encoded by this target include a universally conserved ribosomal structure, termed helix 69 (H69) in the large ribosomal subunit. This region forms the ‘B2a’ intersubunit bridge to the small ribosomal subunit, contacts bound tRNA in the A- and P-sites, and acts as a trigger for ribosome disassembly through its interactions with ribosome recycling factor. We have determined the DNA-bound structure and specificity profile of an archaeal LAGLIDADG homing endonuclease (I-Vdi141I) that recognizes this target site, and compared its specificity with the analogous eukaryal His–Cys box endonuclease I-PpoI. These homodimeric endonuclease scaffolds have arrived at similar specificity profiles across their common biological target and analogous solutions to the problem of accommodating conserved asymmetries within the DNA sequence, but with differences at individual base pairs that are fine-tuned to the sequence conservation of archaeal versus eukaryal ribosomes.
doi:10.1093/nar/gkn846
PMCID: PMC2602781  PMID: 18984620
11.  Multidimensional Profiling Platforms Reveal Metabolic Dysregulation caused by Organophosphorus Pesticides 
ACS chemical biology  2013;9(2):423-432.
We are environmentally exposed to countless synthetic chemicals on a daily basis with an increasing number of these chemical exposures linked to adverse health effects. However, our understanding of the (patho)physiological effects of these chemicals remains poorly understood, due in-part to a general lack of effort to systematically and comprehensively identify the direct interactions of environmental chemicals with biological macromolecules in mammalian systems in vivo. Here, we have used functional chemoproteomic and metabolomic platforms to broadly identify direct enzyme targets that are inhibited by widely used organophosphorus (OP) pesticides in vivo in mice and to determine metabolic alterations that are caused by these chemicals. We find that these pesticides directly inhibit over 20 serine hydrolases in vivo leading to widespread disruptions in lipid metabolism. Through identifying direct biological targets of OP pesticides, we show heretofore unrecognized modes of toxicity that may be associated with these agents and underscore the utility of utilizing multidimensional profiling approaches to obtain a more complete understanding of toxicities associated with environmental chemicals.
doi:10.1021/cb400796c
PMCID: PMC4042408  PMID: 24205821
chlorpyrifos; activity-based protein profiling; metabolomics; organophosphate; pesticides; insecticides; chemoproteomics; serine hydrolase; proteomics; lysophosphatidic acid
12.  Excitation of Multipole Plasmons by Optical Vortex Beams 
Scientific Reports  2015;5:8431.
Localized surface plasmon resonance (LSPR) has been shown to exhibit a strong potential for nanoscale electromagnetic field manipulation beyond the diffraction limit. Particularly dark mode plasmons circumvent radiation loss and store the energy long in time, which raise the prospect of interesting plasmonics applications, for example biochemical sensing and nanoscale lasing. Here we theoretically investigate a method of exciting multipole plasmons, including dark modes, using normally incident light. By performing numerical calculations, we show that multipole plasmons in metal nanodisks can be selectively excited by circularly-polarized optical vortex beams. We study the electromagnetic fields of the beam cross-sections and their correspondence with the excited multipole plasmon modes with respect to spin and orbital angular momenta. The transfer of angular momentum between photons and plasmons is also discussed.
doi:10.1038/srep08431
PMCID: PMC4325316  PMID: 25672226
13.  Fluorescent Immunochromatography for Rapid and Sensitive Typing of Seasonal Influenza Viruses 
PLoS ONE  2015;10(2):e0116715.
Lateral flow tests also known as Immunochromatography (IC) is an antigen-detection method conducted on a nitrocellulose membrane that can be completed in less than 20 min. IC has been used as an important rapid test for clinical diagnosis and surveillance of influenza viruses, but the IC sensitivity is relatively low (approximately 60%) and the limit of detection (LOD) is as low as 10³ pfu per reaction. Recently, we reported an improved IC assay using antibodies conjugated with fluorescent beads (fluorescent immunochromatography; FLIC) for subtyping H5 influenza viruses (FLIC-H5). Although the FLIC strip must be scanned using a fluorescent reader, the sensitivity (LOD) is significantly improved over that of conventional IC methods. In addition, the antibodies which are specific against the subtypes of influenza viruses cannot be available for the detection of other subtypes when the major antigenicity will be changed. In this study, we established the use of FLIC to type seasonal influenza A and B viruses (FLIC-AB). This method has improved sensitivity to 100-fold higher than that of conventional IC methods when we used several strains of influenza viruses. In addition, FLIC-AB demonstrated the ability to detect influenza type A and influenza type B viruses from clinical samples with high sensitivity and specificity (Type A: sensitivity 98.7% (74/75), specificity 100% (54/54), Type B: sensitivity 100% (90/90), specificity 98.2% (54/55) in nasal swab samples) in comparison to the results of qRT-PCR. And furthermore, FLIC-AB performs better in the detection of early stage infection (under 13h) than other conventional IC methods. Our results provide new strategies to prevent the early-stage transmission of influenza viruses in humans during both seasonal outbreaks and pandemics.
doi:10.1371/journal.pone.0116715
PMCID: PMC4317186  PMID: 25650570
14.  A Case of Chondrosarcoma Arising in the Temporomandibular Joint 
Case Reports in Otolaryngology  2015;2015:832532.
Chondrosarcoma is a malignant tumor originating in cartilaginous cells. And there are only few reports of the case of chondrosarcoma in temporomandibular joint. We discuss a case of chondrosarcoma in temporomandibular joint in a 28-year-old man. Tumor was in contact with the dura, but en bloc resection was performed. After surgical resection of the tumor, face defect was reconstructed by rectus abdominis-free flap. And there is no recurrence after ten years from the resection.
doi:10.1155/2015/832532
PMCID: PMC4321848
15.  Effect of prolonged stress on the adrenal hormones of individuals with irritable bowel syndrome 
Background
The purpose of this study was to investigate the effect of prolonged stress on the salivary adrenal hormones (cortisol, dehydroepiandrosterone [DHEA], DHEA-sulfate [DHEA-S]) of individuals with irritable bowel syndrome (IBS).
Methods
The participants were female college students, including 10 with IBS and 16 without IBS (control group), who were scheduled for a 2-week teaching practice at a kindergarten. Participants were asked to collect saliva for determining adrenal hormones immediately and 30 min after awakening and before sleep, 2 weeks before the practice, the first week of the practice, the second week of the practice, and a few days after the practice.
Results
Regarding cortisol/DHEA ratio, significantly increased levels were found during the first week of the practice, and a significant interaction between group and time was found; the ratio at 30 min after awakening in the IBS group was higher than that in the control group. For the other adrenal hormone indexes, no significant differences due to the presence of IBS were found.
Conclusions
Individuals with IBS showed an elevated cortisol/DHEA ratio after awakening compared with individuals without IBS, and the elevated ratio peaked under the prolonged stress. The present study suggests that the cortisol effect is dominant in individuals with IBS under prolonged stress.
doi:10.1186/s13030-015-0031-7
PMCID: PMC4308893  PMID: 25632298
Irritable bowel syndrome; Cortisol; Dehydroepiandrosterone; Saliva; Prolonged stress
16.  Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis 
The Lancet. Oncology  2009;11(2):136-146.
Summary
Background
Analyses of microRNA expression profiles have shown that many microRNAs are expressed aberrantly and correlate with tumorigenesis, progression, and prognosis of various haematological and solid tumours. We aimed to assess the relation between microRNA expression and progression and prognosis of gastric cancer.
Methods
353 gastric samples from two independent subsets of patients from Japan were analysed by microRNA microarray. MicroRNA expression patterns were compared between non-tumour mucosa and cancer samples, graded by diffuse and intestinal histological types and by progression-related factors (eg, depth of invasion, metastasis, and stage). Disease outcome was calculated by multivariable regression analysis to establish whether microRNAs are independent prognostic factors.
Findings
In 160 paired samples of non-tumour mucosa and cancer, 22 microRNAs were upregulated and 13 were downregulated in gastric cancer; 292 (83%) samples were distinguished correctly by this signature. The two histological subtypes of gastric cancer showed different microRNA signatures: eight microRNAs were upregulated in diffuse-type and four in intestinal-type cancer. In the progression-related signature, miR-125b, miR-199a, and miR-100 were the most important microRNAs involved. Low expression of let-7g (hazard ratio 2·6 [95% CI 1·3–4·9]) and miR-433 (2·1 [1·1–3·9]) and high expression of miR-214 (2·4 [1·2–4·5]) were associated with unfavourable outcome in overall survival independent of clinical covariates, including depth of invasion, lymph-node metastasis, and stage.
Interpretation
MicroRNAs are expressed differentially in gastric cancers, and histological subtypes are characterised by specific microRNA signatures. Unique microRNAs are associated with progression and prognosis of gastric cancer.
Funding
National Cancer Institute.
doi:10.1016/S1470-2045(09)70343-2
PMCID: PMC4299826  PMID: 20022810
17.  Simple and Easy Surgical Technique for Infantile Hemangiomas: Intralesional Excision and Primary Closure 
Eplasty  2015;15:e3.
Objective: Infantile hemangioma (IH) is a benign vascular tumor that gradually shrinks over several years. Involuting or involuted IHs usually retain their shape, however, and result in redundant skin or conspicuous scarring due to ulceration in the proliferating phase. We present a case series of 12 patients who underwent intralesional excision and primary closure for treatment of involuting or involuted IH. Methods: Twelve patients (5 boys, 7 girls) underwent our treatment method for involuting or involuted IH. A blinded assessor evaluated clinical result of each patient. Results: Surgical results were excellent in 4 patients, good in 6, and fair in 2. A small dog ear was prominent in 1 patient; nevertheless, all parents were satisfied with the results. Conclusions: Intralesional excision and primary closure for treatment of involuting or involuted IH is an easy and simple procedure that does not result in dog-ear formation or elongated residual scarring.
PMCID: PMC4299471  PMID: 25610518
infantile hemangioma; intralesional excision; primary closure; scar; dog ear
18.  Novel Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes 
Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia. To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6. Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2.
doi:10.1021/ml400339b
PMCID: PMC4027614  PMID: 24900773
Type 2 diabetes; sodium glucose cotransporter 2 inhibitor; urinary glucose excretion; indole-N-glucoside; TA-1887; antihyperglycemic effect
19.  Clinical significance of procoagulant microparticles 
Microparticles (MPs) are small membrane vesicles that are released from many different cell types by exocytic budding of the plasma membrane in response to cellular activation or apoptosis. MPs may also be involved in clinical diseases because they express phospholipids, which function as procoagulants. Although flow cytometry is the most widely used method for studying MPs, some novel assays, such as tissue factor-dependent procoagulant assay or the ELISA method, have been reported. However, the use of quantification of MP as a clinical tool is still controversial. Elevated platelet-derived MP, endothelial cell-derived MP, and monocyte-derived MP concentrations are documented in almost all thrombotic diseases occurring in venous and arterial beds. However, the significance of MPs in various clinical conditions remains controversial. An example of this controversy is that it is unknown if MPs found in peripheral blood vessels cause thrombosis or whether they are the result of thrombosis. Numerous studies have shown that not only the quantity, but also the cellular origin and composition of circulating MPs, are dependent on the type of disease, the disease state, and medical treatment. Additionally, many different functions have been attributed to MPs. Therefore, the number and type of clinical disorders associated with elevated MPs are currently increasing. However, MPs were initially thought to be small particles with procoagulant activity. Taken together, our review suggests that MPs may be a useful biomarker to identify thrombosis.
doi:10.1186/s40560-014-0066-z
PMCID: PMC4336124
Microparticle; Procoagulant activity; Phospholipid; Thrombosis; Flow cytometry
20.  A Case of Fetal Intestinal Volvulus Without Malrotation Causing Severe Anemia 
Fetal intestinal volvulus without malrotation is a rare, life-threatening disease. Left untreated, hemorrhage from necrotic bowel tissue will lead to severe fetal anemia and even intrauterine death. We encountered a case of fetal intestinal volvulus causing severe anemia, which was diagnosed postnatally and successfully treated with surgical intervention.
doi:10.4137/JCM.S20760
PMCID: PMC4285054  PMID: 25628516
fetal midgut volvulus; fetal anemia; non-reassuring fetal status
21.  Genetic Analysis of the Assimilation of C5-Dicarboxylic Acids in Pseudomonas aeruginosa PAO1 
Journal of Bacteriology  2014;196(14):2543-2551.
There is a wealth of information on the genetic regulation and biochemical properties of bacterial C4-dicarboxylate transport systems. In sharp contrast, there are far fewer studies describing the transport and assimilation of C5-dicarboxylates among bacteria. In an effort to better our understanding on this subject, we identified the structural and regulatory genes necessary for the utilization of α-ketoglutarate (α-KG) in Pseudomonas aeruginosa PAO1. The PA5530 gene, encoding a putative dicarboxylate transporter, was found to be essential for the growth of P. aeruginosa PAO1 on both α-KG and glutarate (another C5-dicarboxylate). Metabolite analysis confirmed that the PA5530 gene was necessary for the uptake of extracellular α-KG. Like other substrate-inducible transporter genes, expression of the PA5530 gene was induced by extracellular C5-dicarboxylates. It was later found that the expression of the PA5530 gene was driven solely by a −24/−12 promoter recognized by the alternative sigma factor RpoN. Surprisingly, the enhancer binding protein MifR, which is known to have an essential role in biofilm development, was required for the expression of the PA5530 gene. The MifR protein is homologous to other transcriptional regulators involved in dicarboxylate assimilation, suggesting that MifR might interact with RpoN to activate the expression of the PA5530 gene in response to extracellular C5-dicarboxylates, especially α-KG. The results of this study provide a framework for exploring the assimilation of α-KG in other pseudomonads.
doi:10.1128/JB.01615-14
PMCID: PMC4097582  PMID: 24794562
22.  Global Methylation in the Placenta and Umbilical Cord Blood From Pregnancies With Maternal Gestational Diabetes, Preeclampsia, and Obesity 
Reproductive Sciences  2014;21(1):131-137.
Emerging evidence indicates that maternal medical risk during pregnancy, such as gestational diabetes mellitus (GDM), preeclampsia, and obesity, predisposes the offspring to suboptimal development. However, the underlying biological/epigenetic mechanism in utero is still unknown. The current pilot study (N = 50) compared the levels of global methylation in the placenta and umbilical cord blood among women with and without each risk condition (GDM, preeclampsia, and obesity) and explored whether the levels of global methylation were associated with fetal/infant growth. Results show that global methylation levels in the placenta were lower in patients with gestational diabetes (P = .003) and preeclampsia (P = .05) but higher with obesity (P = .01). Suggestive negative associations were found between global methylation level in the placenta and infant body length and head circumference. While preliminary, it is possible that the placenta tissue, but not umbilical cord blood, may be epigenetically programmed by maternal GDM, preeclampsia, and obesity to carry out its own specific functions that influence fetal growth.
doi:10.1177/1933719113492206
PMCID: PMC3857768  PMID: 23765376
global methylation; fetal programming; placenta; umbilical cord blood; gestational diabetes mellitus; preeclampsia; obesity; birth outcomes
23.  Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer 
Colorectal cancer (CRC) often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which progress and which remain benign is difficult. We developed a novel long-lived murine model of CRC with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk-stratification of colonic tumors. Long-lived ApcMin/+ mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of β-catenin was higher in adenomas that became intratumoral carcinomas as compared to those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to CRC. Further characterization of cellular and molecular features are needed to determine which features can be used to risk-stratify polyps for progression to CRC and potentially guide prevention strategies.
doi:10.1158/1940-6207.CAPR-13-0163
PMCID: PMC4112462  PMID: 24196829
mouse model of colorectal cancer; colon polyp growth patterns; colorectal cancer screening; colon polyp risk stratification; colon polyp characterization
24.  Downregulation of NDUFB6 due to 9p24.1-p13.3 loss is implicated in metastatic clear cell renal cell carcinoma 
Cancer Medicine  2014;4(1):112-124.
This study was conducted to clarify the genomic profiles of metastatic clear cell renal cell carcinomas (ccRCCs) and identify the genes responsible for development of metastasis. We analyzed the genomic profiles of 20 cases of primary ccRCC and their corresponding metastases using array-based comparative genomic hybridization, and identified 32 chromosomal regions in which gene copy number alterations were detected more frequently in metastases than in the primary tumors. Among these 32 regions, 9p24.1-p13.3 loss was the most statistically significant alteration. Furthermore, we found that patients with 9p24.1-p13.3 loss in primary tumors exhibited significantly lower rates of recurrence-free and cancer-specific survival, suggesting that 9p loss in the primary tumor is a potential biomarker predicting early recurrence of metastasis. Interestingly, the genomic profiles of primary tumors with 9p loss resembled those of their corresponding metastases, though 9p loss was accumulated in the metastases derived from the primary tumors without 9p loss. Comparison of the mRNA expression levels revealed that 2 of 58 genes located at 9p24.1-p13.3 were downregulated due to gene copy number loss in ccRCCs. An overexpression study of these two genes in ccRCC cell lines revealed that downregulation of NDUFB6 due to loss at 9p24.1-p13.3 may confer a growth advantage on metastatic ccRCC cells. These results were confirmed by analyzing the data of 405 cases of ccRCC obtained from The Cancer Genome Atlas (TCGA). On the basis of our present data, we propose that NDUFB6 is a possible tumor suppressor of metastatic ccRCCs.
doi:10.1002/cam4.351
PMCID: PMC4312125  PMID: 25315157
9p; array CGH; kidney cancer; metastasis; NDUFB6
25.  A 45,X/46,XY DSD (Disorder of Sexual Development) case with an extremely uneven distribution of 46,XY cells between lymphocytes and gonads 
Abstract
In 45,X/46,XY DSDs, the proportion of the two cell lineages is uneven in different organs and tissues, and 45,X and 46,XY cells can be found throughout the body. The gonadal development of 45,X/46,XY patients depends on the population of 46,XY cells in the gonads and the clinical features are variable. We had a 45,X/46,XY DSD patient whose 46,XY population in peripheral blood was extremely low, less than 0.2%, and was not detected by FISH analysis. However, the patient showed bilateral testicular development and more than 50% of the cells in the gonads had the 46,XY karyotype. This case suggests that a drastically imbalanced distribution could occur in 45,X/46,XY DSD cases.
doi:10.1297/cpe.24.11
PMCID: PMC4322288
45,X/46,XY DSD (disorder of sexual development); mosaicism; chimerism; SRY; FISH (fluorescence in situ hybridization)

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