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1.  Fibrin membrane pupillary-block glaucoma after uneventful cataract surgery treated with intracameral tissue plasminogen activator: a case report 
BMC Ophthalmology  2012;12:3.
Fibrin pupillary-block glaucoma is a rare complication after cataract surgery. The treatment for this condition is still controversial, since Nd:YAG laser fibrin membranotomy tends to reocclude and laser peripheral iridotomy entails the risk of damaging the corneal endothelium in the presence of corneal edema associated with elevated intraocular pressure.
Case presentation
A 62-year-old man with diabetes mellitus developed acute elevation of intraocular pressure with a shallow anterior chamber five days after uneventful cataract surgery. Initially, slit lamp examination provided only limited information due to severe corneal edema. After resolution of corneal edema with systemic glaucoma therapy, a complete fibrin membrane was observed across the pupil by slit lamp examination. Anterior segment optic coherence tomography clearly revealed a thin fibrin membrane covering the entire pupillary space, a shallow anterior chamber, and a deep posterior chamber. The intraocular lens was not observed by anterior segment optic coherence tomography. In contrast, ultrasound biomicroscopy, which has superior penetration depth, was able to visualize the intraocular lens deep in the posterior chamber. Injection of tissue plasminogen activator into the anterior chamber resulted in complete fibrinolysis and released the pupillary block.
This case suggests that ocular anterior segment imaging modalities, especially ultrasound biomicroscopy, serve as powerful diagnostic tools to identify mechanisms of acute angle closure glaucoma, which is often accompanied by poor intraocular visibility. This is the first reported case of fibrin pupillary-block glaucoma after cataract surgery successfully treated with intracameral tissue plasminogen activator.
PMCID: PMC3326710  PMID: 22433746
Pupillary block glaucoma; Fibrin membrane; Cataract surgery; Anterior segment imaging; Tissue plasminogen activator
2.  Effect of Wenxin Keli and Quinidine to Suppress Arrhythmogenesis in an Experimental Model of Brugada Syndrome 
Wenxin Keli (WK), a Chinese herb extract, is reported to be effective in the treatment of atrial and ventricular cardiac arrhythmias. Recent studies suggest that WK inhibits the transient outward current (Ito).
The present study examines the effectiveness of WK, alone and in combination with quinidine, to suppress arrhythmogenesis in an experimental model of Brugada syndrome (BrS).
Methods and Results
Action potential and ECG recordings were obtained from epicardial and endocardial sites of coronary-perfused canine right ventricular wedge preparations. The Ito agonist NS5806 (10–15 μM) was used to pharmacologically mimic a genetic predisposition to BrS. The Ito agonist induced Phase 2 reentry (P2R) in 13/19 preparations and polymorphic ventricular tachycardia (pVT) in 11/19 wedge preparations. WK (10g/L) suppressed P2R and pVT in 100% (3/3) of preparations. A lower concentration of WK (5g/L) suppressed P2R in 60% (3/5) and pVT in 50% (2/4), but in combination with a low concentration of quinidine (5 μM) was 100% effective in suppressing P2R and pVT. Quinidine alone suppressed P2R and pVT in 60% (3/5) and 50% (2/4), respectively and in combination with WK (5g/L) suppressed P2R and pVT by 80% (4/5) and 75% (3/4), respectively. WK reduced Ito, ICa and contractility in single cardiomyocytes, but dose-dependently increased contractility in intact wedge preparations, an effect mimicked by tyramine.
Our data provide support for the hypothesis that Wenxin Keli, particularly in combination with quinidine, effectively suppresses arrhythmogenesis in an experimental model of BrS via inhibition of Ito and indirect adrenergic sympathomimetic effects.
PMCID: PMC3702731  PMID: 23499631
Transient outward potassium channel current; positive inotropic effect; cardiac arrhythmias; sudden cardiac death
3.  A Novel Link Between Circadian Clocks and Adipose Tissue Energy Metabolism 
Diabetes  2013;62(7):2175-2177.
PMCID: PMC3712037  PMID: 23801717
4.  Hypoxia-Inducible Factor 1 Regulation through Cross Talk between mTOR and MT1-MMP 
Molecular and Cellular Biology  2014;34(1):30-42.
Hypoxia-inducible factor 1 (HIF-1) plays a key role in the cellular adaptation to hypoxia. Although HIF-1 is usually strongly suppressed by posttranslational mechanisms during normoxia, HIF-1 is active and enhances tumorigenicity in malignant tumor cells that express the membrane protease MT1-MMP. The cytoplasmic tail of MT1-MMP, which can bind a HIF-1 suppressor protein called factor inhibiting HIF-1 (FIH-1), promotes inhibition of FIH-1 by Mint3 during normoxia. To explore possible links between HIF-1 activation by MT1-MMP/Mint3 and tumor growth signals, we surveyed a panel of 252 signaling inhibitors. The mTOR inhibitor rapamycin was identified as a possible modulator, and it inhibited the mTOR-dependent phosphorylation of Mint3 that is required for FIH-1 inhibition. A mutant Mint3 protein that cannot be phosphorylated exhibited a reduced ability to inhibit FIH-1 and promoted tumor formation in mice. These data suggest a novel molecular link between the important hub proteins MT1-MMP and mTOR that contributes to tumor malignancy.
PMCID: PMC3911284  PMID: 24164895
5.  Excreted/secreted Schistosoma mansoni venom allergen-like 9 (SmVAL9) modulates host extracellular matrix remodelling gene expression 
Graphical abstract
•Schistosoma mansoni VAL9 (SmVAL9) is a secreted N-linked glycoprotein containing a unique, difucosyl modification.•SmVAL9 is found throughout miracidia/sporocyst parenchymal cell inclusions/vesicles and germinal cells.•SmVAL9 differentially regulates murine and snail matrix metalloproteinases.
The Schistosoma mansoni venom allergen-like (SmVAL) protein family consists of 29 members, each possessing a conserved α-β-α sandwich tertiary feature called the Sperm-coating protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) domain. While the SmVALs have been found in both excretory/secretory (E/S) products and in intra/sub-tegumental (non-E/S) fractions, the role(s) of this family in host/parasite relationships or schistosome developmental processes remains poorly resolved. In order to begin quantifying SmVAL functional diversity or redundancy, dissecting the specific activity (ies) of individual family members is necessary. Towards this end, we present the characterisation of SmVAL9; a protein previously found enriched in both miracidia/sporocyst larval transformation proteins and in egg secretions. While our study confirms that SmVAL9 is indeed found in soluble egg products and miracidia/sporocyst larval transformation proteins, we find it to be maximally transcribed/translated in miracidia and subsequently down-regulated during in vitro sporocyst development. SmVAL9 localisation within sporocysts appears concentrated in parenchymal cells/vesicles as well as associated with larval germinal cells. Furthermore, we demonstrate that egg-derived SmVAL9 carries an N-linked glycan containing a schistosome-specific difucosyl element and is an immunogenic target during chronic murine schistosomiasis. Finally, we demonstrate that recombinant SmVAL9 affects the expression of extracellular matrix, remodelling matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) gene products in both Biomphalaria glabrata embryonic cell (BgMMP1) and Mus musculus bone marrow-derived macrophage (MmMMP2, MmMMP9, MmMMP12, MmMMP13, MmMMP14, MmMMP28, TIMP1 and TIMP2) in vitro cultures. These findings importantly suggest that excreted/secreted SmVAL9 participates in tissue reorganisation/extracellular matrix remodelling during intra-mammalian egg translocation, miracidia infection and intra-molluscan sporocyst development/migration.
PMCID: PMC4079936  PMID: 24859313
Schistosoma mansoni; Biomphalaria glabrata; Matrix metalloproteinase; Venom allergen-like
6.  Adoptive immunotherapy with MUC1-mRNA transfected dendritic cells and cytotoxic lymphocytes plus gemcitabine for unresectable pancreatic cancer 
We previously reported the clinical efficacy of adoptive immunotherapy (AIT) with dendritic cells (DCs) pulsed with mucin 1 (MUC1) peptide and cytotoxic T lymphocytes (CTLs). We also reported that gemcitabine (GEM) enhances anti-tumor immunity by suppressing regulatory T cells. Therefore, in the present study, we performed combination therapy with AIT and GEM for patients with unresectable or recurrent pancreatic cancer.
Patients and methods
Forty-two patients with unresectable or recurrent pancreatic cancer were treated. DCs were generated by culture with granulocyte macrophage colony-stimulating factor and interleukin-4 and then exposed to tumor necrosis factor-α. Mature DCs were transfected with MUC1-mRNA by electroporation (MUC1-DCs). MUC1-CTLs were induced by co-culture with YPK-1, a human pancreatic cancer cell line, and then with interleukin-2. Patients were treated with GEM, while MUC1-DCs were intradermally injected, and MUC1-CTLs were intravenously administered.
Median survival time (MST) was 13.9 months, and the 1-year survival rate was 51.1%. Of 42 patients, one patient had complete response (2.4%), three patients had partial response (7.1%) and 22 patients had stable disease (52.4%). The disease control ratio was 61.9%. The MST and 1-year survival rate of 35 patients who received more than 1 × 107 MUC1-DCs per injection was 16.1 months and 60.3%, respectively. Liver metastasis occurred in only 5 patients among 35 patients without liver metastasis before treatment. There were no severe toxicities associated with AIT.
AIT with MUC1-DCs and MUC1-CTLs plus GEM may be a feasible and effective treatment for pancreatic cancer.
PMCID: PMC4074851  PMID: 24947606
Pancreatic cancer; MUC1; Dendritic cell; Cytotoxic lymphocyte; Gemcitabine; Immunotherapy
7.  Increased oxygen load in the prefrontal cortex from mouth breathing: a vector-based near-infrared spectroscopy study 
Neuroreport  2013;24(17):935-940.
Individuals who habitually breathe through the mouth are more likely than nasal breathers to have sleep disorders and attention deficit hyperactive disorder. We hypothesized that brain hemodynamic responses in the prefrontal cortex might be different for mouth and nasal breathing. To test this hypothesis, we measured changes in oxyhemoglobin and deoxyhemoglobin in the prefrontal cortex during mouth breathing and nasal breathing in healthy adults (n=9) using vector-based near-infrared spectroscopy. The angle k, calculated from changes in oxyhemoglobin and deoxyhemoglobin and indicating the degree of oxygen exchange, was significantly higher during mouth breathing (P<0.05), indicating an increased oxygen load. Mouth breathing also caused a significant increase in deoxyhemoglobin, but oxyhemoglobin did not increase. This difference in oxygen load in the brain arising from different breathing routes can be evaluated quantitatively using vector-based near-infrared spectroscopy. Phase responses could help to provide an earlier and more reliable diagnosis of a patient’s habitual breathing route than a patient interview.
PMCID: PMC4047298  PMID: 24169579
hemodynamic response; mouth breathing; nasal breathing; oxygen load; vector-based near-infrared spectroscopy
8.  The significance of serum anti-Müllerian hormone (AMH) levels in patients over age 40 in first IVF treatment 
Although studies of serum anti-Müllerian hormone (AMH) in predicting ovarian reserve are numerous, many studies utilized patients under age 40. However, the assessment of ovarian reserve is especially critical in older infertile women. This study evaluates the significance of AMH level in patients over age 40 at the time of their first in vitro fertilization (IVF) treatment.
Forty-nine women over age 40 were studied. Although serum samples were taken prior to their IVF treatments, the data of serum AMH of patients were not taken into consideration to determine the therapy strategy, including follicle induction in which clomiphene citrate and human menopausal gonadotropin were used.
Twelve out of 49 patients achieved a clinical pregnancy (24.4 %). There was a positive correlation between serum AMH levels and the number of oocytes retrieved (P < 0.0001). The ROC curve analysis for prediction of poor ovarian response, ≤3 retrieved oocytes, showed that the optimum cut-off level was < 1.0 ng/mL for AMH. The lower AMH group (AMH < 1.0 ng/ml) showed less chance of undergoing embryo transfer than the higher AMH group (AMH ≥1.0 ng/ml). There was no difference in pregnancy rate between the two groups. Five out of 12 pregnant women exhibited AMH levels of less than 0.4 ng/ml.
Assessment of serum AMH concentration in older patients is useful for the prediction of oocytes numbers which may be obtained in IVF. A cut-off level of 1.0 ng/ml AMH can be used to predict poor ovarian response. This cut-off level of AMH of 1.0 ng/ml might be useful to predict whether patients could have an embryo transfer, but had no power to predict achieving pregnancy. On the other hand, our data also showed that patients over age 40 with extreme low levels of AMH still had a chance of pregnancy.
PMCID: PMC3696453  PMID: 23640374
AMH; Infertility; Aged; IVF
9.  Profiling of Polar Lipids in Marine Oleaginous Diatom Fistulifera solaris JPCC DA0580: Prediction of the Potential Mechanism for Eicosapentaenoic Acid-Incorporation into Triacylglycerol 
Marine Drugs  2014;12(6):3218-3230.
The marine oleaginous diatom Fistulifera solaris JPCC DA0580 is a candidate for biodiesel production because of its high lipid productivity. However, the substantial eicosapentaenoic acid (EPA) content in this strain would affect the biodiesel quality. On the other hand, EPA is also known as the essential health supplement for humans. EPAs are mainly incorporated into glycerolipids in the microalgal cell instead of the presence as free fatty acids. Therefore, the understanding of the EPA biosynthesis including the incorporation of the EPA into glycerolipids especially triacylglycerol (TAG) is fundamental for regulating EPA content for different purposes. In this study, in order to identify the biosynthesis pathway for the EPA-containing TAG species, a lipidomic characterization of the EPA-enriched polar lipids was performed by using direct infusion electrospray ionization (ESI)-Q-TRAP-MS and MS/MS analyses. The determination of the fatty acid positional distribution showed that the sn-2 position of all the chloroplast lipids and part of phosphatidylcholine (PC) species was occupied by C16 fatty acids. This result suggested the critical role of the chloroplast on the lipid synthesis in F. solaris. Furthermore, the exclusive presence of C18 fatty acids in PC highly indicated the biosynthesis of EPA on PC. Finally, the PC-based acyl-editing and head group exchange processes were proposed to be essential for the incorporation of EPA into TAG and chloroplast lipids.
PMCID: PMC4071573  PMID: 24879545
marine oleaginous diatom; Fistuliferasolaris; lipid synthesis; eicosapentaenoic acid (EPA); PC-based acyl-editing
10.  Relationship Between Cytokine Gene Polymorphisms and Risk of Postoperative Pneumonia with Esophageal Cancer 
We retrospectively evaluated the relationship between cytokine gene polymorphisms and development of postoperative pneumonia after esophagectomy.
In 120 patients who underwent esophagectomy, serum samples were obtained to measure levels of serum interleukin (IL)-6 and IL-10 at four time points (preoperatively, postoperative day (POD)0, POD1, and POD3). DNA extracted from peripheral blood in all patients was analyzed to determine polymorphisms of cytokines such as tumor necrosis factor-α -1031 T/C, IL-1β -511C/T, IL-6 -634C/G, and IL-10 -819 T/C.
Postoperative pneumonia arose in 34 patients (28.3 %). Perioperative serum IL-10 levels were significantly higher for IL-10 -819 C/T + C/C genotypes than for T/T genotypes (POD0 16.7 ± 2.84 vs. 8.54 ± 0.87 pg/ml, p = 0.0002; POD1 14.0 ± 2.64 vs. 8.8 ± 0.87 pg/ml, p = 0.0143; POD3 8.9 ± 2.67 vs. 4.4 ± 0.52 pg/ml, p = 0.0076). The frequency of the IL-10 -819 T/T genotype was significantly higher in patients with postoperative pneumonia than in patients without pneumonia (p = 0.0323). Multivariate analysis of factors such as sex, smoking, length of operation, field of lymph node dissection, and IL-10 polymorphism identified IL-10 polymorphism as independent predictor of postoperative pneumonia.
Patients with IL-10 -819 T/T genotype may be at high risk for postoperative pneumonia after esophagectomy.
PMCID: PMC4057631  PMID: 24804995
IL-10 polymorphism; Postoperative pneumonia; Esophagectomy
11.  High viral load of Merkel cell polyomavirus DNA sequences in Langerhans cell sarcoma tissues 
Langerhans cell (LC) sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytologic features and an LC phenotype. We very recently suggested that LC behaves as a reservoir for common dermotropic Merkel cell polyomavirus (MCPyV) and determined the relationship between LC histiocytosis (LCH), which has an underlining oncogenic capacity, and MCPyV as a trigger for a reactive process rather than a neoplastic process. We propose LC to be a reservoir for MCPyV and hypothesize that some LCS subtypes may be related to the MCPyV agent.
We examined seven LCS tissues using multiplex quantitative PCR (Q-PCR) and immunohistochemistry with anti MCPyV large-T (LT) antigen antibody. High viral loads of MCPyV DNA sequences (viral load = relative levels of MCPyV) were detected (0.328–0.772 copies/cell (Merkel cell carcinoma (MCC) = 1.0)) using Q-PCR in 43% (3/7) tissues, but LT antigen expression was not observed (0/7).
Frequent MCPyV-DNA amplification suggests that LCS in some patients may be related to MCPyV infection. Moreover, the higher viral load of LCS (median, 0.453 copies/cell) than low load of LCH (0.003, median of 12 cases) (P < 0.01) may suggest a virally induced tumorigenic process in some LCS. Although the absence of LT antigen expression may indicate a different role for MCPyV in this pathology, some subtypes of LCS may develop in the background of MCPyV-infected LC. To the best of our knowledge, this is the first report on the relationship between MCPyV and LCS. The recent discovery of MCPyV opened new therapeutic avenues for MCC. These data open novel possibilities for therapeutic interventions against LCS.
PMCID: PMC4022531  PMID: 24834110
Merkel cell polyomavirus; Langerhans cell sarcoma; Langerhans cell; Multiplex quantitative PCR
12.  Molecular and functional characterization of a putative PA28γ proteasome activator orthologue in Schistosoma mansoni 
PA28γ is a proteasome activator involved in the regulation of the cellular proliferation, differentiation and growth. In the present study, we identified and characterized a cDNA from Schistosoma mansoni exhibiting significant homology to PA28γ of diverse taxa ranging from mammals (including humans) to simple invertebrates. Designated SmPA28γ, this transcript has a 753 bp predicted ORF encoding a protein of 250 amino acid residues. Alignment of SmPA28γ with multiple PA28γ orthologues revealed an average similarity of ~40% among the investigated organisms, and 90% similarity with PA28γ from Schistosoma japonicum. In addition, phylogenetic analysis demonstrated a close linkage between SmPA28γ to its sister group that contains well-characterized PA28γ sequences from Drosophila spp., as well as sharing the same branch with PA28γ from S. japonicum. Gene expression profiling of SmPA28γ using real-time quantitative PCR revealed elevated steady-state transcript levels in the eggs, miracidia and paired adult worms compared to other stages. In parallel with gene expression profiles, an affinity-purified anti-SmPA28γ antibody produced against recombinant protein exhibited strongest reactivity in Western blot analyses to endogenous SmPA28γ from miracidia, sporocysts and paired adult worms. Given its known regulatory function in other organisms, we hypothesized that the high level of SmPA28γ transcript and protein in these stages may be correlated with an important role of the PA28γ in the cellular growth and/or development of this parasite. To address this hypothesis, miracidia were transformed in vitro to sporocysts in the presence of SmPA28γ double-stranded RNAs (dsRNAs) and cultivated for 4 days, after which time steady-state transcript and protein levels, and phenotypic changes were evaluated. SmPA28γ dsRNA treatment resulted in gene and protein knockdown of ~60% and ~80%, respectively, which were correlated with a significant decrease in larval length compared to its controls. These findings are consistent with a putative role of SmPA28γ in larval growth/development of the S. mansoni.
PMCID: PMC3712533  PMID: 23611749
Schistosoma mansoni; proteasome activator; PA28γ subunit; protease; stage-specific expression; molecular phylogeny; RNAi
13.  Bactericidal effect of hydroxyl radicals generated from a low concentration hydrogen peroxide with ultrasound in endodontic treatment 
One approach to enhance the disinfection of root canals in endodontic treatment is ultrasonic irrigation with sodium hypochlorite. Reactive oxygen species, such as hydroxyl radical, are generated by biological defense systems to kill invading bacteria. Ultrasonic irrigation with hydrogen peroxide may be a promising option to increase hydroxyl radical generation. We examined the bactericidal effects of hydroxyl radical generated from low concentration hydrogen peroxide with ultrasound in vitro. An ultrasonic tip was submerged in 0.5 or 1.0 M hydrogen peroxide in a microfuge tube. hydrogen peroxide was irradiated with the ultrasound, the tip of which was maintained centered in the tube to mimic ultrasonic irrigation. Hydroxyl radical generation was assessed by electron spin resonance spectroscopy. Subsequently, Enterococcus faecalis suspension in hydrogen peroxide was prepared and irradiated as described above. Bactericidal effects were assessed by viable counting. Electron spin resonance measurements showed that hydroxyl radical generation increased significantly in a time- and dose-dependent manner (two-way analysis of variance and Tukey’s test, p<0.05). Moreover, the bactericidal effects of hydrogen peroxide against Enterococcus faecalis were enhanced by ultrasonic irradiation in a time- and dose-dependent manner. These results suggest that ultrasonic irrigation in the presence of low concentration hydrogen peroxide can serve as a disinfection strategy in endodontic treatment.
PMCID: PMC4042143  PMID: 24895478
hydroxyl radical; ultrasound; hydrogen peroxide; bactericidal effect; electron spin resonance
14.  Tumour-suppressive microRNA-874 contributes to cell proliferation through targeting of histone deacetylase 1 in head and neck squamous cell carcinoma 
British Journal of Cancer  2013;108(8):1648-1658.
Our recent studies of microRNA (miRNA) expression signature demonstrated that microRNA-874 (miR-874) was significantly downregulated in maxillary sinus squamous cell carcinoma (MSSCC), and a putative tumour-suppressive miRNA in human cancers. Our aim of this study was to investigate the functional significance of miR-874 in cancer cells and to identify novel miR-874-mediated cancer pathways and responsible genes in head and neck squamous cell carcinoma (HNSCC).
Gain-of-function studies using mature miR-874 were performed to investigate cell proliferation and cell cycle distribution in HNSCC cell lines (SAS and FaDu). To identify miR-874-mediated molecular pathways and targets, we utilised gene expression analysis and in silico database analysis. Loss-of-function assays were performed to investigate the functional significance of miR-874 target genes.
Expression levels of miR-874 were significantly downregulated in HNSCC tissues (including oral, pharyngeal and laryngeal SCCs) compared with normal counterpart epithelia. Restoration of miR-874 in SAS and FaDu cell lines revealed significant inhibition of cell proliferation and induction of G2/M arrest and cell apoptosis. Our expression data and in silico analysis demonstrated that miR-874 modulated the cell cycle pathway. Moreover, histone deacetylase 1 (HDAC1) was a candidate target of miR-874 regulation. Luciferase reporter assays showed that miR-874 directly regulated HDAC1. Silencing of the HDAC1 gene significantly inhibited cell proliferation and induced G2/M arrest and cell apoptosis in SAS cells.
Downregulation of miR-874 was a frequent event in HNSCC. miR-874 acted as a tumour suppressor and directly targeted HDAC1. Recognition of tumour-suppressive miRNA-mediated cancer pathways provides new insights into the potential mechanisms of HNSCC oncogenesis and suggests novel therapeutic strategies for the disease.
PMCID: PMC3668462  PMID: 23558898
miR-874; HDAC1; cell cycle arrest; apoptosis; HNSCC
15.  A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study) 
We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.
The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.
Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p = 0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p = 0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of < 3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p = 0.289) but showed a delayed response.
Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of < 3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.
Trial registration
Trial registration: UMIN000001791.
PMCID: PMC4021539  PMID: 24884643
Peptide vaccine; Peptide cocktail; Colorectal cancer; Phase II study; FOLFOX; Chemotherapy
16.  Rapidly Progressed Primary Intestinal Follicular Lymphoma with Elevation of Soluble Interleukin-2 Receptor Levels 
A 62-year-old Japanese male was diagnosed with primary intestinal follicular lymphoma involving the duodenum, jejunum, and rectum without lymph node involvement. The patient was classified as low risk by the follicular lymphoma international prognostic index (FLIPI) system. Treatment was deferred because he had no symptoms. Eleven months after the diagnosis, his soluble interleukin-2 receptor (sIL-2R) levels had risen from 383 to 617 U/mL. Lymphoma progression involving an enlarged perigastric lymph node was also documented. This report illustrates a case of rapidly progressed intestinal follicular lymphoma, suggesting the possible usefulness of sIL-2R levels as an indicator of lymphoma progression.
PMCID: PMC4021836  PMID: 24876980
17.  Distribution of D-3-aminoisobutyrate-pyruvate aminotransferase in the rat brain 
BMC Neuroscience  2014;15:53.
D-3-aminoisobutyrate, an intermediary product of thymine, is converted to 2-methyl-3-oxopropanoate using pyruvate as an amino acceptor by D-3-aminoisobutyrate-pyruvate aminotransferase (D-AIB AT; EC A large amount of D-AIB AT is distributed in the kidney and liver; however, small amounts are found in the brain. Recently, D-AIB AT was reported to metabolize asymmetric dimethylarginine (ADMA) in vivo and was suggested to be an important enzyme for nitric oxide metabolism because ADMA is a competitive inhibitor for nitric oxide synthase. In this study, we examined the distribution of D-AIB AT in the rat brain further to understand its role. We measured D-AIB AT mRNA and protein expression using quantitative RT-PCR and Western blotting, and monitored its distribution using immunohistochemical staining.
D-AIB AT was distributed throughout the brain, with high expression in the cortex and hippocampus. Immunohistochemical staining revealed that D-AIB AT was highly expressed in the retrosplenial cortex and in hippocampal neurons.
Our results suggest that D-AIB AT is distributed in the examined- just the regions and may play an important role there.
PMCID: PMC4030283  PMID: 24766736
D-3-aminoisobutyrate-pyruvate aminotransferase; Asymmetric dimethylarginine; RT-PCR; Western blotting; Immunohistochemistry
18.  Expression of Tight Junction Protein Claudin-1 in Human Crescentic Glomerulonephritis 
The origin of crescent forming cells in human glomerulonephritis (GN) remains unknown. Some animal studies demonstrated that parietal epithelial cells of Bowman's capsule (PECs) were the main component of proliferating cells and PEC-specific tight junction protein claudin-1 was expressed in crescentic lesions. We investigated the expression of claudin-1 in human GN. Immunohistochemistry for claudin-1 was performed on 17 kidney biopsy samples with crescent formation. Colocalization of claudin-1 with intracellular tight junction protein ZO-1 was also evaluated by immunofluorescence double staining. Claudin-1 is expressed mainly at the cell to cell contact site of proliferating cells in cellular crescentic lesions in patients with these forms of human GN. Small numbers of crescent forming cells showed extrajunctional localization of claudin-1. Colocalization of claudin-1 with ZO-1 was found at cell to cell contact sites of adjacent proliferating cells. In control samples, staining of claudin-1 was positive in PECs, but not in podocytes. Our findings suggest that claudin-1 contributes to crescent formation as a component of the tight junction protein complex that includes ZO-1. Co-localization of claudin-1 with ZO-1 implies the formation of functional tight junction complexes in crescentic lesions to prevent the interstitial damage caused by penetration of filtered molecules from Bowman's space.
PMCID: PMC4020360  PMID: 24868462
19.  Long-term efficacy of infliximab for refractory ulcerative colitis: results from a single center experience 
BMC Gastroenterology  2014;14:80.
The long-term efficacy of infliximab (IFX) for patients with refractory ulcerative colitis (UC) is unclear. The aim of this study was to assess the long-term outcomes of IFX treatment in patients with refractory UC.
Thirty-three patients with refractory UC who received IFX treatment at Kyoto University Hospital between 2003 and 2013 were retrospectively evaluated. IFX intensification was defined as a dose escalation (up to 10 mg/kg) and/or shorter intervals between infusions (every 4–6 weeks).
Of the 33 patients who received scheduled infusions of IFX, 24 (72.7%) achieved clinical remission within 8 weeks after initiating IFX treatment. Of these 24 responders, 17 (70.8%) experienced a relapse of UC and required IFX intensification, and 16 (66.7%) eventually maintained clinical remission with IFX treatment, including IFX intensification. Of the 33 patients, 6 (18.2%) underwent colectomy during IFX treatment. Multivariate regression analysis showed that a serum C-reactive protein (CRP) concentration <5 mg/L two weeks after starting IFX was a predictor of a positive clinical response to IFX induction therapy. No severe adverse events occurred in UC patients treated with IFX.
IFX intensification was necessary for long-term maintenance of remission and to prevent colectomy in patients with refractory UC.
PMCID: PMC4012244  PMID: 24758588
Ulcerative colitis; Infliximab; Immunomodulator; Infliximab intensification
20.  Clinical study using novel endoscopic system for measuring size of gastrointestinal lesion 
AIM: To verify the performance of a lesion size measurement system through a clinical study.
METHODS: Our proposed system, which consists of a conventional endoscope, an optical device, an optical probe, and a personal computer, generates a grid scale to measure the lesion size from an endoscopic image. The width of the grid scale is constantly adjusted according to the distance between the tip of the endoscope and lesion because the lesion size on an endoscopic image changes according to the distance. The shape of the grid scale was corrected to match the distortion of the endoscopic image. The distance was calculated using the amount of laser light reflected from the lesion through an optical probe inserted into the instrument channel of the endoscope. The endoscopist can thus measure the lesion size without contact by comparing the lesion with the size of the grid scale on the endoscopic image. (1) A basic test was performed to verify the relationship between the measurement error eM and the tilt angle of the endoscope; and (2) The sizes of three colon polyps were measured using our system during endoscopy. These sizes were immediately measured by scale after their removal.
RESULTS: There was no error at α = 0°. In addition, the values of eM (mean ± SD) were 0.24 ± 0.11 mm (α = 10°), 0.90 ± 0.58 mm (α = 20°) and 2.31 ± 1.41 mm (α = 30°). According to these results, our system has been confirmed to measure accurately when the tilt angle is less than 20°. The measurement error was approximately 1 mm in the clinical study. Therefore, it was concluded that our proposed measurement system was also effective in clinical examinations.
CONCLUSION: By combining simple optical equipment with a conventional endoscope, a quick and accurate system for measuring lesion size was established.
PMCID: PMC3983462  PMID: 24744595
Lesion size; Non-contact measurement; Endoscope; Grid scale; Low level laser
21.  A New Era of Therapeutic Strategies for Chronic Thromboembolic Pulmonary Hypertension by Two Different Interventional Therapies; Pulmonary Endarterectomy and Percutaneous Transluminal Pulmonary Angioplasty 
PLoS ONE  2014;9(4):e94587.
Pulmonary endarterectomy (PEA) is established for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Recently, percutaneous transluminal pulmonary angioplasty (PTPA) has been added for peripheral-type CTEPH, whose lesions exist in segmental, subsegmental, and more distal pulmonary arteries. A shift in clinical practice of interventional therapies occurred in 2009 (first mainly PEA, later PTPA). We examined the latest clinical outcomes of patients with CTEPH.
Methods and Results
This study retrospectively included 136 patients with CTEPH. Twenty-nine were treated only with drug (Drug-group), and the other 107 underwent interventional therapies (Interventions-group) (39 underwent PEA [PEA-group] and 68 underwent PTPA [PTPA-group]). Total 213 PTPA sessions (failures, 0%; mortality rate, 1.47%) was performed in the PTPA-group (complications: reperfusion pulmonary edema, 7.0%; hemosputum or hemoptysis, 5.6%; vessel dissection, 2.3%; wiring perforation, 0.9%). Although baseline hemodynamic parameters were significantly more severe in the Interventions-group, the outcome after the diagnosis was much better in the Interventions-group than in the Drug-group (98% vs. 64% 5-year survival, p<0.0001). Hemodynamic improvement in the PEA-group was a 46% decrease in mean pulmonary arterial pressure (PAP) and a 49% decrease in total pulmonary resistance (TPR) (follow-up period; 74.7±32.3 months), while those in the PTPA-group were a 40% decrease in mean PAP and a 49% decrease in TPR (follow-up period; 17.4±9.3 months). The 2-year survival rate in the Drug-group was 82.0%, and the 2-year survival rate, occurrence of right heart failure, and re-vascularization rate in the PEA-group were 97.4%, 2.6%, and 2.8%, and those in the PTPA-group were 98.5%, 2.9%, and 2.9%, respectively.
The patients who underwent interventional therapies had better results than those treated only with drugs. The availability of both of these operative and catheter-based interventional therapies leads us to expect the dawn of a new era of therapeutic strategies for CTEPH.
PMCID: PMC3984177  PMID: 24728482
22.  MRI characteristics of rheumatoid arthritis in the temporomandibular joint 
Dentomaxillofacial Radiology  2013;42(4):31627230.
The aim of this study was to investigate characteristic MRI findings of rheumatoid arthritis (RA) in the temporomandibular joints (TMJs).
61 patients (122 TMJs) with RA in the TMJ and 50 patients (100 TMJs) with temporomandibular disorder (TMD) were included in this study. MR images of these patients were assessed by two oral radiologists for the presence or absence of osseous changes, disc displacement, joint effusion and synovial proliferation. These findings were compared between the two patient groups.
Osseous changes in the condyle and articular eminence/fossa in the RA patient group were significantly more frequent than in the TMD patient group, and were often very severe. Joint effusion was also significantly more frequent in the RA patient group. Synovial proliferation was found in all TMJs in the RA patient group, whereas it was very uncommon in the TMD patient group.
Severe osseous changes in the condyle and synovial proliferation were considered characteristic MRI findings of RA in the TMJs.
PMCID: PMC3667508  PMID: 22842633
rheumatoid arthritis; temporomandibular joints; magnetic resonance imaging; diagnosis
23.  A Case of Membranous Glomerulonephropathy Associated with Takayasu's Arteritis 
Glomerulonephropathy is a rare complication of Takayasu's arteritis (TA). To date, most glomerulonephropathies associated with TA show the histological feature of mesangial proliferation. Membranous glomerulonephropathy (MG) is a form of glomerulonephropathy in which the mesangial proliferation is not conspicuous and its association with TA is extremely rare. A 54-year-old man was referred to our hospital due to progressive edema in the lower limbs and nephrotic range proteinuria. Five years previously, he underwent percutaneous angioplasty for left subclavian artery stenosis. Kidney biopsy revealed stage II MG. General examination including enhanced CT scan confirmed the presence of TA. He started oral prednisolone therapy at a dose of 40 mg daily. The C-reactive protein level normalized 7 days after the prednisolone therapy. Three months later, proteinuria had remitted. Though the true relationship between MG and TA was not revealed in present case, considering the fact that complete remission of nephrotic syndrome occurred following the improvement of C-reactive protein level in response to steroid therapy, TA might be the secondary cause of MG. To our best knowledge, only two case reports described the association of MG and TA previously. Those two patients, however, also demonstrated the feature of systemic lupus erythematosus in addition to TA. This is the first case report that describes a patient who presented as MG associated with TA, but not complicated by systemic lupus erythematosus.
PMCID: PMC4025153  PMID: 24847348
Aortitis syndrome; Membranous glomerulonephropathy; Nephrotic syndrome; Systemic lupus erythematosus; Takayasu's arteritis
24.  Multifocal Cellulitis due to Disseminated Neisseria Gonorrhoeae in a Male Patient 
We report a rare case of disseminated gonococcal infection in a 37-year-old man presenting with multifocal cellulitis. The patient presented with fever and painful swelling of the right foot and left hand, and was admitted to our hospital. CT scanning of the extremities revealed multifocal cellulitis. Transthoracic echocardiography findings were normal, and piperacilin/tazoactam therapy was initiated. On antibiotic day 4, Neisseria gonorrhoeae was cultured from a purulent effusion collected from a focal site. Chlamydia trachomatis was detected in urine samples by PCR. We made the diagnosis of multifocal cellulitis due to N. gonorrhoeae in a patient with chlamydia urethritis. The antibiotic agent was changed from piperacilin/tazobactam to ceftriaxone. Levofloxacin was also administered for chlamydia urethritis. By admission day 14, all lesions had resolved and administration of antibiotic agents was terminated. Disseminated gonococcal infection, although rare, should be included in the differential diagnosis of all sexually active patients who present with multifocal cellulitis - also a rare condition, particularly in light of the fact that in recent times, patterns of sexual activity have changed, which was a pertinent factor in this case.
PMCID: PMC3985565  PMID: 24734149
Neisseria gonorrhoeae; Disseminated gonococcal infection; Cellulitis
25.  Comparison of the Cancer Gene Targeting and Biochemical Selectivities of All Targeted Kinase Inhibitors Approved for Clinical Use 
PLoS ONE  2014;9(3):e92146.
The anti-proliferative activities of all twenty-five targeted kinase inhibitor drugs that are in clinical use were measured in two large assay panels: (1) a panel of proliferation assays of forty-four human cancer cell lines from diverse tumour tissue origins; and (2) a panel of more than 300 kinase enzyme activity assays. This study provides a head-on comparison of all kinase inhibitor drugs in use (status Nov. 2013), and for six of these drugs, the first kinome profiling data in the public domain. Correlation of drug activities with cancer gene mutations revealed novel drug sensitivity markers, suggesting that cancers dependent on mutant CTNNB1 will respond to trametinib and other MEK inhibitors, and cancers dependent on SMAD4 to small molecule EGFR inhibitor drugs. Comparison of cellular targeting efficacies reveals the most targeted inhibitors for EGFR, ABL1 and BRAF(V600E)-driven cell growth, and demonstrates that the best targeted agents combine high biochemical potency with good selectivity. For ABL1 inhibitors, we computationally deduce optimized kinase profiles for use in a next generation of drugs. Our study shows the power of combining biochemical and cellular profiling data in the evaluation of kinase inhibitor drug action.
PMCID: PMC3961306  PMID: 24651269

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