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1.  Long-Term Trends in Esophageal Candidiasis Prevalence and Associated Risk Factors with or without HIV Infection: Lessons from an Endoscopic Study of 80,219 Patients 
PLoS ONE  2015;10(7):e0133589.
The prevalence of candida esophagitis (CE) might be changing in an era of highly active antiretroviral therapy (HAART) among HIV-infected patients or today’s rapidly aging society among non-HIV-infected patients. However, few studies have investigated long-term CE trends, and CE risk factors have not been studied in a large sample, case-control study. This study aimed to determine long-term trends in CE prevalence and associated risk factors for patients with or without HIV infection.
Trends in CE prevalence were explored in a cohort of 80,219 patients who underwent endoscopy between 2002 and 2014. Risks for CE were examined among a subcohort of 6,011 patients. In risk analysis, we assessed lifestyles, infections, co-morbidities, immunosuppressants, and proton-pump inhibitors (PPIs). All patients were tested for HIV, hepatitis B or C virus, and syphilis infection. For HIV-infected patients, sexual behavior, CD4 cell count, history of HAART were also assessed.
CE prevalence was 1.7% (1,375/80,219) in all patients, 9.8% (156/1,595) in HIV-infected patients, and 1.6% (1,219/78,624) in non-HIV-infected patients. CE prevalence from 2002-2003 to 2012-2014 tended to increase in non-HIV-infected patients (0.6% to 2.5%; P<0.01) and decrease in HIV-infected patients (13.6% to 9.0%; P=0.097). Multivariate analysis revealed increasing age (odds ratio [OR], 1.02; p=0.007), HIV infection (OR, 4.92; p<0.001), and corticosteroid use (OR, 5.90; p<0.001) were significantly associated with CE, and smoking (OR, 1.32; p=0.085) and acetaminophen use (OR, 1.70; p=0.097) were marginally associated. No significant association was found with alcohol consumption, hepatitis B or C virus, syphilis, diabetes mellitus, cardiovascular disease, cerebrovascular disease, chronic kidney disease, liver cirrhosis, anticancer, or PPIs use. In HIV-infected patients, CD4 cell count <100/μL (OR, 4.83; p<0.001) and prior HAART (OR, 0.35; p=0.006) were independently associated with CE, but sexual behavior was not. Among corticosteroid users, CE was significantly associated with higher prednisone-equivalent dose (p=0.043 for trend test).
This large, endoscopy-based study demonstrated that CE prevalence increased in non-HIV-infected patients but decreased in HIV-infected patients over 13 years. Risk analysis revealed that increasing age, HIV infection, and corticosteroids use, particularly at higher doses, were independently associated with CE, but alcohol, other infections, diabetes, anticancer drugs, and PPIs use were not.
PMCID: PMC4514810  PMID: 26208220
2.  A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene 
SpringerPlus  2015;4:358.
The hepatocyte growth factor (HGF)/c-Met signal pathway is up-regulated in human mesothelioma and suppression of the HGF/c-Met signaling with a competitive inhibitor, NK4 homologous to HGF in the structure, produced anti-tumor effects to mesothelioma in a preclinical study. Mesothelioma is highly resistant to a number of chemotherapeutic agents but distant metastasis to extra-thoracic organs is relatively infrequent until the late stage.
We planned to conduct a clinical study of gene therapy with adenoviruses expressing the NK4 gene (Ad-NK4) to control the local tumor growth. The study is designed to inject Ad-NK4 into the intrapleural cavity with a dose escalation manner from 1010 to 1012 virus particles per patient and to examine safety and possible clinical benefits. The clinical investigation is a first-in-human trial to use the NK4 gene and to block the HGF/c-Met pathway with gene medicine. We conducted in vivo animal experiments to examine the safety level as one of the preclinical studies, and showed that Ad DNA administered in the pleural cavity was detected in many parenchymal organs. Biochemical and pathological analyses showed that liver damages were the major adverse effects with little toxicity to other organs. These studies firstly demonstrated biodistribution and transgene expression after an intrapleural injection of Ad vectors in an animal study, which contrasts with an intravenous injection showing relatively rapid clearance of Ad-NK4.
The clinical study can also provide information regarding production of NK4 protein and antibody against NK4, and inhibition levels of the HGF/c-Met pathway by detecting dephosphorylation of c-Met in mesothelioma cells. These data will be crucial to judge whether local production of NK4 molecules can be an anti-cancer strategy.
Trial registration: UMIN clinical trials registry, Japan. Register ID: UMIN15771
PMCID: PMC4503710  PMID: 26191485
Mesothelioma; Adenovirus; HGF; c-Met; NK4
3.  Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury 
SpringerPlus  2015;4:346.
To investigate the efficacy and safety of a dipeptidyl peptidase-4 inhibitor, sitagliptin, for treating diabetes mellitus complicated by chronic liver injury.
Sitagliptin was administered for 13.7 ± 10.1 months to 122 patients with DM complicated by chronic liver injury (including 19 patients with liver cirrhosis), and changes in hemoglobin A1c (HbA1c) and liver enzymes (transaminases, etc.) were evaluated.
HbA1c was reduced from 8.48 ± 1.43% to 7.87 ± 1.35% (P < 0.001). Among liver enzymes, alanine aminotransferase (ALT) levels improved from 75.1 ± 45.2 to 65.8 ± 35.8 IU/L (P = 0.012) and gamma-glut amyl-trans peptidase from 155.2 ± 161.1 to 133.2 ± 127.4 IU/L (P = 0.044). Among the causes of liver injury, non-alcoholic fatty liver disease and alcoholic liver disease both showed the reductions in HbA1c with no deterioration of liver enzymes. An analysis of 19 patients with liver cirrhosis also showed reductions in HbA1c with no deterioration of liver enzymes.
It is suggested that sitagliptin can be administered effectively and safely to patients with diabetes mellitus complicated by chronic liver injury, including liver cirrhosis.
PMCID: PMC4501339  PMID: 26191473
Dipeptidyl peptidase-4 inhibitor; Sitagliptin; Diabetes mellitus; Chronic liver injury
4.  Nucleus Accumbens-Associated Protein 1 Expression Has Potential as a Marker for Distinguishing Oral Epithelial Dysplasia and Squamous Cell Carcinoma 
PLoS ONE  2015;10(7):e0131752.
Oral epithelial dysplasia (OED) and carcinoma in situ (CIS) are defined by dysplastic cells in the epithelium. Over a third of oral squamous cell carcinoma (OSCC) patients present with associated OED. However, accurate histopathological diagnosis of such lesions is difficult. Nucleus accumbens-associated protein 1 (NAC1) is a member of the Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad complex family of proteins, and is overexpressed in OSCC. This study aimed to determine whether NAC1 has the potential to be used as a marker to distinguish OED and OSCC.
Methods and Findings
The study included 114 patients (64 men, 50 women). There were 67, 10, and 37 patients with OED, CIS, and OSCC, respectively. NAC1 labeling indices (LIs) and immunoreactivity intensities (IRI) were evaluated. The patients’ pathological classification was significantly associated with age, sex, NAC1 LIs, and NAC1 IRI (p = 0.025, p = 0.022, p < 0.001, and p < 0.001, respectively). As a result of multivariate analysis, a predictive model was made; this identified the NAC1 LIs (OR [95% CI] 1.18 [1.11–1.28], p < 0.001) and NAC1 IRI (0.78 [0.68–0.86], p < 0.001) as predictive factors for CIS/OSCC. The NAC1 LIs/IRI cut-off values which discriminated between OED and CIS/OSCC were 50%/124 pixels. For NAC1 LIs with > 50% positivity the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 0.766, 0.910, 0.857, and 0.847, respectively. For NAC1 IRI with ≤ 124 positive pixels, the sensitivity, specificity, PPV, and NPV were 0.787, 0.866, 0.804, and 0.853, respectively. Though there are several potential limitations to this study and the results were obtained from a retrospective analysis of a single site cohort, the data suggest that the NAC1 LIs/IRI is a strong predictor of CIS/OSCC.
NAC1 has potential as a marker for distinguishing OED from CIS/OSCC.
PMCID: PMC4501714  PMID: 26172271
5.  Ex Vivo Prefabricated Rat Skin Flap Using Cell Sheets and an Arteriovenous Vascular Bundle 
Supplemental Digital Content is available in the text.
Recently, research on tissue-engineered skin substitutes have been active in plastic surgery, and significant development has been made in this area over the past several decades. However, a regenerative skin flap has not been developed that could provide immediate blood flow after transplantation. Here, we make a regenerative skin flap ex vivo that is potentially suitable for microsurgical transplantation in future clinical applications.
In rats, for preparing a stable vascular carrier, a femoral vascular pedicle was sandwiched between collagen sponges and inserted into a porous chamber in the abdomen. The vascular bed was harvested 3 weeks later, and extracorporeal perfusion was performed. A green fluorescent protein positive epidermal cell sheet was placed on the vascular bed. After perfusion culture, the whole construct was harvested and fixed for morphological analyses.
After approximately 10 days perfusion, the epidermal cell sheet cornified sufficiently. The desquamated corneum was positive for filaggrin. The basement membrane protein laminin 332 and type 4 collagen were deposited on the interface area between the vascular bed and the epidermal cell sheet. Moreover, an electron microscopic image showed anchoring junctions and keratohyalin granules. These results show that we were able to produce native-like skin.
We have succeeded in creating regenerative skin flap ex vivo that is similar to native skin, and this technique could be applied to create various tissues in the future.
PMCID: PMC4494494  PMID: 26180725
6.  Designing and testing lightweight shoulder prostheses with hybrid actuators for movements involved in typical activities of daily living and impact absorption 
Unlike forearm amputees, transhumeral amputees have residual stumps that are too small to provide a sufficient range of operation for their prosthetic parts to perform usual activities of daily living. Furthermore, it is difficult for small residual stumps to provide sufficient impact absorption for safe manipulation in daily living, as intact arms do. Therefore, substitution of upper limb function in transhumeral amputees requires a sufficient range of motion and sufficient viscoelasticity for shoulder prostheses under critical weight and dimension constraints. We propose the use of two different types of actuators, ie, pneumatic elastic actuators (PEAs) and servo motors. PEAs offer high power-to-weight performance and have intrinsic viscoelasticity in comparison with motors or standard industrial pneumatic cylinder actuators. However, the usefulness of PEAs in large working spaces is limited because of their short strokes. Servo motors, in contrast, can be used to achieve large ranges of motion. In this study, the relationship between the force and stroke of PEAs was investigated. The impact absorption of both types of actuators was measured using a single degree-of-freedom prototype to evaluate actuator compliance for safety purposes. Based on the fundamental properties of the actuators identified, a four degree-of-freedom robotic arm is proposed for prosthetic use. The configuration of the actuators and functional parts was designed to achieve a specified range of motion and torque calculated from the results of a simulation of typical movements performed in usual activities of daily living. Our experimental results showed that the requirements for the shoulder prostheses could be satisfied.
PMCID: PMC4501219  PMID: 26185472
shoulder prosthesis; hybrid actuation; pneumatic elastic actuator; antagonistic mechanism; compliance
7.  Clinical endocrinological evaluation of the gonadal axis (testosterone, LH and FSH) in prostate cancer patients switched from a GnRH antagonist to a LHRH agonist 
To investigate the levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prostate-specific antigen (PSA) in prostate cancer patients before and after the switch from degarelix to leuprolide treatments.
We enrolled 40 treatment-naïve prostate cancer patients who were treated initially with degarelix and were later switched to leuprolide. The subjects were divided into three groups depending on when they were switched to leuprolide: the 3-month group (3m; switched after 84 days, n=10), the 2-month group (2m; 56 days, n=10), and the 1-month group (1m; 28 days, n=20). Patient symptoms and hormone levels were measured after switching therapy. The castration level was defined as a serum testosterone level ≤50 ng/dl.
Thirty-nine subjects (97.5%) achieved castration levels of testosterone (11±5.8 ng/dl) 2 weeks after degarelix was first administered, and the characteristics of these patients were investigated. Testosterone levels increased and exceeded the castration level in one subject each of the 3m (142 ng/dl), 2m (72 ng/dl), and 1m groups (63 ng/dl). All subjects achieved the castration level by day 5. In contrast to testosterone levels, the LH and FSH surge on day 2 was significantly higher in the 1m group than in the other groups. The clinical symptoms were not exacerbated before or after switching in any patients.
A testosterone surge was observed in 8.3 % of the study patients; however, it was very short-lived and mild. LH and FSH levels were significantly higher 1 month after administration compared with 2 or 3 months after degarelix administration.
PMCID: PMC4490683  PMID: 26146562
Prostate cancer; GnRH-antagonist; LHRH-agonist; Testosterone
8.  Predictors for Mild and Severe Hypoglycemia in Insulin-Treated Japanese Diabetic Patients 
PLoS ONE  2015;10(6):e0130584.
The objective of this study was to explore predictors, including social factors, lifestyle factors, and factors relevant to glycemic control and treatment, for mild and severe hypoglycemia in insulin-treated Japanese diabetic patients. This study included 123 insulin-treated diabetic patients who were referred to the diabetes clinic between January and July 2013 at Shiga University of Medical Science Hospital. After a survey examining the various factors, patients were followed for 6 months. During the follow-up period, blood glucose was self-monitored. Mild hypoglycemia was defined as blood glucose level 50–69 mg/dl, and severe hypoglycemia was defined as blood glucose level ≤49 mg/dl. Multinomial logistic regression was used to estimate the adjusted odds ratio (OR) and 95% confidence interval (CI) of each factor for mild and severe hypoglycemia. During the 6-month follow-up period, 41 (33.3%) patients experienced mild hypoglycemia, and 20 (16.3%) experienced severe hypoglycemia. In multivariable-adjusted analyses, assistance from family members at the time of the insulin injection [presence/absence, OR (95% CI): 0.39 (0.16–0.97)] and drinking [current drinker/non- and ex-drinker, OR (95% CI): 4.89 (1.68–14.25)] affected mild hypoglycemia. Assistance from family members at the time of insulin injection [presence/absence, OR (95% CI): 0.19 (0.05–0.75)] and intensive insulin therapy [yes/no, OR (95% CI): 3.61 (1.06–12.26)] affected severe hypoglycemia. In conclusion, our findings suggest that not only a factor relevant to glycemic control and treatment (intensive insulin therapy) but also a social factor (assistance from family members) and a lifestyle factor (current drinking) were predictors for mild or severe hypoglycemia in Japanese insulin-treated diabetic patients.
PMCID: PMC4477874  PMID: 26102197
9.  Inhibiting the Activity of CA1 Hippocampal Neurons Prevents the Recall of Contextual Fear Memory in Inducible ArchT Transgenic Mice 
PLoS ONE  2015;10(6):e0130163.
The optogenetic manipulation of light-activated ion-channels/pumps (i.e., opsins) can reversibly activate or suppress neuronal activity with precise temporal control. Therefore, optogenetic techniques hold great potential to establish causal relationships between specific neuronal circuits and their function in freely moving animals. Due to the critical role of the hippocampal CA1 region in memory function, we explored the possibility of targeting an inhibitory opsin, ArchT, to CA1 pyramidal neurons in mice. We established a transgenic mouse line in which tetracycline trans-activator induces ArchT expression. By crossing this line with a CaMKIIα-tTA transgenic line, the delivery of light via an implanted optrode inhibits the activity of excitatory CA1 neurons. We found that light delivery to the hippocampus inhibited the recall of a contextual fear memory. Our results demonstrate that this optogenetic mouse line can be used to investigate the neuronal circuits underlying behavior.
PMCID: PMC4468217  PMID: 26075894
10.  The Nogo Receptor NgR1 Mediates Infection by Mammalian Reovirus 
Cell host & microbe  2014;15(6):681-691.
Neurotropic viruses, including mammalian reovirus, must disseminate from an initial site of replication to the central nervous system (CNS), often binding multiple receptors to facilitate systemic spread. Reovirus engages junctional adhesion molecule-A (JAM-A) to disseminate hematogenously. However, JAM-A is dispensable for reovirus replication in the CNS. We demonstrate that reovirus binds Nogo receptor NgR1, a leucine-rich-repeat protein expressed in the CNS, to infect neurons. Expression of NgR1 confers reovirus binding and infection of non-susceptible cells. Incubating reovirus virions with soluble NgR1 neutralizes infectivity. Blocking NgR1 on transfected cells or primary cortical neurons abrogates reovirus infection. Concordantly, reovirus infection is ablated in primary cortical neurons derived from NgR1-null mice. Reovirus virions bind to soluble JAM-A and NgR1, while infectious disassembly intermediates (ISVPs) bind only to JAM-A. These results suggest that reovirus uses different capsid components to bind distinct cell-surface molecules, engaging independent receptors to facilitate spread and tropism.
PMCID: PMC4100558  PMID: 24922571
11.  Cytotoxic effects of replication-competent adenoviruses on human esophageal carcinoma are enhanced by forced p53 expression 
BMC Cancer  2015;15:464.
Improvement of transduction and augmentation of cytotoxicity are crucial for adenoviruses (Ad)-mediated gene therapy for cancer. Down-regulated expression of type 5 Ad (Ad5) receptors on human tumors hampered Ad-mediated transduction. Furthermore, a role of the p53 pathways in cytotoxicity mediated by replication-competent Ad remained uncharacterized.
We constructed replication-competent Ad5 of which the E1 region genes were activated by a transcriptional regulatory region of the midkine or the survivin gene, which is expressed preferentially in human tumors. We also prepared replication-competent Ad5 which were regulated by the same region but had a fiber-knob region derived from serotype 35 (AdF35). We examined the cytotoxicity of these Ad and a possible combinatory use of the replication-competent AdF35 and Ad5 expressing the wild-type p53 gene (Ad5/p53) in esophageal carcinoma cells. Expression levels of molecules involved in cell death, anti-tumor effects in vivo and production of viral progenies were also investigated.
Replication-competent AdF35 in general achieved greater cytotoxic effects to esophageal carcinoma cells than the corresponding replication-competent Ad5. Infection with the AdF35 induced cleavages of caspases and increased sub-G1 fractions, but did not activate the autophagy pathway. Transduction with Ad5/p53 in combination with the replication-competent AdF35 further enhanced the cytotoxicity in a synergistic manner. We also demonstrated the combinatory effects in an animal model. Transduction with Ad5/p53 however suppressed production of replication-competent AdF35 progenies, but the combination augmented Ad5/p53-mediated p53 expression levels and the downstream pathways.
Combination of replication-competent AdF35 and Ad5/p53 achieved synergistic cytotoxicity due to enhanced p53-mediated apoptotic pathways.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1482-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4460641  PMID: 26059686
Esophageal carcinoma; Replication-competent adenovirus; p53; Apoptosis
12.  Large increase in fracture resistance of stishovite with crack extension less than one micrometer 
Scientific Reports  2015;5:10993.
The development of strong, tough, and damage-tolerant ceramics requires nano/microstructure design to utilize toughening mechanisms operating at different length scales. The toughening mechanisms so far known are effective in micro-scale, then, they require the crack extension of more than a few micrometers to increase the fracture resistance. Here, we developed a micro-mechanical test method using micro-cantilever beam specimens to determine the very early part of resistance-curve of nanocrystalline SiO2 stishovite, which exhibited fracture-induced amorphization. We revealed that this novel toughening mechanism was effective even at length scale of nanometer due to narrow transformation zone width of a few tens of nanometers and large dilatational strain (from 60 to 95%) associated with the transition of crystal to amorphous state. This testing method will be a powerful tool to search for toughening mechanisms that may operate at nanoscale for attaining both reliability and strength of structural materials.
PMCID: PMC4458880  PMID: 26051871
13.  A phase II trial of erlotinib monotherapy for pretreated elderly patients with advanced EGFR wild-type non-small cell lung cancer 
BMC Research Notes  2015;8:220.
Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which is an effective treatment for patients with non-small cell lung cancer (NSCLC), especially those harboring activating EGFR mutations. A previous phase III trial suggested that patients with EGFR wild-type (EGFR-wt) NSCLC or elderly patients with disease progression after cytotoxic chemotherapy might benefit from erlotinib monotherapy. However, few studies have prospectively evaluated the efficacy and safety of second- or third-line erlotinib monotherapy for elderly patients with EGFR-wt advanced or recurrent NSCLC.
Pretreated patients aged ≥70 years with EGFR-wt stage IIIB/IV NSCLC or those with postoperative recurrence were enrolled and received oral erlotinib at a dose of 150 mg/day until disease progression. Primary outcome was the objective response rate (ORR). Secondary end points included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile.
This study was terminated early because of the results from a Japanese phase III trial (DELTA trial). Sixteen patients were enrolled between April 2010 and May 2013. The median age was 78 years (range 70–84 years). Six patients were female. Five patients had an Eastern Cooperative Oncology Group performance status of 0. Eleven (69%) patients had adenocarcinoma. Fifteen (94%) patients were treated with erlotinib as a second-line therapy. The ORR was 0% [95% confidence interval (CI) 0–17.1]. DCR was 56.3% (95% CI 33.2–76.9). The median PFS and OS were 1.7 months (95% CI 1.3–2.2) and 7.2 months (95% CI 5.6–8.7), respectively. The most commonly occurring adverse events included acneiform eruption (31.3%) and skin rash (25.0%). One patient developed grade 3 interstitial lung disease, which improved following steroid therapy.
In pretreated elderly patients with advanced or recurrent EGFR-wt NSCLC, daily oral erlotinib was well tolerated; however, administration of the drug should not be considered as a second line therapy.
Trial registration: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004561 (Date of registration: November 15th, 2010)
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-015-1214-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4467621  PMID: 26043909
Non-small cell lung cancer; Erlotinib; Elderly; EGFR wild-type; PCR-invader
14.  A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy: treatment planning and quality assurance 
In Japan, breast-conserving surgery with closed cavity has generally been performed for breast cancer patients, and accelerated partial breast irradiation (APBI) is considered difficult because Asian females generally have smaller breast sizes than Western females. Therefore, common identification of target and treatment plan method in APBI is required. A prospective multicenter study was conducted in Japan to determine institutional compliance with APBI using high-dose-rate interstitial brachytherapy (ISBT) designed for Japanese female patients.
For this study, 46 patients were recruited at eight institutions from January 2009 to December 2011. The reproducibility of the ISBT–APBI plan was evaluated using three criteria: (1) minimum clinical target volume dose with a clip dose ≥ 6 Gy/fraction, (2) irradiated volume constraint of 40-150 cm3, and (3) uniformity of dose distribution, expressed as the dose non-uniformity ratio (DNR, V150/V100) < 0.35. The ISBT–APBI plan for each patient was considered reproducible when all three criteria were met. When the number of non-reproducible patients was ≤ 4 at study completion, APBI at this institution was considered statistically reproducible.
Half of the patients (52 %) had a small bra size (A/B cup). The mean values of the dose-constrained parameters were as follows: Vref, 117 cm3 (range, 40-282), DNR, 0.30 (range, 0.22-0.51), and clip dose, 784 cGy (range, 469-3146). A total of 43/46 treatment plans were judged to be compliant and ISBT–APBI was concluded to be reproducible.
This study showed that multi-institutional ISBT–APBI treatment plan was reproducible for small breast patient with closed cavity.
PMCID: PMC4461989  PMID: 26040632
APBI; HDR; Brachytherapy
15.  Identification of 4-Trimethylaminobutyraldehyde Dehydrogenase (TMABA-DH) as a Candidate Serum Autoantibody Target for Kawasaki Disease 
PLoS ONE  2015;10(5):e0128189.
Kawasaki disease (KD), an acute vasculitis that preferentially affects coronary arteries, is still the leading cause of acquired heart disease in children. Although the involvement of immune system malfunction in the onset of KD is suggested, its etiology still remains to be clarified. We investigated autoantibodies in KD patients, which are frequently found in sera from patients with autoimmune diseases, vasculitides and arteritides. We performed two-dimensional western blotting and LC-MS/MS to analyze the antigens of autoantibodies, detected two protein spots with 4 out of 24 sera from KD patients but not with 6 control sera, and identified the antigens as 4-trimethylaminobutyraldehyde dehydrogenase (TMABA-DH). A slot blot analysis with TMABA-DH as an antigen also revealed higher reactivities of patients' sera than control sera (positive rates: 18/43 vs 3/41). Using an enzyme-linked immunosorbent assay (ELISA), we found that the reactivity of anti-TMABA-DH antibodies in sera from KD patients was significantly higher than that in sera from age-matched controls. The optimal cut-off value of 0.043 had a sensitivity of 83.7% and a specificity of 80.0% in detecting KD patients (positive rates: 37/43 for KD patients, 9/41 for controls). Immunohistochemistry performed on thin sections of rat heart revealed that TMABA-DH colocalized with myosin light chains in cardiac myocytes. Patient sera with high reactivity gave similar immunostaining pattern. These results suggest that the detection of anti-TMABA-DH autoantibody could be a potential strategy for a diagnosis of KD.
PMCID: PMC4444320  PMID: 26010099
16.  Effect of different carbon sources on the biological phosphorus removal by a sequencing batch reactor using pressurized pure oxygen 
The effect of different carbon source on the efficiency of enhanced biological phosphorus removal (EBPR) from synthetic wastewater with acetate and two ratios of acetate/starch as a carbon source was investigated. Three pressurized pure oxygen sequencing batch reactor (POSBR) experiments were operated. The reactors (POSBR1, POSBR2 and POSBR3) were developed and studied at different carbon source ratios of 100% acetate, 75% acetate plus 25% starch and 50% acetate plus 50% starch, respectively. The results showed that POSBR1 had a higher phosphate release-to-uptake ratio and, respectively, in a much higher phosphorus removal efficiency (93.8%) than POSBR2 (84.7%) and POSBR3 (77.3%) within 30 days of operation. This indicated that the phosphorus removal efficiency decreased the higher the starch concentration was. It was also found that POSBR1 produced more polyhydroxyalkanoates (PHAs) than the other reactors. Based on the effect of the carbon source on the PHA concentration and consumption, the conditions of POSBR1 were favourable for the growth of polyphosphate-accumulating organisms and therefore, beneficial for the biological phosphorus removal process.
PMCID: PMC4434035  PMID: 26019532
pressurized pure oxygen sequencing batch reactor (POSBR); polyphosphate-accumulating organisms (PAOs); carbon source; biological phosphorus removal
17.  Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer’s disease mouse model 
Recent studies have shown that several strains of transgenic Alzheimer’s disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.
Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.
We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.
Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0110-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4419386  PMID: 25945128
18.  Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer 
Investigational New Drugs  2015;33(4):881-889.
Background Ipilimumab is an antibody that targets the cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor response. Adding ipilimumab 10 mg/kg to paclitaxel (PTX) and carboplatin (CBDCA) in a phased schedule improved progression-free survival in a phase II non-small-cell lung cancer (NSCLC) study. Methods This dose-escalating, phase I study was designed to identify the recommended dose of ipilimumab (3 or 10 mg/kg) by evaluating dose-limiting toxicity (DLT; Cycles 3 and 4) in phased combination with PTX (175 mg/m2) and CBDCA (area under the curve = 6) in Japanese patients with advanced NSCLC. Treatment was administered intravenously every 3 weeks initially, followed by some eligible patients receiving maintenance ipilimumab once every 12 weeks. Additional endpoints included safety, tumor response, pharmacokinetics, and immunogenicity. Results Fifteen patients were enrolled and 12 received ipilimumab (n = 6, 3 mg/kg; n = 6, 10 mg/kg) in combination with PTX and CBDCA. DLTs occurred in 2 patients (ipilimumab 3 mg/kg) and 1 patient (ipilimumab 10 mg/kg). The most common grade 3/4 adverse events (AEs) were decreased hemoglobin, leukopenia, and neutropenia. The most common immune-related AEs affected the skin, gastrointestinal, and nervous system. The safety profile was similar in both cohorts. Three patients in each cohort achieved a partial response. The pharmacokinetic (PK) profile of ipilimumab in Japanese patients was similar to that observed in previous studies in non-Japanese patients. Conclusions The recommended dose of ipilimumab in phased combination with PTX and CBDCA in Japanese patients with NSCLC was identified as 10 mg/kg. The safety profile was consistent with the previously defined AE profile.
PMCID: PMC4491360  PMID: 25924991
Ipilimumab; Paclitaxel; Carboplatin; Non-small-cell lung cancer; Phase I study; Japanese patients
19.  Effect of Body Mass Index and Intra-Abdominal Fat Measured by Computed Tomography on the Risk of Bowel Symptoms 
PLoS ONE  2015;10(4):e0123993.
This study aims to investigate the association between body mass index (BMI) or intra-abdominal fat measured by computed tomography (CT) and bowel symptoms.
A cohort of 958 Japanese adults who underwent colonoscopy and CT and completed questionnaires after excluding colorectal diseases was analyzed. Six symptoms (constipation, diarrhea, loose stools, hard stools, fecal urgency, and incomplete evacuation) using a 7-point Likert scale were evaluated between baseline and second questionnaire for test-retest reliability. Associations between BMI, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and symptom score were analyzed by a rank-ordered logistic model, adjusting for age, sex, smoking, and alcohol consumption, hypertension, diabetes mellitus, and dyslipidemia.
Some bowel symptom scores were significantly (p<0.05) different between the age groups, sexes, smoking, and alcohol consumption. In multivariate analysis, constipation was associated with low BMI (p<0.01), low VAT area (p = 0.01), and low SAT area (p<0.01). Moreover, hard stools was associated with low BMI (p<0.01) and low SAT area (p<0.01). The remaining symptoms were not significantly associated with BMI or intra-abdominal fat. Test-retest reliability of bowel symptom scores with a mean duration of 7.5 months was good (mean kappa, 0.672).
Both low BMI and low abdominal fat accumulation appears to be useful indicators of increased risk for constipation and hard stools. The long-term test-retest reliability of symptom score suggests that bowel symptoms relevant to BMI or visceral fat remain consistent over several months.
PMCID: PMC4408111  PMID: 25906052
20.  Analysis of the antioxidative function of the radioprotective Japanese traditional (Kampo) medicine, hangeshashinto, in an aqueous phase 
Journal of Radiation Research  2015;56(4):669-677.
Oral mucositis (OM) is a common and painful complication of radiotherapy for head and neck cancer. Hangeshashinto (HST), a Japanese traditional medicine, is known to alleviate radiotherapy- and/or chemotherapy-induced OM; however, the detailed mechanism has not yet been clarified. The aim of the present study was to clarify the details of the antioxidative functions of HST against reactive oxygen species (ROS) produced by radiation. The hydroxyl radical (•OH)–scavenging ability and the reduction ability was simultaneously measured using a modified electron paramagnetic resonance (EPR) spin-trapping method. The superoxide (O2•−)–scavenging ability was estimated by an EPR redox probing method. Water suspensions of powdered HST and of its seven constitutive crude drugs were tested. In addition, some of the main water-soluble ingredients of the crude drugs were also tested. HST was found to scavenge both •OH and O2•−. Furthermore, HST was observed to reduce relatively stable nitroxyl radicals. Glycyrrhizae Radix (kanzo), Ginseng Radix (ninjin), Zizyphi Fructus (taiso) and glycyrrhizin (an ingredient of kanzo) were all found to be relatively good •OH scavengers. Scutellariae Radix (ogon) and Coptidis Rhizoma (oren) demonstrated reducing ability. In addition, acteoside and berberine chloride, which are water-soluble ingredients of ogon and oren, respectively, also demonstrated reducing ability. Oren exhibited oxidative ability at higher concentrations, which may have a function in maintaining catalytic redox action. The antioxidative function of HST probably worked via a balance of scavenging ROS, reducing stable free radicals, and some minor oxidizing activities.
PMCID: PMC4497396  PMID: 25883171
hangeshashinto (HST); oral mucositis (OM); electron paramagnetic resonance (EPR); radiation; reactive oxygen species
21.  A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease 
Despite significant progress, a disease-modifying therapy for Alzheimer’s disease (AD) has not yet been developed. Recent findings implicate soluble oligomeric amyloid beta as the most relevant protein conformation in AD pathogenesis. We recently described a signaling cascade whereby oligomeric amyloid beta binds to cellular prion protein on the neuronal cell surface, activating intracellular Fyn kinase to mediate synaptotoxicity. Fyn kinase has been implicated in AD pathophysiology both in in vitro models and in human subjects, and is a promising new therapeutic target for AD. Herein, we present a Phase Ib trial of the repurposed investigational drug AZD0530, a Src family kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD.
The study was a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. A total of 24 subjects were recruited in three sequential groups, with each randomized to receive oral AZD0530 at doses of 50 mg, 100 mg, 125 mg, or placebo daily for 4 weeks. The drug:placebo ratio was 3:1. Primary endpoints were safety, tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. Secondary endpoints included changes in clinical efficacy measures (Alzheimer’s Disease Assessment Scale – cognitive subscale, MMSE, Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Clinical Dementia Rating Scale – Sum of Boxes) and regional cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography.
AZD0530 was generally safe and well tolerated across doses. One subject receiving 125 mg of AZD0530 was discontinued from the study due to the development of congestive heart failure and atypical pneumonia, which were considered possibly related to the study drug. Plasma/CSF ratio of AZD0530 was 0.4. The 100 mg and 125 mg doses achieved CSF drug levels corresponding to brain levels that rescued memory deficits in transgenic mouse models. One-month treatment with AZD0530 had no significant effect on clinical efficacy measures or regional cerebral glucose metabolism.
AZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central nervous system penetration with oral dosing at 100–125 mg. Targeting Fyn kinase may be a promising therapeutic approach in AD, and a larger Phase IIa clinical trial of AZD0530 for the treatment of patients with AD has recently launched.
Trial registration NCT01864655. Registered 12 June 2014.
PMCID: PMC4396171  PMID: 25874001
22.  Fatal submucosal invasive gastric adenosquamous carcinoma detected at surveillance after gastric endoscopic submucosal dissection 
An 80-year-old man was under annual surveillance esophagogastroduodenoscopy after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Two years after the initial ESD, a 0-IIc type metachronous EGC lesion, 8 mm in size, without an ulcer scar, was found in the gastric antrum. The estimated tumor depth was up to the mucosa, and biopsy revealed well and poorly differentiated adenocarcinoma. ESD was performed for this lesion and en bloc resection with negative margins was achieved. Histopathological examination revealed an adenosquamous carcinoma 8 mm in size invading the deep submucosal layer (1600 μm), with lymphovascular invasion, consistent with the diagnosis of non-curative resection. Additional gastrectomy was recommended for this patient; however, two months after the ESD, preoperative computed tomography revealed multiple liver metastases, and the patient was considered as an unsuitable candidate for surgical resection. Systemic chemotherapy was therefore started; however, the patient died of gastric cancer 27 mo after the second ESD. Early gastric adenosquamous carcinoma localized to the mucosa and submucosa is extremely rare and its clinical behavior is not well known. The present report is very significant in that it underscores the distinct possibility of gastric adenosquamous carcinoma being very aggressive and fatal even when detected at an early cancer.
PMCID: PMC4394102  PMID: 25892891
Early gastric cancer; Endoscopic submucosal dissection; Gastric adenosquamous carcinoma; Gastric cancer-related death; Liver metastasis; Metachronous cancer; Surveillance
23.  Safety and feasibility of adjuvant chemotherapy with S-1 in Japanese breast cancer patients after primary systemic chemotherapy: a feasibility study 
BMC Cancer  2015;15:253.
Advanced breast cancer patients have a higher risk of postoperative recurrence than early-stage breast cancer patients. Recurrence is believed to be caused by the increase in micrometases, which were not eradicated by preoperative or postoperative chemotherapy. Therefore, a new therapeutic strategy that can improve treatment efficacy is mandatory for advanced breast cancer. S-1 was shown to be effective and safe in Japanese metastatic breast cancer patients treated with previous chemotherapy, including anthracyclines. Thus, in this study, we evaluated S-1 as adjuvant chemotherapy in breast cancer patients after standard primary systemic chemotherapy.
The treatment consisted of 18 courses (a 2-week administration and a 1-week withdrawal; one year) administered at 80–120 mg/body/day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on Day 1 of the study. If the estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted, concurrently.
Of the 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. Thirty-two of the 43 (74.4%) patients received concurrent radiotherapy. Twenty-two of the 43 (51.2%) patients completed the scheduled courses of chemotherapy. The most common reasons for withdrawal of treatment were subjective symptoms, such as nausea, anorexia, or general fatigue during the first 9 courses of treatment in 9/43 (20.9%) patients, recurrence in 7/43 (16.3%) patients, and adverse events in 5/43 (11.6%) patients. The cumulative percentage of administration for 365 days was 66.4% (95% confidence interval: 50.8–79.1%). Although grade 3 neutropenia (9.3%), leukopenia (4.7%), and diarrhea (4.7%) were observed, they were manageable. No grade 4 adverse effects were observed.
The percentage of Japanese breast cancer patients completing the 18-course treatment and the cumulative percentage of administration for 365 days using S-1 after standard primary systemic chemotherapy were similar with the results of another study of adjuvant chemotherapy for the Japanese gastric cancer patients with no severe adverse effects. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan, and it is expected that S-1 will have a significant survival benefit in breast cancer patients.
PMCID: PMC4407316  PMID: 25884795
Advanced breast cancer; S-1; Adjuvant chemotherapy; Primary systemic chemotherapy
24.  Laparoscopic Resection of an Intra-Abdominal Esophageal Duplication Cyst: A Case Report and Literature Review 
Case Reports in Surgery  2015;2015:940768.
Duplication of the alimentary tract is a rare congenital malformation that occurs most often in the abdominal region, whereas esophageal duplication cyst develops typically in the thoracic region but occasionally in the neck and abdominal regions. Esophageal duplication cyst is usually diagnosed in early childhood because of symptoms related to bleeding, infection, and displacement of tissue surrounding the lesion. We recently encountered a rare adult case of esophageal duplication cyst in the abdominal esophagus. A 50-year-old man underwent gastroscopy, endoscopic ultrasonography, computed tomography, and magnetic resonance imaging to investigate epigastric pain and dysphagia that started 3 months earlier. Imaging findings suggested esophageal duplication cyst, and the patient underwent laparoscopic resection followed by intraoperative esophagoscopy to reconstruct the esophagus safely and effectively. Histopathological examination of the resected specimen revealed two layers of smooth muscle in the cystic wall, confirming the diagnosis of esophageal duplication cyst.
PMCID: PMC4391505  PMID: 25883826

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