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1.  Effect of hydrofluoric acid on glucose metabolism of the mouse studied by whole-body autoradiography. 
Distribution of radioactive carbon from [U-14C]glucose in the mouse poisoned by hydrofluoric acid has been studied by whole-body autoradiography. Under normal conditions, the highest autoradiographic density was found in the Harder's gland, palatine gland, sublingual gland, large intestinal mucosa, and many regions of the central nervous system 30 minutes after intraperitoneal injection of [U-14C]glucose. On the other hand, after hydrofluoric acid poisoning, it was found that (1) the radioactivity of brain was unchanged throughout all the poisoning; (2) the liver, renal cortex, lung, and blood showed an increase in radioactivity at 180 minutes of poisoning; (3) the abdominal cavity showed a tendency to residual radioactivity with the poisoning; (4) by contrast, Harder's gland, the palatine gland, sublingual gland, and large intestinal mucosa showed a decrease in radioactivity at 180 minutes of poisoning.
PMCID: PMC1008082  PMID: 1201258
2.  A 6-Fr Guiding Catheter (Slim Guide®) for Use with Multiple Microdevices 
Interventional Neuroradiology  2013;19(1):7-15.
A modified technique is required in patients with wide-necked aneurysms whose treatment by the single microcatheter technique is difficult. We developed a 6-Fr guiding catheter (Slim Guide®) that features a large lumen (0.072 inch) for performing the modified technique. To evaluate the usefulness of Slim Guide® we carried out experiments using three types of 6-Fr guiding catheter.
In experiment 1, the shaft hardness and kink resistance were compared among three different guiding catheters (Slim Guide®, Launcher®, Envoy®). In experiment 2, we inserted a microballoon catheter and a microcatheter into the three different guiding catheters and recorded the maximal infusion pressure. In experiment 3, we inserted 13 different types of microdevices into the three different guiding catheters and evaluated the resistance of the microdevices.
Although the shaft of the Slim Guide® was softer than that of the other two guiding catheters, its kink resistance was comparable. The maximal infusion pressure was significantly lower than with Launcher® or Envoy® catheters. Furthermore, with Slim Guide®, in 136 of 143 microdevice combinations examined (95.1%) there was no resistance; this was true for 125 (87.4%) and 116 (81.1%) combinations using the Launcher® - and the Envoy® guiding catheters, respectively. There was a significant difference between Slim Guide® and the other two guiding catheters with respect to their accommodation of double microsystems (p<0.05).
Although the inner diameter of Slim Guide® is slightly larger than of the other two guiding catheters, it significantly increased the combination of microdevices that could be used for the coil embolization of difficult aneurysms.
PMCID: PMC3601621  PMID: 23472717
guiding catheter, interventional neurosurgery, embolization
3.  Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model 
Gene therapy  2011;18(10):10.1038/gt.2011.51.
We previously identified the mouse and human Glipr1 and GLIPR1/RTVP-1 (respectively) genes as direct p53 targets with proapoptotic activities in various cancer cell lines, including prostate cancer. Intratumoral injection of an adenoviral vector capable of efficient transduction and expression of Glipr1 (AdGlipr1) yielded promising therapeutic results in an orthotopic, metastatic mouse model of prostate cancer. AdGlipr1-transduced macrophages (Mϕ/Glipr1) generated greater surface expression of CD40, CD80, and MHC class II molecules and greater production of interleukin (IL)-12 and IL-6 in vitro than control macrophages did. Mechanistic analysis indicated that increased production of IL-12 in Mϕ/Glipr1 depends on activation of the p38 signaling cascade. Mϕ/Glipr1 injected into orthotopic 178-2BMA tumors in vivo resulted in significantly suppressed prostate tumor growth and spontaneous lung metastases and longer survival relative to those observed in control-treated mice. Furthermore, these preclinical data indicate the generation of systemic natural killer-cell activity and tumor-specific cytotoxic T-lymphocyte responses. Trafficking studies confirmed that intratumorally injected Mϕ/Glipr1 could migrate to draining lymph nodes. Overall, our data suggest that this novel gene-modified cell approach is an effective treatment avenue that induces antitumor immune responses in preclinical studies.
PMCID: PMC3881531  PMID: 21512508
prostate cancer; gene-modified cell therapy; Glipr1; macrophages
4.  Upregulation of ERCC1 and DPD expressions after oxaliplatin-based first-line chemotherapy for metastatic colorectal cancer 
British Journal of Cancer  2012;107(12):1950-1955.
The updated randomised phase 2/3 FIRIS study demonstrated the noninferiority of IRIS (irinotecan and S-1) to FOLFIRI (irinotecan, folinic acid, and 5-FU) for metastatic colorectal cancer. Meanwhile, in the subset analysis including patients who previously have undergone oxaliplatin-containing chemotherapy, the IRIS group showed longer survival than the FOLFIRI group. However, the molecular mechanism underlying this result is still unknown.
The National Cancer Institute 60 (NCI60) cell line panel data were utilised to build the hypothesis. A total of 45 irinotecan-naive metastatic colorectal cancer patients who had undergone hepatic resection were included for the validation study. The mRNA expressions of excision repair cross-complementing group 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), and topoisomerase-1 (TOP1) were evaluated by quantitative RT–PCR. The expressions of ERCC1 and DPD were also evaluated by immunohistochemistry.
Sensitivity to oxaliplatin in 60 cell lines was significantly correlated with that of 5-FU. Resistant cells to oxaliplatin showed significantly higher ERCC1 and DPD expression than sensitive cells. In validation study, ERCC1 and DPD but not TOP1 expressions in cancer cells were significantly higher in FOLFOX (oxaliplatin, folinic acid, and 5-FU)-treated patients (N=24) than nontreated patients (N=21). The ERCC1 and DPD protein expressions were also significantly higher in FOLFOX-treated patients.
The ERCC1 and DPD expression levels at both mRNA and protein levels were significantly higher in patients with oxaliplatin as a first-line chemotherapy than those without oxaliplatin. The IRIS regimens with the DPD inhibitory fluoropyrimidine may show superior activity against DPD-high tumours (e.g., tumours treated with oxaliplatin) compared with FOLFIRI.
PMCID: PMC3516688  PMID: 23169295
DPD; ERCC1; metastatic colorectal cancer; National Cancer Institute; oxaliplatin
5.  RPN2 expression predicts response to docetaxel in oesophageal squamous cell carcinoma 
British Journal of Cancer  2012;107(8):1233-1238.
Neoadjuvant chemotherapy – often using docetaxel in various combinatorial regimens – is a standard treatment choice for advanced oesophageal squamous cell carcinoma (ESCC) in Japan. However, no useful markers exist that predict docetaxel's effects on ESCC. Ribophorin II (RPN2) silencing, which reduces glycosylation of P-glycoproteins and decreases membrane localisation, promotes docetaxel-dependent apoptosis. We investigated whether RPN2 expression in ESCC biopsy specimens could be a predictive biomarker in docetaxel-based neoadjuvant chemotherapy.
We evaluated RPN2 expression immunohistochemically in biopsy specimens from 79 patients with node-positive ESCC, who received docetaxel-based adjuvant chemotherapy, and compared clinical and pathological responses between the RPN2-positive and RPN2-negative groups. We also studied susceptibility of RPN2-suppressed ESCC cells to docetaxel.
The RPN2-negative group had better clinical and pathological responses to docetaxel than the RPN2-positive group. We also found RPN2 suppression to alter docetaxel susceptibility in vitro.
Expression of RPN2 in biopsy specimens could be a useful predictive marker for response to docetaxel-based neoadjuvant chemotherapy in ESCC.
PMCID: PMC3494434  PMID: 22955852
docetaxel; neoadjuvant chemotherapy; ESCC; RPN2; predictive marker
6.  Optical pacing of the adult rabbit heart 
Biomedical Optics Express  2013;4(9):1626-1635.
Optical pacing has been demonstrated to be a viable alternative to electrical pacing in embryonic hearts. In this study, the feasibility of optically pacing an adult rabbit heart was explored. Hearts from adult New Zealand White rabbits (n = 9) were excised, cannulated and perfused on a modified Langendorff apparatus. Pulsed laser light (λ = 1851 nm) was directed to either the left or right atrium through a multimode optical fiber. An ECG signal from the left ventricle and a trigger pulse from the laser were recorded simultaneously to determine when capture was achieved. Successful optical pacing was demonstrated by obtaining pacing capture, stopping, then recapturing as well as by varying the pacing frequency. Stimulation thresholds measured at various pulse durations suggested that longer pulses (8 ms) had a lower energy capture threshold. To determine whether optical pacing caused damage, two hearts were perfused with 30 µM of propidium iodide and analyzed histologically. A small number of cells near the stimulation site had compromised cell membranes, which probably limited the time duration over which pacing was maintained. Here, short-term optical pacing (few minutes duration) is demonstrated in the adult rabbit heart for the first time. Future studies will be directed to optimize optical pacing parameters to decrease stimulation thresholds and may enable longer-term pacing.
PMCID: PMC3771833  PMID: 24049683
(140.3460) Lasers; (170.3890) Medical optics instrumentation
Neuroscience  2010;174:50-63.
Clinical and experimental evidence demonstrates that endocannabinoids play either beneficial or adverse roles in many neurological and psychiatric disorders. Their medical significance may be best explained by the emerging concept that endocannabinoids are essential modulators of synaptic transmission throughout the central nervous system. However, the precise molecular architecture of the endocannabinoid signaling machinery in the human brain remains elusive. To address this issue, we investigated the synaptic distribution of metabolic enzymes for the most abundant endocannabinoid molecule, 2-arachidonoylglycerol (2-AG), in the postmortem human hippocampus. Immunostaining for diacylglycerol lipase-α (DGL-α), the main synthesizing enzyme of 2-AG, resulted in a laminar pattern corresponding to the termination zones of glutamatergic pathways. The highest density of DGL-α-immunostaining was observed in strata radiatum and oriens of the cornu ammonis and in the inner third of stratum moleculare of the dentate gyrus. At higher magnification, DGL-α-immunopositive puncta were distributed throughout the neuropil outlining the immunonegative main dendrites of pyramidal and granule cells. Electron microscopic analysis revealed that this pattern was due to the accumulation of DGL-α in dendritic spine heads. Similar DGL-α-immunostaining pattern was also found in hippocampi of wild-type, but not of DGL-α knockout mice. Using two independent antibodies developed against monoacylglycerol lipase (MGL), the predominant enzyme inactivating 2-AG, immunostaining also revealed a laminar and punctate staining pattern. However, as observed previously in rodent hippocampus, MGL was enriched in axon terminals instead of postsynaptic structures at the ultrastructural level. Taken together, these findings demonstrate the post- and presynaptic segregation of primary enzymes responsible for synthesis and elimination of 2-AG, respectively, in the human hippocampus. Thus, molecular architecture of the endocannabinoid signaling machinery supports retrograde regulation of synaptic activity, and its similar blueprint in rodents and humans further indicates that 2-AG’s physiological role as a negative feed-back signal is an evolutionarily conserved feature of excitatory synapses.
PMCID: PMC3678284  PMID: 21035522
2-arachidonoylglycerol; diacylglycerol lipase; monoacylglycerol lipase; CB1 cannabinoid receptor; glutamatergic synapse; hippocampus
8.  Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial 
British Journal of Cancer  2012;106(7):1268-1273.
The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis.
Patients aged 20–80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m−2 per day as tegafur; LV, 75 mg per day on days 1–28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1–28, every 42 days, 4 courses). Treatment status and safety were evaluated.
Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of ⩾grade 3 AEs were 16% and 14%, respectively.
Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.
PMCID: PMC3314794  PMID: 22415232
colon cancer; adjuvant chemotherapy; phase III; S-1; UFT
9.  Methamphetamine-evoked depression of GABAB receptor signaling in GABA neurons of the VTA 
Neuron  2012;73(5):978-989.
Psychostimulants induce neuroadaptations in excitatory and fast inhibitory transmission in the ventral tegmental area (VTA). Mechanisms underlying drug-evoked synaptic plasticity of slow inhibitory transmission mediated by GABAB receptors and G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels, however, are poorly understood. Here, we show that one day after methamphetamine (METH) or cocaine exposure, both synaptically-evoked and baclofen-activated GABABR-GIRK currents were significantly depressed in VTA GABA neurons, and remained depressed for 7 days. Presynaptic inhibition mediated by GABABRs on GABA terminals was also weakened. Quantitative immunoelectron microscopy revealed internalization of GABAB1R and GIRK2, which occurred coincident with dephosphorylation of Ser783 in GABAB2R, a site implicated in regulating GABABR surface expression. Inhibition of protein phosphatases recovered GABABR-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABABR signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system.
PMCID: PMC3560416  PMID: 22405207
10.  Aberrant activation of the mTOR pathway and anti-tumour effect of everolimus on oesophageal squamous cell carcinoma 
British Journal of Cancer  2012;106(5):876-882.
The mammalian target of rapamycin (mTOR) protein is important for cellular growth and homeostasis. The presence and prognostic significance of inappropriate mTOR activation have been reported for several cancers. Mammalian target of rapamycin inhibitors, such as everolimus (RAD001), are in development and show promise as anti-cancer drugs; however, the therapeutic effect of everolimus on oesophageal squamous cell carcinoma (OSCC) remains unknown.
Phosphorylation of mTOR (p-mTOR) was evaluated in 167 resected OSCC tumours and 5 OSCC cell lines. The effects of everolimus on the OSCC cell lines TE4 and TE11 in vitro and alone or in combination with cisplatin on tumour growth in vivo were evaluated.
Mammalian target of rapamycin phosphorylation was detected in 116 tumours (69.5%) and all the 5 OSCC cell lines. Everolimus suppressed p-mTOR downstream pathways, inhibited proliferation and invasion, and induced apoptosis in both TE4 and TE11 cells. In a mouse xenograft model established with TE4 and TE11 cells, everolimus alone or in combination with cisplatin inhibited tumour growth.
The mTOR pathway was aberrantly activated in most OSCC tumours. Everolimus had a therapeutic effect both as a single agent and in combination with cisplatin. Everolimus could be a useful anti-cancer drug for patients with OSCC.
PMCID: PMC3305959  PMID: 22333597
everolimus; RAD001; mTOR; oesophageal squamous cell carcinoma; proliferation
11.  Overexpression of microRNA-223 regulates the ubiquitin ligase FBXW7 in oesophageal squamous cell carcinoma 
British Journal of Cancer  2011;106(1):182-188.
F-box and WD repeat domain-containing 7 (FBXW7) is a cell cycle regulatory gene whose protein product ubiquitinates positive cell cycle regulators such as c-Myc, cyclin E, and c-Jun, thereby acting as a tumour-suppressor gene. This study focused on microRNA-223 (miR-223), which is a candidate regulator of FBXW7 mRNA. The aim of this study was to clarify the clinical significance of miR-223 and FBXW7 in oesophageal squamous cell carcinoma (ESCC) patients, and to elucidate the mechanism by which FBXW7 is regulated by miR-223.
The expression levels of miR-223 and the expression of FBXW7 protein was examined using 109 resected specimens to determine the clinicopathological significance. We also investigated the role of miR-223 in the regulation of FBXW7 expression in ESCC cell lines in an in vitro analysis.
We found that miR-223 expression was significantly higher in cancerous tissues than in the corresponding normal tissues. There was a significant inverse relationship between the expression levels of miR-223 and FBXW7 protein. Moreover, patients with high miR-223 expression demonstrated a significantly poorer prognosis than those with low expression. On the basis of a series of gain-of-function and loss-of-function studies in vitro, we identified FBXW7 as a functional downstream target of miR-223.
Our present study indicates that high expression of miR-223 had a significant adverse impact on the survival of ESCC patients through repression of the function of FBXW7.
PMCID: PMC3251856  PMID: 22108521
microRNA; FBXW7; ubiquitin ligase
12.  Pulmonary thin-section CT findings in acute Moraxella catarrhalis pulmonary infection 
The British Journal of Radiology  2011;84(1008):1109-1114.
Moraxella catarrhalis is an important pathogen in the exacerbation of chronic obstructive pulmonary disease. The aim of this study was to assess the clinical and pulmonary thin-section CT findings in patients with acute M. catarrhalis pulmonary infection.
Thin-section CT scans obtained between January 2004 and March 2009 from 292 patients with acute M. catarrhalis pulmonary infection were retrospectively evaluated. Clinical and pulmonary CT findings in the patients were assessed. Patients with concurrent infection including Streptococcus pneumoniae (n = 72), Haemophilus influenzae (n = 61) or multiple pathogens were excluded from this study.
The study group comprised 109 patients (66 male, 43 female; age range 28–102 years; mean age 74.9 years). Among the 109 patients, 34 had community-acquired and 75 had nosocomial infections. Underlying diseases included pulmonary emphysema (n = 74), cardiovascular disease (n = 44) or malignant disease (n = 41). Abnormal findings were seen on CT scans in all patients and included ground-glass opacity (n = 99), bronchial wall thickening (n = 85) and centrilobular nodules (n = 79). These abnormalities were predominantly seen in the peripheral lung parenchyma (n = 99). Pleural effusion was found in eight patients. No patients had mediastinal and/or hilar lymph node enlargement.
M. catarrhalis pulmonary infection was observed in elderly patients, often in combination with pulmonary emphysema. CT manifestations of infection were mainly ground-glass opacity, bronchial wall thickening and centilobular nodules.
PMCID: PMC3473838  PMID: 21123308
13.  Selective growth inhibition by glycogen synthase kinase-3 inhibitors in tumorigenic HeLa hybrid cells is mediated through NF-κB-dependent GLUT3 expression 
Oncogenesis  2012;1(7):e21-.
Carcinogenesis and cancer progression, driven by mutations in oncogenes and tumor-suppressor genes, result in biological differences between normal and cancer cells in various cellular processes. Specific genes and signaling molecules involved in such cellular processes may be potential therapeutic targets of agents that specifically interact with the key factors in cancer cells. Increased glucose uptake is fundamental to many solid tumors and well associated with increases in glycolysis and the overexpression of glucose transporters (GLUTs) such as GLUT1 and GLUT3 at the plasma membrane. Here, we used cell-based screening to identify glycogen synthase kinase-3β (GSK-3β) inhibitors that selectively target GLUT3-expressing tumorigenic HeLa cell hybrids as compared with non-tumorigenic hybrids that express GLUT1 alone. The GSK-3 inhibitors as well as GSK-3β RNAi suppressed GLUT3 expression at the level of transcription, leading to apoptosis. This suppression was associated with NF-κB in a p53-independent manner. Furthermore, GSK-3 inhibitors exhibited a synergistic effect with anticancer agents such as adriamycin and camptothecin in GULT3-overexpressing colon cancer cells, but little effect in non-producing A431 cells. These results suggest a potential use of GSK-3 inhibitors to selectively kill cancer cells that overexpress GLUT3.
PMCID: PMC3412655  PMID: 23552737
glucose metabolism; glucose transporter; glycogen synthase kinase-3; NF-κB
14.  Superinfection of cytoplasmic incompatibility-inducing Wolbachia is not additive in Orius strigicollis (Hemiptera: Anthocoridae) 
Heredity  2010;106(4):642-648.
Cytoplasmic incompatibility (CI) allows the intracellular, maternally inherited bacterial symbiont Wolbachia to invade arthropod host populations by inducing infertility in crosses between infected males and uninfected females. The general pattern is consistent with a model of sperm modification, rescued only by egg cytoplasm infected with the same strain of symbiont. The predacious flower bug Orius strigicollis is superinfected with two strains of Wolbachia, wOus1 and wOus2. Typically, superinfections of CI Wolbachia are additive in their effects; superinfected males are incompatible with uninfected and singly infected females. In this study, we created an uninfected line, and lines singly infected with wOus1 and wOus2 by antibiotic treatment. Then, all possible crosses were conducted among the four lines. The results indicated that while wOus2 induces high levels of CI, wOus1 induces very weak or no CI, but can rescue CI caused by wOus2 to a limited extent. Levels of incompatibility in crosses with superinfected males did not show the expected pattern. In particular, superinfected males caused extremely weak CI when mated with either singly infected or uninfected females. An analysis of symbiont densities showed that wOus1 densities were significantly higher than wOus2 densities in superinfected males, and wOus2 densities were lower, but not significantly, in superinfected relative to singly infected males. These data lend qualified support for the hypothesis that wOus1 interferes with the ability of wOus2 to cause CI by suppressing wOus2 densities. To our knowledge, this is the first clear case of non-additive CI in a natural superinfection.
PMCID: PMC3183903  PMID: 20700141
reproductive parasites; unidirectional cytoplasmic incompatibility; bidirectional cytoplasmic incompatibility; multiple infections; predacious flower bug
15.  Use of the triaxial microcatheter method in super-selective transcatheter arterial chemoembolisation for hepatocellular carcinoma 
The British Journal of Radiology  2011;84(998):184-187.
Transcatheter arterial chemoembolisation (TACE) has been widely used for inoperable hepatocellular carcinoma (HCC). Super-selective TACE is preferable to non-selective therapy, because it maximises the impact of treatment on the tumour while minimising damage to tumour-free liver parenchyma. It is therefore important to advance the catheter tip as close as possible in the feeding artery. There is now a new microcatheter with a 1.9-Fr tip with no taper, which can be inserted into a 2.7-Fr microcatheter. In this study we describe the new technique of using the two microcatheters called the triaxial microcatheter method.
We evaluated 30 TACE procedures to investigate whether or not the catheter tip could be advanced closer to HCC with the triaxial microcatheter method than with previous TACE using a conventional microcatheter.
With conventional microcatheters, the level of embolisation was a lobar artery in 4 cases, segmental in 8 cases, subsegmental in 15 cases and sub-subsegmental in only 1 case. TACE could not be performed in two cases. When using the triaxial microcatheter method the level of embolisation was subsegmental in 8 cases, including 2 in which the level was the same as that with a conventional microcatheter, sub-subsegmental in 13 cases and more distal in 7 cases. In the two cases in which TACE could not be performed with the conventional microcatheter, it could be performed sufficiently using the new method. As a whole, in 28 of the 30 procedures (93%) we could successfully advance a catheter tip closer than with the previous TACE.
The triaxial microcatheter method appears to be useful.
PMCID: PMC3473862  PMID: 21257838
16.  Amnesia in Frontotemporal Dementia with Amyotrophic Lateral Sclerosis, Masquerading Alzheimer's Disease 
Case Reports in Neurology  2011;3(3):242-247.
A 68-year-old man with a clinical diagnosis of Alzheimer's disease (AD) later developed amyotrophic lateral sclerosis (ALS), which was confirmed at autopsy at age 72 years. Because neuronal loss and AD-type pathologies (Braak stage II for neurofibrillary tangles) were scant, TDP-43-positive intracytoplasmic inclusions in hippocampal dentate granular cells and in neurons in the subiculum and amygdala, even though small in amount, may represent the earliest lesions of ALS-related dementia and could be the cause of dementia in this patient. Although the persistent elevation of creatine kinase from the onset could be a pointer to the presence of motor involvement, more accurate characterization of dementia, which may differentiate ALS-related dementia and AD, is necessary.
PMCID: PMC3224521  PMID: 22125525
Amyotrophic lateral sclerosis; Dementia; Alzheimer's disease; Creatine kinase
17.  A quantitative study of neuronal nitric oxide synthase expression in laminae I–III of the rat spinal dorsal horn 
Neuroscience  2011;192(6-2):708-720.
Nitric oxide produced by neuronal nitric oxide synthase (nNOS) in the spinal cord is required for development of hyperalgesia in inflammatory and neuropathic pain states. nNOS is expressed by some dorsal horn neurons, and an early study that used a histochemical method to identify these cells suggested that they were mainly inhibitory interneurons. We have carried out a quantitative analysis of nNOS-immunoreactivity in laminae I–III of the rat dorsal horn, to determine the proportion of inhibitory and excitatory neurons and axonal boutons that express the protein. nNOS was present in ∼5% of neurons in laminae I and III, and 18% of those in lamina II. Although most cells with strong nNOS immunostaining were GABA-immunoreactive, two-thirds of the nNOS-positive cells in lamina II and half of those in lamina III were not GABAergic, and some of these expressed protein kinase Cγ (PKCγ). We estimate that nNOS is present in 17–19% of the inhibitory interneurons in laminae I–II, and 6% of those in lamina III. However, our results suggest that nNOS is also expressed at a relatively low level by a significant proportion (∼17%) of excitatory interneurons in lamina II. nNOS was seldom seen in boutons that contained vesicular glutamate transporter 2, which is expressed by excitatory interneurons, but was co-localised with the vesicular GABA transporter (VGAT, a marker for GABAergic and glycinergic axons). nNOS was detected in 13% of VGAT boutons in lamina I and in 7–8% of those in laminae II–III. However, it was only found in 2–4% of the VGAT boutons that were presynaptic to PKCγ-expressing interneurons in this region. These results indicate that nNOS is more widely expressed than previously thought, being present in both inhibitory and excitatory neurons. They provide further evidence that axons of neurochemically defined populations of inhibitory interneuron are selective in their post-synaptic targets.
▶nNOS is expressed by nearly 20% of neurons in lamina II and 5% of those in laminae I and III. ▶The majority of nNOS neurons in laminae II and III are not GABAergic. ▶Between 7 and 13% of GABAergic boutons in laminae I–III are nNOS-immunoreactive. ▶nNOS axons form few synapses with PKCγ+ excitatory interneurons.
PMCID: PMC3183229  PMID: 21763759
nNOS; GABA; PKCγ; inhibitory interneurons; confocal microscopy; cGMP, cyclic guanosine monophosphate; GAD67, 67 kDa molecular weight isoform of glutamic acid decarboxylase; GFP, green fluorescent protein; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NK1r, neurokinin 1 receptor; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NPY, neuropeptide Y; PKCγ, protein kinase Cγ; sGC, soluble guanylate cyclase; VGAT, vesicular GABA transporter; VGLUT2, vesicular glutamate transporter 2
18.  MOP Reduction During Long-Term Methamphetamine Withdrawal was Restored by Chronic Post-Treatment with Fluoxetine 
Current Neuropharmacology  2011;9(1):73-78.
Previously, we found fluoxetine reduces methamphetamine preference in mice. However, effects of fluoxetine on developed methamphetamine preference and on methamphetamine induced gene expression changes have been largely unknown. The present study investigates effects of post-treatment with fluoxetine on methamphetamine dependence and on gene expressions after long-term withdrawal in mice. First, we examined whether chronic post-treatment with fluoxetine attenuated methamphetamine-conditioned place preference. Next, we examined the changes in gene expression levels after long-term withdrawal (with saline or fluoxetine treatment) following chronic methamphetamine treatment. Using mRNA from the pooled frontal cortices of 10 mice per group, gene expression analyses were performed using a custom-developed cDNA array and a real-time quantitative reverse transcription-PCR. Chronic post-treatments with fluoxetine abolished the conditioned place preference developed by methamphetamine administrations. Even after long-term withdrawal from repeated methamphetamine administration, µ-opioid receptor (MOP) gene expression was significantly reduced in the frontal cortex. The reduced MOP gene expression in the frontal cortex was restored by chronic administration with fluoxetine. These changes were confirmed by Western blot analyses. These findings suggest that the chronic post-treatments with fluoxetine might be effective for restoring the reduction of MOP levels in the frontal cortex following long-term abstinence from methamphetamine.
PMCID: PMC3137205  PMID: 21886566
Methamphetamine; conditioned place preference; gene expression; withdrawal; fluoxetine; mu-opioid receptor; frontal cortex; mice.
19.  Inverse correlation of HER2 with MHC class I expression on oesophageal squamous cell carcinoma 
British Journal of Cancer  2010;103(4):552-559.
As HER2 is expressed in 30% of oesophageal squamous cell carcinomas (ESCCs), T-cell-based immunotherapy and monoclonal antibodies targeted against HER2 are attractive, novel approaches for ESCCs. However, it was shown that there is an inverse correlation between HER2 and MHC class I expression on tumours. Thus, the correlation between HER2 and MHC class I expressions on ESCC was evaluated.
Expressions of MHC class I and HER2 in ESCC tissues (n=80) and cell lines were assessed by immunohistochemistry, fluorescence in situ hybridisation (FISH), and flow cytometry. We investigated whether HER2 downregulation with small interfering RNA (siRNA) in ESCC cell lines could upregulate the expression of MHC class I and the antigen presentation machinery components, and could increase their sensitivity for tumour antigen-specific CTLs.
There was an inverse correlation between HER2 and MHC class I expressions in both tumour tissues and cell lines. Downregulation of HER2 with siRNA resulted in the upregulation of MHC class I expression, leading to increased CTL recognition by tumour antigen-specific CTLs.
HER2-overexpressing ESCC tumour cells showed a reduced sensitivity for CTLs through the downregulation of MHC class I.
PMCID: PMC2939777  PMID: 20628381
MHC class I; oesophageal cancer; HER-2; CTL
20.  Optical pacing of the embryonic heart 
Nature photonics  2010;4:623-626.
Light has been used to noninvasively alter the excitability of both neural and cardiac tissue 1–10. Recently, pulsed laser light has been shown to be capable of eliciting action potentials in peripheral nerves and in cultured cardiomyocytes 7–10. Here, we demonstrate for the first time optical pacing (OP) of an intact heart in vivo. Pulsed 1.875 μm infrared laser light was employed to lock the heart rate to the pulse frequency of the laser. A laser Doppler velocimetry (LDV) signal was used to verify the pacing. At low radiant exposures, embryonic quail hearts were reliably paced in vivo without detectable damage to the tissue, indicating that OP has great potential as a tool to study embryonic cardiac dynamics and development. In particular, OP can be utilized to control the heart rate, and thereby alter stresses and mechanically transduced signaling.
PMCID: PMC3059323  PMID: 21423854
21.  Interleukin-21 can efficiently restore impaired antibody-dependent cell-mediated cytotoxicity in patients with oesophageal squamous cell carcinoma 
British Journal of Cancer  2009;102(3):520-529.
We previously reported that Trastuzumab- and Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) in cancer patients was impaired in comparison with that in healthy donors because of NK-cell dysfunction. In this study, we evaluated whether IL-21 could improve the impairment of ADCC in patients with oesophageal squamous cell carcinoma (ESCC), as IL-21 was reported to have the ability to activate NK cells.
We examined Trastuzumab- and Cetuximab-mediated ADCC of peripheral blood mononuclear cells (PBMCs) or of enriched NK cells derived from ESCC patients (n=20) and healthy donors (n=16) in the presence of IL-21. We further analysed ADCC-related molecules (perforin, granzyme-B, and CD247) on NK cells in response to IL-21.
Trastuzumab- and Cetuximab-mediated ADCC of PBMCs or of enriched NK cells was enhanced by the addition of IL-21 in a dose-dependent manner and the levels of ADCC enhanced by IL-21 in patients were high enough in comparison with those in healthy donors, paralleling the upregulation of CD247 on NK cells.
IL-21 could efficiently restore impaired ADCC in ESCC patients with the upregulation of CD247 molecules.
PMCID: PMC2822939  PMID: 20029417
IL-21; ADCC; Trastuzumab; Cetuximab
22.  High Ki67, Bax, and thymidylate synthase expression well correlates with response to chemoradiation therapy in locally advanced rectal cancers: proposal of a logistic model for prediction 
British Journal of Cancer  2009;101(1):116-123.
Recently, preoperative chemoradiation therapy (CRT) for rectal cancer has been increasingly used as a neoadjuvant treatment. In the present study, the relation between histological response to CRT and immunohistochemical markers in biopsy specimens was investigated.
Biopsy specimens from a total of 60 patients were collected before preoperative CRT with S-1 and irinotecan, and liniac 45 Gy. Immunohistochemical staining for Ki67, Mcm3, Bax, Bcl-2, ssDNA, Grp78, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), CD34, vascular endothelial growth factor, nestin, and L-type amino-acid transporter 1 was performed to allow comparison of the Ki67 labelling index (LI), Bax score, TS score, DPD score, microvessel density by CD34, and Grp78 score with cancer regression.
When the cases were divided into responders (Dworak grades 3 and 4) and non-responders (grades 1 and 2) groups, good correlations were evident with Ki67 LI, Bax, Grp78, and TS expression. On multiple logistic regression analysis, Ki67 LI, Bax, and TS scores were found to be independent factors. With their use in a logistic model, P-values could predict responder cases with a sensitivity of 82.8% and a specificity of 83.9%.
Using this system, treatment strategy for locally advanced rectal cancers can be determined before chemoradiation.
PMCID: PMC2713712  PMID: 19491899
Ki67; Bax; thymidylate synthase; chemoradiation; rectal cancer
23.  The role of caveolin-1 in prostate cancer: clinical implications 
Caveolin-1 (cav-1) is reportedly overexpressed in prostate cancer cells and is associated with disease progression. Specific oncogenic activities of cav-1 associated with Akt activation also occur in prostate cancer. A membrane-associated protein, cav-1, is nonetheless secreted by prostate cancer cells; results of recent studies showed that secreted cav-1 can stimulate cell survival and angiogenic activities, defining a role for cav-1 in the prostate cancer microenvironment. Serum cav-1 levels were also higher in prostate cancer patients than in control men without prostate cancer, and the preoperative serum cav-1 concentration had prognostic potential in men undergoing radical prostatectomy. Secreted cav-1 is therefore a potential biomarker and therapeutic target for prostate cancer.
PMCID: PMC2887695  PMID: 19581923
caveolin-1; progression; angiogenesis; biomarkers
24.  Detection of enterotoxin genes of Staphylococcus SP isolated from nasal cavities and hands of food handlers 
Food handlers, an important factor in food quality, may contain bacteria that are able to cause foodborne disease. The present study aimed to research coagulase-negative (CNS) and -positive staphylococci (CPS) in 82 food handlers, analyzing nasal and hand swabs, with identification of 62 CNS (75.6%) and 20 CPS strains (24.4%). Staphylococcal enterotoxins genes were investigated by PCR. In 20 CPS strains, 19 were positive for one or more genes. The percentage of CNS presenting genes for enterotoxins was high (46.8%). Despite of the staphylococcal species, the most common gene was sea (35.4%), followed by seh and sej (29.2%). The detection of new staphylococcal enterotoxins (SEs) genes showed a higher pathogenic potential in this genus. The presence of these gene points out the importance of CNS not only as contaminant bacteria but also as a pathogen.
PMCID: PMC3768627  PMID: 24031464
Staphylococcal enterotoxins; coagulase-negative staphylococci; S. aureus; food handler
25.  Mental–physical co-morbidity and its relationship with disability: results from the World Mental Health Surveys 
Psychological medicine  2008;39(1):33-43.
The relationship between mental and physical disorders is well established, but there is less consensus as to the nature of their joint association with disability, in part because additive and interactive models of co-morbidity have not always been clearly differentiated in prior research.
Eighteen general population surveys were carried out among adults as part of the World Mental Health (WMH) Survey Initiative (n=42 697). DSM-IV disorders were assessed using face-to-face interviews with the Composite International Diagnostic Interview (CIDI 3.0). Chronic physical conditions (arthritis, heart disease, respiratory disease, chronic back/neck pain, chronic headache, and diabetes) were ascertained using a standard checklist. Severe disability was defined as on or above the 90th percentile of the WMH version of the World Health Organization Disability Assessment Schedule (WHODAS-II).
The odds of severe disability among those with both mental disorder and each of the physical conditions (with the exception of heart disease) were significantly greater than the sum of the odds of the single conditions. The evidence for synergy was model dependent: it was observed in the additive interaction models but not in models assessing multiplicative interactions. Mental disorders were more likely to be associated with severe disability than were the chronic physical conditions.
This first cross-national study of the joint effect of mental and physical conditions on the probability of severe disability finds that co-morbidity exerts modest synergistic effects. Clinicians need to accord both mental and physical conditions equal priority, in order for co-morbidity to be adequately managed and disability reduced.
PMCID: PMC2637813  PMID: 18366819
Co-morbidity; disability; interaction; mental; physical

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