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1.  Feasibility trial for adjuvant chemotherapy with docetaxel plus cisplatin followed by single agent long-term administration of S-1 chemotherapy in patients with completely resected non-small cell lung cancer: Thoracic Oncology Research Group Study 0809 
British Journal of Cancer  2013;109(3):545-551.
Background:
We conducted a multicentre feasibility study for single agent long-term S-1 chemotherapy following docetaxel plus cisplatin in patients with curatively resected stage II–IIIA non-small cell lung cancer.
Methods:
Patients received three cycles of docetaxel (60 mg m−2) plus cisplatin (80 mg m−2) and then received S-1 (40 mg m−2 twice daily) for 14 consecutive days with a 1-week rest for >6 months (maximum, 1 year). The primary end point was feasibility, which was defined as the proportion of patients who completed eight or more cycles of S-1 chemotherapy. If the lower 95% confidence interval (CI) of this proportion was 50% or more, then the treatment was considered as feasible. The sample size was set at 125 patients.
Results:
One hundred and thirty-one patients were enrolled, of whom 129 patients were eligible and assessable. In all, 109 patients (84.5%) completed 3 cycles of docetaxel plus cisplatin and 66 patients (51.2%, 95% CI: 42.5–59.8) completed 8 or more cycles of S-1 treatment. Grade 3/4 toxicities during the S-1 chemotherapy included anaemia (7.3%), neutropaenia (3.7%), and anorexia (3.7%).
Conclusion:
The toxicity level was acceptable, although the results did not meet our criterion for feasibility. Modification of the treatment schedule for S-1 chemotherapy might improve the treatment compliance.
doi:10.1038/bjc.2013.378
PMCID: PMC3738148  PMID: 23868010
S-1; long-term; adjuvant chemotherapy; non-small cell lung cancer
3.  Clinical evaluation of the additive effect of diquafosol tetrasodium on sodium hyaluronate monotherapy in patients with dry eye syndrome: a prospective, randomized, multicenter study 
Eye  2012;26(10):1363-1368.
Purpose
To assess the additive effect of diquafosol tetrasodium on sodium hyaluronate monotherapy in patients with dry eye syndrome.
Methods
This study evaluated 64 eyes of 32 patients (age: 62.6±12.8 years (mean±SD)) in whom treatment with 0.1% sodium hyaluronate was insufficiently responsive. The eyes were randomly assigned to one of the two regimens in each patient: topical administration of sodium hyaluronate and diquafosol tetrasodium in one eye, and that of sodium hyaluronate in the other. Before treatment, and 2 and 4 weeks after treatment, we determined tear volume, tear film break-up time (BUT), fluorescein and rose bengal vital staining scores, subjective symptoms, and adverse events.
Results
We found a significant improvement in BUT (P=0.049, Dunnett test), fluorescein and rose bengal staining scores (P=0.02), and in subjective symptoms (P=0.004 for dry eye sensation, P=0.02 for pain, and P=0.02 for foreign body sensation) 4 weeks after treatment in the diquafosol eyes. On the other hand, we found no significant change in these parameters after treatment in the control eyes.
Conclusions
In dry eyes, where sodium hyaluronate monotherapy was insufficient, diquafosol tetrasodium was effective in improving objective and subjective symptoms, suggesting its viability as an option for the additive treatment of such eyes.
doi:10.1038/eye.2012.166
PMCID: PMC3470059  PMID: 22878452
diquafosol tetrasodium; P2Y2 receptor antagonist; sodium hyaluronate; dry eye syndrome
5.  Prognostic significance of L-type amino-acid transporter 1 expression in surgically resected pancreatic cancer 
British Journal of Cancer  2012;107(4):632-638.
Background:
The expression of Ltype amino-acid transporter 1 (LAT1) is tumour-specific and has been shown to have essential roles in cell growth and survival. However, little is known regarding the clinical significance of LAT1 expression in pancreatic cancer. This study was conducted to determine the prognostic significance of LAT1 expression.
Methods:
A total of 97 consecutive patients with surgically resected pathological stage I–IV pancreatic ductal adenocarcinoma were retrospectively reviewed. Tumour sections were stained by immunohistochemistry for LAT1, CD98, Ki-67 and vascular endothelial growth factor (VEGF), and microvessel density was determined by CD34 and p53.
Results:
L-type amino-acid transporter 1 and CD98 were highly expressed in 52.6% (51/97) and 56.7% (55/97) of cases, respectively (P=0.568). The expression of LAT1 within pancreatic cancer cells was significantly associated with disease stage, tumour size, Ki-67, VEGF, CD34, p53 and CD98. Ltype amino-acid transporter 1 expression was confirmed to be a significant prognostic factor for predicting poor outcome by multivariate analysis.
Conclusion:
Ltype amino-acid transporter 1 expression is a promising pathological marker for the prediction of outcome in patients with pancreatic cancer.
doi:10.1038/bjc.2012.310
PMCID: PMC3419959  PMID: 22805328
LAT1; CD98; pancreatic cancer; amino-acid transporter; prognostic factor; Ki-67
6.  CLINICOPATHOLOGICAL AND THERAPEUTIC SIGNIFICANCE OF CXCL12 EXPRESSION IN LUNG CANCER 
Interactions between CXCL12 and its receptors CXCR4 or CXCR7 are involved in tumor growth and metastasis in various types of human cancer. However, CXCL12 expression and its role in lung cancer are not fully elucidated. Here we examined the expression of CXCL12 in 54 lung cancer cell lines consisting of 23 small cell lung cancers (SCLCs) and 31 non-small cell lung cancers (NSCLCs). CXCL12 was overexpressed in lung cancer cell lines compared to non-malignant human bronchial epithelial cell lines (N = 6). CXCL12 expression was positively but weakly correlated with the expression of CXCR4 or CXCR7. We also examined CXCL12 expression in 89 NSCLC specimens and found that CXCL12 expression was significantly higher in tumor specimens from female patients, non-smokers and adenocarcinoma patients. Small interfering RNAs targeting CXCL12 inhibited cellular proliferation, colony formation and migration of CXCL12-overexpressing lung cancer cells; however, this inhibition did not occur in lung cancer cells that lacked CXCL12. Furthermore, the anti-CXCL12 neutralizing antibody mediated inhibitory effects in three lung cancer cell lines that overexpressed CXCL12, but not in two CXCL12 non-expressing lung cancer cell lines nor two non-malignant bronchial epithelial cell lines. The present study demonstrates that: CXCL12 is concomitantly overexpressed with CXCR4 or CXCR7 in lung cancers; CXCL12 is highly expressed in NSCLCs from females, non-smokers and adenocarcinoma patients; and disruption of CXCL12 inhibits the growth and migration of lung cancer cells. Our findings indicate that CXCL12 is required for tumor growth and provide a rationale for the anti-CXCL12 treatment strategy in lung cancer.
PMCID: PMC3368436  PMID: 20378003
CXCL12; CXCR4; CXCR7; overexpression; lung cancer
7.  EMX2 is epigenetically silenced and suppresses growth in human lung cancer 
Oncogene  2010;29(44):5969-5975.
Lung cancer is a common cancer and the leading cause of cancer-related death worldwide. Aberrant activation of WNT signaling is implicated in lung carcinogenesis. EMX2, a human homologue of the Drosophila empty spiracles gene is a homeodomain-containing transcription factor. The function of EMX2 has been linked to the WNT signaling pathway during embryonic patterning in mice. However, little is known about the role of EMX2 in human tumorigenesis. In this study, we found that EMX2 was dramatically downregulated in lung cancer tissue samples and this downregulation was associated with methylation of the EMX2 promoter. Restoration of EMX2 expression in lung cancer cells lacking endogenous EMX2 expression suppressed cell proliferation and invasive phenotypes, inhibited canonical WNT signaling, and sensitized lung cancer cells to the treatment of the chemo cytotoxic drug cisplatin. On the other hand, knockdown of EMX2 expression in lung cancer cells expressing endogenous EMX2 promoted cell proliferation, invasive phenotypes and canonical WNT signaling. Taken together, our study suggests that EMX2 may have important roles as a novel suppressor in human lung cancer.
doi:10.1038/onc.2010.330
PMCID: PMC3090446  PMID: 20697358
EMX2; methylation; lung cancer; WNT signaling; tumor suppression
8.  Inhibitory effect of a TGFβ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells 
British Journal of Cancer  2010;102(5):844-851.
Background:
Gastric cancer cells frequently metastasise, partly because of their highly invasive nature. Transforming growth factor-β (TGF-β) receptor signalling is closely associated with the invasion of cancer cells. The aim of this study was to clarify the effect of a TGF-β receptor (TβR) phosphorylation inhibitor on the invasiveness of gastric cancer cells.
Methods:
Four gastric cancer cell lines, including two scirrhous-type cell lines and two non-scirrhous-type cell lines, were used. A TβR type I (TβR-I) kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at an ATP-binding site of TβR-I. We investigated the expression levels of TβR and phospho-Smad2, and the effects of TGF-β in the presence or absence of Ki26894 on Smad2 phosphorylation, invasion, migration, epithelial-to-mesenchymal transition (EMT), Ras homologue gene family member A (RhoA), ZO-2, myosin, and E-cadherin expression of gastric cancer cells.
Results:
TβR-I, TβR-II, and phospho-Smad2 expressions were found in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. Ki26894 decreased Smad2 phosphorylation induced by TGF-β1 in scirrhous gastric cancer cells. Transforming growth factor-β1 upregulated the invasion, migration, and EMT ability of scirrhous gastric cancer cells. Transforming growth factor-β1 significantly upregulated the activity of RhoA and myosin phosphorylation, whereas TGF-β1 decreased ZO-2 and E-cadherin expression in scirrhous gastric cancer cells. Interestingly, Ki26894 inhibited these characteristics in scirrhous gastric cancer cells. In contrast, non-scirrhous gastric cancer cells were not affected by TGF-β1 or Ki26894 treatment.
Conclusion:
A TβR-I kinase inhibitor decreases the invasiveness and EMT of scirrhous gastric cancer cells. Ki26894 is therefore considered to be a promising therapeutic compound for the metastasis of scirrhous gastric carcinoma.
doi:10.1038/sj.bjc.6605561
PMCID: PMC2833252  PMID: 20145621
scirrhous gastric cancer; TGF-β; epithelial-to-mesenchymal transition; Smad2; phosphorylation inhibitor
9.  Characterization of a caspase-3-substrate kinome using an N- and C-terminally tagged protein kinase library produced by a cell-free system 
Cell Death & Disease  2010;1(10):e89-.
Caspase-3 (CASP3) cleaves many proteins including protein kinases (PKs). Understanding the relationship(s) between CASP3 and its PK substrates is necessary to delineate the apoptosis signaling cascades that are controlled by CASP3 activity. We report herein the characterization of a CASP3-substrate kinome using a simple cell-free system to synthesize a library that contained 304 PKs tagged at their N- and C-termini (NCtagged PKs) and a luminescence assay to report CASP3 cleavage events. Forty-three PKs, including 30 newly identified PKs, were found to be CASP3 substrates, and 28 cleavage sites in 23 PKs were determined. Interestingly, 16 out of the 23 PKs have cleavage sites within 60 residues of their N- or C-termini. Furthermore, 29 of the PKs were cleaved in apoptotic cells, including five that were cleaved near their termini in vitro. In total, approximately 14% of the PKs tested were CASP3 substrates, suggesting that CASP3 cleavage of PKs may be a signature event in apoptotic-signaling cascades. This proteolytic assay method would identify other protease substrates.
doi:10.1038/cddis.2010.65
PMCID: PMC3035903  PMID: 21368862
caspase; protein kinases; apoptosis; cell-free protein synthesis; protein library
10.  Microinjection of IL-1β into the trigeminal transition zone produces bilateral NMDA receptor-dependent orofacial hyperalgesia involving descending circuitry 
The open pain journal  2009;2:76-83.
Our recent studies indicate that the prototypic proinflammatory cytokine IL-1β is upregulated in astroglial cells in the trigeminal interplolaris/caudalis (Vi/Vc) transition zone, a region of the spinal trigeminal complex involved in trigeminal pain processing, after masseter muscle inflammation. Here we investigated the effect of microinjection of IL-1β into the Vi/Vc transition zone on orofacial nociception. The mechanical sensitivity of the orofacial site was assessed with von Frey microfilaments. The EF50 values, defined as the von Frey filament force (g) that produces a 50% response frequency, were derived and used as a measure of mechanical sensitivity. A significant reduction in EF50 indicates the occurrence of mechanical hyperalgesia/allodynia. Unilateral intra-Vi/Vc IL-1β (0.016–160 fmol) produced hyperalgesia/allodynia dose-dependently, which appeared at bilateral facial sites. The hyperalgesia was detectable as early as 30 min and lasted for 2–6 h (n=6, p<0.01). Intra-Vi/Vc pretreatment with an IL-1receptor antagonist (1 nmol) attenuated the IL-1β-induced hyperalgesia (p<0.01). Pre-injection of AP-5 (10 pmol) and MK-801 (20 pmol), two NMDA receptor antagonists, significantly attenuated IL-1β-induced hyperalgesia (p<0.05). Pretreatment with glial inhibitors fluorocitrate (120 pmol), minocycline (200 pmol) and propentofylline (10 pmol) did not attenuate IL-1β-induced hyperalgesia. Excitotoxic lesions of the rostral ventromedial medulla with ibotenic acid (2 μg) abolished IL-1β-induced contralateral hyperalgesia, suggesting a contribution of descending facilitatory drive. These results suggest that the IL-1β-produced effect on nociception was downstream to glial activation and involves interaction with NMDA receptors.
doi:10.2174/1876386300902010076
PMCID: PMC2835306  PMID: 20221418
spinal trigeminal complex; Vi/Vc; NMDA receptor antagonists; inflammatory cytokine; glial inhibitors; rat
11.  Oesophageal squamous cell carcinoma may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa 
Gut  2006;56(1):13-19.
Background
Oesophageal squamous cell carcinoma (OSCC) often arises from preceding dysplastic lesions in the oesophageal epithelium. However, the molecular changes occurring in premalignant lesions are not well understood. An epigenetic change is an example of OSCC that may occur within the epithelium.
Aim
To investigate the methylation status of multiple promoters in cancer‐derived DNA, as well as in the background epithelium of OSCC, including dysplastic lesions and non‐neoplastic mucosa. The normal epithelium from patients without cancer was also examined. The findings were correlated with the mutational status of p53.
Patients and methods
56 patients with advanced OSCC, 21 patients with intraepithelial neoplasia (IEN), 56 patients with a background of non‐neoplastic epithelium, adjacent to the OSCC, and 42 normal control epithelia from healthy volunteers were studied. The promoter methylation status of SFRP1, SFRP2, DCC, APC, p16INK4a, p14ARF, MINT1, MINT2, MINT31, CACNA1G, COX2, DAPK, hMLH1 and MGMT was examined by methylation‐specific single polymerase chain reaction or combined bisulphite restriction analysis. The mutation of p53 by direct sequencing was assessed.
Results
DNA methylation was observed in OSCC and in its background epithelium. The frequency of CpG island methylation increased from a baseline level in the background non‐neoplastic epithelium, through IEN, to advanced OSCC. However, mutations in p53 were almost exclusively observed in IEN and OSCC. More extensive DNA methylation was seen in the neoplastic lesions (OSCC or IEN) having a p53 mutation than in those with wild‐type p53.
Conclusion
DNA methylation is present at low levels in the non‐neoplastic oesophageal epithelium and appears to contribute to the progression of the dysplasia–carcinoma sequence in OSCC carcinogenesis.
doi:10.1136/gut.2005.089813
PMCID: PMC1856655  PMID: 16785283
12.  Actions anchored by concepts: defective action comprehension in semantic dementia 
Objective
To study the ability of patients with semantic dementia to understand actions, in order to examine the contribution of semantic memory to action comprehension.
Methods
The ability to comprehend symbolic and instrumental actions was assessed in 6 patients with semantic dementia and 10 healthy controls. The patients were also given the imitation test of meaningful and meaningless actions.
Results
In all patients with semantic dementia, comprehension of both symbolic and instrumental actions was defective. The comprehension of symbolic actions was more impaired than that of instrumental actions. Their ability to imitate other's actions was well preserved.
Conclusion
This study showed that comprehension of action was impaired in semantic dementia, suggesting that semantic memory has an important role in comprehension of human action.
doi:10.1136/jnnp.2006.096297
PMCID: PMC2077425  PMID: 16891383
13.  MAGE-A protein and MAGE-A10 gene expressions in liver metastasis in patients with stomach cancer 
British Journal of Cancer  2008;99(2):350-356.
Tumour samples from 71 patients with stomach cancer, 41 patients with liver metastasis (group A) and 15 patients each in stages II–IV (group B) and stage I (group C) without liver metastasis were analysed. MAGE-A protein expression was evaluated by immunohistochemistry using a 6C1 monoclonal antibody and MAGE-A10 mRNA expression was detected by highly sensitive in situ hybridisation using a cRNA probe. Expressions of MAGE-A protein and MAGE-A10 mRNA in group A were detected in 65.9 and 80.5%, respectively. Both protein and gene showed significantly higher expression in group A than those in groups B (6.7, 26.7%) and C (0, 0%) (P=0.0003, P=<0.0001, respectively). MAGE-A10 mRNA expression in liver metastasis was found in eight (88.9%) out of nine patients. The concordant rate between MAGE-A family protein expression and MAGE-A10 mRNA expression in the primary sites was 81.7% (P<0.0001). MAGE-A10 gene expression was associated with reduced survival duration. The results of this study suggest that MAGE-A10 is a possible target in active immunotherapy for advanced stomach cancer.
doi:10.1038/sj.bjc.6604476
PMCID: PMC2480964  PMID: 18594524
MAGE-A protein; MAGE-A10 mRNA; highly sensitive in situ hybridisation; stomach cancer; liver metastasis; active immunotherapy
14.  Prognostic significance of CDC25B expression in gliomas 
Journal of Clinical Pathology  2006;59(7):725-728.
Background
CDC25B is a cell‐cycle regulatory protein, which is considered to be related to tumorigenesis and progression of tumours.
Aims
To elucidate the role of CDC25B in glioma, the expression of CDC25B and the association of the CDC25B expression with the clinicopathological parameters were investigated.
Methods
Fifty seven gliomas, which included 21 low‐grade astrocytomas, 17 anaplastic astrocytomas and 19 glioblastomas, were studied. Protein expressions of CDC25B were evaluated by immunohistochemical methods. Semiquantitative and real‐time RT‐PCR analyses for the expression of CDC25B mRNA were also carried out. Disease‐free survival (DFS) data were analysed by using the Kaplan–Meier method.
Results
High expression of CDC25B was identified in 18 of the 19 glioblastomas, in 10 of the 17 anaplastic astrocytomas, but not in any of the 21 low‐grade astrocytomas. The CDC25B mRNA expression increased with the rise in histological grade. Increased CDC25B expression was correlated significantly with a shorter period of DFS, as shown by multivariate analysis.
Conclusions
Patients with an unfavourable clinical outcome are characterised by the increased expression of CDC25B in their glioma samples. Useful clinical information, especially on its relevance as a prognostic indicator, is provided by the evaluation of CDC25B expression in gliomas.
doi:10.1136/jcp.2005.029546
PMCID: PMC1860415  PMID: 16803948
15.  Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I–III nonsmall cell lung cancer 
British Journal of Cancer  2008;98(4):742-748.
The clinical significance of L-type amino acid transporter 1 (LAT1) expression remains unclear, whereas many experimental studies have demonstrated that LAT1 is associated with the proliferation of cancer cells. The purpose of this study was to evaluate the prognostic value of LAT1 in patients with nonsmall cell lung cancer (NSCLC). A total of 321 consecutive patients with completely resected pathologic stage I–III NSCLC were retrospectively reviewed. Expression of LAT1 and proliferative activity, as determined by the Ki-67 labelling index, was also evaluated immunohistochemically and correlated with the prognosis of patients who underwent complete resection of the tumour. Expression of LAT1 was positive in 163 patients (51%) (29% of adenocaricnoma (58 of 200 patients), 91% of squamous cell carcinoma (91 of 100 patients), and 67% of large cell carcinoma (14 of 21 patients)). The 5-year survival rate of LAT1-positive patients (51.8%) was significantly worse than that of LAT1-negative patients (87.8%; P<0.001). L-type amino acid transporter 1 expression was significantly associated with lymph node metastasis and disease stage. Multivariate analysis confirmed that positive expression of LAT1 was an independent factor for predicting a poor prognosis. There was a significant correlation between LAT1 expression and Ki-67 labelling index. LAT1 expression is a promising pathological factor to predict the prognosis in patients with resectable stage I–III NSCLC.
doi:10.1038/sj.bjc.6604235
PMCID: PMC2259171  PMID: 18253116
LAT1; nonsmall cell lung cancer; amino acid transporter; prognostic factor; Ki-67
16.  NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel 
British Journal of Cancer  2005;92(7):1240-1246.
Paclitaxel (PTX) is one of the most effective anticancer agents. In clinical practice, however, high incidences of adverse reactions of the drug, for example, neurotoxicity, myelosuppression, and allergic reactions, have been reported. NK105, a micellar nanoparticle formulation, was developed to overcome these problems and to enhance the antitumour activity of PTX. Via the self-association process, PTX was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interactions between the drug and the well-designed block copolymers for PTX. NK105 was compared with free PTX with respect to their in vitro cytotoxicity, in vivo antitumour activity, pharmacokinetics, pharmacodynamics, and neurotoxicity. Consequently, the plasma area under the curve (AUC) values were approximately 90-fold higher for NK105 than for free PTX because the leakage of PTX from normal blood vessels was minimal and its capture by the reticuloendothelial system minimised. Thus, the tumour AUC value was 25-fold higher for NK105 than for free PTX. NK105 showed significantly potent antitumour activity on a human colorectal cancer cell line HT-29 xenograft as compared with PTX (P<0.001) because the enhanced accumulation of the drug in the tumour has occurred, probably followed by its effective and sustained release from micellar nanoparticles. Neurotoxicity was significantly weaker with NK105 than with free PTX. The neurotoxicity of PTX was attenuated by NK105, which was demonstrated by both histopathological (P<0.001) and physiological (P<0.05) methods for the first time. The present study suggests that NK105 warrants a clinical trial for patients with metastatic solid tumours.
doi:10.1038/sj.bjc.6602479
PMCID: PMC2361981  PMID: 15785749
NK105; paclitaxel; polymer micelles; DDS; EPR effect
17.  Procollagen II C propeptide level in the synovial fluid as a predictor of radiographic progression in early knee osteoarthritis 
Objective: To investigate the prognostic value of procollagen type II carboxy-terminal propeptide (PIICP) level in synovial fluid in relation to early tibiofemoral joint osteoarthritis (OA).
Methods: Data were collected on 172 women (age 40 to 59 years) who had knee pain and tibiofemoral joint OA in the early stage. Standing semiflexed knee radiographs were obtained by fluoroscopy at baseline and at four year follow up and a computerised, magnification corrected measurement system was applied to measurement of minimal joint space width in the tibiofemoral compartment. Synovial fluid sampling was performed at baseline and at the four year follow up. Levels of PIICP in the synovial fluid were measured by enzyme immunoassay. The outcome measures were assessed by radiographic joint space narrowing (JSN) in the tibiofemoral joints over four years. Multiple linear regression analyses were used to examine the relation between radiographic JSN and synovial fluid level of PIICP.
Results: The number of women available at both baseline and at four year follow up was 110. The average of radiographic JSN over four years was 0.53 mm (range 0.00-2.01). Body mass index showed a slightly positive association with baseline PIICP level. In multiple linear regression analyses adjusted for age and body mass index, radiographic JSN over four years had a direct positive correlation with baseline PIICP level (r=0.395; 95% confidence interval (95% CI) 0.231 to 0.529; p<0.001).
Conclusion: In a four year prospective study of women, quantification of synovial fluid PIICP was able to predict subsequent radiographic progression in early tibiofemoral joint OA.
doi:10.1136/ard.62.1.27
PMCID: PMC1754298  PMID: 12480665
18.  Plasma leptin levels and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome 
Thorax  2002;57(5):429-434.
Background: The control of body weight and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome (OSAHS) are important because both factors have significant effects on the mortality of these patients. It has recently been reported that OSAHS has a significant effect on the secretion of leptin, a hormone involved in the control of body weight and sympathetic nerve activity. In addition to the circadian rhythm of leptin secretion, the effects of one night of treatment with nasal continuous positive airway pressure (nCPAP) and the mechanism of the effects of nCPAP on nocturnal leptin secretion in patients with OSAHS has not yet been elucidated.
Methods: Blood samples were obtained at 21.00 hours, 00.00 hours, 03.00 hours, and 06.30 hours from 21 subjects with OSAHS (mean apnoea and hypopnoea index 52.4/h), with and without nCPAP treatment. Iodine-123 (I123)-meta-iodobenzylguanidine (MIBG) imaging was used to evaluate myocardial sympathetic function before nCPAP treatment.
Results: Plasma leptin reached a peak level at 00:00 hours (p<0.01) in patients with OSAHS, both with and without nCPAP treatment. The first night of nCPAP treatment significantly decreased the plasma leptin levels at 03.00 hours (without nCPAP: mean (SE) 21.6 (4.7) ng/ml; with nCPAP: 19.3 (4.1) ng/ml, p<0.02) and at 06.30 hours (without nCPAP: 17.6 (3.8) ng/ml; with nCPAP: 15.2 (3.2) ng/ml, p<0.01). The magnitude of the decrease in leptin levels after nCPAP treatment was significantly correlated with cardiac sympathetic function measured before nCPAP treatment (p<0.03).
Conclusions: Patients with OSAHS undergo nocturnal increases in leptin levels in spite of interruption of sleep due to apnoea and hypopnoea, a trend seen in normal subjects. Plasma leptin levels in patients with OSAHS decreased significantly after the first night of nCPAP treatment. Enhanced cardiac sympathetic function in these patients may contribute to the leptin levels before nCPAP treatment and vice versa.
doi:10.1136/thorax.57.5.429
PMCID: PMC1746321  PMID: 11978920
19.  Locoregional immunotherapy of malignant effusion from colorectal cancer using the streptococcal preparation OK-432 plus Interleukin-2 
British Journal of Cancer  2003;89(10):1876-1884.
doi:10.1038/sj.bjc.6601379
PMCID: PMC2394446  PMID: 14612896
OK-432; IL-2; malignant effusion; colorectal cancer; T-cell receptor (TCR); clonotypic PCR
20.  Spontaneous and cytokine regulated c-fos gene expression in rheumatoid synovial cells: resistance to cytokine stimulation when the c-fos gene is overexpressed 
Annals of the Rheumatic Diseases  2000;59(8):636-640.
OBJECTIVE—To study the effect of cytokines on the transactivation of the c-fos gene in relation to the contribution of overexpression of c-fos/AP-1 in rheumatoid joint destruction.
METHODS—The promoter region (−447 to +109) of the human c-fos gene was integrated upstream of the chloramphenicol acetyltransferase (CAT) reporter gene, and the effect of cytokines on the expression of the c-fos gene was studied in the rheumatoid synovial cells of early (3-4) or late (14-18) passages, in the presence or absence of cytokines, by the transient transfection assay.
RESULTS—Expression of c-fos gene was enhanced by tumour necrosis factor α (TNFα) and interleukin 6 (IL6) in the synovial cells of early passage, whereas it was not enhanced in the synovial cells of late passage. The c-fos gene expression was also enhanced by 13-O-tetradecanoyl phorbol-13-acetate (TPA) in early passage but was somewhat suppressed in the late passage. It was found that the c-fos gene and c-Fos protein were both increased in the synovial cells of late passage. Similarly, c-fos gene expression was also not increased by TPA or cytokine stimulation in the stable c-fos transformants (fos-pH8) or H-ras transformed NIH3T3 cells (NIH H-ras cells) that constitutively expressed c-fos genes.
CONCLUSIONS—Although TNFα and IL6 augmented c-fos gene expression of rheumatoid synovial cells, transactivation of c-fos gene became resistant against cytokine stimulation under prolonged expression of c-fos gene, which may impart a tumour-like characteristic to rheumatoid synovial cells.


doi:10.1136/ard.59.8.636
PMCID: PMC1753200  PMID: 10913062
22.  Preferential down-regulation of phospholipase C- β in Ewing's sarcoma cells transfected with antisense EWS-Fli-1 
British Journal of Cancer  1999;82(1):16-19.
EWS-Fli-1, a fusion gene found in Ewing's sarcoma and primitive neuro-ectodermal tumour (PNET), encodes a transcriptional activator and promotes cellular transformation. We have made stable Ewing's sarcoma cells expressing antisense EWS-Fli-1 transcripts by transfecting the antisense EWS-Fli-1 expression plasmid. These cells showed partial loss of endogenous EWS-Fli-1 proteins and suppression of the cell growth. To elucidate the molecular mechanisms underlying the growth inhibition, we examined the changes of signal transducing proteins by immunoblot analysis in Ewing's sarcoma cells stably expressing antisense EWS-Fli-1 transcripts. Western blotting of the cell proteins revealed that expressions of phospholipase Cβ2 and β3 (PLCβ2, PLCβ3), and also protein kinase C α and β (PKCα, β) were significantly reduced by transfecting with antisense EWS-Fli-1. The inositol phosphates production by bradykinin (BK), but not platelet-derived growth factor (PDGF), was suppressed in these cells. These results suggest that the PLCβ2 and PLCβ3 may play a role in tumour proliferation in Ewing's sarcoma cells. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.1998.0870
PMCID: PMC2363212  PMID: 10638960
phospholipase C; signal transduction; Ewing's sarcoma; antisense EWS-Fli-1; growth inhibition
23.  Monoclonal antibody ONS-M21 recognizes integrin α3 in gliomas and medulloblastomas 
British Journal of Cancer  1999;79(2):333-339.
The monoclonal antibody ONS-M21 recognizes an antigen found on the surface of glioma and medulloblastoma cells but does not react with the antigens of normal brain tissue. We purified and identified the 140-kDa protein by means of an antibody-binding affinity column. This 140-kDa antigen has sequences homologous to the amino-terminal region and five parts of the internal domain of integrin α3. When the integrin α3-related sequences was amplified and used to analyse the mRNA of glioma and medulloblastoma surgical specimens, the transcription level of integrin α3 mRNA appeared to be quantitatively correlated with the grade of malignancy. These findings suggest that the ONS-M21 antibody, which reacts with integrin α3, might be useful in the diagnosis of gliomas and medulloblastomas. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690053
PMCID: PMC2362207  PMID: 9888477
glioma; medulloblastoma; monoclonal antibody; integrin α3
24.  Systemic interleukin 12 displays anti-tumour activity in the mouse central nervous system. 
British Journal of Cancer  1998;78(4):446-453.
In various systemic cancers, interleukin 12 (IL-12) induces anti-tumour immunity mediated by T lymphocytes and natural killer cells. To determine whether IL-12 has anti-tumour activity against malignant gliomas in the central nervous system (CNS), which is considered to be an immunologically privileged site, we treated mice with meningeal gliomatosis by intraperitoneal (i.p.) or intrathecal (i.t.) administration of recombinant murine IL-12. Although untreated mice revealed symptoms, such as body weight loss or paraplegia as a result of the meningeal gliomatosis within 8 days after tumour inoculation, 80% of the mice treated with IL-12 at 0.5 microg i.p. were cured. Many lymphocytes, mostly CD4+ and CD8+ cells, infiltrated to the tumours of IL-12-treated mice. The numbers of these cells increased in the cervical lymph nodes, into which the cerebrospinal fluid drains, and there they secreted a considerable amount of interferon-gamma. Mice cured by IL-12 rejected subcutaneous or i.t. rechallenge with their original glioma cells, but the same mice were not able to reject other syngeneic tumour cells. These results indicate that the immune system recognizes malignant glioma cells in the subarachnoid space of the CNS and that systemic IL-12 may produce effective anti-tumour activity and long-lasting tumour-specific immunity.
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PMCID: PMC2063094  PMID: 9716025
25.  Regulation of interferon responses in medulloblastoma cells by interferon regulatory factor-1 and -2. 
British Journal of Cancer  1998;77(12):2081-2087.
Transcriptional activator interferon regulatory factor (IRF)-1 and repressor IRF-2 are known to play a critical role in the regulation of interferon (IFN) responses and oncogenesis in fibroblasts. Although these two factors are expressed in many tissues, including the brain, the role of IRFs in the central nervous system (CNS) has not been elucidated. We analysed a medulloblastoma cell line, ONS-76, as a CNS-derived model system and generated its derivatives, R1 and R2 cells, which constitutively expressed each mouse IRF-1 and IRF-2 cDNA at high levels. By viral infection, R1 and R2 cells showed IFN-beta gene expression 3 h earlier than the control ONS-76 (C-76) cells, with 2.46- and 2.24-fold increase in IFN-beta production respectively. In the presence of cycloheximide, virally induced IFN-beta gene expression of C-76 cells was suppressed, whereas R1 and R2 cells produced IFN-beta 7.5- and 2.2-fold higher than C-76 cells respectively. On the other hand, induction of IFN-inducible genes was enhanced in R1 cells but was suppressed in R2 cells compared with C-76 cells. These results demonstrate that IRF-1 and IRF-2 may play an important role in the regulation of IFN-beta and IFN-inducible genes and that IRF-2 may have dual functions as an activator and repressor in CNS-derived cells.
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PMCID: PMC2150382  PMID: 9649118

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