Tomoaki Hoshino

NCI-Frederick, Фредерик, Maryland, United States

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Publications (141)427.53 Total impact

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    ABSTRACT: All plakin family proteins are known to be autoantigens in paraneoplastic pemphigus (PNP). In this study, we first examined whether PNP sera also react with epiplakin, another plakin protein, by various immunological methods using 48 Japanese PNP sera. Immunofluorescence confirmed that cultured keratinocytes expressed epiplakin. Epiplakin was detected by 72.9% of PNP sera by immunoprecipitation-immunoblotting with KU-8 cell extract, but not by immunoblotting of either normal human epidermal extract or KU-8 cell extract. Epiplakin was essentially not detected by 95 disease and normal control sera. Statistical analyses of various clinical and immunological findings revealed significant correlation of the presence of anti-epiplakin antibodies with both bronchiolitis obliterans and mortality. No epiplakin-negative PNP case developed bronchiolitis obliterans. However, although 29.4% of European PNP patients had bronchiolitis obliterans, significant correlation with anti-epiplakin autoantibodies was not observed. In further studies for lung, immunofluorescence showed the presence of epiplakin in normal human lung, particularly respiratory bronchiole, immunoprecipitation-immunoblotting showed that PNP sera reacted with epiplakin in cultured lung cells, and mice injected with polyclonal antibody specific to epiplakin histopathologically showed abnormal changes in small airway epithelia. These results indicated that epiplakin is one of major PNP autoantigens and is related to PNP-related bronchiolitis obliterans.Journal of Investigative Dermatology accepted article preview online, 19 October 2015. doi:10.1038/jid.2015.408.
    Journal of Investigative Dermatology 10/2015; DOI:10.1038/jid.2015.408 · 7.22 Impact Factor
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    ABSTRACT: The newly characterized cytokine IL-38 (IL-1F10) belongs to the IL-1 family of cytokines. Previous work has demonstrated that IL-38 inhibited Candida albicans-induced IL-17 production from peripheral blood mononuclear cells. However, it is still unclear whether IL-38 is an inflammatory or an anti-inflammatory cytokine. We generated anti-human IL-38 monoclonal antibodies in order to perform immunohistochemical staining and an enzyme-linked immunosorbent assay. While human recombinant IL-38 protein was not cleaved by recombinant caspase-1, chymase, or PR3 in vitro, overexpression of IL-38 cDNA produced a soluble form of IL-38 protein. Furthermore, immunohistochemical analysis showed that synovial tissues obtained from RA patients strongly expressed IL-38 protein. To investigate the biological role of IL-38, C57BL/6 IL-38 gene-deficient (-/-) mice were used in an autoantibody-induced rheumatoid arthritis (RA) mouse model. As compared with control mice, IL-38 (-/-) mice showed greater disease severity, accompanied by higher IL-1β and IL-6 gene expression in the joints. Therefore, IL-38 acts as an inhibitor of the pathogenesis of autoantibody-induced arthritis in mice and may have a role in the development or progression of RA in humans.
    10/2015; DOI:10.1016/j.bbrep.2015.10.015
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    ABSTRACT: Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, is anticipated to prolong survival with inhibition of angiogenesis in patients with non-small-cell lung cancer. Rare life-threatening adverse events affecting the digestive tract have been reported, such as gastrointestinal hemorrhage and bowel perforation. A 62-year-old Japanese woman who was diagnosed as having stage IIIB (cT4N2M0) lung adenocarcinoma received chemotherapy with bevacizumab, pemetrexed and carboplatin every 3 weeks for four cycles, which resulted in a partial response, and then continued with maintenance bevacizumab monotherapy. Fourteen days after completion of the seventh cycle of bevacizumab maintenance therapy, the patient developed sudden abdominal pain with more than 10 episodes of hematochezia per day. On the basis of colonoscopic and pathological findings, ulcerative colitis (UC) with severe pancolitis was diagnosed. This case was unresponsive to medical treatment and required subtotal colectomy for management of the ulcerative colitis. This is the first reported case of ulcerative colitis occurring during bevacizumab therapy. The anti-angiogenesis activity of bevacizumab may have been involved in the development and exacerbation of UC in this patient.
    Investigational New Drugs 08/2015; 33(5). DOI:10.1007/s10637-015-0279-6 · 2.92 Impact Factor
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    ABSTRACT: As the development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has become an issue of concern, identification of the mechanisms responsible has become an urgent priority. However, for research purposes, it is not easy to obtain tumor samples from patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) that has relapsed after treatment with EGFR-TKIs. Here, using digital PCR assay as an alternative and noninvasive method, we examined plasma and tumor samples from patients with relapsed NSCLC to establish the inter-relationships existing among T790M mutation, activating EGFR mutations, HER2 amplification, and MET amplification. Paired samples of tumor and blood were obtained from a total of 18 patients with NSCLC after they had developed resistance to EGFR-TKI treatment, and the mechanisms of resistance were analyzed by digital PCR. Digital PCR analysis of T790M mutation in plasma had a sensitivity of 81.8% and specificity of 85.7%, the overall concordance between plasma and tissue samples being 83.3%. MET gene copy number gain in tumor DNA was observed by digital PCR in three patients, of whom one exhibited positivity for MET amplification by FISH, whereas no patient demonstrated MET and HER2 copy number gain in plasma DNA. Digital PCR analysis of plasma is feasible and accurate for detection of T790M mutation in NSCLC that becomes resistant to treatment with EGFR-TKIs.
    Oncotarget 08/2015; DOI:10.18632/oncotarget.5068 · 6.36 Impact Factor
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    ABSTRACT: The aim of the current study was to examine whether it would be possible to detect epidermal growth factor receptor (EGFR) mutations in cytology cell-free DNA (ccfDNA) from the supernatant fluids of bronchial cytology samples. This study investigated cell damage via immunostaining with a cleaved caspase 3 antibody and the quantity of cell-free DNA in supernatant fluid from 2 cancer cell lines, and the EGFR mutation status was evaluated via polymerase chain reaction (PCR) analysis. EGFR mutations were also evaluated via PCR analysis in 74 clinical samples of ccfDNA from bronchial washing samples with physiological saline or from bronchial brushing liquid-based cytology samples with CytoRich Red. The quantity and fragmentation of cell-free DNA in the supernatant fluid and the cell damage and cleaved caspase 3 expression in the sediment gradually increased in a time-dependent manner in the cell lines. In the 74 clinical samples, the quantity of ccfDNA extracted from the supernatant was adequate to perform the PCR assay, whereas the quality of ccfDNA in physiological saline was often decreased. The detection of EGFR mutations with ccfDNA showed a sensitivity of 88.0%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 89.7%, and an accuracy of 94.1% in samples with malignant or atypical cells. These results suggest that activating EGFR mutations can be detected with ccfDNA extracted from the supernatant fluid of liquid-based samples via a PCR assay. This could be a rapid and sensitive method for achieving a parallel diagnosis by both morphology and DNA analysis in non-small cell lung cancer patients. Cancer (Cancer Cytopathol) 2015. © 2015 American Cancer Society. © 2015 American Cancer Society.
    Cancer Cytopathology 07/2015; DOI:10.1002/cncy.21583 · 3.35 Impact Factor
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    ABSTRACT: Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in a subset of patients with non-small cell lung cancer (NSCLC). We have now examined PD-L1 expression and its regulation in NSCLC positive for the EML4-ALK fusion gene. The expression of PD-L1 at the protein and mRNA levels in NSCLC cell lines was examined by flow cytometry and by reverse transcription and real-time PCR analysis, respectively. The expression of PD-L1 in 134 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis. The PD-L1 expression level was higher in NSCLC cell lines positive for EML4-ALK than in those negative for the fusion gene. Forced expression of EML4-ALK in Ba/F3 cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in EML4-ALK-positive NSCLC cells was attenuated by treatment with the specific ALK inhibitor alectinib or by RNA interference with ALK siRNAs. Furthermore, expression of PD-L1 was down-regulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the epidermal growth factor receptor (EGFR). Finally, the expression level of PD-L1 was positively associated with the presence of EML4-ALK in NSCLC specimens. Our findings that both EML4-ALK and mutant EGFR up-regulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 05/2015; 21(17). DOI:10.1158/1078-0432.CCR-15-0016 · 8.72 Impact Factor
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    ABSTRACT: Objective: There is a discrepancy in the intensity of breath sounds in chronic obstructive pulmonary disease (COPD) patients between subjective studies, which have reported a diminished intensity, and objective studies using airflow-standardized measurements, which have not demonstrated a diminished intensity. We herein evaluated the breath sound intensity in COPD patients during tidal breathing in order to obtain clinically relevant results. Methods: The subjects included 20 stable COPD patients and 20 normal controls. Microphones were attached to six sites on the chest wall, and breath sounds at the chest wall and airflow in the mouth were measured during resting tidal and deep tidal breathing. The octave-band power values of the breath sounds were subsequently calculated. Results: 1. During resting breathing, the intensity of breath sounds during both inspiration and expiration was significantly greater in the COPD group than in the control group; the difference was prominent at higher frequency bands (>400 Hz). In addition, the power of the high frequency bands tended to be positively correlated with the CT visual emphysema scores but not the forced expiratory volume in one second, The airflow during resting breathing did not differ between the two groups. 2. During deep breathing, the intensity of inspiratory breath sounds at the dominant frequency band (200-400 Hz) was diminished over the upper and middle lung fields in the COPD group compared to that observed in the control group, while the intensity during expiration was not. The airflow during deep breathing was lower in the COPD group than in the control group. Conclusion: In the present study, the breath sound intensity in the COPD patients was diminished during deep inspiration due to a reduced airflow and increased during both resting inspiration and expiration.
    Internal Medicine 05/2015; 54(10):1183-91. DOI:10.2169/internalmedicine.54.3161 · 0.90 Impact Factor
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    ABSTRACT: The standard diagnostic method for echinoderm microtubule-associated protein-like 4-anaplastic lymphoma receptor tyrosine kinase translocation is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has been reported as a potential method in screening for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinomas (NSCLC), whereas several authors have reported a discordance between FISH and IHC results. We investigated the heterogeneity of ALK gene rearrangement in excision specimens by FISH and also examined whether the FISH score of ALK gene rearrangement corresponded in excision and biopsy samples from the same patient. Twenty ALK IHC-positive patients including six patients treated with crizotinib therapy were evaluated for the presence of ALK FISH. For evaluation of heterogeneity of ALK gene rearrangement in excision specimens, we defined six to 10 observation areas in each case, and the number of ALK FISH positive observation areas (≥15% rearrangement detected) was investigated. ALK FISH score in small biopsy samples was classified as positive (≥15% rearrangement detected), equivocal (5-14% rearrangement detected), or negative (<4% rearrangement detected). Of a total of 64 tumor observation areas from nine excision specimens, 50 areas were positive for ALK gene rearrangement (81.8%). In the comparison of excision and small biopsy samples, all excision specimens were ALK FISH-positive (100%; 6 of 6), whereas only three of the small biopsy samples in these patients were positive (50%; 3 of 6), two were equivocal (33%; 2 of 6), and one was negative (17%; 1 of 6). The two equivocal patients received crizotinib and showed a response. ALK gene rearrangement heterogeneity was observed in NSCLC specimens by FISH. Our findings suggested that IHC-positive/FISH-equivocal cases should not be considered true "false-negatives" when a small biopsy sample was used for ALK analysis.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2015; 10(5):800-5. DOI:10.1097/JTO.0000000000000507 · 5.28 Impact Factor
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    ABSTRACT: KL-6 and surfactant proteins A and D are the only established serum biomarkers of idiopathic pulmonary fibrosis (IPF). We have previously shown that serum levels of periostin, a unique matricellular protein, are elevated and correlated with pulmonary function in patients with IPF. We sought to determine whether the serum periostin levels correlate with overall survival (OS) and time-to-event (TTE), as a parameter reflecting long-term outcome, and with the extent of abnormality on chest high-resolution computed tomography (HRCT) scores in patients with IPF. Twenty-nine patients with IPF were analyzed retrospectively. The mean observation period was 1035.2±663.1 days (range, 112-1800 days). High-resolution computed tomography (HRCT) scores were calculated based on the extent of abnormality evidenced by HRCT. We evaluated if there were any correlations between the serum periostin levels and clinical parameters, including HRCT score, using Spearman׳s rank correlation coefficients and analyzed predictors of OS and TTE using the log-rank tests. We showed that the serum periostin levels significantly correlated with the increase of honeycombing score on HRCT during a 6-month period. Log-rank tests showed that a higher serum periostin level was a predictor of a shortened OS and TTE. Greater extents of fibrotic lesions on HRCT scan were predictors of shortened OS and TTE. In IPF patients, the serum periostin level may be a good predictive biomarker for an increase in the radiological fibrotic area and long-term outcome. Copyright © 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
    Respiratory Investigation 01/2015; 53(2). DOI:10.1016/j.resinv.2014.12.003
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    ABSTRACT: Background: The usefulness of paired maximum inspiratory and expiratory (I/E) plain chest radiography (pCR) for diagnosis of chronic obstructive pulmonary disease (COPD) is still unclear. Objectives: We examined whether measurement of the I/E ratio using paired I/E pCR could be used for detection of airflow limitation in patients with COPD. Methods: Eighty patients with COPD (GOLD stage I=23, stage II=32, stage III=15, stage IV=10) and 34 control subjects were enrolled. The I/E ratios of frontal and lateral lung areas, and lung distance between the apex and base on pCR views were analyzed quantitatively. Pulmonary function parameters were measured at the same time. Results: The I/E ratios for the frontal lung area (1.25±0.01), the lateral lung area (1.29±0.01), and the lung distance (1.18±0.01) were significantly (p<0.05) reduced in COPD patients compared with controls (1.31±0.02 and 1.38±0.02, and 1.22±0.01, respectively). The I/E ratios in frontal and lateral areas, and lung distance were significantly (p<0.05) reduced in severe (GOLD stage III) and very severe (GOLD stage IV) COPD as compared to control subjects, although the I/E ratios did not differ significantly between severe and very severe COPD. Moreover, the I/E ratios were significantly correlated with pulmonary function parameters. Conclusions: Measurement of I/E ratios on paired I/E pCR is simple and reproducible, and can detect airflow limitation in patients with severe and very severe COPD.
    European Journal of Radiology 01/2015; 84(4). DOI:10.1016/j.ejrad.2014.12.021 · 2.37 Impact Factor
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    ABSTRACT: Factors predicting the efficacy of erlotinib treatment in patients with EGFR mutation-negative non-small-cell lung cancer (NSCLC) have not been well studied. This retrospective study investigates whether patient characteristics, such as site of metastasis, can predict the efficacy of erlotinib treatment in NSCLC patients. In total, 53 EGFR mutation-negative NSCLC patients treated with erlotinib were enrolled, and the associations between clinicopathological characteristics and patient survival were analyzed. The EGFR mutation status was determined using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Survival curves were obtained using the Kaplan-Meier method. Among the NSCLC patients treated with erlotinib, 27 patients with pulmonary metastasis exhibited significantly longer progression-free survival (PFS) and overall survival (OS) times than those without pulmonary metastasis (median PFS time, 2.9 versus 1.2 months; P=0.0010 and median OS time, 12.4 versus 4.1 months; P=0.0007). Multivariate analyses also revealed that pulmonary metastasis independently correlated with PFS and OS times (hazard ratio, 0.39; P=0.0055 and hazard ratio, 0.33; P=0.0022, respectively). Patients with pulmonary metastasis exhibited significantly longer PFS and OS times than those without pulmonary metastasis. The presence of pulmonary metastasis may be a predictive factor in patients with EGFR mutation-negative NSCLC treated with erlotinib.
    Oncology letters 12/2014; 8(6):2699-2704. DOI:10.3892/ol.2014.2548 · 1.55 Impact Factor
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    ABSTRACT: Background: Programmed cell death 1 receptor-ligand interaction is a major pathway often hijacked by tumors to suppress immune control. The aim of this retrospective study was to investigate the prevalence and prognostic roles of programmed cell death -ligand 1 (PD-L1) expression in small cell lung cancer (SCLC). Methods: The expression of PD-L1 was evaluated by immunohistochemical analysis in 102 specimens of SCLC. Tumors with staining in over 5% of tumor cells were scored as positive for PD-L1 expression. Survival analysis was performed using the Kaplan-Meier method. Results: Expression of PD-L1 in tumor cells was observed in 71.6% (73 of 102) of SCLCs, and was significantly correlated with a limited disease (LD) stage. SCLC patients with PD-L1-positive tumors showed significantly longer overall survival (OS) than those with PD-L1-negative (median OS, 16.3 versus 7.3 months; p < 0.001, respectively). Multivariate analyses demonstrated that a good performance status, LD stage, and expression of PD-L1 were significantly predictive of better OS, independently of other factors. We found no relevance between PD-L1 expression and progression-free survival for first-line treatment in LD- and extensive disease-SCLC patients. Conclusions: In patients with SCLC, expression of PD-L1 is positively correlated with a LD stage, and is independently predictive of a favorable outcome.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2014; 10(3). DOI:10.1097/JTO.0000000000000414 · 5.28 Impact Factor
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    ABSTRACT: Background Guidelines recommend chronic obstructive pulmonary disease (COPD) assessment tests (CATs) for evaluation of symptoms and management risks. To investigate whether CAT can predict moderate or severe exacerbations in Japanese COPD patients, a single-blinded prospective study was performed. Methods A 123 Japanese COPD patients were classified into high-CAT (n=64) and low-CAT (n=59) groups. The frequencies and periods of moderate or severe exacerbation and hospitalization were compared between the two groups. Multivariate logistic regression analysis was performed to investigate whether CAT could predict exacerbations. A receiver operating characteristic (ROC) curve analysis was employed to find an appropriate CAT score for exacerbation. Results The high-CAT group was significantly older, had a lower body mass index, and had a lower airflow obstruction as compared to the low CAT group. The frequency of moderate or severe exacerbation (1.3±1.3 events per patient per year, p<0.0001) and hospitalizations (0.2±0.4, p=0.0202) in the high-CAT group was significantly higher than in the low-CAT group (0.4±0.7 and 0.0±0.1, respectively). Multivariate logistic regression analysis showed that both high CAT score and low airflow obstruction were independently predictive of frequent moderate or severe COPD exacerbation. ROC analysis showed that the best cut-off CAT score for moderate or severe COPD exacerbation was 8 points. Conclusion Our present results indicate that COPD Japanese patients showing high CAT scores have a poor prognosis, and that the CAT score is able to predict exacerbation in Japanese COPD.
    Respiratory Investigation 09/2014; 52(5). DOI:10.1016/j.resinv.2014.04.004
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    ABSTRACT: Background: Recent clinical trials have shown that immune-checkpoint blockade yields a clinical response in a subset of individuals with advanced nonsmall-cell lung cancer (NSCLC). We examined whether the expression of programmed death-ligand 1 (PD-L1) is related to clinicopathologic or prognostic factors in patients with surgically resected NSCLC. Patients and methods: The expression of PD-L1 was evaluated by immunohistochemical analysis in 164 specimens of surgically resected NSCLC. Cell surface expression of PD-L1 in NSCLC cell lines was quantified by flow cytometry. Results: Expression of PD-L1 in tumor specimens was significantly higher for women than for men, for never smokers than for smokers, and for patients with adenocarcinoma than for those with squamous cell carcinoma. Multivariate analysis revealed that the presence of epidermal growth factor receptor gene (EGFR) mutations and adenocarcinoma histology were significantly associated with increased PD-L1 expression in a manner independent of other factors. Cell surface expression of PD-L1 was also significantly higher in NSCLC cell lines positive for activating EGFR mutations than in those with wild-type EGFR. The EGFR inhibitor erlotinib downregulated PD-L1 expression in the former cell lines but not in the latter, suggesting that PD-L1 expression is increased by EGFR signaling conferred by activating EGFR mutations. A high level of PD-L1 expression in resected tumor tissue was associated with a significantly shorter overall survival for NSCLC patients. Conclusions: High expression of PD-L1 was associated with the presence of EGFR mutations in surgically resected NSCLC and was an independent negative prognostic factor for this disease.
    Annals of Oncology 07/2014; 25(10). DOI:10.1093/annonc/mdu242 · 7.04 Impact Factor
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    ABSTRACT: The primary objective of this study was to evaluate the safety and tolerability of carboplatin plus pemetrexed for elderly patients (≥75 years) with chemotherapy-naïve advanced non-squamous non-small cell lung cancer. Patients received escalated doses of carboplatin at an area under the concentration-time curve of 4 (Level 1) or 5 (Level 2) plus pemetrexed (500 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation was decided according to whether dose-limiting toxicity occurred in the first cycle of chemotherapy. A total of 20 patients (6 at Level 1, 14 at Level 2) were enrolled. No dose-limiting toxicities were observed in patients at Level 1 or the first six patients at Level 2, and therefore the combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was considered to be the recommended dose. Among a total of 14 patients in Level 2, only 1 patient experienced dose-limiting toxicity: Grade 3 febrile neutropenia and urticaria. The major toxicities were neutropenia, thrombocytopenia and anemia. Liver dysfunction, fatigue and anorexia were also common, but generally manageable. Six patients showed partial responses, giving the overall response rate of 30%. The median progression-free survival period was 4.8 months (95% confidence interval 2.9-6.7 months). The combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was determined as the recommended dose in chemotherapy-naïve elderly patients (≥75 years) with advanced non-squamous non-small cell lung cancer, in view of overall safety and tolerability.
    Japanese Journal of Clinical Oncology 03/2014; 44(5). DOI:10.1093/jjco/hyu030 · 2.02 Impact Factor
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    ABSTRACT: Most NSCLC patients with EGFR mutations benefit from treatment with EGFR-TKIs, but the clinical efficacy of EGFR-TKIs is limited by the appearance of drug resistance. Multiple kinase inhibitors of EGFR family proteins such as afatinib have been newly developed to overcome such drug resistance. We established afatinib-resistant cell lines after chronic exposure of activating EGFR mutation-positive PC9 cells to afatinib. Afatinib-resistant cells showed following specific characteristics as compared to PC9: [1] Expression of EGFR family proteins and their phosphorylated molecules was markedly downregulated by selection of afatinib resistance; [2] Expression of FGFR1 and its ligand FGF2 was alternatively upregulated; [3] Treatment with anti-FGF2 neutralizing antibody blocked enhanced phosphorylation of FGFR in resistant clone; [4] Both resistant clones showed collateral sensitivity to PD173074, a small-molecule FGFR-TKIs, and treatment with either PD173074 or FGFR siRNA exacerbated suppression of both afatinib-resistant Akt and Erk phosphorylation when combined with afatinib; [5] Expression of twist was markedly augmented in resistant sublines, and twist knockdown specifically suppressed FGFR expression and cell survival. Together, enhanced expression of FGFR1 and FGF2 thus plays as an escape mechanism for cell survival of afatinib-resistant cancer cells, that may compensate the loss of EGFR-driven signaling pathway.
    Oncotarget 03/2014; 5(15). DOI:10.18632/oncotarget.1866 · 6.36 Impact Factor
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    ABSTRACT: Patients with severe COPD are known to have comorbidities such as emaciation, cor pulmonale and right heart failure, muscle weakness, hyperlipemia, diabetes mellitus, osteoporosis, muscle atrophy, arterial sclerosis, hypertension, and depression. Therefore, treatment for COPD needs to focus on these comorbidities as well as the lungs. We previously reported a new mouse model of COPD utilizing the human surfactant protein C promoter SP-C to drive the expression of mature mouse IL-18 cDNA; constitutive IL-18 overproduction in the lungs of transgenic (Tg) mice induces severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension with aging. In the present study, we evaluated the progression of comorbidity in our COPD model. In female Tg mice, significant weight loss was observed at 16 weeks and beyond, when compared with control wild-type (WT) mice. This weight loss was suppressed in IL-13-deficient (knockout; KO) Tg mice. Muscle weight and bone mineral density were significantly decreased in aged Tg mice relative to control WT and IL-13 KO Tg mice. The aged Tg mice also showed impaired glucose tolerance. IL-18 and IL-13 may play important roles in the pathogenesis of comorbidity in COPD patients.
    Biochemical and Biophysical Research Communications 02/2014; 445(3). DOI:10.1016/j.bbrc.2014.02.052 · 2.30 Impact Factor
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    ABSTRACT: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with clinical response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, in patients with non-small cell lung cancer (NSCLC). However, humoral immune responses to EGFR in NSCLC patients have not been well studied. In this study, we investigated the clinical significance of immunoglobulin G (IgG) responses to EGFR-derived peptides in NSCLC patients receiving gefitinib. Plasma IgG titers to each of 60 different EGFR-derived 20-mer peptides were measured by the Luminex system in 42 NSCLC patients receiving gefitinib therapy. The relationships between the peptide-specific IgG titers and presence of EGFR mutations or patient survival were evaluated statistically. IgG titers against the egfr_481–500, egfr_721–740, and egfr_741–760 peptides were significantly higher in patients with exon 21 mutation than in those without it. On the other hand, IgG titers against the egfr_841–860 and egfr_1001–1020 peptides were significantly lower and higher, respectively, in patients with deletion in exon 19. Multivariate Cox regression analysis showed that IgG responses to egfr_41_ 60, egfr_61_80 and egfr_481_500 were significantly prognostic for progression-free survival independent of other clinicopathological characteristics, whereas those to the egfr_41_60 and egfr_481_500 peptides were significantly prognostic for overall survival. Detection of IgG responses to EGFR-derived peptides may be a promising method for prognostication of NSCLC patients receiving gefitinib. Our results may provide new insight for better understanding of humoral responses to EGFR in NSCLC patients.
    PLoS ONE 01/2014; 9(1):e86667. DOI:10.1371/journal.pone.0086667 · 3.23 Impact Factor
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    ABSTRACT: The primary objective of this study was to re-evaluate the feasibility of docetaxel at doses of up to 75 mg/m(2) in Japanese patients with previously treated non-small cell lung cancer. Patients received escalated doses of docetaxel at 70 mg/m(2) (level 1) or 75 mg/m(2) (level 2) every 3 weeks until disease progression or unacceptable toxicities. Dose escalation was decided on the basis of dose-limiting toxicity in the first cycle of chemotherapy. At dose level 1, dose-limiting toxicity-Grade 3 febrile neutropenia-was observed in one of the six patients and at dose level 2, it was seen in one of the first six patients. Therefore, an additional 14 patients were enrolled at dose level 2, as originally planned. Among the total of 20 patients at dose level 2, 6 (<33%) developed dose-limiting toxicity in the first cycle: febrile neutropenia in 5 and pneumonia in 1. Finally, 10 (50%) of the 20 patients experienced toxicities that met the dose-limiting toxicity criteria, including 8 with febrile neutropenia throughout the treatment period, but this was manageable with dose reduction or appropriate supportive care. Other observed toxicities were predictable from the safety profile of decetaxel and were also well managed. Four partial responses were observed, giving an overall response rate of 15.4%. The median progression-free survival period of the patients overall was 4.0 months (95% confidence interval 1.4-6.6 months). Although docetaxel administration at an initial dose of 75 mg/m(2) requires careful attention because of the high incidence of febrile neutropenia, this dose is considered feasible according to the protocol definition in Japanese patients with previously treated non-small cell lung cancer.
    Japanese Journal of Clinical Oncology 01/2014; 44(4). DOI:10.1093/jjco/hyt236 · 2.02 Impact Factor
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    ABSTRACT: We have previously reported that the lungs of patients with very severe chronic obstructive pulmonary disease (COPD) contain significantly higher numbers of alveolar macrophages than those of non-smokers or smokers. M1 and M2 macrophages represent pro- and anti-inflammatory populations, respectively. However, the roles of M1 and M2 alveolar macrophages in COPD remain unclear. Immunohistochemical techniques were used to examine CD163, CD204 and CD206, as M2 markers, expressed on alveolar macrophages in the lungs of patients with mild to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I (mild) n = 11, II (moderate) n = 9, III (severe) n = 2, and IV (very severe) n = 16). Fifteen smokers and 10 non-smokers were also examined for comparison. There were significantly higher numbers of alveolar macrophages in COPD patients than in smokers and non-smokers. The numbers and percentages of CD163(+), CD204(+) or CD206(+) alveolar macrophages in patients with COPD at GOLD stages III and IV were significantly higher than in those at GOLD stages I and II, and those in smokers and non-smokers. In patients with COPD, there was a significant negative correlation between the number of CD163(+), CD204(+) or CD206(+) alveolar macrophages and the predicted forced expiratory volume in one second. Overexpression of CD163, CD204 and CD206 on lung alveolar macrophages may be involved in the pathogenesis of COPD.
    PLoS ONE 01/2014; 9(1):e87400. DOI:10.1371/journal.pone.0087400 · 3.23 Impact Factor

Publication Stats

3k Citations
427.53 Total Impact Points


  • 2015
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 1991-2015
    • Kurume University
      • • Division of Respirology, Neurology, and Rheumatology
      • • Department of Internal Medicine
      • • School of Medicine
      • • Department of Immunology
      • • Department of Ophthalmology
      Куруме, Fukuoka, Japan
  • 1999-2007
    • National Cancer Institute (USA)
      • Laboratory of Experimental Immunology
      베서스다, Maryland, United States