Naoto Imamura

Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma

BACKGROUND The overexpression of receptor tyrosine kinase EphA2 has been reported in various cancers. In non-small cell lung cancer (NSCLC), a positive correlation has been reported between high EphA2 immunohistochemical staining level and poor prognosis. However, its ligand, ephrin-A1, is supposed to act as a tumor suppressor via the kinase activity of EphA2. Thus, the biphasic roles of this system are not fully elucidated. We retrospectively evaluated the expression levels of EphA2 and ephrin-A1 in surgically treated pathological (p-) stage I NSCLC tumor samples, and their relation to clinicopathologic features or postoperative prognoses. METHODS The levels of EphA2 and ephrin-A1 mRNA expression were quantified by real-time reverse-transcription polymerase chain reaction in tissue samples from p-stage I NSCLC patients who had undergone complete resection in our facility (n=195). They were divided into two (EphA2/ephrin-A1-Low and -High) groups based on the median expression level, and their respective clinicopathologic features and prognoses were analyzed. Furthermore, samples were stained immunohistochemically and classified into four groups according to their staining levels, and their prognoses analyzed. RESULTS Marked demographic differences were found between EphA2/ephrin-A1-Low and -High groups. Both EphA2-High and ephrin-A1-High groups had more females, no smoking history, adenocarcinoma histology, well-differentiated carcinomas, p-stage IA patients, and patients with EGFR gene mutations. Five-year overall survival rates of the EphA2-Low and the EphA2-High patient groups were 68.9% and 86.1%, respectively (P=0.017), and five-year disease-free survival rates were 69.9% and 83.2%, respectively (P=0.035). There were no statistical differences between ephrin-A1-Low and ephrin-A1-High groups concerning postoperative survival. Although showing smaller differences, the findings from the immunohistochemical analyses supported the above results. CONCLUSIONS Higher expression of EphA2 and ephrin-A1 was more related to the female sex, reduced smoking status, adenocarcinoma, well differentiated carcinomas, p-stage IA, and EGFR gene mutations. Higher EphA2 mRNA expression in p-stage I NSCLC patients was positively related to improved prognoses. These results may reflect a tumor suppressive role for the EphA2/ephrin-A1 system in a population of patients restricted to p-stage I NSCLC.

A mesh-free method with arbitrary-order accuracy for acoustic wave propagation

In the present study, we applied a novel mesh-free method to solve acoustic wave equation. Although the conventional finite difference methods determine the coefficients of its operator based on the regular grid alignment, the mesh-free method is not restricted to regular arrangements of calculation points. We derive the mesh-free approach using the multivariable Taylor expansion. The methodology can use arbitrary-order accuracy scheme in space by expanding the influence domain which controls the number of neighboring calculation points. The unique point of the method is that the approach calculates the approximation of derivatives using the differences of spatial variables without parameters as e.g. the weighting functions, basis functions. Dispersion analysis using a plane wave reveals that the choice of the higher-order scheme improves the dispersion property of the method although the scheme for the irregular distribution of the calculation points is more dispersive than that of the regular alignment. In numerical experiments, a model of irregular distribution of the calculation points reproduces acoustic wave propagation in a homogeneous medium same as that of a regular lattice. In an inhomogeneous model which includes low velocity anomalies, partially fine arrangement improves the effectiveness of computational cost without suffering from accuracy reduction. Our result indicates that the method would provide accurate and efficient solutions for acoustic wave propagation using adaptive distribution of the calculation points. A mesh free method with arbitrary-order accuracy has been developed.Dispersion analyses showed that sufficient number of nodes provide better results.The method can treat numerical models with high velocity contrast in a simple manner.

Snail expression is associated with a poor prognosis in malignant pleural mesotheliomas.

BACKGROUND Malignant pleural mesotheliomas (MPMs) are aggressive tumors with a poor prognosis. We aimed to clarify the mechanisms of epithelial-to-mesenchymal transition (EMT) in MPMs by analyzing the expressions of EMT-associated transcription factors and E-cadherin in relation to tumor proliferation rates and patient survival. METHODS One hundred nine patients with MPMs were investigated. Among these patients, there were 61 epithelioid tumors, 21 sarcomatoid tumors, 20 biphasic tumors, and 7 desmoplastic tumors. Immunohistochemical analyses were performed to evaluate the expressions of Snail, ZEB1, Twist, E-cadherin, and the Ki-67 proliferation index. RESULTS The expressions of Snail and ZEB1 were significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p<0.0001 and p=0.0051, respectively). Furthermore, the E-cadherin expression was significantly lower in the Snail-high tumors than in the Snail-low tumors (p=0.0423). The E-cadherin expression was significantly lower in the nonepithelioid tumors than in the epithelioid tumors (p=0.0126). The Ki-67 proliferation index was significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p=0.025). Patient survival was significantly lower in patients with Snail-high MPMs than in those with Snail-low MPMs (p=0.0016), especially in patients with nonepithelioid tumors (p=0.0089). The multivariate analysis also demonstrated that nuclear Snail expression was a significant predictor of poor prognosis in patients with MPMs (p=0.0142). CONCLUSIONS The Snail expression is associated with EMT and a poor prognosis in MPMs. Snail could be a potential molecular target for the treatment of patients with MPMs.

Expression of the GLI family genes is associated with tumor progression in advanced lung adenocarcinoma.

BackgroundThe hedgehog (Hh) signaling pathway is aberrantly activated in various cancers. Expression of the GLI family of genes, which encode for transcriptional factors of the Hh pathway, has not been fully assessed in clinical samples of advanced lung adenocarcinoma. In this study, we retrospectively evaluated the expression of the GLI family of genes in advanced stage lung adenocarcinoma samples and determined their relation to patient survival.MethodsThe levels of GLI1, GLI2, and GLI3 mRNA expression were measured by quantitative real-time polymerase chain reaction in surgically obtained tissue samples from stage II-IV lung adenocarcinoma patients (n = 102). Pairwise comparisons between all three GLI mRNA expression were performed, and after dichotomizing the patients into low and high expression groups according to each GLI mRNA expression level, survival curves were calculated and multivariate analyses were conducted.ResultsSignificant positive correlation was found between GLI1 and GLI3 mRNA expression (P <0.001). Tumors with higher expression (upper 15%) of GLI1 or GLI3 mRNA were associated with poor survival in stage II-IV (5-year overall survival rates: GLI1 mRNA low, 41.7% vs. high, 20.0%, P = 0.0074; GLI3 mRNA low, 43.1% vs. high, 13.3%, P = 0.0062) and stage III-IV (5-year overall survival rates: GLI1 mRNA low, 34.0% vs. high, 0%, P = 0.0012; GLI3 mRNA low, 33.4% vs. high, 7.7%, P = 0.057) lung adenocarcinoma patients. GLI2 mRNA expression did not appear to have great clinical significance. Multivariate analysis revealed higher GLI1 mRNA expression as an independent factor for unfavorable patient survival (P = 0.0030, hazard ratio = 3.1, 95% confidence interval = 1.5-6.2), as well as tumor differentiation and stage.ConclusionsExpression of GLI1 and GLI3 mRNA was strongly correlated, and their overexpression, especially that of GLI1, was found to be predictive of aggressive tumor behavior. This study indicates that the Hh pathway may be a key oncogenic signaling network in tumor pathogenesis and, thus, a potential therapeutic target in advanced lung adenocarcinoma.

Application of Marine Controlled-source Electromagnetic Sounding to Submarine Massive Sulphides Explorations

In conventional marine CSEM methods, we need a survey vessel that tows a long cable to which both an EM transmitter and receivers are attached. Therefore, it is difficult to survey shallow sub-seafloor structure below the seafloor of complex topography around submarine massive sulphides (SMS) because of the risk of cable-tangling. In this research, we propose a new marine CSEM method to solve this problem using two autonomous underwater vehicles (AUV). Using this method, it is possible to keep a low height of diving AUVs from the seafloor, so we can carry out the exploration of SMS effectively. We discussed the possibility of new CSEM method employing the 2.5-D FEM program. From numerical results, it is possible to detect the rough existent area of SMS and the rough thickness of SMS.

Aortico-pulmonary paraganglioma: case report and Japanese review.

Aortico-pulmonary paraganglioma (APPG) is a rare middle mediastinal tumor. We experienced a case of APPG in a 52-year-old man. Chest computed tomography and magnetic resonance imaging revealed a multi-cystic mass in the subaortic area. A left thoracotomy was performed without definitive preoperative diagnosis. The tumor was strongly adherent to the pericardium and the surrounding large vessels, but a complete resection was undertaken. Histological and immunohistochemical examination revealed that it was a malignant paraganglioma with a microscopically positive surgical margin. After radiotherapy of 50 Gy for the mediastinum, the patient almost recovered from his hoarseness by thyroplasty. We also reviewed nine Japanese cases of APPG reported previously. Though APPG is rare, we must consider that a middle mediastinal tumor may be APPG, and preoperative examination and preoperative planning are necessary to prevent massive bleeding and microscopic residual tumor.

Ciliated muconodular papillary tumor of the lung: report of five cases

We report five serial cases of ciliated muconodular papillary tumor (CMPT) of the lung. CMPT is characterized as a low-grade malignant tumor with ciliated columnar epithelial cells combined with goblet cells, typically presenting as peripheral lung tumor and often causing diagnostic or therapeutic problems. In the cases described here, all patients presented with abnormal chest shadow but no definitive symptoms. Although all tumors were peripheral, computed tomography (CT) revealed various radiographic findings including small lung nodules, ground-grass opacity or irregular-shaped consolidation. All patients underwent complete surgical resection, and no recurrence has been noted over follow-up. In all cases, pathological findings included columnar ciliated cells with mucus lakes, consistent with the immunohistochemical staining. As there are few reports on this tumor entity, which has not yet received a WHO classification, we believe our case series may be of interest.

Topographic Modelling Using a Particle Method in 3D Controlled-source Electromagnetic Exploration

We show how a particle method can be utilized for topographic modelling in 3D controlled-source electromagnetic (CSEM) exploration, and developed topographic 3D inversion in CSEM survey. This paper describes how the accuracy of forward simulation in topographic model, and subsequently presents a synthetic example for 3D CSEM inversion using particle modelling approach from a synthetic submarine hydrothermal model. Two advantages of the particle method are (1) that a numerical model can flexibly create an arbitrary topography shape; and (2) that three components of electric or magnetic fields can be defined at the same particles.

Electromagnetic survey around the seafloor massive sulfide using autonomous underwater vehicle

The recent growth of world-wide requirement of metals demands advanced explorations for finding metal mine and deposits. The feasibility studies demonstrated that the electromagnetic responses are very sensitive to the conductive layer simulating the submarine massive sulfide (SMS) deposits, which is buried at the depth of several tens meters. On the basis of the results, we developed instruments for the marine controlled-source electromagnetic (CSEM) survey with autonomous underwater vehicle (AUV), on which a transmitter was attached. For the real field test, R/V Yokosuka and AUV Urashima were used. The target region is a real deep-sea mine in a caldera structure called Bayonnaise, located in the Izu-Bonin island arc, south of Japan. We succeeded in the test experiment along four survey lines with current shooting from AUV. Six ocean-bottom receivers (OBEM) simultaneously recorded those signals. The maximum source-receiver distance, in which we can detect the artificial current signals, exceeds to about 500m. Therefore, the inferred maximum sounding depth will be 150m or more below the seafloor. For evaluating the anomalous attenuation or amplification of received electric field at OBEMs, the three-dimensional forward modeling including the real bathymetry and a simple subsurface structure having an uniform resistivity (1 Ohm-m) was employed. Comparison between the observed and synthesized received field gives us a three-dimensional pseudo-section of anomalous received field, which can visualize heterogeneity of sub seafloor structure qualitatively. On the basis of the preliminary result of our AUV-CSEM survey around the SMS, high conductive features are observed not only in the SMS exposed area, but also the surrounding area of SMS. It would reflect both the mineral deposits in and around the SMS and highly conductive pore water below the surface due to warm temperature by hydrothermal activities below the SMS. We conclude that our new technology imaging the near sub-seafloor structures will be useful for discussion about the geological background of SMS, and also be a powerful tool for the SMS detection and developments.

The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non–small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB‐resistant (VR) lung cancer cells (NCI‐H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP‐binding Cassette Sub‐family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB‐resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies.