Noriko Tada

Elevated Neutrophil to Lymphocyte Ratio Predicts Poor Prognosis in Advanced Colorectal Cancer Patients Receiving Oxaliplatin-Based Chemotherapy

Background: The aim of this study was to assess whether the neutrophil to lymphocyte ratio (NLR) and other laboratory markers may predict the prognosis of advanced colorectal cancer (CRC) patients receiving palliative chemotherapy. Methods: The study population included 50 patients with far advanced or recurrent unresectable CRC who received oxaliplatin-based combination chemotherapy as first-line treatment in our hospital between June 2005 and November 2010. Seven clinical variables and 7 laboratory indices before chemotherapy were evaluated retrospectively as the possible prognostic factors of overall and progression-free survival. Results: During the study period, 27 patients (54%) died of CRC. Elevated NLR (≥4.0) was observed in 15 patients (30%). By univariate analysis, elevated NLR, performance status and hypoalbuminemia were significantly associated with both poor overall and progression-free survivals. Multivariate analysis showed that elevated NLR (hazard ratio 4.39, 95% confidence interval 1.82–10.7; p = 0.0013) and thrombocytosis (hazard ratio 5.02, 95% confidence interval 1.69–13.4; p = 0.0066) were independently associated with overall survival. Conclusion: Elevated NLR is a powerful predictor of poor response to oxaliplatin-based chemotherapy in patients with unresectable CRC. The ratio is a simply accessible and inexpensive but useful biomarker in CRC patients receiving chemotherapy.

Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study.

Autophagy is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemotherapy. Recently, chloroquine diphosphate (CQ), a widely used antimalarial drug, has been studied as a potential inhibitor of autophagy. Here, we aimed to investigate the role of CQ in potentiating the effect of 5-fluorouracil (5-FU), the chemotherapeutic agent of first choice for the treatment of colorectal cancer, in an animal model of colon cancer. The mouse colon cancer cell line colon26 was used. For the in-vivo study, colon26 cells were injected subcutaneously into BALB/c mice, which were treated with saline as a control, CQ (50 mg/kg/day), 5-FU (30 mg/kg/day), or the combination therapy (CQ plus 5-FU). The tumor volume ratio and body weight were monitored. After the sacrifice, tumor tissue protein extracts and tumor sections were prepared and subjected to immunoblotting for the analysis of autophagy-related and apoptosis-related proteins, and the terminal transferase uridyl end labeling assay. The combination of CQ resulted in the inhibition of 5-FU-induced autophagy and a significant enhancement in the 5-FU-induced inhibition of tumor growth. Furthermore, the combination treatment of CQ and 5-FU resulted in a significant increase in the ratio of apoptotic cells compared with other treatments. The expression levels of the proapoptotic proteins, namely Bad and Bax, were increased by the CQ treatment in the protein extracts from tumors. Our findings suggest that the combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of colorectal cancer.

TIARES Project—Tomographic investigation by seafloor array experiment for the Society hotspot

We conducted geophysical observations on the French Polynesian seafloor in the Pacific Ocean from 2009 to 2010 to determine the mantle structure beneath the Society hotspot, which is a region of underlying volcanic activity responsible for forming the Society Islands. The network for Tomographic Investigation by seafloor ARray Experiment for the Society hotspot (TIARES, named after the most common flower in Tahiti) is composed of multi-sensor stations that include broadband ocean-bottom seismometers, ocean-bottom electro-magnetometers, and differential pressure gauges. The network is designed to obtain seismic and electrical conductivity structures of the mantle beneath the Society hotspot. In addition to providing data to study the mantle structure, the TIARES network recorded unprecedented data of pressure and electromagnetic (EM) signals by tsunamis associated with large earthquakes in the Pacific Ocean, including the 2010 Chilean earthquake (Mw 8.8).

Hypoxia enhances colon cancer migration and invasion through promotion of epithelial-mesenchymal transition.

BACKGROUND A hypoxic environment exists in most solid tumors because in rapidly growing tumors, the development of angiogenic vasculature is heterogenous, usually not enough to overcome the necessary oxygen supply. In an ischemic condition, cancer cells develop escape mechanisms to survive and leave the unfavorable environment. That result in the acquisition of increased potential for local invasion and evasion to distant organs. However, the escape mechanisms of cancer cells from hypoxic stress have not been fully characterized. MATERIALS AND METHODS The human colon cancer cell line LoVo was cultured in hypoxia, and the adhesive and migratory properties were analyzed. The expression of cell surface and cytoplasmic molecules was also investigated. RESULTS Under hypoxic conditions, cells developed epithelial-mesenchymal transition. The expression levels of α2, α5, and β1 integrins were significantly upregulated and, as a consequence, the ability to adhere to and migrate on collagen and fibronectin was increased. On the other hand, the expression of 67-kDa laminin receptor and the abilities to adhere to and migrate on laminin were decreased. Additionally, the expression of CXCR4 was significantly increased on cells cultured in hypoxia, and the chemotactic activity to stromal cell-derived factor 1α was remarkably increased. CONCLUSIONS Hypoxic stress induced active epithelial-mesenchymal transition in colon cancer cells, with the typical morphologic and functional changes. These morphologic and functional changes of β1 integrins, the 67-kDa laminin receptor, and CXCR4 may be essential for the acquisition of the invasive and metastatic features in colorectal cancer.

Tsunami: Ocean dynamo generator

Secondary magnetic fields are induced by the flow of electrically conducting seawater through the Earths primary magnetic field (‘ocean dynamo effect’), and hence it has long been speculated that tsunami flows should produce measurable magnetic field perturbations, although the signal-to-noise ratio would be small because of the influence of the solar magnetic fields. Here, we report on the detection of deep-seafloor electromagnetic perturbations of 10-micron-order induced by a tsunami, which propagated through a seafloor electromagnetometer array network. The observed data extracted tsunami characteristics, including the direction and velocity of propagation as well as sea-level change, first to verify the induction theory. Presently, offshore observation systems for the early forecasting of tsunami are based on the sea-level measurement by seafloor pressure gauges. In terms of tsunami forecasting accuracy, the integration of vectored electromagnetic measurements into existing scalar observation systems would represent a substantial improvement in the performance of tsunami early-warning systems.

Approximate treatment of seafloor topographic effects in three-dimensional marine magnetotelluric inversion

Seafloor magnetotelluric (MT) observations using ocean bottom electromagnetometers (OBEMs) provide information on the electrical conductivity structure of the oceanic mantle. A three-dimensional (3-D) analysis is particularly important for marine MT data because the electric and magnetic fields observed on the seafloor are distorted by the rugged seafloor topography and the distribution of land and ocean. Incorporating topography into 3-D models is crucial to making accurate estimates of the oceanic mantle’s conductivity structure. Here we propose an approximate treatment of seafloor topography to accurately incorporate the effect of topography without significantly increasing the computational burden. First, the topography (lateral variation in water depth) is converted to lateral variation in effective conductivity by volumetric averaging. Second, we compute the electric and magnetic field components used to calculate the MT responses at arbitrary points from the electric field components on staggered grids, using a modified interpolation and extrapolation scheme. To verify the performance of this approximate treatment of seafloor topography in 3-D inversions, we tested the method using synthetic seafloor datasets and both 3-D forward modeling and inversion. The results of the synthetic inversions show that a given conductivity anomaly in the oceanic upper mantle can be recovered with sufficient accuracy after several iterations.

Three‐dimensional inversion of seafloor magnetotelluric data collected in the Philippine Sea and the western margin of the northwest Pacific Ocean

We report a result of three-dimensional (3-D) upper mantle electrical conductivity inversion of seafloor magnetotelluric data. We used existing data at 25 sites in the Philippine Sea and the western margin of the Pacific Ocean. In order to obtain a reliable model by 3-D inversion, we evaluated the large and small-scale topographic effects. We also conducted a comprehensive search of the one-dimensional (1-D) profiles of the study area in order to determine the best initial and prior models. A two-phase inversion method was applied so that the error floors for the diagonal and off-diagonal elements of the impedance tensor could be separately controlled. Through this first attempt at inverting real data, we obtained basic knowledge about tuning the inversion parameters and conditions. We also proposed a procedure to evaluate the reliability of the 3-D conductivity anomalies imaged by the inversion by conducting checkerboard and sensitivity tests. After the iterations converged, 13 distinct anomalies were found in the inverted 3-D conductivity model; four conductive and two resistive anomalies were confirmed to be resolved enough by the data through the checkerboard test. Then the sensitivity tests were conducted to quantify how each anomaly was required by the observed data, and we confirmed that the intensities of three conductive anomalies and one resistive anomaly were statistically significant. This paper presented an example of possible approach in 3-D seafloor electromagnetic inversion procedure for imaging reliable electrical conductivity structure of the oceanic mantle, which will be useful in understanding dynamics and evolution of solid Earth.

Prediction of the preoperative chemoradiotherapy response for rectal cancer by peripheral blood lymphocyte subsets

BackgroundAlthough neoadjuvant chemoradiotherapy (CRT) has become a standard procedure to downstage locally advanced rectal cancer prior to surgery, markers to predict the response to CRT have not been fully identified. The aim of this study was to identify predictive factors of response to CRT, especially focusing on peripheral blood leukocyte subsets.MethodsA total of 45 consecutive patients diagnosed with primary rectal cancer were prospectively enrolled and received CRT followed by curative resection. The numbers of each lymphocyte subset in peripheral blood pre- and post-CRT were analyzed using flow cytometry. According to the pathological response to CRT, patients were classified into high (Hi-R) and low (Lo-R) response groups.ResultsHi-R cases had significantly higher numbers of pre-CRT lymphocytes (p = 0.018), T lymphocytes (p = 0.009) and helper T lymphocytes (Th lymphocytes, p = 0.015) compared to the Lo-R cases. With the receiver-operating characteristic curve for numbers of pre-CRT T lymphocytes, the area under the curve (AUC) was 0.733, and the optimal cutoff value was 1196/μl, with 76.5% sensitivity, 67.8% specificity, 59.1% positive and 82.6% negative predictive values. The numbers of pre-CRT Th lymphocytes and cytotoxic lymphocytes were both independent predictors of the high CRT response in the multivariate analysis.ConclusionsIn addition to the direct cytotoxicity of CRT, recent studies have demonstrated the induction of an immunological host response, which also contributed to the tumor regression induced by CRT. Our result suggested the potential role of circulating T lymphocytes in predicting the response to CRT in colorectal cancer patients.

Temsirolimus and chloroquine cooperatively exhibit a potent antitumor effect against colorectal cancer cells.

PurposeTemsirolimus (TEM) is a novel, water-soluble mammalian target of rapamycin (mTOR) inhibitor that has shown activity against a wide range of cancers in preclinical models, but its efficacy against colorectal cancer (CRC) has not been fully explored.MethodsWe evaluated the antitumor effect of TEM in CRC cell lines (CaR-1, HT-29, Colon26) in vitro and in vivo. In vitro, cell growth inhibition was assessed using a MTS assay. Apoptosis induction and cell cycle effects were measured using flow cytometry. Modulation of mTOR signaling was measured using immunoblotting. Antitumor activity as a single agent was evaluated in a mouse subcutaneous tumor model of CRC. The effects of adding chloroquine, an autophagy inhibitor, to TEM were evaluated in vitro and in vivo.ResultsIn vitro, TEM was effective in inhibiting the growth of two CRC cell lines with highly activated AKT, possibly through the induction of G1 cell cycle arrest via a reduction in cyclin D1 expression, whereas TEM reduced HIF-1α and VEGF in all three cell lines. In a mouse subcutaneous tumor model, TEM inhibited the growth of tumors in all cell lines, not only through direct growth inhibition but also via an anti-angiogenic effect. We also explored the effects of adding chloroquine, an autophagy inhibitor, to TEM. Chloroquine significantly potentiated the antitumor activity of TEM in vitro and in vivo. Moreover, the combination therapy triggered enhanced apoptosis, which corresponded to an increased Bax/Bcl-2 ratio.ConclusionsBased on these data, we propose TEM with or without chloroquine as a new treatment option for CRC.

Changes in the plasma levels of cytokines/chemokines for predicting the response to chemoradiation therapy in rectal cancer patients.

In the present study, we aimed to characterize the predictive value of cytokines/chemokines in rectal cancer (RC) patients receiving chemoradiation therapy (CRT). Blood samples were obtained pre- and post-CRT from 35 patients with advanced RC, who received neoadjuvant CRT followed by surgery, and the correlation between plasma levels of cytokines/chemokines and the response to CRT was analyzed. The pre-CRT levels of soluble CD40-ligand (sCD40L) and the post-CRT levels of chemokine ligand-5 (CCL-5) were significantly associated with the depth of tumor invasion and with venous invasion. In addition, a significant decrease in sCD40L and CCL-5, as well as in platelet counts, was associated with a favorable response to CRT. A significant correlation between pre-CRT platelet counts and sCD40L was observed in patients with a favorable response. By contrast, higher post-CRT interleukin (IL)-6 was associated with a poor response. Platelets, immune system and cancer cells, cross-linked through various cytokines/chemokines, appear to play an important role in the response to CRT, and by understanding their roles, new approaches for the improvement of the therapy might be proposed.