Description: We present mid-infrared (MIR) luminosity functions (LFs) of local ( z  〈 0.3) star-forming (SF) galaxies in the AKARI 's North Ecliptic Pole (NEP)-Wide survey field. In order to derive more accurate LF, we used spectroscopic sample only. Based on the NEP-Wide point source catalogue containing a large number of infrared (IR) sources distributed over the wide (5.4 deg 2 ) field, we incorporated the spectroscopic redshift ( z ) data for ~1790 selected targets obtained by optical follow-up surveys with MMT/Hectospec and WIYN/Hydra. The AKARI 's continuous 2–24 μm wavelength coverage as well as photometric data from optical u * band to near-infrared H band with the spectroscopic redshifts for our sample galaxies enable us to derive accurate spectral energy distributions (SEDs) in the MIR. We carried out SED fit analysis and employed 1/ V max method to derive the MIR (e.g. 8, 12, and 15 μm rest-frame) LFs. We fit our 8 μm LFs to the double power-law with the power index of α = 1.53 and β = 2.85 at the break luminosity 4.95  x  10 9 L . We made extensive comparisons with various MIR LFs from several literatures. Our results for local galaxies from the NEP region are generally consistent with other works for different fields over wide luminosity ranges. The comparisons with the results from the NEP-Deep data as well as other LFs imply the luminosity evolution from higher redshifts towards the present epoch.

Description: We present herein galaxy number counts of the nine bands in the 2–24 μm range on the basis of the AKARI North Ecliptic Pole (NEP) surveys. The number counts are derived from NEP-deep and NEP-wide surveys, which cover areas of 0.5 and 5.8 deg 2 , respectively. To produce reliable number counts, the sources were extracted from recently updated images. Completeness and difference between observed and intrinsic magnitudes were corrected by Monte Carlo simulation. Stellar counts were subtracted by using the stellar fraction estimated from optical data. The resultant source counts are given down to the 80 per cent completeness limit; 0.18, 0.16, 0.10, 0.05, 0.06, 0.10, 0.15, 0.16 and 0.44 mJy in the 2.4, 3.2, 4.1, 7, 9, 11, 15, 18 and 24 μm bands, respectively. On the bright side of all bands, the count distribution is flat, consistent with the Euclidean universe, while on the faint side, the counts deviate, suggesting that the galaxy population of the distant universe is evolving. These results are generally consistent with previous galaxy counts in similar wavebands. We also compare our counts with evolutionary models and find them in good agreement. By integrating the models down to the 80 per cent completeness limits, we calculate that the AKARI NEP survey revolves 20–50 per cent of the cosmic infrared background, depending on the wavebands.

Description: We present infrared (IR) galaxy luminosity functions (LFs) in the AKARI North Ecliptic Pole (NEP) deep field using recently-obtained, wider Canada–France–Hawaii Telescope (CFHT) optical/near-IR images. AKARI has obtained deep images in the mid-infrared (IR), covering 0.6 deg 2 of the NEP deep field. However, our previous work was limited to the central area of 0.25 deg 2 due to the lack of optical coverage of the full AKARI NEP survey. To rectify the situation, we recently obtained CFHT optical and near-IR images over the entire AKARI NEP deep field. These new CFHT images are used to derive accurate photometric redshifts, allowing us to fully exploit the whole AKARI NEP deep field. AKARI 's deep, continuous filter coverage in the mid-IR wavelengths (2.4, 3.2, 4.1, 7, 9, 11, 15, 18, and 24 μm) exists nowhere else, due to filter gaps of other space telescopes. It allows us to estimate rest-frame 8 and 12 μm luminosities without using a large extrapolation based on spectral energy distribution fitting, which was the largest uncertainty in previous studies. Total infrared (TIR) luminosity is also obtained more reliably due to the superior filter coverage. The resulting rest-frame 8 and 12 μm, and TIR LFs at 0.15 〈  z  〈 2.2 are consistent with previous works, but with reduced uncertainties, especially at the high-luminosity end, thanks to the wide-field coverage. In terms of cosmic infrared luminosity density ( IR ), we found that the IR evolves as (1 +  z ) 4.2 ± 0.4 .

Description: Purpose: Circulating endothelial cells (CEC) have been widely used as a prognostic biomarker and regarded as a promising strategy for monitoring the response to treatment in several cancers. However, the presence and biologic roles of CECs have remained controversial for decades because technical standards for the identification and quantification of CECs have not been established. Here, we hypothesized that CECs detected by flow cytometry might be monocytes rather than endothelial cells. Experimental Design: The frequency of representative CEC subsets (i.e., CD45 – /CD31 + , CD45 – /CD31 + /CD146 + , CD45 – /CD31 + /CD105 + ) was analyzed in the peripheral blood of patients with gynecologic cancer ( n = 56) and healthy volunteers ( n = 44). CD45 – /CD31 + cells, which are components of CECs, were isolated and the expression of various markers (CD146, CD105, vWF, and CD144 for endothelial cells; CD68 and CD14 for monocytes) was examined by immunocytochemistry. Results: CD45 – /CD31 + /CD105 + cells were significantly increased in the peripheral blood of patients with cancer, whereas evaluation of CD45 – /CD31 + /CD146 + cells was not possible both in patients with cancer and healthy controls due to the limited resolution of the flow cytometry. Immunocytochemistry analyses showed that these CD45 – /CD31 + /CD105 + cells did not express vWF and CD146 but rather CD144. Furthermore, CD45 – /CD31 + /CD105 + cells uniformly expressed the monocyte-specific markers CD14 and CD68. These results suggest that CD45 – /CD31 + /CD105 + cells carry the characteristics of monocytes rather than endothelial cells. Conclusions: Our data indicate that CD45 – /CD31 + /CD105 + circulating cells, which are significantly increased in the peripheral blood of patients with gynecologic cancer, are monocytes rather than endothelial cells. Further investigation is required to determine the biologic significance of their presence and function in relation with angiogenesis. Clin Cancer Res; 19(19); 5340–50. ©2013 AACR .

Description: Purpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET). Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors. Results: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, P 〈 0.001). ALT also strongly correlated with lymphovascular ( P 〈 0.001) and perineural invasion ( P = 0.001) and the presence of lymph node ( P 〈 0.001) and distant metastases ( P = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83–6.27; P 〈 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08–0.68; P = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT ( P 〈 0.001), aggressive clinical behavior, and reduced recurrence-free survival ( P 〈 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival ( P = 0.003). Conclusions: Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease. Clin Cancer Res; 23(6); 1598–606. ©2016 AACR .

Description: Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most invasive human cancers and has a poor prognosis. Molecular targets of ATC that determine its highly aggressive nature remain unidentified. This study investigated L1 cell adhesion molecule (L1CAM) expression and its role in tumorigenesis of ATCs. Experimental Design: Expression of L1CAM in thyroid cancer was evaluated by immunohistochemical analyses of tumor samples from patients with thyroid cancer. We investigated the role of L1CAM in proliferation, migration, invasion, and chemoresistance using short hairpin RNA (shRNA) knockdown experiments in human ATC cell lines. Finally, we evaluated the role of L1CAM on tumorigenesis with ATC xenograft assay in a nude mouse model. Results: L1CAM expression was not detectable in normal follicular epithelial cells of the thyroid or in differentiated thyroid carcinoma. In contrast, analysis of ATC samples showed specifically higher expression of L1CAM in the invasive area of the tumor. Specific knockdown of L1CAM in the ATC cell lines, FRO and 8505C, caused a significant decrease in the proliferative, migratory, and invasive capabilities of the cells. Suppression of L1CAM expression in ATC cell lines increased chemosensitivity to gemcitabine or paclitaxel. Finally, in an ATC xenograft model, depletion of L1CAM markedly reduced tumor growth and increased the survival of tumor-bearing mice. Conclusions: We report that L1CAM is highly expressed in the samples taken from patients with ATCs. L1CAM plays an important role in determining tumor behavior and chemosensitivity in cell lines derived from ATCs. Therefore, we suggest that L1CAM may be an important therapeutic target in patients with ATCs. Clin Cancer Res; 18(11); 3071–8. ©2012 AACR .

Description: Purpose: Durable complete remission of metastatic renal cell carcinoma (RCC) has rarely been achieved with current treatment modalities. To solve this problem, alternative therapeutic options with high efficacy and minimal side effects are strongly needed. Experimental Design: Mesenchymal stem cells (MSC) were engineered to coexpress dodecameric TRAIL and herpes simplex virus thymidine kinase (MSC/dTRAIL-TK). The antitumor effects of MSCs expressing dTRAIL (MSC/dTRAIL) or HSV-TK alone (MSC/TK) and MSC/dTRAIL-TK were compared with murine RCC cells using in vitro coculture system and in vivo experimental lung metastasis model. The effects of different doses and schedules of engineered MSCs on mice survival were also evaluated. Results: MSC/dTRAIL-TK exerted stronger apoptotic response in Renca cells than did MSC/TK or MSC/dTRAIL after ganciclovir (GCV) treatment. In vivo imaging results suggest that MSCs reside longer in the lungs of metastatic tumor-bearing mice, compared with that of control mice, regardless of genetic engineering. In addition, MSC/dTRAIL-TK treatment followed by ganciclovir administrations significantly decreased the number of tumor nodules in the lung, to a greater degree than MSC/dTRAIL or MSC/TK, and led to a prolonged survival. More importantly, the antimetastatic effect of MSC/dTRAIL-TK was markedly enhanced by repeated injections but not by increased dose, and resulted in 100% survival of tumor-bearing mice after three injections. Conclusion: Sequential combination gene therapy using MSC/dTRAIL-TK achieved long-term remission of metastatic RCC without noticeable toxicity. Our findings provide an innovative therapeutic approach to completely eradicate metastatic tumors by simple, repeated administrations of MSC/dTRAIL-TK. Clin Cancer Res; 19(2); 415–27. ©2012 AACR .

Description: We present numerical studies of the imaging and caustic properties of the singular isothermal sphere (SIS) under a wide range of external shear (from 0.0 to 2.0). Using a direct inverse-mapping formula for this lensing system,we investigate various lensing properties for both low-shear (i.e.  〈 1.0) and high-shear (i.e.  〉 1.0) cases: the image separations, the total or individual magnifications, the flux ratios of two images, the maximum number of images and the lensing cross-sections. We systematically analyse the effective lensing cross-sections of double-lensing and quadruple-lensing systems, based on the radio luminosity function obtained by the Jodrell–VLA Astrometric Survey (JVAS) and the Cosmic Lens All-Sky Survey (CLASS). We find that the limit of a survey selection bias (i.e. between brighter and fainter images) preferentially reduces the effective lensing cross-sections of two-image lensing systems. By considering the effects of survey selection bias, we demonstrate that the long-standing anomaly over the high quads-to-doubles ratios (i.e. 50–70 per cent for JVAS and CLASS) can be explained by the moderate effective shear of 0.16–0.18, which is half that of previous estimates. The derived inverse-mapping formula could make the SIS + shear lensing model useful for galaxy-lensing simulations.

Description: We present the first galaxy counts at 18 μm using the Japanese AKARI satellite's survey at the North Ecliptic Pole (NEP), produced from the images from the NEP-Deep and NEP-Wide surveys covering 0.6 and 5.8 deg 2 , respectively. We describe a procedure using a point source filtering algorithm to remove background structure and a minimum variance method for our source extraction and photometry that delivers the optimum signal to noise for our extracted sources, confirming this by comparison with standard photometry methods. The final source counts are complete and reliable over three orders of magnitude in flux density, resulting in sensitivities (80 per cent completeness) of 0.15 and 0.3 mJy for the NEP-Deep and NEP-Wide surveys, respectively, a factor of 1.3 deeper than previous catalogues constructed from this field. The differential source counts exhibit a characteristic upturn from Euclidean expectations at around a milliJansky and a corresponding evolutionary bump between 0.2–0.4 mJy consistent with previous mid-infrared surveys with ISO and Spitzer at 15 and 24 μm. We compare our results with galaxy evolution models confirming the striking divergence from the non-evolving scenario. The models and observations are in broad agreement implying that the source counts are consistent with a strongly evolving population of luminous infrared galaxies at redshifts higher than unity. Integrating our source counts down to the limit of the NEP survey at the 150 μJy level we calculate that AKARI has resolved approximately 55 per cent of the 18 μm cosmic infrared background relative to the predictions of contemporary source count models.

Description: Purpose: The objective of the study was to determine whether astrocytes and brain endothelial cells protect glioma cells from temozolomide through an endothelin-dependent signaling mechanism and to examine the therapeutic efficacy of the dual endothelin receptor antagonist, macitentan, in orthotopic models of human glioblastoma. Experimental Design: We evaluated several endothelin receptor antagonists for their ability to inhibit astrocyte- and brain endothelial cell–induced protection of glioma cells from temozolomide in chemoprotection assays. We compared survival in nude mice bearing orthotopically implanted LN-229 glioblastomas or temozolomide-resistant (LN-229 Res and D54 Res ) glioblastomas that were treated with macitentan, temozolomide, or both. Tumor burden was monitored weekly with bioluminescence imaging. The effect of therapy on cell division, apoptosis, tumor-associated vasculature, and pathways associated with cell survival was assessed by immunofluorescent microscopy. Results: Only dual endothelin receptor antagonism abolished astrocyte- and brain endothelial cell–mediated protection of glioma cells from temozolomide. In five independent survival studies, including temozolomide-resistant glioblastomas, 46 of 48 (96%) mice treated with macitentan plus temozolomide had no evidence of disease ( P 〈 0.0001), whereas all mice in other groups died. In another analysis, macitentan plus temozolomide therapy was stopped in 16 mice after other groups had died. Only 3 of 16 mice eventually developed recurrent disease, 2 of which responded to additional cycles of macitentan plus temozolomide. Macitentan downregulated proteins associated with cell division and survival in glioma cells and associated endothelial cells, which enhanced their sensitivity to temozolomide. Conclusions: Macitentan plus temozolomide are well tolerated, produce durable responses, and warrant clinical evaluation in glioblastoma patients. Clin Cancer Res; 21(20); 4630–41. ©2015 AACR .