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Krebs von den Lungen-6 (KL-6), a mucinous sialylated sugar chain on human mucin-1 glycoprotein (MUC1), is a diagnostic marker for interstitial lung diseases. Furthermore, elevated serum KL-6 levels have been observed in certain malignant tumor types of epithelial origin. The expression of MUC1 has been observed in patients with epithelial ovarian cancer (EOC) and is considered a potential therapeutic target. In the present study, KL-6 serum levels were investigated in patients clinically suspected of having malignant ovarian tumors. A total of 219 patients were enrolled in the study, which analyzed their serum KL-6 levels in addition to tumor expression of MUC1 using immunohistochemistry. High serum KL-6 levels were predominantly observed in patients with EOC, and did not occur in patients with benign or borderline tumors. The level of serum KL-6 was highly correlated with tumor stage, grade and histological type, and demonstrated superior sensitivity for the detection of ovarian cancer compared with that of serum cancer antigen 125. High serum KL-6 was significantly associated with shorter progression-free survival. In addition, tumor MUC1 expression status was significantly correlated with serum KL-6 levels. These data suggest that serum KL-6 may be a useful, non-invasive biomarker surrogate for tumor MUC1 expression in future clinical trials of MUC1-targeted therapy.

Viral vectors that can infect neurons transsynaptically and can strongly express foreign genes are useful for investigating the organization of neural circuits. We previously developed a propagation-competent rabies virus (RV) vector based on a highly attenuated HEP-Flury strain (rHEP5.0-CVSG), which selectively infects neurons and propagates between synaptically connected neurons in a retrograde direction. Its relatively low level of transgene expression, however, makes immunostaining necessary to visualize the morphological features of infected neurons. To increase the transgene expression level of this RV vector, in this study we focused on two viral proteins: the large protein (L) and matrix protein (M). We first attempted to enhance the expression of L, which is a viral RNA polymerase, by deleting the extra transcription unit and shortening the intergenic region between the G and L genes. This viral vector (rHEP5.0-GctL) showed increased transgene expression level with efficient transsynaptic transport. We next constructed an RV vector with a rearranged gene order (rHEP5.0-GML) with the aim to suppress the expression of M, which plays a regulatory role in virus RNA synthesis. Although this vector showed high transgene expression level, the efficiency of transsynaptic transport was low. To further evaluate the usability of rHEP5.0-GctL as a transsynaptic tracer, we inserted a fluorescent timer as a transgene, which changes the color of its fluorescence from blue to red over time. This viral vector enabled us the differentiation of primary infected neurons from secondary infected neurons in terms of the fluorescence wavelength. We expect this propagation-competent RV vector to be useful for elucidating the complex organization of the central nervous system.

In this paper, we propose a method to recommend Japanese books to university students through machine learning modules based on several features, including library loan records. We determine the most effective method among the ones that used (a) a support vector machine (SVM), (b) a random forest, and (c) Adaboost. Furthermore, we assess the most effective combination of relevant features among (1) the association rules derived from library loan records, (2) book titles, (3) Nippon Decimal Classification (NDC) categories, (4) publication years, and (5) frequencies with which books were borrowed. We conducted an experiment involving 60 subjects who were students at T University. The books recommended by our candidate methods as well as the loan records used were obtained from the T University library. The results showed that books recommended by the method that employs an SVM based on features (2), (3), and (5) were rated most favorably by subjects. The method outperforms previous book recommendation techniques, such as that proposed by Tsuji et al. (2013), and is comparable in recommendation performance to the website Amazon.co.jp. The results obtained were independent of student grades, NDC categories, and the publication years of books.

A high power, long pulse modulator aimed at application to international linear collider (ILC) is being developed. The target parameters are: 120 kV (±0.5%), 140 A, 1.7 ms, and 5 pps, with consideration on compactness, reliability, and cost reduction. A solid state, chopper controlled pulsed power generator using Marx-topology has been proposed. This paper shows the experimental results of the prototype.

Background In this study, we investigated the advantages of fluorescence-guided surgery (FGS) in mice of a portable hand-sized imaging system compared with a large fluorescence imaging system or a long-working-distance fluorescence microscope. Methods Mouse models of human pancreatic cancer for FGS included the following: (1) MiaPaCa-2-expressing green fluorescent protein, (2) BxPC3 labeled with Alexa Fluor 488-conjucated anti-carcinoembryonic antigen (CEA) antibody, and (3) patient-derived orthotopic xenograft (PDOX) labeled with Alexa Fluor 488-conjugated anti-carbohydrate antigen 19-9 antibody. Results Each device could clearly detect the primary MiaPaCa-2-green fluorescent protein tumor and any residual tumor after FGS. In the BxPC3 model labeled with Alexa Fluor 488-conjugated anti-CEA, each device could detect the primary tumor, but the MVX10 could not clearly detect the residual tumor remaining after FGS whereas the other devices could. In the PDOX model labeled with Alexa Fluor 488-conjugated anti-carbohydrate antigen 19-9, only the portable hand-held device could distinguish the residual tumor from the background, and complete resection of the residual tumor was achieved under fluorescence navigation. Conclusions The results described in the present report suggest that the hand-held mobile imaging system can be applied to the clinic for FGS because of its convenient size and high sensitivity which should help make FGS widely used.

BackgroundFluorescence-guided surgery (FGS) can enable successful cancer surgery where bright-light surgery often cannot. There are three important issues for FGS going forward toward the clinic: (a) proper tumor labeling, (b) a simple portable imaging system for the operating room, and (c) patient-like mouse models in which to develop the technology. The present report addresses all three.Materials and methodsPatient colon tumors were initially established subcutaneously in nonobese diabetic (NOD)/severe combined immune deficiency (SCID) mice immediately after surgery. The tumors were then harvested from NOD/SCID mice and passed orthotopically in nude mice to make patient-derived orthotopic xenograft (PDOX) models. Eight weeks after orthotopic implantation, a monoclonal anti-carcinoembryonic antigen (CEA) antibody conjugated with AlexaFluor 488 (Molecular Probes Inc., Eugene, OR) was delivered to the PDOX models as a single intravenous dose 24 hours before laparotomy. A hand-held portable fluorescence imaging device was used.ResultsThe primary tumor was clearly visible at laparotomy with the portable fluorescence imaging system. Frozen section microscopy of the resected specimen demonstrated that the anti-CEA antibody selectively labeled cancer cells in the colon cancer PDOX. The tumor was completely resected under fluorescence navigation. Histologic evaluation of the resected specimen demonstrated that cancer cells were not present in the margins, indicating successful tumor resection. The FGS animals remained tumor free for over 6 months.ConclusionsThe results of the present report indicate that FGS using a fluorophore-conjugated anti-CEA antibody and portable imaging system improves efficacy of resection for CEA-positive colorectal cancer. These data provide the basis for clinical trials.

Because there is no perfect technique for automatic identification of bibliographic records, cleaning the identification results manually is indispensable. However, to recruit human resources for the task is often difficult. This paper discusses a microtask-based crowdsourcing approach to the problem. An important issue is to design a good strategy for generating tasks to be assigned to workers, maintaining the quality and reducing the number of tasks. In this study, we explore a design space defined by two criteria to reduce the number of assigned microtasks for finding misidentifications caused by automatic identification techniques. We compare four task-generation strategies using bibliographic records of the National Diet Library. One of the strategies reduced 55.7% of tasks from the baseline strategy and statistic analysis showed that the quality of its result is comparable to those of the other three strategies.

Objective To assess the association between risk of sudden cardiac death and stressful law enforcement duties compared with routine/non-emergency duties. Design Case distribution study (case series with survey information on referent exposures). Setting United States law enforcement. Participants Summaries of deaths of over 4500 US police officers provided by the National Law Enforcement Officers Memorial Fund and the Officer Down Memorial Page from 1984 to 2010. Main outcome measures Observed and expected sudden cardiac death counts and relative risks for sudden cardiac death events during specific strenuous duties versus routine/non-emergency activities. Independent estimates of the proportion of time that police officers spend across various law enforcement duties obtained from surveys of police chiefs and front line officers. Impact of varying exposure assessments, covariates, and missing cases in sensitivity and stability analyses. Results 441 sudden cardiac deaths were observed during the study period. Sudden cardiac death was associated with restraints/altercations (25%, n=108), physical training (20%, n=88), pursuits of suspects (12%, n=53), medical/rescue operations (8%, n=34), routine duties (23%, n=101), and other activities (11%, n=57). Compared with routine/non-emergency activities, the risk of sudden cardiac death was 34-69 times higher during restraints/altercations, 32-51 times higher during pursuits, 20-23 times higher during physical training, and 6-9 times higher during medical/rescue operations. Results were robust to all sensitivity and stability analyses. Conclusions Stressful law enforcement duties are associated with a risk of sudden cardiac death that is markedly higher than the risk during routine/non-emergency duties. Restraints/altercations and pursuits are associated with the greatest risk. Our findings have public health implications and suggest that primary and secondary cardiovascular prevention efforts are needed among law enforcement officers.

We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment serum WFA+-M2BP levels were quantified and the hazard ratios (HRs) for HCC development were retrospectively analyzed by Cox proportional hazard analysis. During the median follow-up time of 2.9 years, 12 patients developed HCC. Multivariate analysis demonstrated that high serum WFA+-M2BP (≥2.80 cut off index (COI), HR = 15.20, p = 0.013) and high fibrosis-4 (FIB-4) index (≥3.7, HR = 5.62, p = 0.034) were independent risk factors for HCC development. The three- and five-year cumulative incidence of HCC in patients with low WFA+-M2BP were 0.4% and 0.4%, respectively, whereas those of patients with high WFA+-M2BP were 7.7% and 17.6%, respectively (p < 0.001). In addition, combination of serum WFA+-M2BP and FIB-4 indices successfully stratified the risk of HCC: the five-year cumulative incidences of HCC were 26.9%, 6.8%, and 0.0% in patients with both, either, and none of these risk factors, respectively (p < 0.001). In conclusion, pretreatment serum WFA+-M2BP level is a useful predictor for HCC development after achieving SVR.

The glycoprotein (G) of rabies virus (RV) is required for binding to neuronal receptors and for viral entry. G-deleted RV vector is a powerful tool for investigating the organization and function of the neural circuits. It gives the investigator the ability to genetically target initial infection to particular neurons and to control trans-synaptic propagation. In this study we have quantitatively evaluated the effect of G gene deletion on the cytotoxicity and transgene expression level of the RV vector. We compared the characteristics of the propagation-competent RV vector (rHEP5.0-CVSG-mRFP) and the G-deleted RV vector (rHEP5.0-ΔG-mRFP), both of which are based on the attenuated HEP-Flury strain and express monomeric red fluorescent protein (mRFP) as a transgene. rHEP5.0-ΔG-mRFP showed lower cytotoxicity than rHEP5.0-CVSG-mRFP, and within 16 days of infection we found no change in the basic electrophysiological properties of neurons infected with the rHEP5.0-ΔG-mRFP. The mRFP expression level of rHEP5.0-ΔG-mRFP was much higher than that of rHEP5.0-CVSG-mRFP, and 3 days after infection the retrogradely infected neurons were clearly visualized by the expressed fluorescent protein without any staining. This may be due to the low cytotoxicity and/or the presumed change in the polymerase gene (L) expression level of the G-deleted RV vector. Although the mechanisms remains to be clarified, the results of this study indicate that deletion of the G gene greatly improves the usability of the RV vector for studying the organization and function of the neural circuits by decreasing the cytotoxicity and increasing the transgene expression level.

Behavioral, anatomical, and gene expression studies have shown functional dissociations between the dorsal and ventral hippocampus with regard to their involvement in spatial cognition, emotion, and stress. In this study we examined the difference of the multisynaptic inputs to the dorsal and ventral dentate gyrus (DG) in the rat by using retrograde trans-synaptic tracing of recombinant rabies virus vectors. Three days after the vectors were injected into the dorsal or ventral DG, monosynaptic neuronal labeling was present in the entorhinal cortex, medial septum, diagonal band, and supramammillary nucleus, each of which is known to project to the DG directly. As in previous tracing studies, topographical patterns related to the dorsal and ventral DG were seen in these regions. Five days after infection, more of the neurons in these regions were labeled and labeled neurons were also seen in cortical and subcortical regions, including the piriform and medial prefrontal cortices, the endopiriform nucleus, the claustrum, the cortical amygdala, the medial raphe nucleus, the medial habenular nucleus, the interpeduncular nucleus, and the lateral septum. As in the monosynaptically labeled regions, a topographical distribution of labeled neurons was evident in most of these disynaptically labeled regions. These data indicate that the cortical and subcortical inputs to the dorsal and ventral DG are conveyed through parallel disynaptic pathways. This second-order input difference in the dorsal and ventral DG is likely to contribute to the functional differentiation of the hippocampus along the dorsoventral axis. © 2013 Ohara et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

To study how organism responds to periodic stimulation is meaningful since it may be an approach to an elementary capacity of time memory and learning in chronological events. We reported here that the ability of time memory found in true slime mold Physarum was also found in a protozoan ciliate, Blepharisma japonicum and a green plant Chara. Stimulation of temperature or light was repeated several times in a regular period, and the creature anticipated the next timing of stimulation. After the anticipatory behavior disappeared some time later, another single stimulation triggered recalling of periodicity of the previous stimulation. We discuss that the observed capacity is expected to be common in a range of species as the similar capacity has been reported in true slime mold Physarum. The observed responses were, however, dependent of individual of organism and a wide range of different responses was observed. We need an extensive study of both experimental characterization and mathematical modeling of ethological dynamics. abstract environment.

Fibroblast growth factor 4 (FGF4) is considered a crucial gene in the proper development of bovine embryos. We recently determined the FGF4 gene sequence in eight cattle derived from three breeds and revealed a common nucleotide sequence of the structural gene encoding FGF4, which leads to the deletion and mutation of amino acid sequences in the mature FGF4 (Pro(32) -Leu(206) ) compared with the sequence previously reported. In the present study, HisbFGF4, a 6× histidine-tagged bovine FGF4 (Pro(32) -Leu(206) ), was produced in Escherichia coli based on the validated nucleotide sequence and purified by heparin column chromatography. In primary bovine fibroblasts, HisbFGF4 showed significant mitogenic activity, whereas, intriguingly, the activity of a commercially available recombinant human FGF4 (Gly(25) -Leu(206) ) produced in E. coli was weaker than that of HisbFGF4. In conclusion, the present study provides a simple method for the production of a bioactive bovine FGF4 derivative in E. coli utilizing its structural gene elucidated by us.

Embryoid bodies were prepared from mouse embryonic stem cells expressing exogenous EGAM1C to analyze their ability to differentiate toward terminally differentiated cell types. The generation of cardiomyocytes was severely suppressed in Egam1c transfectants without upregulation of Nkx2-5, a crucial gene for cardiomyogenesis. These results indicate that EGAM1C is capable of affecting terminal differentiation in mouse embryonic stem cells.

Fibroblast growth factor 4 (FGF4) is considered as a crucial gene for the proper development of bovine embryos. However, the complete nucleotide sequences of the structural genes encoding FGF4 in identified breeds are still unknown. In the present study, direct sequencing of PCR products derived from genomic DNA samples obtained from three Japanese Black, two Japanese Shorthorn and three Holstein cattle, revealed that the nucleotide sequences of the structural gene encoding FGF4 matched completely among these eight cattle. On the other hand, differences in the nucleotide sequences, leading to substitutions, insertions or deletions of amino acid residues were detected when compared with the already reported sequence from unidentified breeds. We cannot rule out a possibility that the structural gene elucidated in the present study is widely distributed in cattle. To the best of our knowledge, this is the first determination of the complete nucleotide sequence of the structural gene encoding bovine FGF4 in identified breeds.

The homeoprotein EGAM1C was identified in preimplantation mouse embryos and embryonic stem (ES) cells. To explore the impact of EGAM1C on the hallmarks of mouse ES cells, MG1.19 cells stably expressing EGAM1C at levels similar to those in blastocysts were established using an episomal expression system. In the presence of leukemia inhibitory factor (+LIF), control transfectants with an empty vector formed flattened cell colonies, whileEgam1ctransfectants formed compacted colonies with increased E-CADHERIN expression. InEgam1ctransfectants, the cellular contents of POU5F1 (OCT4), SOX2, TBX3, and NANOG increased. Cell growth was accelerated in an undifferentiated state sustained by LIF and in the course of differentiation. During clonal proliferation, EGAM1C stabilized the undifferentiated state. In adherent culture conditions, EGAM1C partly inhibited the progression of differentiation at least within a 4-day culture period in the presence of retinoic acid by preventing the downregulation of LIF signaling with a robust increase in TBX3 expression. Conversely, EGAM1C enhanced the expression of lineage marker genesFgf5(epiblast),T(mesoderm),Gata6(primitive endoderm), andCdx2(trophectoderm) in −LIF conditions. In embryoid bodies expressing EGAM1C, the expression of marker genes for extraembryonic cell lineages, includingTpbpa(spongiotrophoblast) andPlat(parietal endoderm), increased. These results demonstrated that the ectopic expression of EGAM1C is capable of affecting the stabilization of an undifferentiated state and the progression of differentiation in MG1.19 ES cells, in addition to affecting cellular morphology and growth.

To evaluate how the deposition of journal articles in Institutional Repositories (IRs) affects the number of citations and e-journal usage, we placed some articles published in Zoological Science in two IRs, and compared their use in IRs with e-journals, as well as with the number of resulting citations between 2008 and 2009. The results reveal that deposit in IRs did not reduce e-journal usage. Moreover, whereas the journals gained new readers, this did not have an effect on the number of citations., IFLA Satellite Pre-Conference Open Access to Scientific Information: Trends, Models and Strategies for Libraries. Chania, Crete, Greece, 2010-08-06/08, IFLA’s Science and Technology Libraries and Health and Biosciences Sections, 2010., 9783110263749

** * † ‡ This paper presents results from a NASA sponsored program to evaluate subsonic fixed wing transport aircraft entering service in the 2030-2035 time frame. The paper describes the effects of propulsion system configuration and fuel type on the fuel burn performance of a Hybrid Wing Body (HWB) aircraft designed for a long-haul international market. The wide centerbody of the HWB can accommodate a highly integrated, distributed propulsion system, the large design space offers the possibility of performance improvements from the extended use of boundary layer ingestion (BLI), and the large internal volume of a HWB aircraft can accommodate low density, high specific energy fuels. In this work, mechanically geared (planetary and beveled) and electrical transmissions systems were considered with varied numbers of turbogenerators and propulsors alongside either Liquefied Natural Gas (LNG) or conventional jet fuel. For all of the proposed propulsion system configurations, the minimum fuel burn corresponds to the case with the largest amount of boundary layer ingestion, in contrast to results presented previously by the authors. The minimum fuel burn for the conventional jet fuel design is 55% below that of the Boeing 777-200LR reference aircraft. The use of LNG fuel with laminar flow on the outer wing bottom and a turboelectric transmission system results in a 57% fuel burn reduction.

To determine the most effective book recommendation method for libraries, we conducted a recommendation experiment using (1) collaborative filtering based on the library loan records, (2) association rule mining based on the same data, and (3) Amazon. The library loan records of a certain university library for the period 2006 to 2011 were used. We recommended books to 33 students and asked them to describe the books' level of interest. The results show that books recommended by collaborative filtering were least favorably evaluated, followed by those recommended by association rule and Amazon. Collaborative filtering carries the risk of breaching users' privacy and its computational costs are higher compared to those of association rule mining. Therefore, if we recommend books based on library loan records, association rule mining should be adopted instead of collaborative filtering. In addition, given the fact that the recommendations by Amazon were most favorably evaluated, utilization of Amazon should also be considered.

This paper presents the results of the conceptual design and optimization of Hybrid Wing Body (HWB) aircraft that were designed to meet aggressive targets for fuel burn, noise, and landing / takeoff nitrogen oxide emissions for the 2030 timeframe. To address the aggressive targets, the HWB airframe design expands upon the work of the Silent Aircraft Initiative by using advanced subsystem level technological concepts with system-level, simultaneous optimization of airframe, propulsion, and operations. To assess the impact of payload and range on scalability, aircraft were designed at three scales, denoted as H1, H2, and H3, with similar payloads and range as the Boeing 737-800, 787-8, and 777-200LR, respectively. Due to cabin aisle height restrictions, the unusable “white” space for the H1 design resulted in a large empty weight fraction. Even with this, the H1 design achieved 45% lower fuel burn than the Boeing 737-800 due to the efficiencies of the all-lifting configuration, advanced propulsion system and assumed structural advancements. The H2 and H3 designs mitigated unused white space by carrying increased payload in a larger, more efficiently packaged centerbody, and their fuel burn was superior to the H1 design. The final H3 conceptual design achieved 54% lower fuel burn than the B777-200LR, noise levels 46 EPNdB below Stage 4 standards, and LTO NOX emissions that are 81.6% below CAEP 6 standards.

Modern technological developments, especially in controls, materials, and thrust vectoring have allowed a second look at large airships over the past decade. One especially promising concept is that of hybrid lift airships; vehicles producing lift through both dynamic and buoyant forces. Although simpler than conventional aircraft and more maneuverable than traditional airships, there still remain challenges related to their large size, ground handling, and perceived risk. This paper is a summary of work performed in the conceptual design of such a hybrid aircraft as part of a larger endeavor to develop an economically feasible intra-regional air transportation system. In the completion of this project, part of an air transportation system architecting course at the Massachusetts Institute of Technology, the authors did not attempt to completely solve all of the above problems but to minimize their impact through a systems level approach and through certain technology enablers where appropriate. Emphasis is on the design and technical aspects of the vehicle, with some focus on the overall system architecture where it drove key requirements or was able to alleviate some of the aforementioned barriers. Speciflc topics include a method for sizing and constraint analysis, an innovative system for lift management, and a discussion of important operational constraints as related to hybrid lift vehicles.

A propulsion system for a Nano-Air Vehicle (NAV), defined as an air vehicle smaller than 7.5 cm and weighing about 10 grams, has been designed, fabricated, and tested. The design features a novel gearless torque-canceling propeller mechanism, with a tightly-integrated counter-rotating electric drive motor. A design procedure that strongly couples the design tradeoff for the electrical motor and the propellers was developed and used to obtain an optimum design minimizing the power consumption at hover thrust. From the test results, the prototype: demonstrated maximum thrust of 17.28 g; provided hover thrust at a power consumption of 1.26 Watts and input voltage of 3.3 Volts, which translates to 20 minutes of hovering endurance; and provided a torque-canceling mechanism capable of canceling up to 99% of torque generated in the motor. Using a combination of 5-bladed and 3-bladed propellers with an operating motor speed of 9,000 rpm, this propulsion system had a noise footprint of 42.55 dBA 1m away from the vehicle, quieter than typical indoor background noise during the day. It is concluded that the propulsion system developed was capable of meeting all the requirements imposed by DARPA.

Fluorescence-guided surgery (FGS) has shown great promise, but has not been shown to be curative. Human MiaPaCa-2 pancreatic cancer cells, expressing green fluorescent protein (GFP), were implanted orthotopically in nude mice. Brightlight surgery (BLS) was performed on 24 tumor-bearing mice. After BLS, mice were randomized to BLS-only (n = 8) or FGS (n = 8) or FGS-UVC (n = 8) groups. The residual tumors were resected using a portable imaging system. FGS or FGS followed by UVC irradiation with 2700 J/m2 UVC (254 nm) was performed. Residual tumor area after FGS was significantly smaller than after BLS only (p = 0.007). The BLS treated mice had reduced survival compared to FGS- and FGS-UVC-treated mice for both relapse-free survival (RFS) (p,0.001 and p,0.001, respectively) and overall survival (OS) (p,0.001 and p,0.001, respectively). With FGS-UVC, RFS lasted at least 150 days indicating the animals were cured. UVC irradiation in combination with FGS has curative potential in the clinic. Citation Format: Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Curative fluorescence-guided surgery of pancreatic cancer in combination with UVC irradiation in orthotopic mouse models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5123. doi:10.1158/1538-7445.AM2015-5123

In this study, we determined the effectiveness of fluorescence-guided surgery (FGS) using a fluorophore-conjugated anti-carcinoembryonic antigen (CEA) antibody on a colon-cancer patient-derived orthotopic xenografts (PDOX™) nude mouse model. The patient tumor was established in NOD/SCID mice and passed orthotopically in nude mice to make PDOX™ models. Eight weeks after orthotopic implantation in nude mice, a monoclonal anti-CEA antibody conjugated with Alexa 488 was delivered to the PDOX™ models as a single intravenous dose 24 hours before laparotomy. The tumor was completely resected under fluorescence guidance using a hand-held portable fluorescence imaging system. Frozen section microscopy of the resected specimen demonstrated that the anti-CEA antibody selectively labeled cancer cells in the colon cancer PDOX™. Histologic evaluation of the resected specimen demonstrated that cancer cells were not present in the margins. The results of the present report predict that FGS using a fluorophore-conjugated anti-CEA antibody and hand-held portable imaging system should improve intraoperative staging and efficacy of resection for colorectal cancer in the clinic. Citation Format: Yukihiko Hiroshima, Ali Maawy, Sharmeela Kaushal, Yong Zhang, Fuminari Uehara, Shinji Miwa, Shuya Yano, Sho Sato, Takashi Murakami, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. A portable imaging system for fluorescence-guided surgery on a human colon cancer patient-derived orthotopic xenograft (PDOX™) nude mouse model. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B01.

The aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) in combination with fluorescence-guided surgery (FGS) on pancreatic cancer patient derived orthotopic xenograft (PDOX). We established the PDOX from the patient suffering from metastatic CA19-9-positive pancreatic cancer. Forty nude mice were implanted with tumor using surgical orthotopic implantation (SOI) on the nude mouse pancreas. Four weeks after implantation, the mice with tumor were randomized into 4 treatment groups: (1) bright-light surgery (BLS) only; (2) FGS; (3) NAC-BLS; (4) NAC-FGS. Gemcitabine (80 mg/kg, ip, weekly, 3 weeks) was used for NAC. Seven weeks after implantation, BLS was performed on all tumor-bearing mice. A monoclonal anti-human CA19-9 antibody conjugated with Dylight 650 was delivered to tumor-bearing mice in the FGS groups as a single intravenous dose 24 hours before BLS. Postoperatively, the surgical resection bed of FGS mice were imaged with the OV100 fluorescence imaging system to detect fluorescent residual tumors. The fluorescent residual tumors of FGS groups were then resected under fluorescence navigation. The average resected tumor weight of each group was as follows: (1) BLS, 188.5 ± 50.0 mg; (2) FGS, 278.0 ± 111.4 mg; (3) NAC-BLS, 84.5 ± 48.7 mg; (4) NAC-FGS, 141.8 ± 48.9 mg. The average resected tumor weight of NAC groups was significantly less than the non-NAC groups (113.1 ± 57.0 mg and 235.6 ± 94.3 mg, respectively; p>0.001). The average resected tumor weight of the FGS groups was significantly larger than the BLS groups (213.4 ± 107.1 mg and 136.5 ± 73.8 mg, respectively; p=0.016). Eight weeks after resection, we performed laparotomy to examine recurrence. The recurrence rate of each group was as follows: (1) BLS, 9 / 9 (100%); (2) FGS, 4 / 8 (50%); (3) NAC-BLS, 6 / 9 (66.7%); (4) NAC-FGS, 2 / 8 (25%). The recurrence rate of FGS groups was significantly lower than BLS groups (6 /16; 37.5% and 15 / 18; 83.3%, respectively; p=0.012), whereas there was no significant difference between FGS and NAC-FGS groups (p=0.608). There was no significant difference in the total recurrence rate between NAC and non-NAC groups (p=0.157). However NAC significantly reduced peritoneal recurrence (29.4 % and 0%, respectively; p=0.044). The results indicate that NAC in combination with FGS might reduce or even eliminate the peritoneal recurrence of pancreatic cancer. Citation Format: Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Efficacy of neoadjuvant chemotherapy in combination with fluorescence-guided surgery on a pancreatic cancer patient-derived orthotopic xenograft (PDOX). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3486. doi:10.1158/1538-7445.AM2014-3486

We have previously developed the genetically-modified Salmonella typhimurium A1-R (A1-R) strain that selectively targets tumors and demonstrated that A1-R was able to eradicate primary and metastatic tumors in monotherapy in nude mouse models of various cancers including pancreatic cancer. The aim of this study was to examine the efficacy of A1-R treatment on VEGF-positive human pancreatic cancer in a patient derived orthotopic xenograft (PDOX) model in combination with anti-VEGF therapy. A VEGF-positive human pancreatic cancer cell line (MiaPaCa-2-GFP) and VEGF-positive pancreatic cancer PDOX were orthotopically implanted in nude mice. The nude mice were treated in the following groups: (1) gemcitabine (GEM) (80 mg/kg, ip, weekly, 4 weeks); (2) GEM (80 mg/kg, ip, weekly, 4 weeks) + Bevacizumab (Bev) (5 mg/kg, ip, twice a week, 4 weeks); (3) GEM (80 mg/kg, ip, weekly, 2 weeks) + Bev (5 mg/kg, ip, twice a week, 2 weeks) → A1-R (1.5x108 CFU/body, ip, weekly, 2 weeks); and (4) saline (vehicle/control, ip, weekly, 4 weeks). The mean tumor weight of each group in the MiaPaCa-2-GFP model was as follows: (1) GEM; 775.9 ± 273.8 mg; (2) GEM/Bev; 413.5 ± 108.3 mg; (3) GEM/Bev→A1-R; 257.5 ± 57.1 mg; and (4) Control; 2655.4 ± 583.9 mg. GEM/Bev→A1-R significantly reduced tumor weight compared to GEM/Bev treatment in the MiaPaCa-2-GFP model (p=0.022). The tumor weight of each group in the PDOX model was as follows: (1) GEM; 263.1 ± 129.1 mg, (2) GEM/Bev; 65.9 ± 41.9 mg, (3) GEM/Bev→A1-R; 21.9 ± 6.2 mg and (4) Control; 998.8 ± 377.7 mg. GEM/Bev→A1-R significantly reduced tumor weight compared to GEM/Bev treatment in the PDOX model (p=0.029). These results demonstrate that A1-R is effective on pancreatic cancer in combination with anti-VEGF, including the PDOX model indicating the clinical potential of this combination. Citation Format: Yukihiko Hiroshima, Ming Zhao, Matthew H.G. Katz, Jason B. Fleming, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Yong Zhang, Ali Maawy, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Efficacy of Salmonella typhimurium A1-R and anti-VEGF therapy on a patient-derived orthotopic xenograft (PDOX) pancreatic cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1230. doi:10.1158/1538-7445.AM2014-1230

The aim of this study was to determine the efficacy of UVC irradiation in combination with fluorescence-guided surgery (FGS) in an orthotopic model of pancreatic cancer. Two weeks after orthotopic implantation of human MiaPaCa-2-GFP pancreatic cancer cells, bright-light surgery (BLS) was performed on all tumor-bearing mice (n=24). Postoperatively, the surgical resection bed was imaged with the OV100 variable magnification imaging system with a magnification of 0.56x to detect residual tumor. The mice which underwent BLS were randomized into 3 groups; BLS only (n=8) or FGS (n=8) or FGS-UVC (n=8). The residual tumors were resected with FGS using a portable, hand-held imaging system. After FGS, the surgical resection bed was imaged with the OV100 with a magnification of 0.89x, to detect minimal residual tumor and was irradiated with 2700 J/m2 UVC (emission peak 254 nm) from the bottom of a chamber using a Benchtop 3UV transilluminator (UVP, LLC, Upland, CA). The average residual tumor area after FGS was significantly smaller than BLS (0.135 ± 0.137 mm2 and 3.338 ± 2.929 mm2, respectively; p=0.007). Relapse-free survival (RFS) and overall survival (OS) were determined in 3 groups. Three-month RFS in the BLS, FGS and FGS-UVC were 0%, 50% and 100%, respectively. Five-month OS in BLS, FGS and FGS-UVC was 10%, 90% and 100%, respectively. FGS and FGS-UVC resulted in significantly increased survival compared to BLS for both RFS and OS. FGS-UVC showed significantly increased survival compared to the FGS for both RFS and OS (p=0.008 and p=0.025, respectively). These results suggests that UVC irradiation in combination with FGS could be a curative strategy for human pancreatic cancer. Citation Format: Yukihiko Hiroshima, Ali Maawy, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. UVC irradiation in combination with fluorescence-guided surgery cures metastatic human pancreatic cancer in orthotopic mouse models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4375. doi:10.1158/1538-7445.AM2014-4375

Macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors were defined as “tumor-educated macrophages” (EMϕ) and macrophages harvested from mice without tumors were defined as “naïve macrophages” (NMϕ). EMϕ promote tumor growth and metastasis. The aim of the present study was to determine the efficacy of Zoledronic acid (ZA) on EMϕ in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model. In this study, EMϕ and NMϕ were compared for their ability to enhance tumor progression. We initially demonstrated that the cancer cells exposed to the conditioned medium harvested from EMϕ culture significantly increased proliferation (p = 0.016) and had more migration stimulation capability (p < 0.001) compared to cultured cancer cells treated with the conditioned medium from NMϕ. Next, we examined the efficacy of ZA on EMϕ, and NMϕ and found that ZA had the ability to kill both EMϕ and NMϕ in vitro. We then demonstrated that EMϕ promoted tumor growth and metastasis in an orthotopic mouse model of a human pancreatic cancer cell line, ZA reduced the tumor growth (p = 0.006) and metastasis (p = 0.025) promoted by EMϕ. Finally, we examined the efficacy of ZA for pancreatic cancer in the PDOX model, and found that the combination of gemcitabine (GEM) and ZA reduced tumor weight (p = 0.016) and tumor growth (p = 0.005) compared to GEM alone. ZA alone reduced metastasis (p = 0.009). These results suggest that ZA inhibits the proliferation and the metastasis of human pancreatic cancer by targeting EMϕ. Citation Format: Yukihiko Hiroshima, Mohamed K. Hassenein, Rhiana Menen, Matthew H.g. Katz, Jason B. Fleming, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Ali Maawy, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Zoledronic acid inhibits proliferation and metastasis of human pancreatic cancer in the patient-derived orthotopic xenograft (PDOX) model by targeting tumor-educated macrophages. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3130. doi:10.1158/1538-7445.AM2014-3130

In this study, we demonstrated the advantage of a patient derived orthotopic xenograft (PDOX) compared to a subcutaneous patient cervical cancer. We originally established the PDX (F1) from the patient with a metastatic HER-2-positive cervical cancer in nude mice. We implanted to the small fragments of F1 PDX to 30 nude mice subcutaneously and 30 nude mice orthotopically to examine the efficacy of various drugs for this tumor. Six weeks after implantation, the mice in each model were randomized to 5 groups and treated in the following groups: (1) Trastuzumab (20 mg/kg, ip, weekly, 5 weeks) + Lapatinib (100 mg/kg, orally, daily, 5 weeks); (2) Entinostat (5 mg/kg, orally, daily, 5 weeks); (3) Trastuzumab (20 mg/kg, ip, weekly, 5 weeks) + Lapatinib (100 mg/kg, orally, daily, 5 weeks) + Entinostat (5 mg/kg, orally, daily, 5 weeks); (4) Carboplatin (30 mg/kg, ip, weekly, 5 weeks); and (5) saline (vehicle/control, ip, weekly, 5 weeks). The relative tumor volume, compared to time zero, of each group in the PDX model was as follows: (1) 1.23 ± 0.50; (2) 3.07 ± 1.79; (3) 0.38 ± 0.18; (4) 0.39 ± 0.23; (5) 10.23 ± 2.91. All regimens had significant efficacy compared to the untreated control group. The Trastuzumab/Lapatinib/Entinostat combination and Carboplatin were the most effective regimens in the subcutaneous model. The relative primary tumor volume of each group in the PDOX model was as follows: (1) 1.00 ± 0.23; (2) 3.25 ± 1.16; (3) 0.54 ± 0.34; (4) 0.48 ± 0.39; (5) 4.45 ± 1.09. The metastatic tumor weight of each group in PDOX model was as follows: (1) 5.7 ± 9.8 mg; (2) 20.1 ± 25.1 mg; (3) 4.7 ± 8.1 mg; (4) 0 ± 0 mg; (5) 112.0 ± 32.5 mg. All regimens had significant efficacy on the primary tumors compared to the control group except for the Entinostat alone group. However, Entinostat alone significantly reduced the metastatic tumor weight compared to the control. The Trastuzumab/Lapatinib/Entinostat combination and Carboplatin were the most effective regimens on both primary and metastatic tumors in the PDOX model. However, only the PDOX model metastasized and could be used to discover the anti-metastatic activity of the Entinostat alone. These results suggest that PDOX is the suitable model for individualized therapy as well as drug discovery for metastatic cervical cancer. Citation Format: Yukihiko Hiroshima, Yong Zhang, Ali Maawy, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. The advantages of patient-derived orthotopic xenograft (PDOX) of metastatic cervical cancer for individualized therapy compared to the PDX model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2014-1229

BACKGROUND: Ezrin is a member of the ezrin, radixin, and moesin family that provides a functional link between the plasma membrane and the cortical actin cytoskeleton. A correlation between ezrin overexpression and aggressive cancer behavior has been recently reported in various tumor types. However, its roles in the mechanisms underlying progression of tongue squamous cell carcinoma (SCC) are unclear. METHOD: We used human tongue SCC and noncancerous tissue microarrays to immunohistochemically analyze the ezrin expression level and its relationship with proliferative activity. The human tongue SCC cell line HSC-3 was used to determine the effects of ezrin RNA interference (RNAi) on cancer cells during MTT; wound healing and invasion assays; immunofluorescence of the actin cytoskeleton; and western blotting of E-cadherin, N-cadherin, β-catenin, and the active and total RhoA/Rac1/cdc42. RESULTS: Ezrin was overexpressed in 46.4% of the tumors examined in human tongue SCC tissue microarrays. Ezrin expression was correlated with the Ki-67 index. Ezrin depletion by RNAi in the HSC-3 cells significantly reduced cell proliferation, migration, and invasiveness and disturbed actin reorganization during podia formation. Its effects on RhoA/Rac1/cdc42 expression were not significant, whereas it enhanced E-cadherin and β-catenin expression and decreased N-cadherin expression. CONCLUSIONS: Ezrin is often overexpressed in primary tongue SCCs and may have an important role in their growth, migration, and invasiveness possibly via its relationship with the E-cadherin/β-catenin complex and the cadherin switch. Thus, ezrin could be a therapeutic target in tongue SCC.

Polarization control of the optical guided wave in a new configuration using a reverse-proton-exchanged (RPE) LiNbO3 straight waveguide and a leaky surface acoustic wave (LSAW) which propagates perpendicular to the straight waveguide was proposed. First, the perturbation of the dielectric tensor was estimated by using coupled mode theory. When a Love-type SAW on a proton-exchanged layer/YX-LiNbO3 was assumed, comparable perturbations to those in conventional Bragg diffraction due to a Rayleigh wave were confirmed. Next, a sample device with an LSAW wavelength Λ of 136 µm was fabricated on YX-LiNbO3 using an RPE channel waveguide. It was found that the incident linearly polarized wave was rotated by -90° in addition to the inherent rotation due to the perturbation of the LSAW without adding the LSAW wavenumber vector to the propagation constant of the incident optical guided mode. The maximum conversion efficiencies for optical wavelengths of 633, 532, and 473 nm were 87, 43, and 40%, respectively. The measured response time of 280 ns was almost equivalent to the time required for the propagation of the LSAW through the interdigital transducer width.

In order to show the effectiveness of using (a) library loan records and (b) information about book contents as a basis for book recommendations, we entered various data into a support vector machine (SVM), used it to recommend books to subjects, and asked them for evaluations of the recommendations that were given. The data that we used were (1) confidence and support with an association rule that was based on the loan records, (2) similarities between book titles, (3) matches/mismatches between the Nippon Decimal Classification (NDC) categories of the books, and (4) similarities between the outlines of the books in the BOOK Database . The subjects were 32 students who belonged to T University. The books that we recommended and the loan records that we used were obtained from the T University Library. The results showed that the combinations of (1), (2), (3) and (1), (2) were rated more favorably by the subjects than the other combinations. However, the books that were recommended by Amazon were rated even more favorably by the subjects. This is a topic for further research.

Changes in relative density and grain size of magnesium oxide (MgO) compact containing magnisium phosphate equivalent to 0.5mol% P2O5 were investigated between 1200°C and 1700°C; the bending strength, thermal expansion and water resistivity were examined for sintered compacts. The relative densities of MgO compacts with phosphate additions attained 96-99% as the sintering times at 1300°C and at 1400°C were prolonged from 5 to 30h. The bending strength and the thermal expansion coefficient of MgO compact with phosphate addition sintered at 1400°C for 30h were 185MPa (estimated value of nonporous compact: 300MPa) and 13.3×10-6°C-1 (30°-1000°C), respectively; the water-resistivity test (3h-immersion at 90°C) showed that the weight increase due to the hydration of MgO to Mg(OH)2 amounted only to 0.03%. The bending strength and water-resistivity of MgO compact was enhanced by the addition of phosphate.