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Funding Acknowledgements Type of funding sources: None. Introduction Chronotropic incompetence (CI) is sometimes observed during exercise training of cardiac rehabilitation in patients who underwent cardiac surgery, however, little is known which factors affect to the incidence of CI and exercise capacity of those patients. Purpose Because the possibility exists that cardiac sympathetic nerves might be impaired by surgical procedure, moreover CI is sometimes observed in patients after mitral valve surgery, we hypothesized that the incidence of CI was higher in patients with left atrium incision (LAI) during surgical operation as compared with those without LAI. And if so, which factor determines the exercise capacity of patients after cardiac surgery with LAI. We thus aimed this study to elucidate the hypothesis with cardiopulmonary exercise testing (CPX). Methods We performed CPX in total 153 patients who had undergone elective cardiac operation (45 patients with LAI, age 60.5±11.0; 108 patients without LAI, age 62.0±11.7). We analyzed chronotropic response index (CRI), peak oxygen uptake (peak VO2/W), anaerobic threshold (AT), and peak oxygen pulse (peak VO2/HR) with CPX, echocardiography, and blood hemoglobin concentration (Hb). Results The value of CRI was significantly reduced in the patients with LAI as compared with those without LAI (with LAI 0.24±0.22 vs. without LAI; 0.44±0.18, p Conclusions The present study demonstrated that higher incidence of CI was shown in patients with LAI as compared with those without LAI. Moreover peak VO2 of patients with LAI showed significant correlations with peak VO2/HR, Hb and LAD. These results suggest that 1) left atrium incision impairs cardiac sympathetic nerves and causes CI, 2) peak VO2/HR and Hb which is essential element of oxygen pulse are important factors for exercise capacity in patients after LAI with CI. Left atrium enlargement may indicates pre-operative damages of left atrium, 3) LAD which may indicate left atrium function, also is an important factor of exercise capacity in those patients.

Figure S2: Engineered murine T cells exhibit effector function in response to cognate peptide.

Figure Legends for Supplemental Figures

Adoptive T-cell therapy using high-affinity T-cell receptors (TCR) to target tumor antigens has potential for improving outcomes in high-grade serous ovarian cancer (HGSOC) patients. Ovarian tumors develop a hostile, multicomponent tumor microenvironment containing suppressive cells, inhibitory ligands, and soluble factors that facilitate evasion of antitumor immune responses. Developing and validating an immunocompetent mouse model of metastatic ovarian cancer that shares antigenic and immunosuppressive qualities of human disease would facilitate establishing effective T-cell therapies. We used deep transcriptome profiling and IHC analysis of human HGSOC tumors and disseminated mouse ID8VEGF tumors to compare immunologic features. We then evaluated the ability of CD8 T cells engineered to express a high-affinity TCR specific for mesothelin, an ovarian cancer antigen, to infiltrate advanced ID8VEGF murine ovarian tumors and control tumor growth. Human CD8 T cells engineered to target mesothelin were also evaluated for ability to kill HLA-A2+ HGSOC lines. IHC and gene-expression profiling revealed striking similarities between tumors of both species, including processing/presentation of a leading candidate target antigen, suppressive immune cell infiltration, and expression of molecules that inhibit T-cell function. Engineered T cells targeting mesothelin infiltrated mouse tumors but became progressively dysfunctional and failed to persist. Treatment with repeated doses of T cells maintained functional activity, significantly prolonging survival of mice harboring late-stage disease at treatment onset. Human CD8 T cells engineered to target mesothelin were tumoricidal for three HGSOC lines. Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC.

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CD8 T lymphocytes are able to eliminate nascent tumor cells through a process referred to as immunosurveillance. However, multiple inhibitory mechanisms within the tumor microenvironment have been described that impede tumor rejection by CD8 T cells, including increased signaling by inhibitory receptors. Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that has been shown repeatedly to promote diverse cellular processes benefiting tumorigenesis. Accordingly, the exaggerated expression of LPA and LPA receptors is a common feature of diverse tumor cell lineages and can result in elevated systemic LPA levels. LPA is recognized by at least six distinct G protein–coupled receptors, several of which are expressed by T cells, although the precise function of LPA signaling in CD8 T-cell activation and function has not been defined. Here, we show that LPA signaling via the LPA5 receptor expressed by CD8 T cells suppresses antigen receptor signaling, cell activation, and proliferation in vitro and in vivo. Importantly, in a mouse melanoma model tumor-specific CD8 T cells that are LPA5-deficient are able to control tumor growth significantly better than wild-type tumor-specific CD8 T cells. Together, these data suggest that the production of LPA by tumors serves not only in an autocrine manner to promote tumorigenesis, but also as a mechanism to suppress adaptive immunity and highlights a potential novel target for cancer treatment. Cancer Immunol Res; 1(4); 245–55. ©2013 AACR.

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Funding Acknowledgements Type of funding sources: None. Background Orthostatic hypotension (OH) is sometimes observed during cardiac rehabilitation in patients with surgery for aortic dissection. However, little is known about the primary determinant of OH and influence of surgical range on incidence of OH. Purpose The aim of this study was to elucidate the incidence of OH in patients with surgery for aortic dissection, and compare it between the patients with ascending aortic replacement surgery (ascending group) and those with ascending aorta and hemiarch or total arch replacement surgery (arch group). Methods We analyzed 59 patients who underwent emergent surgery due to Stanford type A aortic dissection from January 2014 to March 2018, and compared the incidence of OH between ascending group (n = 28, age 69.8 ± 11.3 years) and arch group (n = 31, age 64.1 ± 13.0 years). Results The incidence of OH in total patients was 30.5%. There were no significant differences in patient characteristics including body tall, body weight, antihypertensive use and progress of rehabilitation between 2 groups. The arch group showed a significant higher incidence of OH as compared with ascending group (arch group: 46.4% vs. ascending group: 16.1%, p = 0.03). Moreover, the patients who occurred OH were significantly taller than those who did not occur OH. Conclusions OH was observed in about one third of patients with surgery for aortic dissection and it showed a close relationship with patient’s height and the range repaired by surgical operation. More careful cardiac rehabilitation is needed for tall patients with large area replacement of aorta.

BackgroundIn the U.S., more than 50% of ovarian cancer patients die within 5 years of diagnosis, highlighting the need for innovations such as engineered T cell therapies. Mesothelin (Msln) is an attractive immunotherapy target for this cancer, as it is overexpressed by the tumor and contributes to malignant and invasive phenotypes, making antigen loss disadvantageous to the tumor. We previously showed that adoptively transferred T cells engineered to be Msln-specific (TCR1045) preferentially accumulate within established ovarian tumors, delay tumor growth and significantly prolong survival in the ID8VEGF mouse model. However, T cell persistence and anti-tumor activity were not sustained, and we and others have previously detected FasL in the tumor vasculature and the tumor microenvironment (TME) of human and murine ovarian cancers, which can induce apoptosis in infiltrating lymphocytes expressing Fas receptor (Fas).MethodsTo concurrently overcome this mechanism for potential immune evasion and enhance T cell responses, we generated an immunomodulatory fusion protein (IFP) containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain, rather than the natural death domain. T cells engineered to express TCR1045 alone or in combination with the IFP were transferred into ID8VEGF-tumor bearing mice and evaluated for persistence, proliferation, anti-tumor cytokine production, and therapeutic efficacy.ResultsRelative to T cells modified only to express TCR1045, T cells engineered to express both TCR1045 and a Fas IFP preferentially persisted in the TME of tumor-bearing mice due to improved T cell proliferation and survival. Moreover, adoptive immunotherapy with IFP+ T cells significantly prolonged survival in tumor-bearing mice, relative to TCR1045 T cells lacking the IFP.ConclusionsFas/FasL signaling can mediate T cell death in the ovarian cancer microenvironment, as well as induce activation-induced cell death, an apoptotic mechanism responsible for regulating T cell expansion. Upregulation of FasL by tumor cells and tumor vasculature represents a mechanism for protecting growing tumors from attack by tumor-infiltrating lymphocytes. As many solid tumors overexpress FasL, an IFP that converts the Fas-mediated death signal into pro-survival and proliferative signals may provide an opportunity to enhance engineered adoptive T cell therapy against many malignancies.

A method of estimating traffic loads on a highway by the deformation of a bridge is called bridge-weigh-in-motion (BWIM). The conventional BWIM is based on the strain measurement of main girders. To obtain supplemental information, strains of transverse stiffeners are also measured. Previously, it has been shown that the estimation of the truck loads by the strains of transverse stiffeners solely was possible. The method is competitive from the viewpoint of cost-effectiveness. Involving the integration of time-history response of strain, the method is called BWIM by Integration Method with Transverse Stiffeners. The present study tries to modify it so as to estimate the axle loads, concluding that it works fine for the axle load as well. Yet it is noticed that when two trucks run side by side, accuracy may be deteriorated. The way to improve the accuracy in such a case is also presented.

Adoptive T-cell therapy using high-affinity T-cell receptors (TCR) to target tumor antigens has potential for improving outcomes in high-grade serous ovarian cancer (HGSOC) patients. Ovarian tumors develop a hostile, multicomponent tumor microenvironment containing suppressive cells, inhibitory ligands, and soluble factors that facilitate evasion of antitumor immune responses. Developing and validating an immunocompetent mouse model of metastatic ovarian cancer that shares antigenic and immunosuppressive qualities of human disease would facilitate establishing effective T-cell therapies. We used deep transcriptome profiling and IHC analysis of human HGSOC tumors and disseminated mouse ID8VEGF tumors to compare immunologic features. We then evaluated the ability of CD8 T cells engineered to express a high-affinity TCR specific for mesothelin, an ovarian cancer antigen, to infiltrate advanced ID8VEGF murine ovarian tumors and control tumor growth. Human CD8 T cells engineered to target mesothelin were also evaluated for ability to kill HLA-A2+ HGSOC lines. IHC and gene-expression profiling revealed striking similarities between tumors of both species, including processing/presentation of a leading candidate target antigen, suppressive immune cell infiltration, and expression of molecules that inhibit T-cell function. Engineered T cells targeting mesothelin infiltrated mouse tumors but became progressively dysfunctional and failed to persist. Treatment with repeated doses of T cells maintained functional activity, significantly prolonging survival of mice harboring late-stage disease at treatment onset. Human CD8 T cells engineered to target mesothelin were tumoricidal for three HGSOC lines. Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC.

Leukemia is the most common pediatric cancer and the second leading cause of cancer deaths in children. Adoptive cell therapy (ACT) has been validated in pediatric B cell acute lymphoblastic leukemia, where engineered cancer-targeting T cells can effectively eradicate tumor and tumor recurrence, generally more safely than drug and radiation therapy. However, ACT is not approved for patients with pediatric AML, other leukemias or solid tumors. Of note, pediatric AML patients have a worse 5-year survival rate than ALL. AML cells can severely diminish ACT efficacy by expressing ligands that activate T cell inhibitory receptors and by downregulating costimulatory ligand expression. To address these issues, we developed fusion proteins that combine the ectodomain of an inhibitory T cell receptor with an intracellular costimulatory signaling domain. We have shown that this effectively “replaces a brake with an accelerator” in CD8 T cells, and have now developed FPs with different costimulatory domains to confer different attributes to T cells. Despite improved outcomes with single FP T cell therapy, we hypothesized that combining differently costimulated T cells would provide a synergistically diverse T cell response and improve outcomes. We tested 1:1 pairwise combinations of differently costimulated T cells that are also transduced with a tumor-specific TCR in serial killing over-time (SKO) assays and in vivo persistence studies. In survival studies, dual T cell therapy resulted in enhanced survival. We propose that a synergistically diverse T cell therapy provides enhanced antitumor efficacy over a monogenic cell product.

In the field of non-destructive investigations, the arrival time of the elastic waves is the important parameters to visualize the locations of the failures and/or elastic wave velocity distributions that are generally used for the soundness evaluation. The accuracy of the visualization depends on the accuracy of the arrival times, and it is demanded that the arrival times are detected automatically with required accuracy from huge amount of the elastic wave measurement data for the practical applications. In this paper, a method of the arrival time detection is proposed on the basis of the sparse matrix computation. The root mean square voltages in the noise of the wave form, is used as an index to separate the elastic waves between the noise and the signal, and the boundary of the index between the noise and the signal in the wave forms is determined in the sparse matrix. Therefore, the arrival times located in the boundary of the noise and it is detected by sparse matrix computations. The proposed method is verified on the model tests and compared with the conventional method, and it was confirmed that the proposed method detects more arrival time accurately in comparison with the conventional method.

This paper verifies the compressive sampling(CS)-based elastic wave velocity tomography(EWT) technique. Conventional elastic wave velocity tomography necessitates the quantity of effort and time. Nevertheless, because the central premise of CS algorithm is to recover the original velocity distribution from random measurement subsampling, compressive sampling is adopted at overcoming this challenge. CS algorithm chose fewer paths from entire measurements during the measurement stage. After that, the L1-minimization optimization method adopts to recover the damage area and magnitude in the visualization stage. Because of hugely reduces the measurement workload and a high level of accuracy reconstruction, CS algorithm is more effective in comparison with the conventional algorithms of elastic wave velocity tomography.

We report here the first successful synthesis of planar triphenylborane 1 with the phenyl groups bridged by oxygen and nitrogen atoms via double nucleophilic aromatic substitution reaction. The hetero atom-bridged 1 has excellent planarity. Its structural and photophysical properties are tunable by altering the bridging atoms.

Background Chronotropic incompetence (CI) is sometimes observed during exercise training of cardiac rehabilitation in patients with cardiac surgery, however, little is known concerning the differences between patients with mitral valve (MV) and aortic valve (AV) surgery. Purpose Because the possibility exists that cardiac sympathetic nerves might be impaired by left atrium incision, we hypothesized that the incidence of CI was higher in patients with MV surgery (Mitral Valve Replacement and Mitral Valvuloplasty) as compared with patients with AV surgery (Aortic Valve Replacement). And if so, which factor determines the exercise capacity of patients after MV surgery. We thus aimed this study to elucidate the hypothesis with cardiopulmonary exercise testing (CPX). Methods We performed CPX by ramp loading with ergometer exercise in total 61 patients who had undergone elective cardiac valve operation (25 patients with MV surgery, age 59.2±9.9 years; 36 patients with AV surgery, age 64.6±12.3 years). We analyzed chronotropic response index (CRI), peak oxygen uptake (peak VO2/W), anaerobic threshold (AT), and peak oxygen pulse (peak VO2/HR) with CPX, and blood hemoglobin concentration (Hb). Results The value of CRI was significantly decreased in the patients with MV surgery compared with those with AV surgery (MV; 0.19±0.10 vs. AV; 0.41±0.17, p Conclusions The present study demonstrated that higher incidence of CI was shown in patients with MV surgery as compared with those with AV surgery. The exercise capacity of patients with MV surgery was determined by peak VO2/HR and Hb. These results suggest that 1) left atrium incision impairs cardiac sympathetic nerves and causes CI, 2) peak VO2/HR which is consisted of arterio-venous oxygen difference and Hb is critical indicator for exercise capacity in patients with MV surgery with CI. Main results Funding Acknowledgement Type of funding source: None

BackgroundIn the USA, more than 50% of patients with ovarian cancer die within 5 years of diagnosis, highlighting the need for therapeutic innovations. Mesothelin (MSLN) is a candidate immunotherapy target; it is overexpressed by ovarian tumors and contributes to malignant/invasive phenotypes, making tumor antigen loss disadvantageous. We previously showed that MSLN-specific T cell receptor (TCR)-engineered T cells preferentially accumulate within established tumors, delay tumor growth, and significantly prolong survival in the ID8VEGF mouse model that replicates many aspects of human disease. However, T cell persistence and antitumor activity were not sustained. We therefore focused on Fas/FasL signaling that can induce activation-induced cell death, an apoptotic mechanism that regulates T cell expansion. Upregulation of FasL by tumor cells and tumor vasculature has been detected in the tumor microenvironment (TME) of human and murine ovarian cancers, can induce apoptosis in infiltrating, Fas (CD95) receptor-expressing lymphocytes, and can protect ovarian cancers from tumor-infiltrating lymphocytes.MethodsTo overcome potential FasL-mediated immune evasion and enhance T cell responses, we generated an immunomodulatory fusion protein (IFP) containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain, rather than the natural death domain. Murine T cells were engineered to express an MSLN-specific TCR (TCR1045), alone or with the IFP, transferred into ID8VEGF tumor-bearing mice and evaluated for persistence, proliferation, cytokine production and efficacy. Human T cells were similarly engineered to express an MSLN-specific TCR (TCR530) alone or with a truncated Fas receptor or a Fas-4-1BB IFP and evaluated for cytokine production and tumor lysis.ResultsRelative to murine T cells expressing only TCR1045, T cells expressing both TCR1045 and a Fas-4-1BB IFP preferentially persisted in the TME of tumor-bearing mice, with improved T cell proliferation and survival. Moreover, TCR1045/IFP+ T cells significantly prolonged survival in tumor-bearing mice, compared with TCR1045-only T cells. Human T cells expressing TCR530 and a Fas-4-1BB IFP exhibit enhanced functional activity and viability compared with cells with only TCR530.ConclusionsAs many ovarian tumors overexpress FasL, an IFP that converts the Fas-mediated death signal into pro-survival and proliferative signals may be used to enhance engineered adoptive T cell therapy for patients.

A Fas-4-1BB immunomodulatory fusion protein converts a pro-death to a pro-survival signal, enhancing T cell function and improving the efficacy of adoptive T cell therapy in immunocompetent murine models of liquid and solid tumors., Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor–positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to convert negative into positive signals. We developed a Fas-4-1BB IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function, and altered metabolism in vitro. In vivo, Fas-4-1BB ACT eradicated leukemia and significantly improved survival in the aggressive KPC pancreatic cancer model. Fas-4-1BB IFP expression also enhanced primary human T cell function in vitro. Thus, Fas-4-1BB IFP expression is a novel strategy to improve multiple T cell functions and enhance ACT against solid tumors and hematologic malignancies., Graphical Abstract

The interior and surface degradation of a multicrystalline silicon (mc-Si) solar cell module was investigated using the laser beam-induced current (LBIC) technique. Reverse voltage was applied to avoid the influence of the solar cells not irradiated with light and to evaluate the LBIC intensity only of the illuminated solar cell. In addition, we found that the mc-Si, but not the solar cell surface, is comprised of homogeneous crystals and the degraded layer is estimated to be $\sim 0.6~\mu\text{m}$ . The LBIC technique was applied at several wavelengths under reverse bias conditions in order to analyze degraded solar cells.

Diversos setores de negócio conferem aos seres humanos tarefas repetitivas, exaustivas, de pouca complexidade e que não demandam muita técnica ou pensamento estratégico. O objetivo deste projeto consiste na aplicação de tecnologia capaz de executar tais tarefas de maneira mais rápida e assertiva, economizando tempo e reduzindo custos para as organizações, o Robotic Process Automation (RPA). Sob forma de estudo de caso, foi analisada a solução em implementação da tecnologia no Recebimento Fiscal da empresa Votorantim S.A, um processo extenso e que consome horas de dedicação humana em atividades repetitivas que não exigem pensamento analítico. Serão avaliados seus benefícios (custos, otimização de tempo, produtividade, digitalização), impacto sobre operação e resultados financeiros obtidos com a implementação da ferramenta na companhia.

Acute myeloid leukemia (AML), the most common adult acute leukemia in the United States, has the poorest survival rate, with 26% of patients surviving 5 years. Adoptive immunotherapy with T cells genetically modified to recognize tumors is a promising and evolving treatment option. However, antitumor activity, particularly in the context of progressive leukemia, can be dampened both by limited costimulation and triggering of immunoregulatory checkpoints that attenuate T-cell responses. Expression of CD200 (OX2), a negative regulator of T-cell function that binds CD200 receptor (CD200R), is commonly increased in leukemia and other malignancies and is associated with poor prognosis in leukemia patients. To appropriate and redirect the inhibitory effects of CD200R signaling on transferred CD8+ T cells, we engineered CD200R immunomodulatory fusion proteins (IFPs) with the cytoplasmic tail replaced by the signaling domain of the costimulatory receptor, CD28. An analysis of a panel of CD200R-CD28 IFP constructs revealed that the most effective costimulation was achieved in IFPs containing a dimerizing motif and a predicted tumor-T-cell distance that facilitates localization to the immunological synapse. T cells transduced with the optimized CD200R-CD28 IFPs exhibited enhanced proliferation and effector function in response to CD200+ leukemic cells in vitro. In adoptive therapy of disseminated leukemia, CD200R-CD28-transduced leukemia-specific CD8 T cells eradicated otherwise lethal disease more efficiently than wild-type cells and bypassed the requirement for interleukin-2 administration to sustain in vivo activity. The transduction of human primary T cells with the equivalent human IFPs increased proliferation and cytokine production in response to CD200+ leukemia cells, supporting clinical translation. This trial was registered at www.clinicaltrials.gov as #NCT01640301.

Improved therapies are urgently needed for several cancers, including acute myeloid leukemia (AML) and pancreatic cancers. Adoptive cell therapy (ACT) with genetically-modified T cells has shown impressive results against B cell malignancies, but limited efficacy in other hematologic and solid tumors. To address this need, we have developed immunomodulatory fusion proteins (IFPs) that combine the ectodomain of an inhibitory receptor with a costimulatory endodomain, providing positive signals exclusively delivered to the T cells concurrently engineered to target tumor-expressed antigens, avoiding the systemic T cell activation seen with immune checkpoint-blocking therapies. We developed an IFP to target Fas ligand (FasL), which is commonly over-expressed in TMEs and induces apoptosis in tumor-infiltrating T cells. We replaced the Fas intracellular tail with the costimulatory, pro-survival 4-1BB signaling domain since both Fas and 4-1BB signal as trimers. After exposure to a murine AML cell line, IFP-transduced murine T cells effectively generated 4-1BB signaling, with metabolic reprogramming, and showed enhanced in vitro proliferation, accumulation and function. IFP T cells resisted exhaustion and effectively eradicated AML, improving survival to 71% in the FBL disseminated AML murine model (vs.11% survival with control T cells). We next engineered T cells with a single-vector that combined the IFP with a tumor-targeted mesothelin-targeted T cell receptor (TCR), for studies with the KPC mouse model of PDA that recapitulates the immunosuppressive characteristics of human disease. TCR/Fas-4-1BB T cells showed increased intratumoral concentration over control TCR-only T cells and increased median survival (65 vs. 37 days, P=0.0042). Human TCR/Fas-4-1BB T cells induced significantly more PDA tumor cell lysis than a dominant negative Fas receptor, supporting the increased benefit of the costimulatory signal. Single-cell RNA sequencing results suggest that IFP-ACT can also improve endogenous antitumor immunity, and Fas-4-1BB primary human T cells showed increased in vitro expansion and cytokine production, relative to TCR-only human T cells. We have now developed a toolbox of IFPs with distinct costimulatory domains and we show that IFPs can substantially improve therapeutic efficacy against liquid and solid tumors, supporting clinical translation. Citation Format: Margot McMurray, Shannon Oda. A FasL-targeted immunomodulatory fusion protein replaces a pro-death with a costimulatory signal, enhancing T cell function, adoptive cell therapy, and altering the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1542.

In this study, to consider a method for detecting the sediment portion of avalanches containing sediment using microwave Doppler sensors, we confirmed whether the signal processing obtained by the sensors can differentiate the objects. Since microwaves in this frequency band are not easily affected by rain and snowfall, these are being developed for use in dashboard camera and other applications. However, it is necessary to understand the attenuation of the microwave for the snow in order to apply this technology to detect the sediment in the avalanche. It is also necessary to know the rate of reflection of microwaves from the snow and sand. Therefore, it is necessary to verify whether the reflection of the microwave from the sediment is correctly measured or not. In this report, we discuss the results of the verification to see if the distance between the sensor and the object, which is known in advance, can be detected correctly.

In order to investigate the progressive failure of soil-structures, non-destructive inspections have been applied in recent. Use of Acoustic Emission (AE), the elastic wave which is generated by the occurrence of cracks, is attractive in this field to detail the progressive failure if the measurement is conducted with sufficiently small time interval. Although this technique potentially detects the cracks clearly, conventional methods of AE source localization consider that elastic wave velocity distribution is homogenous, and there are the limitations of its application due to the diffraction and the refraction of elastic wave if the heterogeneity of the elastic wave velocity distribution is not negligible. In this study, AE-Tomography (AET), which performs the identification elastic wave velocity distribution and the localization of AE sources with consideration of the diffraction and the refraction of elastic wave, is validated about the performance of the identification of the elastic wave velocity distribution and the AE sources localizations on numerical tests and model tests. Artificial AE events are generated in the soil specimen that have some parts of different relative density and validation of AET is conducted by using the arrival times of the artificial AE. According to the results of the validation, it is suggested that AET identifies elastic wave velocity distributions and AE source locations adequately on the heterogeneous elastic wave velocity distributions.

In the soundness evaluation method based on waveform analysis in time domain, the response waveforms that are measured while the target is in sound condition is indispensable. Therefore, it is expected that this method is for the evaluation of precast concrete products because the state of the products is almost identical and it is able to measure the response waveforms before using the products. On the other hand, although there are difficulties to apply this method for the evaluation of the existing structures because the response waveform is not measured before using, it is expected that this method can be applied to the evaluation of the existing structures by making the response waveform on the basis of the numerical simulation. The computational conditions should be set properly based on the actual measurement conditions for the numerical simulation. Among the computational conditions, the input frequency is determined based on the diameter of the steel ball and contact time if the excitation is given by making an impact with the steel ball by using the theory proposed by Sansalone et al. However, Kubo et al. reported that the measured contact time is different from the theoretical value and the difference reaches maximum twice. The influence of the difference would not be negligible for the soundness evaluation and should be considered carefully to perform the soundness evaluation accurately. Therefore, in this study, the response waveforms are computed on a numerical model with excitations of various input frequencies, and the influence of the input frequency to the response waveform is discussed by comparing the computed response waveforms.

Background:The roles of rheumatologists include patient education and information provision, and there is a report that patient care led by nurses gives high satisfaction. In addition, it has been reported that rheumatologists will no longer provide sufficient care for rheumatism and nurses may make up for the shortage (1). In order for patients to deal with diseases for a long time, it is necessary to communicate with patients through team approach to healthcare including nurses specialized in rheumatology, and to make efforts to further improve patient satisfaction.Objectives:The satisfaction of patients who had undergone joint ultrasound (MSKUS) by rheumatologist nurses who had been registered as sonographers by the Japan College of Rheumatology was evaluated using a net promoter score (NPS®) to investigate whether medical intervention by nurses improved patient satisfaction.Methods:A questionnaire survey was performed in 103 RA patients who visited our department. The contents were 2 points, and (1) MSKUS’s level of patient satisfaction and (2) MSKUS’s level of recommendation to others were investigated. In (1), whether or not (1) the echo test was good, (2) whether the test was done with peace of mind, (3) whether the time of the test was appropriate, and (4) whether or not the disease status was better understood after the test, and (5) whether or not the patient wished to undergo the echo test periodically, were asked on a 5 point scale (high evaluation to low evaluation, 1 ~ 5). Regarding (2), the doctor said “Would you like to recommend the joint echo test to other patients? This question was evaluated using NPS®, which is said to have strong correlation with patient satisfaction, growth, and business performance in various industries.Measurement method of NPS®The customer with the 9 ~ 10 point score is classified as a “recommendation” the customer with the 7 ~ 8 point score is classified as a “neutral person” and the customer with the 0 ~ 6 point score is classified as a “critical person” The value of NPS® is the value that comes out after subtracting the percentage of a critical person (%) from the percentage of a recommended person (%).Results:Questionnaires were administered to 103 RA patients and responses were obtained from all.(1) For the 5 items of patient satisfaction, 85% or more of the patients had high scores (1 and 2) for all the questions.(2) NPS® score was high at 67. The NPS® score was even higher in the group of patients without progression of joint destruction (Stage 1 and 2) at 79.Conclusion:It was suggested that when the nurse who usually coaches explained the symptoms immediately using POCUS, the patient’s satisfaction would be improved, and a sense of security would be provided for the test. In addition, NPS® is a unified questioning method and said to be highly correlated with customer satisfaction, and it was considered that POCUS leads to benefits in medical management.References:[1]Fusama M et al. Mod Rheumatol. 2017 Sep;27(5):886-893.; Survey on attitudes regarding EULAR recommendations for the role of nurses involved in medical care of patients with chronic inflammatory arthritis in Japan.Disclosure of Interests:None declared

Over half of patients diagnosed with high grade serous ovarian cancer will die within five years, highlighting the need for therapy innovation. Engineering T cells to target proteins uniquely overexpressed in tumors has the potential to limit tumor growth without toxicity—mesothelin (Msln) is a rational immunotherapy target as it contributes to the malignant/invasive phenotype and has limited expression in healthy cells. T cells were engineered to express a high-affinity Msln-specific T cell receptor (TCRMsln) and adoptively transferred into a disseminated ID8VEGF murine model, which recapitulates many features of human ovarian cancer. TCRMsln+ T cells preferentially accumulated within established tumors, delayed tumor growth, and significantly prolonged survival. However, T cell persistence and anti-cancer activity were limited by elements in the tumor microenvironment (TME), including Fas Ligand (FasL) that can induce apoptosis in infiltrating lymphocytes expressing Fas receptor (Fas). To overcome this potential T cell evasion mechanism, we generated a panel of immunomodulatory fusion proteins (IFPs) containing the Fas extracellular binding domain fused to a co-stimulatory domain, replacing the natural death domain. Relative to T cells modified with only TCRMsln, T cells that expressed both TCRMsln and a Fas IFP preferentially infiltrated tumors and expanded/persisted in the TME of tumor-bearing mice. Moreover, adoptive immunotherapy with TCRMsln+IFP+ T cells significantly prolonged survival in tumor-bearing mice, relative to TCRMsln+ only T cells. As many solid tumors overexpress FasL, IFPs may provide an opportunity to enhance engineered adoptive T cell therapy against many malignancies.

We have been exploring in preclinical models and clinical trials methods to reproducibly provide therapeutic T-cell responses by transfer of genetically engineered T cells. Our largest clinical experience has been in treating human acute myelogenous leukemia (AML), in which we have utilized a high-affinity TCR specific for WT1, a protein associated with promoting leukemic transformation that is overexpressed in human leukemic stem cells, to genetically engineer CD8 T cells. We recently reported a study (Chapuis et al., Nat Med 2019) in which we treated leukemia patients at high risk of relapse (after hematopoietic cell transplant) that demonstrated all treated patients remain alive and relapse free at a median of 48 months, compared to a relapse rate of ~35% in the concurrent matched cohort (p Citation Format: Philip D. Greenberg, Kristin G. Anderson, Dan Egan, Sunil R. Hingorani, Luigi Nezi, Teresa Manzo, Shannon K. Oda, Kelly G. Paulson, Rachel Perret, Leah Schmidt, Tom M. Schmitt, Ingunn M. Stromnes, Aude G. Chapuis. Targeting pancreatic cancer with TCR-engineered T cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I11.

The effect of cisplatin-induced acute renal failure (ARF) on the function and expression of multidrug resistanceassociated proteins (MRPs) was evaluated in rats. Rats received an intraperitoneal injection of cisplatin (9 mg/kg), and the induction of ARF state with high plasma concentrations of indoxyl sulfate and creatinine was observed 72 h after cisplatin treatment. The function of MRPs in the liver, kidney and brain was evaluated by measuring the tissue accumulation and biliary excretion of 2,4-dintrophenyl-S-glutathione (DNP-SG), a substrate for MRPs, after administration of 1-chloro-2,4-dintrobenzene (CDNB), a precursor of DNP-SG, in rats. The levels of MRP1-4 expression were evaluated by Western blot analysis. Effect of ARF plasma components on MRP function was also examined by using calcein acetoxymethyl ester (calcein-AM) in HepG2 cells. In ARF rats (72 h after cisplatin treatment), the accumulation of DNP-SG in the liver, kidney and brain was significantly higher than those in control and cisplatin-treated rats (1 h after treatment). In ARF rats, intrinsic biliary excretion clearance of DNP-SG, estimated by dividing the biliary excretion rate of DNP-SG with the liver concentration, was also significantly reduced, though the expression levels of MRP1-4 in the liver remained unchanged. ARF rat plasma (5%) significantly increased the accumulation of calcein, a MRP substrate, in HepG2 cells after application of calcein-AM. In conclusion, MRP function was found to be suppressed not only in the kidney but also in the liver and brain in cisplatin-induced ARF rats, possibly due to the accumulation of some MRP substrates/inhibitors in plasma.

Five-point algorithm is a powerful tool for relative orientation, because it requires no initial assumption of camera position. This algorithm determines an essential matrix from five point correspondences between two calibrated cameras, but results multiple solutions and some selecting process is required. This paper proposes Quasi-Five-Point Algorithm which is non-linear solver with seed solution of 8 point algorithm. The method tries to calculate the appropriate essential matrix without selecting process among multiple solutions. It is one of non-linear approach, but tries to find an appropriate seed before non-linear calculation. Using correspondences of 3 or more additional points, seed values of the solution is calculated. In this paper relationship between traditional parametric relative orientation and essential matrix is discussed, and after that quasi-five-point algorithm is introduced.