In recent years, there has been strong focus on sustainable development goals (SDGs). In Japan, Society 5.0, which is proposed as a future vision to be achieved towards the realization of SDGs, is ...being promoted by various organizations. In particular, “i-Construction” is being promoted in the construction industry. As a result, hydraulic excavators are becoming increasingly automated and semi-automated. Furthermore, if operators achieve high productivity, it helps them maintain a sense of accomplishment and motivation to work. In this study, a control system that results in the desired output is proposed for a hydraulic excavator; in this system, the degree of interference depends on the human input and controller input. Attachments on hydraulic excavators cause interference owing to the characteristics of the hydraulic system. Therefore, a control system that can adaptively adjust the controller input to the human operation, considering the interference with information caused by human operation stored in the database, was constructed. The proposed method was implemented on a hydraulic excavator and its effectiveness was verified.
In contrast to a second dose of the SARS-CoV-2 mRNA vaccine, a third dose elicits potent neutralizing activity against the Omicron variant. To address the underlying mechanism for this differential ...antibody response, we examined spike receptor-binding domain (RBD)-specific memory B cells in vaccinated individuals. Frequency of Omicron-reactive memory B cells increased ∼9 mo after the second vaccine dose. These memory B cells show an altered distribution of epitopes from pre-second memory B cells, presumably due to an antibody feedback mechanism. This hypothesis was tested using mouse models, showing that an addition or a depletion of RBD-induced serum antibodies results in a concomitant increase or decrease, respectively, of Omicron-reactive germinal center (GC) and memory B cells. Our data suggest that pre-generated antibodies modulate the selection of GC and subsequent memory B cells after the second vaccine dose, accumulating more Omicron-reactive memory B cells over time, which contributes to the generation of Omicron-neutralizing antibodies elicited by the third vaccine dose.
In designing database-driven PID control systems, the offline learning scheme of PID gains included in the database has been proposed. However, it is difficult to apply this conventional scheme to ...real systems with unknown time-delays. In this study, a design method of database-driven PID controller using the response prediction is newly proposed. Plural databases are prepared corresponding to different time-delays and rise times. Furthermore, data-driven response predictive method is also introduced to predict responses and time-delays for each databases. As a result, the database with the desired control performance for the controlled object is adopted. The effectiveness of the proposed scheme for unknown time-delay systems is numerically verified in simulation examples.
Therapeutic efficacy of retroviral replicating vector (RRV)-mediated prodrug activator gene therapy has been demonstrated in a variety of tumor models, but clinical investigation of this approach has ...so far been restricted to glioma and gastrointestinal malignancies. In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer. RRV delivering GFP as a reporter gene showed rapid viral replication in a panel of lung cancer cells in vitro, as well as robust intratumoral replication and high levels of tumor transduction in subcutaneous and orthotopic pleural dissemination models of lung cancer in vivo. Toca 511 (
), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies.
Prodrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. ...Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects.
Here we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts.
In both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells.
These results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity.
The effectiveness of several vaccines against coronavirus disease (COVID-19) has been reported in the real-world setting. However, it is still unknown how long antibodies persist following ...vaccination and whether or not the persistence of antibodies has a protective effect against COVID-19.
Healthcare workers who had received two doses of the BNT162b2 mRNA COVID-19 vaccine were enrolled, and a single-center study was conducted at the National Hospital Organization Hakodate National Hospital. Serum samples from all participants were collected 13–21 weeks (median: 20 weeks) after the second dose of vaccination. The antibody titers were measured using an electrochemiluminescence immunoassay (Elecsys® Anti-SARS-CoV-2 S). Data on characteristics of the participants were gathered from patient records and interview sheets.
A total of 401 participants, among whom 70.1% were women and the median age was 42 years, were evaluated in this study. None of the participants had a definite COVID-19 history, and all participants who received complete vaccination showed positive antibody titers. The antibody titer was observed to be higher in participants with younger age (p < 0.001) and those who were females (p = 0.028). Despite the higher risk of infection than that of the general public, no vaccinated staff developed breakthrough infections.
This study demonstrates the significant contribution of the BNT162b2 vaccine in the acquisition of anti-SARS-CoV-2S antibodies; therefore, the general population should benefit from these two vaccine doses, which are expected to be protective for at least five months.
In lung cancer, chest wall infiltration caused by a tumor with a small diameter is extremely rare. The pathophysiologic features and prognosis of this phenomenon are poorly understood. Here, we ...report on a case in which a small peripheral lung cancer showed marked invasion into the chest wall. Although complete resection and postoperative adjuvant treatment were performed, lymph node recurrence developed and the patient died in one and a half years. Peripheral lung cancer can show exophytic development and infiltration of the chest wall, leading to poor prognosis, even if the tumor size is relatively small.
•Chest wall invasion by small-sized lung carcinoma•Lung tumor adjacent to intrapulmonary air space can show exophytic development•Lymph node metastasis with lung cancer with chest wall invasion after complete resection
Primary UPS of the lung, so‐called MFH, is a rare aggressive neoplasm and known to be a high risk of recurrence and metastasis. Surgical resection without residual tumor is the main option of ...treatment and the best chance for long‐term survival.
Primary UPS of the lung, so‐called MFH, is a rare aggressive neoplasm and known to be a high risk of recurrence and metastasis. Surgical resection without residual tumor is the main option of treatment and the best chance for long‐term survival.
Toca 511, a retroviral replicating vector (RRV) encoding the yeast cytosine deaminase (yCD) prodrug activator gene, which mediates conversion of the prodrug 5-fluorocytosine (5-FC) to the anticancer ...drug 5-fluorouracil (5-FU), is currently being evaluated in Phase II/III clinical trials for glioma, and showing highly promising evidence of therapeutic activity. Here we evaluated RRV-mediated prodrug activator gene therapy as a new therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). RRV spread rapidly and conferred significant cytotoxicity with prodrug in a panel of PDAC cells. Efficient intratumoral replication and complete inhibition of tumor growth upon 5-FC administration were observed in both immunodeficient and immunocompetent subcutaneous PDAC models. Biodistribution of RRV was highly restricted in normal tissues, especially in immunocompetent hosts. Tumor growth inhibition by Toca 511 followed by 5-FC was also confirmed in the orthotopic PDAC model. This study provides the first proof-of-concept for application of Toca 511 and Toca FC (extended release 5-FC) to the treatment of human PDAC, and provided support for inclusion of PDAC in a Phase I study evaluating Toca 511 in various systemic malignancies, (NCT02576665), which has recently been initiated.
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