A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant ...prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b
Gr1
) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.
Summary
Previous studies have identified various factors related to masticatory performance. This study was aimed to investigate variations and impacts of factors related to masticatory performance ...among different occlusal support areas in general urban population in Japan. A total of 1875 Japanese subjects (mean age: 66·7 years) were included in the Suita study. Periodontal status was evaluated using the Community Periodontal Index (CPI). The number of functional teeth and occlusal support areas (OSA) were recorded, and the latter divided into three categories of perfect, decreased and lost OSA based on the Eichner Index. Masticatory performance was determined by means of test gummy jelly. For denture wearers, masticatory performance was measured with the dentures in place. The multiple linear regression analysis showed that, when controlling for other variables, masticatory performance was significantly associated with sex, number of functional teeth, maximum bite force and periodontal status in perfect OSA. Masticatory performance was significantly associated with number of functional teeth, maximum bite force and periodontal status in decreased OSA. In lost OSA, masticatory performance was significantly associated with maximum bite force. Maximum bite force was a factor significantly influencing masticatory performance that was common to all OSA groups. After controlling for possible confounding factors, the number of functional teeth and periodontal status were common factors in the perfect and decreased OSA groups, and only sex was significant in the perfect OSA group. These findings may help in providing dietary guidance to elderly people with tooth loss or periodontal disease.
The Time-Of-Propagation (TOP) counter is a novel device for particle identification for the barrel region of the Belle II experiment, where, information of Cherenkov light propagation time is used to ...reconstruct its ring image. We successfully finished the detector production and installation to the Belle II structure in 2016. Commissioning of the installed detector has been on going, where the detector operation in the 1.5-T magnetic field was studied. Although we found a problem where photomultipliers were mechanically moved due to the magnetic force, it was immediately fixed. Performance was evaluated with cosmic ray data, the number of photon hits was confirmed to be consistent with simulation within 15–30%.
Summary
Although dysphagia is a life‐threatening problem in patients with Parkinson's disease (PD), the pathophysiology of oropharyngeal dysphagia is yet to be understood. This study investigated the ...tongue motor function during swallowing in relation to dysphagia and the severity of PD. Thirty patients with PD (14 males and 16 females; average age, 69.4 years), Hoehn and Yahr stage II‐IV, in Osaka University Hospital are participated in this study. During swallowing 5 ml of water, tongue pressure on the hard palate was measured using a sensor sheet with 5 measuring points. The maximal tongue pressure at each measuring point during swallowing was compared between patients with PD and healthy controls. Subjective assessment of oropharyngeal dysphagia was performed using Swallowing Disturbance Questionnaire‐Japanese. The maximal tongue pressure at each measuring point was significantly lower in patients with PD than in healthy controls (8 males and 12 females; average age, 71.6 years). Furthermore, the maximal tongue pressure was significantly lower in dysphagic PD patients than non‐dysphagic PD patients. Loss of tongue pressure production at the anterior part of the hard palate was strongly related to dysphagia in the oral phase as well as in the pharyngeal phase. An abnormal pattern of tongue pressure production was more frequently observed in dysphagic PD patients than in non‐dysphagic PD patients. The results suggest that tongue pressure measurement might be useful for early and quantitative detection of tongue motor disability during swallowing in patients with PD.
Abstract
In this study, a new test method using protruding punch was proposed, that can separate bending and stretching deformations. In this test, the blank makes simultaneous contact with the punch ...head and shoulder to ensure a constant bending angle during the test. After the simultaneous contact, increasing the punch stroke increases the amount of stretch deformation without changing the bending deformation. In addition, this test method can control the inflow of materials by controlling the BHF, and it is possible to evaluate cracks during stretch bending deformation even for materials with low forming limits. This test can control the distribution of strain through the thickness. As a result, the measurable surface formation limit strain in this test was higher than FLC with uniform strain along the thickness. It is suggested that this is because the strain gradient through the thickness delayed the timing of necking occurrence. There is a linear relationship between this strain gradient and the maximum principal strain on the sheet surface, which can be applied to the prediction of stretch-bending cracks in FEM analysis.
A series of accidents at the Fukushima Dai-ichi Nuclear Power Plant following the Great East Japan Earthquake and tsunami of 11 March 2011 resulted in the release of radioactive materials to the ...ocean by two major pathways: direct release from the accident site and atmospheric deposition. A 1 yr, regional-scale simulation of 137 Cs activity in the ocean offshore of Fukushima was carried out, the sources of radioactivity being direct release, atmospheric deposition, and the inflow of 137 Cs deposited into the ocean by atmospheric deposition outside the domain of the model. Direct releases of 137 Cs were estimated for 1 yr after the accident by comparing simulated results and measured activities adjacent to the accident site. The contributions of each source were estimated by analysis of 131 I/137 Cs and 134 Cs/137 Cs activity ratios and comparisons between simulated results and measured activities of 137 Cs. The estimated total amounts of directly released 131 I, 137 Cs, and 137 Cs were 11.1 ± 2.2 PBq, 3.5 ± 0.7 PBq, and 3.6 ± 0.7 PBq, respectively. Simulated 137 Cs activities attributable to direct release were in good agreement with measured 137 Cs activities not only adjacent to the accident site, but also in a wide area in the model domain, therefore this implies that the estimated direct release rate was reasonable. Employment of improved nudging data by JCOPE2 improved both the offshore transport result and the reproducibility of 137 Cs activities 30 km offshore. On the other hand, simulated 137 Cs activities attributable to atmospheric deposition were low compared to measured activities. The rate of atmospheric deposition into the ocean was underestimated because of a lack of measurements of deposition into the ocean when atmospheric deposition rates were being estimated. Simulated 137 Cs activities attributable to the inflow of 137 Cs deposited into the ocean outside the domain of the model were in good agreement with measured activities in the open ocean within the model domain after June 2012. The consideration of inflow is important to simulate the 137 Cs activity in this model region in the later period of the simulation. The contribution of inflow increased with time and was dominant (more than 99%) by the end of February 2012. The activity of directly released 137 Cs, however, decreased exponentially with time and was detectable only in the coastal zone by the end of February 2012.
The gamma strength function and level density of 1^{-} states in ^{96}Mo have been extracted from a high-resolution study of the (pover →, pover →^{'}) reaction at 295 MeV and extreme forward angles. ...By comparison with compound nucleus γ decay experiments, this allows a test of the generalized Brink-Axel hypothesis in the energy region of the pygmy dipole resonance. The Brink-Axel hypothesis is commonly assumed in astrophysical reaction network calculations and states that the gamma strength function in nuclei is independent of the structure of the initial and final state. The present results validate the Brink-Axel hypothesis for ^{96}Mo and provide independent confirmation of the methods used to separate gamma strength function and level density in γ decay experiments.
The batch transesterification of vegetable oil with methanol, in the presence of potassium hydroxide as catalyst, by means of low frequency ultrasound (40
kHz) was studied with the aim of gaining ...more knowledge on intimate reaction mechanism. The concentration of fatty acid methyl esters, of mono-, di- and triglycerides of the actual reaction mixture were determined at short reaction time by HPLC. The effect of ultrasounds on the lipids transesterification correlated with triglyceride structures is discussed. It was found that under ultrasonic activation the rate-determining reaction switches from DG
→
MG (classical mechanic agitation) to MG
+
ROH
→
Gly
+
ME (ultrasonically driven transesterification).
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