Explore the vast range of titles available.

A new chimaeric mouse model of metastatic castration-resistant prostate cancer to efficiently test combination therapies in an autochthonous setting. Combination cancer therapies Metastatic castration-resistant prostate cancer (mCRPC) does not show strong responses to immunotherapies, such as immune checkpoint blockade (ICB), which have produced durable therapeutic responses in other cancer types. The authors develop a new chimaeric mouse model of mCRPC in which they test different combinations of immunotherapies, including ICB, and targeted therapies. They found that the most efficacious combinations were those that depleted myeloid-derived suppressor cells, suggesting the potential clinical relevance of this cell population. 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) 1 . 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 2 . However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade 3 , 4 , 5 , 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 6 . The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer 7 , 8 , 9 . Mouse models of prostate cancer show that MDSCs (CD11b + Gr1 + ) promote tumour initiation 10 and progression 11 . 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.

High-intensity, short-pulse lasers are crucial for generating energetic electrons that produce high-energy-density (HED) states in matter, offering potential applications in igniting dense fusion fuels for fast ignition laser fusion. High-density targets heated by these electrons exhibit spatially non-uniform and highly transient conditions, which have been challenging to characterize due to limitations in diagnostics that provide simultaneous high spatial and temporal resolution. Here, we employ an X-ray Free Electron Laser (XFEL) to achieve spatiotemporally resolved measurements at sub-micron and femtosecond scales on a solid-density copper foil heated by laser-driven fast electrons. Our X-ray transmission imaging reveals the formation of a solid-density hot plasma localized to the laser spot size, surrounded by Fermi degenerate, warm dense matter within a picosecond, and the energy relaxation occurring within the hot plasma over tens of picoseconds. These results validate 2D particle-in-cell simulations incorporating atomic processes and provide insights into the energy transfer mechanisms beyond current simulation capabilities. This work significantly advances our understanding of rapid fast electron heating and energy relaxation in solid-density matter, serving as a key stepping stone towards efficient high-density plasma heating and furthering the fields of HED science and inertial fusion energy research using intense, short-pulse lasers. Intense, short-pulse laser irradiation generates energetic electrons that heat targets to extreme conditions relevant to laser fusion. Here, authors used an X-ray Free Electron Laser to perform spatiotemporal measurements in solid-density copper foil with sub-micron and femtosecond resolutions.

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.

Background Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established. Methods To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven Braf V600E /Pten −/− /Cxcr2 −/− and NRas Q61R /INK4a −/− /Cxcr2 −/− melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in Braf V600E /Pten −/− and NRas Q61R /INK4a −/− mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, ChIPseq, and qRT-PCR; flow cytometry, and reverse phosphoprotein analysis (RPPA). Results Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1 , a key tumor suppressive transcription factor, was the only gene significantly induced with a log 2 fold-change greater than 2 in these three different melanoma models . Conclusions Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.

Background:Although rheumatoid arthritis (RA) patients with large joint involvement (LJI) have higher disease activity and lower physical function compared to patients without LJI,[1] the association between LJI and drug retention has not been examined. In addition, the pathophysiologies of patients with and without LJI may differ,[2] and therefore the characteristics and treatments of patients to modify the association between LJI and disease activity may exist.Objectives:The objectives of the multicenter longitudinal cohort study are twofold: (1) to examine the association of LJI with disease activity and drug retention, and (2) to explore the potential effect modifiers of changes in disease activity in patients with RA who started receiving biological disease-modifying antirheumatic drugs or Janus kinase inhibitors.Methods:Patients with RA from a Japanese multicenter observational registry were enrolled. According to the American College of Rheumatology/European League Against Rheumatism 2010 criteria,[3] we defined large joints as the shoulder, elbow, hip, knee, and ankle joints. Linear mixed-effects models were used to examine changes in the clinical disease activity index (CDAI) score at week 24 as the primary outcome, and drug retention rates were compared between patients with and without LJI using Cox proportional hazards models. We also examined the potential effect modifications of changes in CDAI by baseline characteristics.Results:A total of 2507 treatment courses from 1721 patients were included (LJI, 1744; no LJI, 763). Although LJI was associated with significantly higher changes in the CDAI score from baseline at week 24 (difference in change in CDAI: -5.84 [-6.65 to -5.03], P < 0.001), CDAI scores were significantly higher in patients with LJI over time (Figure 1A). Retention rates were similar in both groups (hazard ratio: 0.99 [0.85–1.14], P = 0.87) (Figure 1B). The association of LJI compared with that of no LJI with change in the CDAI score was more prominent in patients with short disease duration than in patients with long duration (Δ = -2.94, 95% CI: -6.86 to 0.98, P for interaction = 0.14), in patients with negative ACPA than in patients with positive ACPA (Δ = 0.94, 95% CI: -0.39 to -2.28, P for interaction = 0.17), and in patients using a IL-6 receptor inhibitor than in patients using a tumor necrosis factor inhibitor (Δ = -1.19, 95% CI: -2.29 to -0.08, P for interaction = 0.035) (Table 1).Conclusion:Although LJI was associated with a greater reduction in disease activity from baseline, higher disease activity at baseline was not offset over time in patients with LJI, demonstrating that LJI is an unfavorable predictor. An early treat-to-target strategy using an IL-6 receptor inhibitor may be beneficial for patients with LJI.REFERENCES:[1] Rubbert-Roth A, et al. Ann Rheum Dis. Jul 2018;77(7):1085-1086.[2] Chen DY, et al. Gerontology. 2009;55(3):250-258.[3] Aletaha D, et al. Ann Rheum Dis. 2010;69(9):1580-1588.Acknowledgements:NIL.Disclosure of Interests:Iku Shirasugi: None declared, Akira Onishi Pfizer Inc., Bristol-Myers Squibb., Advantest, Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K. K., Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd., Pfizer Inc., Bristol-Myers Squibb., Advantest, Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K. K., Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd., Keisuke Nishimura Pfizer Inc., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K. K., Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Janssen Pharmaceutical K.K., Taisho Pharmaceutical Co., Ltd, and Viatris Inc., Wataru Yamamoto: None declared, Kosaku Murakami Eisai Co. Ltd., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd., Daiichi Sankyo Co. Ltd., and Astellas Pharma Inc., Eisai Co. Ltd., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd., Daiichi Sankyo Co. Ltd., and Astellas Pharma Inc., Hideo Onizawa AbbVie, Asahi Kasei, Astellas Pharma Inc., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Daiichi Sankyo Co. Ltd., AbbVie, Asahi Kasei, Astellas Pharma Inc., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Daiichi Sankyo Co. Ltd., Yuichi Maeda Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol Myers Squibb, and Mitsubishi Tanabe Pharma Corporation., Kosuke Ebina AbbVie, Amgen, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Pfizer, Sanofi, Taisho Teijin Pharma, and UCB Japan., AbbVie, Amgen, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Pfizer, Sanofi, Taisho Teijin Pharma, and UCB Japan., Yonsu Son Bristol-Myers Squibb, Chugai, Janssen, Eisai, and Abbvie., Hideki Amuro: None declared, Masaki Katayama: None declared, Ryota Hara AbbVie, Eli Lilly, Eisai, and Asahi-Kasei., Koji Nagai Pfizer Inc., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K. K., Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Janssen Pharmaceutical K.K., Taisho Pharmaceutical Co., Ltd, and Viatris Inc., Yuri Hiramatsu Bristol-Myers Squibb, Astellas Pharma Inc, Asahi-Kasei, and UCB Japan Co. Ltd., Motomu Hashimoto Abbvie, Asahi Kasei, Astellas, Brystol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, Taisho Toyama, Tanabe Mitsubishi., Tadashi Okano Asahi-Kasei, Eisai, Mitsubishi-Tanabe, AbbVie, Chugai, Eli Lilly, Janssen and Novartis Pharma., Toshihisa Maeda: None declared, Shinya Hayashi: None declared, Sadao Jinno AbbVie, Asahi Kasei Pharma., Bristol-Myers Squibb., Chugai, Ltd., Eisai, Eli Lilly, Janssen, and Mitsubishi Tanabe, and Ono., Yuzuru Yamamoto: None declared, Hirotaka Yamada AbbVie, Asahi Kasei Pharma, Astellas, Chugai, Eisai, Gilead Sciences, and Taiho Pharmaceutical., Sho Sendo: None declared, Yo Ueda AbbVie, Asahi Kasei Pharma, Astellas, Bristol Meyers Squibb, Chugai, Eisai, Eli Lilly, Gilead Sciences, and Taiho Pharmaceutical., Jun Saegusa Asahi Kasei Pharma, Abbie Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K, Pfizer Inc., Eisai, Janssen Pharmaceutical K.K., and Mitsubishi Tanabe Pharma.

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.

Background In the tumor microenvironment, factors inhibiting the targeting of cancer cells by activated T cells have recently been noted. B7-H3 belongs to the B7 superfamily of immune regulatory ligands and plays an important role in the adaptive immune response of co-inhibitory/stimulatory factors in regulating T cells. However, the degree to which B7-H3 directly affects tumor immune evasion mechanisms remains unclear, particularly in patients with breast cancer. Regulatory T cells (Tregs) are known as a key player in the inhibition of immune mechanisms. The present study demonstrated that expression of B7-H3 on tumor cells and the number of Tregs in the tumor microenvironment independently affected prognosis in breast cancer patients. Methods We immunohistochemically investigated the presence of B7-H3 and forkhead box P3 (Foxp3)-positive Tregs in pathological specimens from 90 patients with breast cancer. Results Positive B7-H3 expression was associated with shorter recurrence-free survival (RFS) ( p   =  0.014). A higher percentage of Foxp3-positive cells also correlated with shorter RFS ( p   =  0.039). Multivariate analysis showed B7-H3 as an independent factor on RFS. Foxp3 expression in tumor-infiltrating lymphocytes (TILs) correlated significantly with larger tumor size (>2 cm), expression of human epidermal growth factor receptor 2 (HER2), and higher nuclear grade ( p   =  0.003, p   <  0.001, p   =  0.001, respectively). No correlation was identified between expression of B7-H3 and the percentage of Foxp3-positive TILs. Conclusions B7-H3 and Foxp3 can be regarded as markers of poor prognosis in breast cancer. These expressions were not correlated, suggesting that B7-H3 expression plays an independent role in tumor immune evasion, regardless of Tregs.

Incident delirium in older patients is associated with prolonged hospitalization and mortality. A recent study suggested an association between emergency department (ED) length of stay (LOS), time in ED hallways, and incident delirium. In this study we further evaluated the emerging association between incident delirium with ED LOS, time in ED hallways, and number of non-clinical patient moves in the ED. We performed this retrospective cohort study at a single, urban, academic medical center. All data were extracted from the electronic health record. We included patients aged ≥65 years presenting to the ED and admitted to family or internal medicine services over a two-year period. Patients admitted to any other service, transferred from another hospital, discharged from the ED, or who underwent procedural sedation were excluded. The primary outcome was incident delirium, defined as a positive delirium screen, receipt of sedative medications, or use of physical restraints. Multivariable logistic regression models including age, gender, language, history of dementia, Elixhauser Comorbidity Index, number of non-clinical patient moves within the ED, total time spent in the ED hallway, and ED LOS were fitted. We studied 5,886 patients ≥65 years of age; median age was 77 (69-83) years; 3,031 (52%) were female, and 1,361 (23%) reported a history of dementia. Overall, 1,408 (24%) patients experienced incident delirium. In multivariable models, ED LOS was associated with development of delirium (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01-1.03, per hour), while non-clinical patient moves [OR 0.97, (95% CI 0.91-1.04) and ED hallway time [OR 0.99, 95% CI 0.98-1.01, per hour) was not associated with development of delirium. In this single-center study, ED length of stay was associated with incident delirium in older adults, while non-clinical patient moves and ED hallway time in the ED were not. Health systems should systemically limit time in the ED for admitted older adults.

The X-ray Astronomy Recovery Mission (XARM) is a recovery mission of ASTRO-H/ Hitomi , which is expected to be launched in Japanese Fiscal Year of 2020 at the earliest. The Resolve instrument on XARM consists of an array of 6 × 6 silicon-thermistor microcalorimeters cooled down to 50 mK and a high-throughput X-ray mirror assembly with the focal length of 5.6 m. Hitomi was launched into orbit in February 2016 and observed several celestial objects, although the operation of Hitomi was terminated in April 2016. The soft X-ray spectrometer (SXS) on Hitomi demonstrated high-resolution X-ray spectroscopy of ~ 5 eV FWHM in orbit for most of the pixels. The Resolve instrument is planned to mostly be a copy of the Hitomi SXS and soft X-ray telescope designs, though several changes are planned based on the lessons learned from Hitomi . We report a brief summary of the SXS performance and the status of the Resolve instrument.

Helicobacter pylori infection induces chronic inflammation that contributes to gastric tumorigenesis. Tumor necrosis factor (TNF-α) is a proinflammatory cytokine, and polymorphism in the TNF-α gene increases the risk of gastric cancer. We herein investigated the role of TNF-α in gastric tumorigenesis using Gan mouse model, which recapitulates human gastric cancer development. We crossed Gan mice with TNF-α (Tnf) or TNF-α receptor TNFR1 (Tnfrsf1a) knockout mice to generate Tnf-/- Gan and Tnfrsf1a-/- Gan mice, respectively, and examined their tumor phenotypes. Notably, both Tnf-/- Gan mice and Tnfrsf1a-/- Gan mice showed similar, significant suppression of gastric tumor growth compared with control Tnf+/+ or Tnfrsf1a+/+ Gan mice. These results indicate that TNF-α signaling through TNFR1 is important for gastric tumor development. Bone marrow (BM) transplantation experiments showed that TNF-α expressed by BM-derived cells (BMDCs) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner, which is important for gastric tumor promotion. Moreover, the microarray analysis and colony formation assay indicated that NADPH oxidase organizer 1 (Noxo1) and Gna14 are induced in tumor epithelial cells in a TNF-α-dependent manner, and have an important role in tumorigenicity and tumor-initiating cell property of gastric cancer cells. Accordingly, it is possible that the activation of TNF-α/TNFR1 signaling in the tumor microenvironment promotes gastric tumor development through induction of Noxo1 and Gna14, which contribute to maintaining the tumor cells in an undifferentiated state. The present results indicate that targeting the TNF-α/TNFR1 pathway may be an effective preventive or therapeutic strategy for gastric cancer.