Explore the vast range of titles available.

Background: Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin’s effects on the balance between epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) in human breast cancer cells were investigated. Methods: Triple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER−)/progesterone receptor (PR−)/human epithelial growth receptor 2 (HER2−) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF- β /Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo , the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting. Results: Treatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF- β induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model. Conclusions: Eribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo , consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo . These preclinical findings may provide a plausible scientific basis for clinical observations of prolonged OS by suppression of further spread of metastasis in breast cancer patients treated with eribulin.

A long-standing crucial question with atomic nuclei is whether or not α clustering occurs there. An α particle (helium-4 nucleus) comprises two protons and two neutrons, and may be the building block of some nuclei. This is a very beautiful and fascinating idea, and is indeed plausible because the α particle is particularly stable with a large binding energy. However, direct experimental evidence has never been provided. Here, we show whether and how α (-like) objects emerge in atomic nuclei, by means of state-of-the-art quantum many-body simulations formulated from first principles, utilizing supercomputers including K/Fugaku. The obtained physical quantities exhibit agreement with experimental data. The appearance and variation of the α clustering are shown by utilizing density profiles for the nuclei beryllium-8, -10 and carbon-12. With additional insight by statistical learning, an unexpected crossover picture is presented for the Hoyle state, a critical gateway to the birth of life. Alpha particles are considered the building blocks for some nuclei in alpha-clustering. Here the authors discuss quantum many-body simulations with nucleon-nucleon interaction to characterize the Hoyle state, the first excited 0+ state of the 12C nucleus, and find complexity in its alpha-clustering.

Background:In recent years, the number of patients with late-onset rheumatoid arthritis (LORA) has been increasing [1]. LORA patients are often subject to various treatment restrictions due to their advanced age from the time of onset, and it has been reported that rheumatologists tend to hesitate to treat older patients aggressively [2]. However, no treatment strategy or treatment recommendation that takes age of onset into consideration has been proposed. Furthermore, it is suggested that there is diversity within LORA due to differences in the age of onset.Objectives:To compare the patient attributes, treatment approach and disease activity during the early stages of onset between late-onset rheumatoid arthritis (LORA) and younger-onset rheumatoid arthritis (YORA), and to clarify the differences between younger-onset LORA (“early LORA”) and older-onset LORA (“late LORA”).Methods:Among the 17,181 patients registered in NinJa (National Database of Rheumatic Diseases in Japan) [3], a nationwide RA database in Japan) in 2021, 1,154 patients with onset of disease less than 2 years were extracted. They were divided into three groups based on the age of onset: those under 65 years old in the YORA group (491 cases), those between 65 and 74 years old in the early LORA group (336 cases), and those over 75 years old in the late LORA group (327 cases). Their characteristics, disease activity, remission rates, and drugs used were compared.Results:The ages (mean [SD]) of the YORA, early LORA, and late LORA groups were 51.4 [10.3] years, 70.4 [2.8] years, and 81.1 [3.9] years. The proportion of men (24.2% in YORA, 37.8% in early LORA, and 33.0% in late LORA) was higher in LORA groups than in YORA, with BMI (22.8 [4.2], 22.9 [3.5], 22.2 [2.9]) and current plus past smoking rate (47.8 %, 48.7%, 33.0%) were significantly lower in late LORA. The mean estimated glomerular filtration rate (mL/min/1.73m2) (80.3 [16.0], 71.5 [16.0], 61.0 [17.7]), rheumatoid factor positive rate (69.3%, 61.5%, 58.8%) and anti-cyclic citrullinated peptide antibody positive rate (71.1%, 57.0%, 50.0%) showed a significant difference between YORA and LORA groups. No significant difference was observed in the mean values of DAS28-ESR (2.84 [1.27], 3.06 [1.37], 3.04 [1.23]) and CDAI (7.10 [7.44], 7.43 [8.60], 6.23 [7.30]). The remission rate evaluated by DAS28-ESR (2.84 [1.27], 3.06 [1.37], 3.04 [1.23]) was not different among groups, but that by CDAI (35.0%, 37.8%, 44.3%) was significantly higher in late LORA than in YORA. MTX usage rate (76.4%, 66.8%, 58.7%), any csDMARDs usage rate other than MTX (39.9%, 43.0%, 55.5%), corticosteroid usage rate (31.2%, 40.8%, 47.0%), and NSAIDs usage rate (41.1%, 38.6%, 29.3%) showed significant differences between groups. No significant difference was observed in total biologics usage (12.6%, 11.7%, 11.3%), non-TNF inhibitors usage (5.5%, 7.0%, 8.5%), and JAK inhibitors usage (3.4%, 4.4%, 6.0%), however, there was a significant difference in the TNF inhibitors usage (7.1%, 4.7%, 2.8%) and the selection rate of non-TNF inhibitors among biologics users (43.6%, 59.5%, 75.0%).Conclusion:During the early stage of disease onset, LORA achieved disease activity control equivalent to that of YORA, but the treatment content differed significantly. Furthermore, differences were observed in patient attributes and treatment content between early LORA and late LORA, clarifying that there is also diversity within LORA.REFERENCES:[1] Int J Rheum Dis. 2017; 20:839-45.[2] J Rheumatol. 2018; 45:590-594.[3] Expert Rev Clin Immunol. 2012; 8:455-65.Acknowledgements:NIL.Disclosure of Interests:Toshihiro Matsui AbbVie, AsahiKASEI, Astellas, Chugai, Eisai, Eli Lilly, Ono, Pfizer, AsahiKASEI, Chugai, Tomoya Yoshida: None declared, Takahiro Nishino: None declared, Shigeto Tohma AsahiKASEI, Pfizer, AbbVie, Chugai, Mitsubishi Tanabe.

Phytic acid (inositol hexakisphosphate [InsP₆]) is the storage compound of phosphorus in seeds. As phytic acid binds strongly to metallic cations, it also acts as a storage compound of metals. To understand the mechanisms underlying metal accumulation and localization in relation to phytic acid storage, we applied synchrotron-based x-ray microfluorescence imaging analysis to characterize the simultaneous subcellular distribution of some mineral elements (phosphorus, calcium, potassium, iron, zinc, and copper) in immature and mature rice (Oryza sativa) seeds. This fine-imaging method can reveal whether these elements colocalize. We also determined their accumulation patterns and the changes in phosphate and InsP₆ contents during seed development. While the InsP₆ content in the outer parts of seeds rapidly increased during seed development, the phosphate contents of both the outer and inner parts of seeds remained low. Phosphorus, calcium, potassium, and iron were most abundant in the aleurone layer, and they colocalized throughout seed development. Zinc was broadly distributed from the aleurone layer to the inner endosperm. Copper localized outside the aleurone layer and did not colocalize with phosphorus. From these results, we suggest that phosphorus translocated from source organs was immediately converted to InsP₆ and accumulated in aleurone layer cells and that calcium, potassium, and iron accumulated as phytic acid salt (phytate) in the aleurone layer, whereas zinc bound loosely to InsP₆ and accumulated not only in phytate but also in another storage form. Copper accumulated in the endosperm and may exhibit a storage form other than phytate.

Background:In recent decades, immune checkpoint inhibitors (ICIs) have gained popularity in the treatment of various cancers, but immune-related adverse events (irAEs) can impact the effectiveness of ICIs in killing tumors. Arthritis, occurring in approximately 10% of ICI-treated cancer patients, not only diminishes the quality of life but may also lead to prolonged inflammation [1]. Inbred lab mice are essential for researching and evaluating immune-based treatments for cancer and autoimmune diseases. However, a preclinical model for irAE arthritis has not yet been established. There is a need for treatment strategies that can control arthritis without compromising the efficacy of cancer immunotherapy. To address this, it is essential to establish an animal model inducing arthritis through the administration of immune checkpoint inhibitors in the presence of malignant tumors [2].Objectives:The aim of this study is to establish a preclinical model for ICI-induced arthritis in the presence of tumors.Methods:Collagen-Induced Arthritis (CIA) was selected as the arthritis model. Each mouse was transplanted with a tumor, followed by the administration of anti-PD-1 antibody and anti-CTLA4 antibody a few days later. Joint swelling alterations were examined to evaluate arthritis exacerbation by tumors/ICIs. After sacrifice, cytokine concentrations in the plasma were measured between groups. Additionally, gene expression in bulk joints was assessed using nCounter (Nanostring Technologies).Results:Using the CIA model, the study protocol was stratified based on tumor presence, arthritis induction (utilizing a non-arthritis-induced model immunized with bovine serum albumin and adjuvant), and administration of ICI alone, anti-PD-1 antibody monotherapy, or combined therapy with anti-PD-1 and anti-CTLA4 antibodies (Figure 1). We observed a significant suppression of CIA induction by tumor transplantation, and this inhibitory effect was counteracted by combination ICI therapy, leading to arthritis exacerbation. Furthermore, tumor reduction effects were found only under CIA induction with combination ICI therapy. Gene analysis revealed a significant increase in IFNAR1 expression in the joint locality of Group 6 (with tumor/with ICIs) compared to Group 2 (without tumor/without ICIs), both of which induced arthritis equivalently. Plasma cytokine analysis showed that Group 6 had significantly lower IL-6 concentrations and significantly higher IFN-γ concentrations compared to Group 4 (with tumor/without ICIs).Conclusion:CIA demonstrates a potent anti-arthritogenic effect in the presence of malignant tumors. The recurrence of arthritis with combination ICI therapy validates the CIA model as an appropriate animal experimental system for ICI-induced arthritis. This model has the potential to develop agents that improve arthritis without compromising therapeutic effects on malignant tumors and to investigate the pharmacological mechanisms underlying such effects.REFERENCES:[1] Leipe J, Christ LA, Arnoldi AP, Mille E, Berger F, Heppt M, et al. Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy. RMD Open. 2018;4(2):e000714.[2] Bayless NL, Bluestone JA, Bucktrout S, Butterfield LH, Jaffee EM, Koch CA, et al. Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR. J Immunother Cancer. 2021;9(9).Acknowledgements:NIL.Disclosure of Interests:None declared.

In the hole-doped cuprates, a small number of carriers suppresses antiferromagnetism and induces superconductivity. In the electron-doped cuprates, on the other hand, superconductivity appears only in a narrow window of high-doped Ce concentration after reduction annealing, and strong antiferromagnetic correlation persists in the superconducting phase. Recently, Pr 1.3− x La 0.7 Ce x CuO 4 (PLCCO) bulk single crystals annealed by a protect annealing method showed a high critical temperature of around 27 K for small Ce content down to 0.05. Here, by angle-resolved photoemission spectroscopy measurements of PLCCO crystals, we observed a sharp quasi-particle peak on the entire Fermi surface without signature of an antiferromagnetic pseudogap unlike all the previous work, indicating a dramatic reduction of antiferromagnetic correlation length and/or of magnetic moments. The superconducting state was found to extend over a wide electron concentration range. The present results fundamentally challenge the long-standing picture on the electronic structure in the electron-doped regime. In cuprates, superconductivity exists in a narrow window at high electron doping concentration with strong antiferromagnetic correlations. Here, the authors demonstrate superconductivity with no effect of antiferromagnetic order in a cuprate for a wide electron doping range following a protect anneal process.

LiteBIRD is a next-generation satellite mission to measure the polarization of the cosmic microwave background (CMB) radiation. On large angular scales the B-mode polarization of the CMB carries the imprint of primordial gravitational waves, and its precise measurement would provide a powerful probe of the epoch of inflation. The goal of LiteBIRD is to achieve a measurement of the characterizing tensor to scalar ratio r to an uncertainty of δ r = 0.001 . In order to achieve this goal we will employ a kilo-pixel superconducting detector array on a cryogenically cooled sub-Kelvin focal plane with an optical system at a temperature of 4 K. We are currently considering two detector array options; transition edge sensor (TES) bolometers and microwave kinetic inductance detectors. In this paper we give an overview of LiteBIRD and describe a TES-based polarimeter designed to achieve the target sensitivity of 2  μ K arcmin over the frequency range 50–320 GHz.

Cities have become the focus of global climate mitigation efforts because as they are responsible for 60%-70% of energy-related CO2 emissions. As the world is increasingly urbanized, it is crucial to identify cost-effective pathways to decarbonize and enhance the resilience of cities, which ensure the well-being of their dwellers. Here, we propose a 'SolarEV City' concept, in which integrated systems of cities' roof-top photovoltaics and electric vehicles (EVs) supply affordable and dispatchable CO2-free electricity to urban dwellers. Our analyses indicate that implementations of the concept can meet 53%-95% of electricity demands in nine major Japanese urban areas by 2030. CO2 emission from vehicle use and electricity generation in these areas can be reduced by 54%-95% with potential cost savings of 26%-41%. High cost-effectiveness and seasonally stable insolation in low latitudes may imply that the concept may be more effective to decarbonize urban environments in emerging economies in low latitudes. Among several factors, governmental interventions will play a crucial role in realizing such systems, particularly in legislating regulations that enhance penetration of the integrated system of PV and EV and enable formation of decentralized power systems. As bottom-up processes are critical, policy makers, communities, industries, and researchers should work together to build such systems overcoming social and regulatory barriers.

The hydrogen adsorption on surfaces and on defect sites of ZnO nanoparticles (NPs) has been studied by using Raman and Fourier transform infrared spectroscopic methods. The presence of hydrogen at defect sites bound to zinc vacancy with different coordinations has been confirmed. To further identify the existence of isolated V Zn and H–V Zn complexes in the ZnO NPs, coincidence Doppler broadening (CDB) spectroscopic studies have been performed with respect to the CDB spectra of a 99.9999% pure Al single crystal. The broad momentum dip ρ L showed between 15–17 × 10 −3 m 0 c suggests the trapping of positrons with the core electrons of 3 p Zn. However, positron annihilation takes place between ρ L 20–25 × 10 −3  m 0 c and this may occur with an electron belonging to OH bonds (V Zn –H i –O). Here the lattice hydrogen H + ion acts as a compensating centre, and it can bind with the V Zn around the dislocation and stacking faults (SFs) core, which may produce the acceptor-type complex defect for p-type conductivity. Finally, the existence of SFs and dislocation defects, including edges and steps, was confirmed by transmission electron microscopy.