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SABRE aims to directly measure the annual modulation of the dark matter interaction rate with NaI(Tl) crystals. A modulation compatible with the standard hypothesis, in which our Galaxy is immersed in a dark matter halo, has been measured by the DAMA experiment in the same target material. Other direct detection experiments, using different target materials, seem to exclude the interpretation of such modulation in the simplest scenario of WIMP-nucleon elastic scattering. The SABRE experiment aims to carry out an independent search with sufficient sensitivity to confirm or refute the DAMA claim. The goal of the SABRE experiment is to achieve the lowest background rate for a NaI(Tl) experiment (order of 0.1 cpd/kg/keVee in the energy region of interest for dark matter). This challenging goal could be achievable by operating high-purity crystals inside a liquid scintillator veto for active background rejection. In addition, twin detectors will be located in the northern and southern hemispheres to identify possible contributions to the modulation from seasonal or site-related effects. The SABRE project includes an initial Proof-of-Principle phase at LNGS (Italy), to assess the radio-purity of the crystals and the efficiency of the liquid scintillator veto. This paper describes the general concept of SABRE and the expected sensitivity to WIMP annual modulation.

Plasma parameters of an ECR discharge excited in a compact ion source with a replaceable plasma electrode (PE) were measured with a Langmuir probe. The PE was installed to investigate how an electride PE changes the plasma parameters from those with a Mo PE. The effect upon the plasma parameters in front of the PE due to the material will be elucidated by changing the probe position axially along the beam extraction direction. Analyses of the measured probe characteristics revealed that electride PE has a higher electron density (ne) and lower electron temperature (Te) than the Mo PE. When the PE was biased negatively, the ratio of the positive saturation current ( I i ) to the negative saturation current ( I e + I h- ) for the electride PE was about 1.6 times of the ratio for the Mo PE.

The outlook for T-cell malignancies remain poor due to the lack of effective therapeutic options. Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies, however, designing CARs for T-cell based disease remain a challenge due to the shared surface antigen pool between normal and malignant T-cells. Normal T-cells express CD5 but NK (natural killer) cells do not, positioning NK cells as attractive cytotoxicity cells for CD5CAR design. Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). Here, we report a robust anti-CD5 CAR (CD5CAR) transduced into a human NK cell line NK-92 that can undergo stable expansion ex vivo. We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL. The data suggest that CAR redirected targeting for T-cell malignancies using NK cells may be a viable method for new and complementary therapeutic approaches that could improve the current outcome for patients.

In the recent years, argon-based experiments looking for Dark Matter in the Universe have explored the non-standard scenario in which Dark Matter is made by low-mass Weakly Interacting Massive Particles, of mass in the range of 1–10 GeV instead of the canonical hundreds of GeV. Detecting such particles is challenging, as their expected signatures are nuclear recoils with energies below 10 keV, observable solely via ionization. This necessitates a precise understanding of the detector response in this energy regime, which remains incomplete for argon. To address this, the ReD experiment was developed within the framework of the DarkSide-20k Collaboration to produce and characterize few-keV nuclear recoils. A compact dual-phase argon Time Projection Chamber (TPC) was irradiated with neutrons from a$$^{252}$$252 Cf source, to produce Ar recoils in the energy range of interest via (n,n’) elastic scattering. A downstream spectrometer composed of 18 plastic scintillators detected the neutrons scattered off Ar nuclei, enabling recoil energy reconstruction via two-body kinematics. The ionization yield$$Q_{y}$$Q y of argon, defined as the number of electrons produced per unit energy deposit, was measured in a model-independent way between 2 and 10 keV. These measurements extend direct experimental coverage well below the previous limit of approximately 7 keV. The results are consistent with existing data above 7 keV, while they indicate a higher$$Q_{y}$$Q y at lower energies.

Ultra-pure NaI(Tl) crystals are the key element for a model-independent verification of the long standing DAMA result and a powerful means to search for the annual modulation signature of dark matter interactions. The SABRE collaboration has been developing cutting-edge techniques for the reduction of intrinsic backgrounds over several years. In this paper we report the first characterization of a 3.4 kg crystal, named NaI-33, performed in an underground passive shielding setup at LNGS. NaI-33 has a record low 39K contamination of 4.3 ± 0.2 ppb as determined by mass spectrometry. We measured a light yield of 11.1 ± 0.2 photoelectrons/keV and an energy resolution of 13.2% (FWHM/E) at 59.5 keV. We evaluated the activities of 226Ra and 228Th inside the crystal to be 5.9±0.6μBq/kg and 1.6±0.3μBq/kg, respectively, which would indicate a contamination from 238U and 232Th at part-per-trillion level. We measured an activity of 0.51 ± 0.02 mBq/kg due to 210Pb out of equilibrium and a α quenching factor of 0.63 ± 0.01 at 5304 keV. We illustrate the analyses techniques developed to reject electronic noise in the lower part of the energy spectrum. A cut-based strategy and a multivariate approach indicated a rate, attributed to the intrinsic radioactivity of the crystal, of ∼1 count/day/kg/keV in the [5–20] keV region.

The protein p38 mitogen-activated protein kinase (MAPK) delta isoform (p38δ) is a poorly studied member of the MAPK family. Data analysis from The Cancer Genome Atlas database revealed that p38δ is highly expressed in all types of human breast cancers. Using a human breast cancer tissue array, we confirmed elevation in cancer tissue. The breast cancer mouse model, MMTV-PyMT (PyMT), developed breast tumors with lung metastasis; however, mice deleted in p38δ (PyMT/ p38δ −/− ) exhibited delayed primary tumor formation and highly reduced lung metastatic burden. At the cellular level, we demonstrate that targeting of p38δ in breast cancer cells, MCF-7 and MDA-MB-231 resulted in a reduced rate of cell proliferation. In addition, cells lacking p38δ also displayed an increased cell–matrix adhesion and reduced cell detachment. This effect on cell adhesion was molecularly supported by the regulation of the focal adhesion kinase by p38δ in the human breast cell lines. These studies define a previously unappreciated role for p38δ in breast cancer development and evolution by regulating tumor growth and altering metastatic properties. This study proposes MAPK p38δ protein as a key factor in breast cancer. Lack of p38δ resulted in reduced primary tumor size and blocked the metastatic potential to the lungs.

BackgroundConnective tissue disease-associated interstitial lung disease (CTD-ILD) is a serious complication and an important prognostic factor of various autoimmune diseases. Many cell types and both innate and adaptive immune systems are implicated in the pathogenesis of fibrotic lung injury. The presentation and clinical course of CTD-ILD are diverse, and the heterogeneity reflects differences in underlying pathogenic mechanisms.ObjectivesThe objective of this study is to reveal the different characteristics of immune cells among diseases.MethodsWe collected bronchoalveolar lavage fluid (BALF) and peripheral blood from patients who newly complicated interstitial lung disease and agreed to participate in this study; 5 patients with Sjögren syndrome (SS), 8 patients with dermatomyositis (DM), 6 patients with rheumatoid arthritis (RA), 7 patients with systemic sclerosis (SSc), 4 patients with ANCA-associated vasculitis (AAV), and 12 patients with idiopathic interstitial pneumonia (IIP) included. We applied Seq-Well, a portable platform of single-cell RNA sequencing[1], to analyze gene expressions in immune cells in BALF and blood. We compared the distribution of immune cells and differential gene expressions in BALF and blood among diseases.ResultsWe compared immune cell numbers in BALF among diseases. We found more T cells in patients with DM and SS, more B cells in patients with SS, more neutrophils in patients with RA, and more alveolar macrophages (AMs) in patients with AAV or SSc. We further performed gene ontology enrichment analysis of each immune cells in BALF. In patients with DM, the gene expression pathways related to the response to virus was increased in T cells. On the other hand, in patients with SS, the gene expression pathways involved in innate immunity and antigen presentation were enhanced in B cells. In addition, the gene expression associated with T cell activation was enhanced in T cells. In neutrophils from patients with RA, the gene expression involved in inflammation was increased. We next performed gene ontology enrichment analysis of blood. In monocytes and neutrophils, patients with DM had increased gene expression pathways associated with viruses, while patients with SS had increased gene expression of both innate immune pathways and acquired immunity. These results suggested that the common pathways were enhanced in BALF lymphocytes and in blood monocytes and neutrophils in patients with DM and SS.ConclusionOur comprehensive single-cell analysis of BALF and blood from CTD-ILD patients has revealed that the phenotypes and states of immune cells differ among diseases (Figure 1). We found that the common pathways were enhanced in BALF and blood, i.e., pathways associated with response to virus were enhanced in DM while innate immunity and antigen presentation pathways were enhanced in SS, suggesting the relationship between systemic immune abnormality and ILD. These results may lead to the optimal diagnosis and the precision medicine for patients with CTD-ILDs.Reference[1]Gierahn TM et al, Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput. Nat Methods 2017;14(4):395-398.Figure 1.Acknowledgements:NIL.Disclosure of InterestsAiko Hirano Speakers bureau: Sanofi K.K., Wataru Fujii Speakers bureau: Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, Grant/research support from: Boehringer Ingelheim Japan, Inc., GlaxoSmithKline K.K., Takeda Pharmaceutical Co.,Ltd., Aki Sakashita: None declared, Kevin Baßler: None declared, Masatoshi Kadoya: None declared, Atsushi Omoto Speakers bureau: AbbVie GK, Chugai Pharmaceutical Co. Ltd., Ono Pharmaceutical Co., Ltd., Daiichi-Sankyo Inc., Astellas Pharma Inc., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Asahi Kasei Pharma Corp, Novartis Pharma KK, Gilead Sciences Inc., Janssen Pharmaceutical K.K., GlaxoSmithKline K.K, Eli Lilly Japan K.K, Wataru Fukuda Speakers bureau: Chugai Pharmaceutical Co., Eisai Co., Ltd., Eli Lilly Japan K.K., AbbVie GK, Ono Pharmaceutical Co. Ltd., Astellas Pharma Inc., UCB Japan Co. Ltd., Pfizer Japan Inc., Giread Science K.K., Asahikasei Pharma Co., Daiichi-Sankyo Inc., Takahiro Seno Speakers bureau: Asahi Kasei Pharma, Janssen Pharmaceutical K.K., Boehringer Ingelheim Japan, Inc, Makoto Wada Speakers bureau: AbbVie GK, Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Sanofi Japan K.K., Masataka Kohno Speakers bureau: AbbVie GK, Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Asahikasei Pharma Co., Pfizer Japan Inc., Sanofi Japan K.K., Boehringer Ingelheim Co. Ltd., UCB Japan Co. Ltd., Eisai Co. Ltd., GlaxoSmithKline K.K., Yutaka Kawahito Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corp, Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., UCB Japan Co. Ltd., GlaxoSmithKline K.K., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Sanofi Japan K.K., Gilead Sciences Inc., Mylan EPD, Grant/research support from: AbbVie GK, Asahi Kasei Pharma Corp, Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., GlaxoSmithKline K.K., Gilead Sciences Inc.

Ion and electron current signals produced from a solid graphite target under 1064 nm nanosecond laser pulse irradiation were investigated. A cavity is formed by laser incidence at the center of the target surface at 10 Hz repetition rate while being rotated along its axis. Ion mass distributions were recorded via a time-of-flight spectrum coupled with a detector assembly attached along the propagation axis. Peak shifts towards slower times were observed for increasing number of pulses. The effect of magnetic detection on the ion current signals is investigated, and showed significant peak shifts for 20 GW/cm 2 laser power density.

We developed an ion trap system for triply charged thorium-229 ( 229 Th 3+ ). We used uranium-233 as the ion source, which supplied 229 Th 3+ ions in the nuclear ground state and low-lying isomeric state ( 229m Th 3+ ) at 8.3 eV. Our ion trap system allows the laser spectroscopy of 229m Th 3+ toward the nuclear clock.

Objective: To test the hypothesis that dynamic load at baseline can predict radiographic disease progression in patients with medial compartment knee osteoarthritis (OA). Methods: During 1991–93 baseline data were collected by assessment of pain, radiography, and gait analysis in 106 patients referred to hospital with medial compartment knee OA. At the six year follow up, 74 patients were again examined to assess radiographic changes. Radiographic disease progression was defined as more than one grade narrowing of minimum joint space of the medial compartment. Results: In the 32 patients showing disease progression, pain was more severe and adduction moment was higher at baseline than in those without disease progression (n=42). Joint space narrowing of the medial compartment during the six year period correlated significantly with the adduction moment at entry. Adduction moment correlated significantly with mechanical axis (varus alignment) and negatively with joint space width and pain score. Logistic regression analysis showed that the risk of progression of knee OA increased 6.46 times with a 1% increase in adduction moment. Conclusions: The results suggest that the baseline adduction moment of the knee, which reflects the dynamic load on the medial compartment, can predict radiographic OA progression at the six year follow up in patients with medial compartment knee OA.