In this phase Ib study, four combination therapies of nivolumab 10 mg/kg and standard chemotherapy (cisplatin/gemcitabine, cisplatin/pemetrexed, carboplatin/paclitaxel/bevacizumab, or docetaxel) ...showed acceptable toxicity profiles in patients with advanced non-small-cell lung cancer. Furthermore, these combination therapies presented encouraging antitumor activities.
The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).
Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle.
As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively.
Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC.
Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071.
Geodetic observations of interseismic surface deformation in the vicinity of subduction zones are frequently interpreted using simple kinematic elastic dislocation models (EDM). In this theoretical ...study, we develop a kinematic EDM that simulates plate subduction over the interseismic period (the elastic subducting plate model (ESPM)) having only 2 more degrees of freedom than the well‐established back slip model (BSM): an elastic plate thickness and the fraction of flexural stresses due to bending at the trench that are released continuously. Unlike the BSM, in which steady state deformation in both plates is assumed to be negligible, the ESPM includes deformation in the subducting and overriding plates (owing to plate thickness), while still preserving the correct sense of convergence velocity between the subducting and overriding plates, as well as zero net steady state vertical offset between the two plates when integrated over many seismic cycles. The ESPM links elastic plate flexure processes to interseismic deformation and helps clarify under what conditions the BSM is appropriate for fitting interseismic geodetic data at convergent margins. We show that the ESPM is identical to the BSM in the limiting case of zero plate thickness, thereby providing an alternative motivation for the BSM. The ESPM also provides a consistent convention for applying the BSM to any megathrust interface geometry. Even in the case of nonnegligible plate thickness, the deformation field predicted by the ESPM reduces to that of the BSM if stresses related to plate flexure at the trench are released either continuously and completely at shallow depths during the interseismic period or deep in the subduction zone (below ∼100 km). However, if at least a portion of these stresses are not continuously released in the shallow portion of the subduction zone (via seismic or aseismic events), then the predicted surface velocities of these two models can differ significantly at horizontal distances from the trench equivalent to a few times the effective interseismic locking depth.
A hydrogen-like atom consisting of a positive muon and an electron is known as muonium. It is a near-ideal two-body system for a precision test of bound-state theory and fundamental symmetries. The ...MuSEUM collaboration performed a new precision measurement of the muonium ground-state hyperfine structure at J-PARC using a high-intensity pulsed muon beam and a high-rate capable positron counter. The resonance of hyperfine transition was successfully observed at a near-zero magnetic field, and the muonium hyperfine structure interval of νHFS=4.463302(4)GHz was obtained with a relative precision of 0.9 ppm. The result was consistent with the previous ones obtained at Los Alamos National Laboratory and the current theoretical calculation. We present a demonstration of the microwave spectroscopy of muonium for future experiments to achieve the highest precision.
The KISS1/Kiss1/kiss1 gene product kisspeptin is suggested to be involved in the steroid feedback system in vertebrates. In addition to kiss1, kiss2 has been identified in many vertebrates, including ...some mammals, suggesting that the both genes were originally expressed in the common ancestor of teleosts and tetrapods. Moreover, peptides from both genes have been shown to activate the kisspeptin receptors. To investigate the involvement of kiss1 or kiss2 neurones in steroid feedback, we used a seasonal breeder, the goldfish (Carassius auratus). We found that kiss2 is expressed in the preoptic area (POA), nucleus lateralis tuberis and nucleus recessus lateralis, and that kiss1 is expressed in the habenula. Greater mRNA expression in breeding than in nonbreeding condition animals and conspicuous up‐regulation of gene expression by gonadal steroids was seen only in the kiss2 neurones of the POA. Furthermore, double in situ hybridisation suggested that these neurones express oestrogen receptors. Given that amphibians express kiss2 in POA and mammalian anteroventral periventricular nucleus/POA Kiss1 neurones show similar expression dynamics as goldfish POA Kiss2 neurones, we hypothesise that kiss1 and kiss2 share the same evolutionary origin; and, after the loss of kiss2, kiss1 became active for steroid feedback in mammals.
The kiss1 gene product kisspeptin is now considered to be an essential regulator of the hypothalamic–pituitary–gonadal (HPG) axis in most vertebrate species. Recent findings in fishes are beginning ...to set a new stage for the kisspeptin study; the existence of paralogous kisspeptin genes as well as kisspeptin receptor (formerly called GPR54) genes has quite recently been reported in several fish and amphibian species. The fishes may provide excellent animal models for the study of general principles underlying the kisspeptin and kisspeptin receptor systems of vertebrates from the evolutionary viewpoint. Unlike placental and marsupial mammalian species mainly studied so far, many teleost species have two paralogous genes of kisspeptin, kiss1 and kiss2. Medaka, Oryzias latipes, in which kiss1 and kiss2 are expressed in distinctive hypothalamic neuron populations, is a good model system for the study of central regulation of reproduction. Here, the kiss1 system but not the kiss2 system shows expression dynamics strongly indicative of its direct involvement in the HPG axis regulation via its actions on GnRH1 neurons. On the other hand, the kiss1 gene is missing, and only kiss2 is expressed in some fish species. Also, there are some recent reports that Kiss2 peptide may be a potent regulator of reproduction in some fish species. The ancestral vertebrate probably already had two paralogous kiss genes, and their main function was the HPG axis regulation. In the species that retained both paralogues during evolution, either Kiss1 or Kiss2 predominantly retains its ability for the HPG axis regulation, while the other may assume new non‐reproductive functions (neofunctionalization). Alternatively, both the paralogues may assume complementary functions in the HPG axis regulation (subfunctionalization). After the divergence of teleost and tetrapod lineages, either one of the two paralogues, or even both in birds, have been lost (degradation) or became a pseudogene (non‐functionalization), but the remaining paralogue retained its original function of HPG axis regulation. The identification of multiple forms of kisspeptin receptors and the rather promiscuous ligand–receptor relationships has led to the further proposal that such promiscuousness may be the basis for the functional robustness of kisspeptin and kisspeptin receptor systems in the HPG axis regulation, when one or both paralogous genes are lost or functionally partitioned during evolution.
Muonic helium atom hyperfine structure (HFS) measurements are a sensitive tool to test the three-body atomic system and bound-state quantum electrodynamics theory, and determine fundamental constants ...of the negative muon magnetic moment and mass. The world's most intense pulsed negative muon beam at the Muon Science Facility of the Japan Proton Accelerator Research Complex allows improvement of previous measurements and testing further CPT invariance by comparing the magnetic moments and masses of positive and negative muons (second-generation leptons). We report new ground-state HFS measurements of muonic helium-4 atoms at a near-zero magnetic field, performed for the first time using a small admixture of CH_{4} as an electron donor to form neutral muonic helium atoms efficiently. Our analysis gives Δν=4464.980(20) MHz (4.5 ppm), which is more precise than both previous measurements at weak and high fields. The muonium ground-state HFS was also measured under the same conditions to investigate the isotopic effect on the frequency shift due to the gas density dependence in He with CH_{4} admixture and compared with previous studies. Muonium and muonic helium can be regarded as light and heavy hydrogen isotopes with an isotopic mass ratio of 36. No isotopic effect was observed within the current experimental precision.
In this paper, we propose a low-power area-efficient redundant flip-flop for soft errors, called DICE-ACFF. Its structure is based on the reliable DICE (Dual Interlocked storage CEll) and the ...low-power ACFF (Adaptive-Coupling Flip-Flop). It achieves lower power at lower data-activity. We designed DICE-FF and DICE-ACFF using 65 nm conventional bulk and thin-BOX FD-SOI (Silicon on Thin-BOX, SOTB) processes. Its area is twice as large as the conventional DFF. As for power dissipation, DICE ACFF achieves lower power than the conventional DFF below 20% data activity. When data activity is 0%, its power is half of the DFF. As for soft error rates DICE ACFFs are 1.5x better than conventional DICE FFs based on circuit-level simulations to estimate critical charge. No SEU is observed on the DICE ACFF by α-particle and neutron irradiations on the bulk and SOTB chips. From neutron irradiation results, the soft error rate of the DFF of the SOTB chip is 1/15 compared with that of the bulk chip.
Abstract
A small-momentum-width muon beam, so-called ultra-slow muon beam, can be generated by laser ionization of muonium. To realize efficient ultra-slow muon generation, the Lyman-alpha and below ...360 nm coherent light are required to resonantly excite the muonium from the ground state to 2
p
and sequentially ionizes excited muonium to the unbound state. At the J-PARC MLF Ultra-Slow Muon beamline, we have successfully generated Lyman-alpha coherent light exceeding 10 μJ using an all-solid-state laser and high-efficiency vacuum ultraviolet light generation technologies. In this paper, we will describe the intense Lyman-alpha light source.
Present status of J-PARC MUSE Shimomura, K; Koda, A; Pant, A D ...
Journal of physics. Conference series,
03/2023, Letnik:
2462, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
At J-PARC MUSE, since the
µ
SR2017 conference and up to FY2022, there have been several new developments at the facility, including the completion of a new experimental area S2 at the ...surface muon beamline S-line and the first muon beam extraction to the H1 area in the H-line, mainly to carry out high-statistics fundamental physics experiments. Several new studies are also underway, such as applying negative muon non-destructive elemental analysis to the analysis of samples returned from the asteroid Ryugu in the D2 area of the D-line. This paper reports on the latest status of MUSE.
Abstract
The Super-Omega beamline at J-PARC Materials and Life Science Experimental Facility provides an intense pulsed slow positive muon beam. Combined with a muonium production target and laser ...light for muonium ionization, the pulsed ultra-slow muon facility has been developed. At the facility, a spectrometer for muon spin rotation measurements using ultra-slow muons is under commissioning. In this paper, we will report on the current status of the beam optics optimization of slow muon transport and ultra-slow muon extraction to improve the intensity and quality of the ultra-slow muon beam.
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