Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.
In this phase 3 trial, we ...randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.
At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients 18.5% in the daratumumab group vs. 116 of 283 41.0% in the control group; hazard ratio, 0.37; 95% confidence interval CI, 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10
white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.
The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).
•Attachment disturbance in infancy predicts larger left amygdala volume in adulthood.•Prediction is independent of later maltreatment and later attachment quality.•Attachment disturbance also ...predicts adult dissociation and limbic irritability.•Left volume mediates the relation between early attachment and limbic irritability.•Disturbed infant attachment may affect adult amygdala volume and psychopathology.
Early life stress in rodents is associated with increased amygdala volume in adulthood. In humans, the amygdala develops rapidly during the first two years of life. Thus, disturbed care during this period may be particularly important to amygdala development. In the context of a 30-year longitudinal study of impoverished, highly stressed families, we assessed whether disorganization of the attachment relationship in infancy was related to amygdala volume in adulthood. Amygdala volumes were assessed among 18 low-income young adults (8M/10F, 29.33±0.49years) first observed in infancy (8.5±5.6months) and followed longitudinally to age 29. In infancy (18.58±1.02mos), both disorganized infant attachment behavior and disrupted maternal communication were assessed in the standard Strange Situation Procedure (SSP). Increased left amygdala volume in adulthood was associated with both maternal and infant components of disorganized attachment interactions at 18 months of age (overall r=0.679, p<0.004). Later stressors, including childhood maltreatment and attachment disturbance in adolescence, were not significantly related to left amygdala volume. Left amygdala volume was further associated with dissociation and limbic irritability in adulthood. Finally, left amygdala volume mediated the prediction from attachment disturbance in infancy to limbic irritability in adulthood. Results point to the likely importance of quality of early care for amygdala development in human children as well as in rodents. The long-term prediction found here suggests that the first two years of life may be an early sensitive period for amygdala development during which clinical intervention could have particularly important consequences for later child outcomes.
Extensive evidence has indicated that a high rate of cholesterol biogenesis and abnormal neuronal energy metabolism play key roles in Alzheimer's disease (AD) pathogenesis. Here, for we believe the ...first time, we used osmotin, a plant protein homolog of mammalian adiponectin, to determine its therapeutic efficacy in different AD models. Our results reveal that osmotin treatment modulated adiponectin receptor 1 (AdipoR1), significantly induced AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) activation and reduced SREBP2 (sterol regulatory element-binding protein 2) expression in both in vitro and in vivo AD models and in Adipo
mice. Via the AdipoR1/AMPK/SIRT1/SREBP2 signaling pathway, osmotin significantly diminished amyloidogenic Aβ production, abundance and aggregation, accompanied by improved pre- and post-synaptic dysfunction, cognitive impairment, memory deficits and, most importantly, reversed the suppression of long-term potentiation in AD mice. Interestingly, AdipoR1, AMPK and SIRT1 silencing not only abolished osmotin capability but also further enhanced AD pathology by increasing SREBP2, amyloid precursor protein (APP) and β-secretase (BACE1) expression and the levels of toxic Aβ production. However, the opposite was true for SREBP2 when silenced using small interfering RNA in APPswe/ind-transfected SH-SY5Y cells. Similarly, osmotin treatment also enhanced the non-amyloidogenic pathway by activating the α-secretase gene that is, ADAM10, in an AMPK/SIRT1-dependent manner. These results suggest that osmotin or osmotin-based therapeutic agents might be potential candidates for AD treatment.
Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this ...study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA-MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells.
The passage of time is tracked by counting oscillations of a frequency reference, such as Earth's revolutions or swings of a pendulum. By referencing atomic transitions, frequency (and thus time) can ...be measured more precisely than any other physical quantity, with the current generation of optical atomic clocks reporting fractional performance below the 10
level
. However, the theory of relativity prescribes that the passage of time is not absolute, but is affected by an observer's reference frame. Consequently, clock measurements exhibit sensitivity to relative velocity, acceleration and gravity potential. Here we demonstrate local optical clock measurements that surpass the current ability to account for the gravitational distortion of space-time across the surface of Earth. In two independent ytterbium optical lattice clocks, we demonstrate unprecedented values of three fundamental benchmarks of clock performance. In units of the clock frequency, we report systematic uncertainty of 1.4 × 10
, measurement instability of 3.2 × 10
and reproducibility characterized by ten blinded frequency comparisons, yielding a frequency difference of -7 ± (5)
± (8)
× 10
, where 'stat' and 'sys' indicate statistical and systematic uncertainty, respectively. Although sensitivity to differences in gravity potential could degrade the performance of the clocks as terrestrial standards of time, this same sensitivity can be used as a very sensitive probe of geopotential
. Near the surface of Earth, clock comparisons at the 1 × 10
level provide a resolution of one centimetre along the direction of gravity, so the performance of these clocks should enable geodesy beyond the state-of-the-art level. These optical clocks could further be used to explore geophysical phenomena
, detect gravitational waves
, test general relativity
and search for dark matter
.
We present IRAM-30 m Telescope 12CO and 13CO observations of a sample of 55 luminous and ultraluminous infrared galaxies (LIRGs and ULIRGs) in the local universe. This sample is a subset of the Great ...Observatory All-Sky LIRG Survey (GOALS), for which we use ancillary multi-wavelength data to better understand their interstellar medium and star formation properties. Fifty-three (96%) of the galaxies are detected in 12CO, and 29 (52%) are also detected in 13CO above a 3σ level. The median full width at zero intensity (FWZI) velocity of the CO line emission is 661 km s−1, and ∼54% of the galaxies show a multi-peak CO profile. Herschel photometric data is used to construct the far-IR spectral energy distribution of each galaxy, which are fit with a modified blackbody model that allows us to derive dust temperatures and masses, and infrared luminosities. We make the assumption that the gas-to-dust mass ratio of (U)LIRGs is comparable to local spiral galaxies with a similar stellar mass (i.e., gas/dust of mergers is comparable to their progenitors) to derive a CO-to-H2 conversion factor of ⟨α⟩ = 1.8−0.8+1.3 M⊙ ⟨ α ⟩ = 1 . 8 − 0.8 + 1.3 M ⊙ $ \langle\alpha\rangle=1.8^{+1.3}_{-0.8}\,M_\odot $ (K km s−1 pc2)−1; such a value is comparable to that derived for (U)LIRGs based on dynamical mass arguments. We derive gas depletion times of 400 − 600 Myr for the (U)LIRGs, compared to the 1.3 Gyr for local spiral galaxies. Finally, we re-examine the relationship between the 12CO/13CO ratio and dust temperature, confirming a transition to elevated ratios in warmer systems.
Context. The near-Earth asteroid 3200 Phaethon (1983 TB) is an attractive object not only from a scientific viewpoint but also because of JAXA’s DESTINY+ target. The rotational lightcurve and spin ...properties were investigated based on the data obtained in the ground-based observation campaign of Phaethon. Aims. We aim to refine the lightcurves and shape model of Phaethon using all available lightcurve datasets obtained via optical observation, as well as our time-series observation data from the 2017 apparition. Methods. Using eight 12-m telescopes and an optical imager, we acquired the optical lightcurves and derived the spin parameters of Phaethon. We applied the lightcurve inversion method and SAGE algorithm to deduce the convex and non-convex shape model and pole orientations. Results. We analysed the optical lightcurve of Phaethon and derived a synodic and a sidereal rotational periods of 3.6039 h, with an axis ratio of a∕b = 1.07. The ecliptic longitude (λp) and latitude (βp) of the pole orientation were determined as (308°, −52°) and (322°, −40°) via two independent methods. A non-convex model from the SAGE method, which exhibits a concavity feature, is also presented.
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