Summary
Background
GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma HCC and Of its treatment with sorafeNib) is a global, prospective, non‐interventional study ...undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real‐life practice, including Child‐Pugh B patients who were excluded from clinical trials.
Methods
Patients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow‐up visits. The second interim analysis was undertaken when ~1500 treated patients were followed up for ≥ 4 months.
Results
Of the 1571 patients evaluable for safety, 61% had Child‐Pugh A status and 23% Child‐Pugh B. The majority of patients (74%) received the approved 800 mg initial sorafenib dose, regardless of Child‐Pugh status; however, median duration of therapy was shorter in Child‐Pugh B patients. The majority of drug‐related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug‐related AEs were broadly similar across Child‐Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population.
Conclusions
Consistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child‐Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in > 3000 patients are ongoing.
The ionized upper layer of Saturn's atmosphere, its ionosphere, provides a closure of currents mediated by the magnetic field to other electrically charged regions (for example, rings) and hosts ...ion-molecule chemistry. In 2017, the Cassini spacecraft passed inside the planet's rings, allowing in situ measurements of the ionosphere. The Radio and Plasma Wave Science instrument detected a cold, dense, and dynamic ionosphere at Saturn that interacts with the rings. Plasma densities reached up to 1000 cubic centimeters, and electron temperatures were below 1160 kelvin near closest approach. The density varied between orbits by up to two orders of magnitude. Saturn's A- and B-rings cast a shadow on the planet that reduced ionization in the upper atmosphere, causing a north-south asymmetry.
Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and ...oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis—using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling—revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by reactivation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.
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► The efficacy of combination treatments for cancer depends on drug order and timing ► Dynamic rewiring of signaling networks by drugs can provide therapeutic benefit ► Sustained EGFR inhibition sensitizes triple-negative breast cancer cells to DNA damage ► EGFR activity, but not EGFR expression, is a biomarker of response to this treatment
The effectiveness of combination therapy for triple-negative breast cancer may be increased by delivering the drugs sequentially. Inhibiting EGFR dynamically rewires tumor cell signaling networks to enhance subsequent susceptibility to DNA-damaging agents, an effect not seen when the drugs are applied simultaneously.
Using state-of-the-art dynamical simulations of globular clusters, including radiation reaction during black hole encounters and a cosmological model of star cluster formation, we create a realistic ...population of dynamically formed binary black hole mergers across cosmic space and time. We show that in the local universe, 10% of these binaries form as the result of gravitational-wave emission between unbound black holes during chaotic resonant encounters, with roughly half of those events having eccentricities detectable by current ground-based gravitational-wave detectors. The mergers that occur inside clusters typically have lower masses than binaries that were ejected from the cluster many Gyrs ago. Gravitational-wave captures from globular clusters contribute 1 – 2 Gpc−3 yr−1 to the binary merger rate in the local universe, increasing to ≳ 10 Gpc−3 yr−1 at z ∼ 3 . Finally, we discuss some of the technical difficulties associated with post-Newtonian scattering encounters, and how care must be taken when measuring the binary parameters during a dynamical capture.
The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. ...In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33
MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33
MDSCs (P<0.01). Subsequently, we demonstrated that CD45
CD33
CD11b
HLA-DR
MDSCs from fresh BC tissues displayed high levels of suppressive molecules, including Arg1, iNOS, ROS, PDL-1 and P-STAT3, and stronger suppression of T-cell proliferation. Interestingly, these CD45
CD33
CD11b
HLA-DR
MDSCs exhibited increased CXCR2 expression compared with that in peripheral blood from BC patients or healthy controls (P<0.05). Chemotaxis assay revealed that bladder cancer cell line J82 induced MDSC migration via CXCL2/MIF-CXCR2 signaling in vitro. Mechanistic studies demonstrated that J82-induced MDSC trafficking and CXCR2 expression were associated with increased phosphorylation of p38, ERK and p65. Conversely, inhibition of the phosphorylation of p38, ERK or p65 decreased J82-induced MDSC trafficking and CXCR2 expression. CXCL2/MIF-stimulated activation of the mitogen-activated protein kinase and nuclear factor kappa B pathways in MDSCs was MyD88 dependent. Overall, our results identify the CXCL2/MIF-CXCR2 axis as an important mediator in MDSC recruitment and as predictors and potential therapeutic targets in BC patients.
The formation and evolution of binary stars are critical components of several fields in astronomy. The most numerous sources for gravitational wave observatories are inspiraling or merging compact ...binaries, while binary stars are present in nearly every electromagnetic survey regardless of the target population. Simulations of large binary populations serve to both predict and inform observations of electromagnetic and gravitational wave sources. Binary population synthesis is a tool that balances physical modeling with simulation speed to produce large binary populations on timescales of days. We present a community-developed binary population synthesis suite, COSMIC, which is designed to simulate compact-object binary populations and their progenitors. As a proof of concept, we simulate the Galactic population of compact binaries and their gravitational wave signals observable by the Laser Interferometer Space Antenna.
Ice grains in the Enceladus plume have been observed by several Cassini instruments during many Enceladus encounters. In this paper we study the ice grains ranging from less than one nanometer to ...micrometers in size based on multiple instrument observations. We have analyzed the nanograin data from the E17 and E18 Cassini Plasma Spectrometer (CAPS) energy spectra using the approach of Hill et al. (2012) and studied the charging of the grains using the E3–E6 Radio and Plasma Wave Spectrometer (RPWS)‐Langmuir Probe (LP) data presented by Morooka et al. (2011). To bridge the gap between CAPS nanograin observations and Cosmic Dust Analyzer and RPWS micrograin observations, we propose a composite size distribution and fit it to the E3, E5, E17, and E18 CAPS and RPWS data. The resulting size distribution peaks at ~2 nm and provides a total grain mass density ~20% that of the water vapor measured by Ion and Neutral Mass Spectrometer at the densest part of the plume and a total grain charge density much smaller than that inferred from the RPWS‐LP plasma data. Charge balance with the RPWS‐LP plasma data would require many more grains than provided by the best fit composite distribution to the CAPS and RPWS data and would provide a grain mass density comparable to that of the water vapor. On the basis of these results, we study the subsequent motion of the ice grains and estimate the resulting grain current (~104 to ~105A) and grain mass production rate (~15–65 kg/s).
Key Points
Ice grains in the Enceladus plume have been detected by the Cassini instruments
A composite grain size distribution is constructed based on CAPS and RPWS data
The grain densities, mass production rates, and currents are studied
ABSTRACT
The empirical literature on farmer cooperatives is now fast emerging and developing in the areas of performance, ownership and governance, finance, and member attitude. We discuss 56 ...peer‐reviewed publications to illustrate the main findings and conclusions while outlining challenges and opportunities for future research. Generally, cooperative membership is found to positively impact price, yield, input adoption, income, and other indicators of member performance, yet there is growing evidence of an uneven distribution of benefits for small and large producers. In terms of structure, evidence of a causal relationship of ownership and governance to performance has been elusive, yet there are now many findings of inherent equity and long‐term debt constraints, often in the context of consolidation to drive scale and scope economies. Further inefficiency is observed to be driven by increased heterogeneity in member attitudes and objectives, in particular in terms of commitment and participation. Thus, overall, empirical work portrays farmer cooperatives as flawed and complex business organizations which nonetheless have a strong positive impact on its members. While applied research may progress in various directions, a general improvement in empirical methodologies is needed to allow robust analysis of mixed objectives in dynamic environments.
Abstract Gravitational-wave detectors are unveiling a population of binary black hole (BBH) mergers out to redshifts z ≈ 1, and are starting to constrain how the BBH population evolves with redshift. ...We present predictions for the redshift evolution of the BBH mass and spin distributions for systems originating from dense star clusters. Utilizing a grid of 144 state-of-the-art dynamical models for globular clusters, we demonstrate that BBH merger rates peak at higher redshifts for larger black hole primary masses M 1 . Specifically, for M 1 ≳ 40 M ⊙ , the BBH merger rate reaches its peak at redshift z ≈ 2.1, while for M 1 ≲ 20 M ⊙ , the peak occurs at z ≈ 1.1, assuming that the cluster formation rate peaks at z = 2.2. The average BBH primary mass also increases from ∼10 M ⊙ at z = 0 to ∼30 M ⊙ at z = 10. We show that ∼20% BBHs contain massive remnants from next-generation mergers, with this fraction increasing (decreasing) for larger (smaller) primary masses. This difference is not large enough to significantly alter the effective spins of the BBH population originating from globular clusters, and we find that their effective spin distribution does not evolve across cosmic time. These findings can be used to distinguish BBHs from dense star clusters by future gravitational-wave observations.
We present simultaneous observations of aurorae at Jupiter from the Hubble Space Telescope and Hisaki, in combination with the in situ measurements of magnetic field, particles, and radio waves from ...the Juno Spacecraft in the outer magnetosphere, from ~ 80RJ to 60RJ during 17 to 22 March 2017. Two cycles of accumulation and release of magnetic flux, named magnetic loading/unloading, were identified during this period, which correlate well with electron energization and auroral intensifications. Magnetic reconnection events are identified during both the loading and unloading periods, indicating that reconnection and unloading are independent processes. These results show that the dynamics in the middle magnetosphere are coupled with auroral variability.
Key Points
Accumulation and release of magnetic flux in the middle Jovian magnetosphere modulate auroral intensifications
Magnetic reconnection process occurs independently of Jupiter's global loading and unloading of magnetic flux
We provide direct evidence that unloading of magnetic flux causes enhancements of auroral kilometric emissions
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