In a randomized trial involving more than 900 patients undergoing resection of advanced melanoma, adjuvant nivolumab was associated with a higher rate of 12-month recurrence-free survival than ...ipilimumab (70.5% vs. 60.8%) and with fewer adverse events.
We use the new ultra-deep, near-infrared imaging of the Hubble Ultra-Deep Field (HUDF) provided by our UDF12 Hubble Space Telescope (HST) Wide Field Camera 3/IR campaign to explore the rest-frame ...ultraviolet (UV) properties of galaxies at redshifts z > 6.5. We present the first unbiased measurement of the average UV power-law index, 〈β〉, (f
λ ∝ λβ) for faint galaxies at z 7, the first meaningful measurements of 〈β〉 at z 8, and tentative estimates for a new sample of galaxies at z 9. Utilizing galaxy selection in the new F140W (J
140) imaging to minimize colour bias, and applying both colour and power-law estimators of β, we find 〈β〉 = −2.1 ± 0.2 at z 7 for galaxies with M
UV −18. This means that the faintest galaxies uncovered at this epoch have, on average, UV colours no more extreme than those displayed by the bluest star-forming galaxies at low redshift. At z 8 we find a similar value, 〈β〉 = −1.9 ± 0.3. At z 9, we find 〈β〉 = −1.8 ± 0.6, essentially unchanged from z 6 to 7 (albeit highly uncertain). Finally, we show that there is as yet no evidence for a significant intrinsic scatter in β within our new, robust z 7 galaxy sample. Our results are most easily explained by a population of steadily star-forming galaxies with either solar metallicity and zero dust, or moderately sub-solar ( 10-20 per cent) metallicity with modest dust obscuration (A
V
0.1-0.2). This latter interpretation is consistent with the predictions of a state-of-the-art galaxy-formation simulation, which also suggests that a significant population of very-low metallicity, dust-free galaxies with β −2.5 may not emerge until M
UV > −16, a regime likely to remain inaccessible until the James Webb Space Telescope.
We present a new determination of the ultraviolet (UV) galaxy luminosity function (LF) at redshift z 7 and 8, and a first estimate at z 9. An accurate determination of the form and evolution of the ...galaxy LF during this era is of key importance for improving our knowledge of the earliest phases of galaxy evolution and the process of cosmic reionization. Our analysis exploits to the full the new, deepest Wide Field Camera 3/infrared imaging from our Hubble Space Telescope (HST) Ultra-Deep Field 2012 (UDF12) campaign, with dynamic range provided by including a new and consistent analysis of all appropriate, shallower/wider area HST survey data. Our new measurement of the evolving LF at z 7 to 8 is based on a final catalogue of 600 galaxies, and involves a step-wise maximum-likelihood determination based on the photometric redshift probability distribution for each object; this approach makes full use of the 11-band imaging now available in the Hubble Ultra-Deep Field (HUDF), including the new UDF12 F140W data, and the latest Spitzer IRAC imaging. The final result is a determination of the z 7 LF extending down to UV absolute magnitudes M
1500 = −16.75 (AB mag) and the z 8 LF down to M
1500 = −17.00. Fitting a Schechter function, we find M1500
* = −19.90+0.23
−0.28, log φ* = −2.96+0.18
−0.23 and a faint-end slope α = −1.90+0.14
−0.15 at z 7, and M1500* = −20.12+0.37
−0.48, log φ* = −3.35+0.28
−0.47 and α = −2.02+0.22
+0.23 at z 8. These results strengthen previous suggestions that the evolution at z > 7 appears more akin to 'density evolution' than the apparent 'luminosity evolution' seen at z 5 − 7. We also provide the first meaningful information on the LF at z 9, explore alternative extrapolations to higher redshifts, and consider the implications for the early evolution of UV luminosity density. Finally, we provide catalogues (including derived z
phot, M
1500 and photometry) for the most robust z ∼ 6.5-11.9 galaxies used in this analysis. We briefly discuss our results in the context of earlier work and the results derived from an independent analysis of the UDF12 data based on colour-colour selection.
There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have ...failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.
Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10mg/kg by intravenous infusion every 2weeks or physician’s choice of chemotherapy (paclitaxel 80mg/m2 on days 1, 8, and 15 or irinotecan 150mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0months; hazard ratio (HR)=1.1 95% confidence interval (CI) 0.9–1.4; P=0.81} or the secondary end points of PFS median, 1.4 versus 2.7months; HR=1.73 (95% CI 1.4–2.2); P>0.99 or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.
Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.
ClinicalTrials.gov: NCT02625623.
We present the results of a photometric redshift analysis designed to identify z≥ 6 galaxies from the near-infrared Hubble Space Telescope imaging in three deep fields Hubble Ultra Deep Field (HUDF), ...HUDF09-2 and Early Release Science covering a total area of 45 square arcmin. By adopting a rigorous set of criteria for rejecting low-redshift interlopers, and by employing a deconfusion technique to allow the available ultradeep IRAC imaging to be included in the candidate-selection process, we have derived a robust sample of 70 Lyman break galaxies (LBGs) spanning the redshift range 6.0 < z < 8.7. Based on our final sample, we investigate the distribution of ultraviolet (UV) spectral slopes (f
λ∝λβ), finding a variance-weighted mean value of 〈β〉=−2.05 ± 0.09 which, contrary to some previous results, is not significantly bluer than displayed by lower redshift starburst galaxies. We confirm the correlation between UV luminosity and stellar mass reported elsewhere, but based on fitting galaxy templates featuring a range of star formation histories (SFHs), metallicities and reddening, we find that, at z≥ 6, the range in mass-to-light ratio (M
★/L
UV) at a given UV luminosity could span a factor of ≃50. Focusing on a subsample of 21 candidates with IRAC detections at
m, we find that L
★ LBGs at z≃ 6.5 have a median stellar mass of M
★= (2.1 ± 1.1) × 109 M⊙ (Chabrier initial mass function) and a median specific star formation rate (sSFR) of 1.9 ± 0.8 Gyr−1. Using the same subsample, we have investigated the influence of nebular continuum and line emission, finding that for the majority of candidates (16 out of 21), the best-fitting stellar masses are reduced by less than a factor of 2.5. However, galaxy template fits exploring a plausible range of SFHs and metallicities provide no compelling evidence of a clear connection between SFR and stellar mass at these redshifts. Finally, a detailed comparison of our final sample with the results of previous studies suggests that, at faint magnitudes, several high-redshift galaxy samples in the literature are significantly contaminated by low-redshift interlopers.
Modern scientific knowledge of how memory functions are organized in the human brain originated from the case of Henry G. Molaison (H.M.), an epileptic patient whose amnesia ensued unexpectedly ...following a bilateral surgical ablation of medial temporal lobe structures, including the hippocampus. The neuroanatomical extent of the 1953 operation could not be assessed definitively during H.M.'s life. Here we describe the results of a procedure designed to reconstruct a microscopic anatomical model of the whole brain and conduct detailed 3D measurements in the medial temporal lobe region. This approach, combined with cellular-level imaging of stained histological slices, demonstrates a significant amount of residual hippocampal tissue with distinctive cytoarchitecture. Our study also reveals diffuse pathology in the deep white matter and a small, circumscribed lesion in the left orbitofrontal cortex. The findings constitute new evidence that may help elucidate the consequences of H.M.'s operation in the context of the brain's overall pathology.
Observations of H2O masers from circumnuclear disks in active galaxies for the Megamaser Cosmology Project (MCP) allow accurate measurement of the mass of supermassive black holes (BH) in these ...galaxies. We present the Very Long Baseline Interferometry images and kinematics of water maser emission in six active galaxies: NGC 1194, NGC 2273, NGC 2960 (Mrk 1419), NGC 4388, NGC 6264 and NGC 6323. We use the Keplerian rotation curves of these six megamaser galaxies, plus a seventh previously published, to determine accurate enclosed masses within the central ~0.3 pc of these galaxies, smaller than the radius of the sphere of influence of the central mass in all cases. We also set lower limits to the central mass densities of between 0.12 X 1010 and 61 X 1010 M pc--3. For six of the seven disks, the high central densities rule out clusters of stars or stellar remnants as the central objects, and this result further supports our assumption that the enclosed mass can be attributed predominantly to a supermassive BH. The seven BHs have masses ranging between 0.75 X 107 and 6.5 X 107 M , with the mass errors dominated by the uncertainty of the Hubble constant. We compare the megamaser BH mass determination with BH mass measured from the virial estimation method. The virial estimation BH mass in four galaxies is consistent with the megamaser BH mass, but the virial mass uncertainty is much greater. Circumnuclear megamaser disks allow the best mass determination of the central BH mass in external galaxies and significantly improve the observational basis at the low-mass end of the M- Delta *s relation. The M- Delta *s relation may not be a single, low-scatter power law as originally proposed. MCP observations continue and we expect to obtain more maser BH masses in the future.
To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA ...trial with a 2-year minimum follow-up.
Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs.
With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months hazard ratio 0.72 (95% confidence interval 0.61-0.86); 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation.
With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer.
•Nivolumab + ipilimumab + two cycles of chemotherapy (chemo) significantly prolonged survival versus chemo in first-line advanced NSCLC.•At 2 years, overall survival benefits were durable with nivolumab + ipilimumab + chemo versus chemo.•Benefits of nivolumab + ipilimumab + chemo were seen across most patient subgroups, including by PD-L1 and histology.•Discontinuing nivolumab + ipilimumab + chemo due to treatment-related AEs did not negatively impact long-term benefits.•Nivolumab + ipilimumab + two cycles of chemo is an efficacious first-line treatment option for advanced non-oncogene-driven NSCLC.
► We measure the flow induced by a sonic horn in a consise volume using PIV. ► We compare the resulting flow with the theoretical flow field of a turbulent free jet. ► we use the results to make a ...numerical model with few input parameters. ► The results enable the computation of ultrasonic treatment times for many volumes.
The flow in a confined container induced by an ultrasonic horn is measured by Particle Image Velocimetry (PIV). This flow is caused by acoustic streaming and highly influenced by the presence of cavitation. The jet-like experimentally observed flow is compared with the available theoretical solution for a turbulent free round jet. The similarity between both flows enables a simplified numerical model to be made, whilst the phenomenon is very difficult to simulate otherwise. The numerical model requires only two parameters, i.e. the flow momentum and turbulent kinetic energy at the position of the horn tip. The simulated flow is used as a basis for the calculation of the time required for the entire liquid volume to pass through the active cavitation region.
Neural changes that occurred during human evolution to support language are poorly understood. As a basis of comparison to humans, we used design-based stereological methods to estimate volumes, ...total neuron numbers, and neuron densities in Brodmann's areas 44 and 45 in both cerebral hemispheres of 12 chimpanzees (Pan troglodytes), one of our species’ closest living relatives. We found that the degree of interindividual variation in the topographic location and quantitative cytoarchitecture of areas 44 and 45 in chimpanzees was comparable to that seen in humans from previous studies. However, in contrast to the documented asymmetries in humans, we did not find significant population-level hemispheric asymmetry for any measures of areas 44 and 45 in chimpanzees. Furthermore, there was no relationship between asymmetries of stereological data and magnetic resonance imaging–based measures of inferior frontal gyrus morphology or hand preference on 2 different behavioral tasks. These findings suggest that Broca's area in the left hemisphere expanded in relative size during human evolution, possibly as an adaptation for our species’ language abilities.
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