The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell ...carcinoma (aRCC). We report updated efficacy data from the second interim analysis.
Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1–positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population.
Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 95% confidence interval (CI) 0.490–0.777}; one-sided P < 0.0001; median 13.8 (95% CI 10.1–20.7) versus 7.0 months (95% CI 5.7–9.6); overall population: HR 0.69 (95% CI 0.574–0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1–15.3) versus 8.0 months (95% CI 6.7–9.8). OS data were immature PD-L1+ population: HR 0.828 (95% CI 0.596–1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616–1.027); one-sided P = 0.0392.
Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.
NCT02684006.
•Avelumab plus axitinib significantly prolonged progression-free survival versus sunitinib in advanced renal cell carcinoma.•Although overall survival data were immature, results favored the combination over sunitinib across prespecified subgroups.•Adjusting for subsequent use of PD-1/PD-L1 inhibitors in the sunitinib arm predicted a survival benefit for the combination.•Among all randomized patients, avelumab plus axitinib had a longer mean duration of response than sunitinib.•Avelumab plus axitinib prolonged progression-free survival on next-line therapy versus sunitinib.
Background and purpose
Branch atheromatous disease (BAD) is one of the stroke subtypes caused by occlusion at the origin of a deep penetrating artery of the brain and is associated with a ...microatheroma or a junctional plaque. Patients with BAD often develop progressive worsening of neurologic deficits, although these patients often present minor stroke with clinical characteristics of lacunar syndrome at the onset. Pentraxin 3 (PTX3) is known to be a key molecule involved in the pathogenesis of atherosclerosis. Although a high level of serum PTX3 is observed in patients with acute coronary syndrome, there are no reports on PTX3 levels in patients with BAD. This study aimed to investigate whether serum PTX3 levels can distinguish BAD from other stroke subtypes.
Methods
We investigated 93 patients with ischaemic stroke. Serum PTX3 levels on admission were measured using enzyme‐linked immunosorbent assay in patients with BAD and those with other stroke subtypes (each n ≥ 20).
Results
The median PTX3 levels in patients with BAD (4840 pg/mL) were higher than those with other subtypes of stroke (3397 pg/mL in lacunar stroke, 1298 pg/mL in large‐artery atherosclerosis, 1470 pg/mL in cardioaortic embolism and 1006 pg/mL in control) (all P < 0.01).
Conclusion
Our results suggest that elevated serum PTX3 levels might predict the diagnosis of BAD at a very early stage.
The detailed investigation of the broadband flux variability in the blazar 3C 273 allowed us to probe the location and size of emission regions and their physical conditions. We conducted correlation ...studies of the flaring activity in 3C 273, which was observed for the period between 2008 and 2012. The observed broadband variations were investigated using the structure function and the discrete correlation function methods. Starting from the commonly used power spectral density (PSD) analysis at X-ray frequencies, we extended our investigation to characterise the nature of variability at radio, optical, and γ-ray frequencies. The PSD analysis showed that the optical and infrared light-curve slopes are consistent with the slope of white-noise processes, while the PSD slopes at radio, X-ray, and γ-ray energies are consistent with red-noise processes. We found that the estimated fractional variability amplitudes strongly depend on the observed frequency. The flux variations at γ-ray and mm-radio bands are found to be significantly correlated. Using the estimated time lag of (110 ± 27) days between γ-ray and radio light-curves, where γ-ray variations lead the radio bands, we constrained the location of the γ-ray emission region at a de-projected distance of 1.2 ± 0.9 pc from the jet apex. Flux variations at X-ray bands were found to have a significant correlation with variations at both radio and γ-ray energies. The correlation between X-ray and γ-ray light curves indicates two possible time lags, which suggests that two components are responsible for the X-ray emission. A negative time lag of −(50 ± 20) days, where the X-rays are leading the emission, suggests that X-rays are emitted closer to the jet apex from a compact region (0.02–0.05 pc in size), most likely from the corona at a distance of (0.5 ± 0.4) pc from the jet apex. A positive time lag of (110 ± 20) days (γ-rays are leading the emission) suggests a jet-base origin of the other X-ray component at ~4 to 5 pc from the jet apex. The flux variations at radio frequencies were found to be well correlated with each other such that the variations at higher frequencies are leading the lower frequencies, which is expected from the standard shock-in-jet model.
N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, ...membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2
, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 s than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.
SIRT4, which is localised in the mitochondria, is one of the least characterised members of the sirtuin family of nicotinamide adenine dinucleotide-dependent enzymes that play key roles in multiple ...cellular processes such as metabolism, stress response and longevity. There are only a few studies that have characterised its function and assessed its clinical significance in human cancers.
We established colorectal cancer cell lines (SW480, HCT116, and HT29) overexpressing SIRT4 and investigated their effects on proliferation, migration and invasion, as well as E-cadherin expression, that negatively regulates tumour invasion and metastases. The associations between SIRT4 expression in colorectal cancer specimens and clinicopathological features including prognosis were assessed by immunohistochemistry.
SIRT4 upregulated E-cadherin expression and suppressed proliferation, migration and invasion through inhibition of glutamine metabolism in colorectal cancer cells. Moreover, SIRT4 expression in colorectal cancer decreased with the progression of invasion and metastasis, and a low expression level of SIRT4 was correlated with a worse prognosis.
SIRT4 has a tumour-suppressive function and may serve as a novel therapeutic target in colorectal cancer.
We report on a recent multiband optical photometric and polarimetric observational campaign of the blazar OJ 287 that was carried out during 2016 September-2017 December. We employed nine telescopes ...in Bulgaria, China, Georgia, Japan, Serbia, Spain, and the United States. We collected over 1800 photometric image frames in BVRI bands and over 100 polarimetric measurements over ∼175 nights. In 11 nights with many quasi-simultaneous multiband (V, R, I) observations, we did not detect any genuine intraday variability in flux or color. On longer timescales, multiple flaring events were seen. Large changes in color with respect to time and in a color-magnitude diagram were seen, and while only a weak systematic variability trend was noticed in color with respect to time, the color-magnitude diagram shows a bluer-when-brighter trend. Large changes in the degree of polarization and substantial swings in the polarization angle were detected. The fractional Stokes parameters of the polarization showed a systematic trend with time in the beginning of these observations, followed by chaotic changes and then an apparently systematic variation at the end. These polarization changes coincide with the detection and duration of the source at very high energies as seen by VERITAS. The spectral index shows a systematic variation with time and V-band magnitude. We briefly discuss possible physical mechanisms that could explain the observed flux, color, polarization, and spectral variability.
The gamma-ray emission offers a powerful diagnostic tool to probe jets and their surroundings in flat-spectrum radio quasars (FSRQs). This motivates us to start a systematic study of flares with ...bright emission above 10 GeV, examining archival data of the Fermi-LAT gamma-ray telescope. Among others, we investigate the SED of a peculiar flare of 3C 454.3, showing a remarkably hard gamma-ray spectrum, quite different from the brightest flares of this source, and a bright flare of CTA 102. We modeled the SED in the framework of the one-zone leptonic model, using also archival optical spectroscopic data to derive the luminosity of the broad lines and thus estimate the disk luminosity, from which the structural parameters of the FSRQ nucleus can be inferred. We discussed the observed spectra and variability timescales in terms of injection and cooling of energetic particles, arguing that these flares could be triggered by magnetic reconnection events or turbulence in the flow.
Abstract
We study the optical flux and polarization variability of the binary black hole blazar OJ 287 using quasi-simultaneous observations from 2015 to 2023 carried out using telescopes in the USA, ...Japan, Russia, Crimea, and Bulgaria. This is one of the most extensive quasi-simultaneous optical flux and polarization variability studies of OJ 287. OJ 287 showed large amplitude, ∼3.0 mag flux variability, large changes of ∼37% in degree of polarization, and a large swing of ∼215° in the angle of the electric vector of polarization. During the period of observation, several flares in flux were detected. Those flares are correlated with a rapid increase in the degree of polarization and swings in electric vector of polarization angle. A peculiar behavior of anticorrelation between flux and polarization degree, accompanied by a nearly constant polarization angle, was detected from JD 2,458,156 to JD 2,458,292. We briefly discuss some explanations for the flux and polarization variations observed in OJ 287.
Abstract We report the study of a huge optical intraday flare on 2021 November 12 at 2 a.m. UT in the blazar OJ 287. In the binary black hole model, it is associated with an impact of the secondary ...black hole on the accretion disk of the primary. Our multifrequency observing campaign was set up to search for such a signature of the impact based on a prediction made 8 yr earlier. The first I -band results of the flare have already been reported by Kishore et al. (2024). Here we combine these data with our monitoring in the R -band. There is a big change in the R – I spectral index by 1.0 ± 0.1 between the normal background and the flare, suggesting a new component of radiation. The polarization variation during the rise of the flare suggests the same. The limits on the source size place it most reasonably in the jet of the secondary BH. We then ask why we have not seen this phenomenon before. We show that OJ 287 was never before observed with sufficient sensitivity on the night when the flare should have happened according to the binary model. We also study the probability that this flare is just an oversized example of intraday variability using the Krakow data set of intense monitoring between 2015 and 2023. We find that the occurrence of a flare of this size and rapidity is unlikely. In machine-readable Tables 1 and 2, we give the full orbit-linked historical light curve of OJ 287 as well as the dense monitoring sample of Krakow.
The quasar 3C 454.3 is a blazar known for its rapid and violent outbursts seen across the electromagnetic spectrum. Using γ-ray, X-ray, multiband optical, and very-long-baseline interferometric data ...we investigate the nature of two such events that occurred in 2013 and 2014 accompanied by strong variations in optical polarization, including a ∼230° electric vector position angle (EVPA) rotation. Our results suggest that a single disturbance was responsible for both flaring events. We interpret the disturbance as a shock propagating down the jet. Under this interpretation the 2013 flare originated most likely due to changes in the viewing angle caused by perhaps a bent or helical trajectory of the shock upstream of the radio core. The 2014 flare and optical polarization behavior are the result of the shock exiting the 43 GHz radio core, suggesting that shock crossings are one of the possible mechanisms for EVPA rotations.
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