We present detailed multiwavelength observations of GRB 161219B at z = 0.1475, spanning the radio to X-ray regimes, and the first Atacama Large Millimeter/submillimeter Array (ALMA) light curve of a ...γ-ray burst (GRB) afterglow. The centimeter- and millimeter-band observations before 8.5 days require emission in excess of that produced by the afterglow forward shock (FS). These data are consistent with radiation from a refreshed reverse shock (RS) produced by the injection of energy into the FS, signatures of which are also present in the X-ray and optical light curves. We infer a constant-density circumburst environment with an extremely low density, , and show that this is a characteristic of all strong RS detections to date. The Karl G. Lansky Very Large Array (VLA) observations exhibit unexpected rapid variability on roughly minute timescales, indicative of strong interstellar scintillation. The X-ray, ALMA, and VLA observations together constrain the jet break time, days, yielding a wide jet opening angle of , implying beaming-corrected γ-ray and kinetic energies of erg and erg, respectively. Comparing the RS and FS emission, we show that the ejecta are only weakly magnetized, with relative magnetization, , compared to the FS. These direct, multifrequency measurements of a refreshed RS spanning the optical to radio bands highlight the impact of radio and millimeter data in probing the production and nature of GRB jets.
The KEYNOTE-365 study assessed the efficacy and safety of pembrolizumab combination therapies in metastatic castration-resistant prostate cancer (mCRPC). In cohort A, pembrolizumab plus olaparib ...showed antitumor activity and manageable safety in patients with molecularly unselected, docetaxel-pretreated mCRPC.
Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC).
To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC.
Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening.
Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily.
The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS).
Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range IQR, 65–76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22–47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval CI, 4.0–6.5) and median OS was 14 mo (95% CI, 10.4–18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3–5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design.
Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC.
Pembrolizumab plus olaparib showed antitumor activity and expected safety in patients with metastatic castration-resistant prostate cancer.
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple ...prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed
by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth
and
. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. SIGNIFICANCE: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.
We assembled age at onset or death data from 1,094 ...individuals with high penetrance mutations in the prion protein gene (
) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.
Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor
codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.
The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
Abstract
We present a comprehensive catalog of observations and stellar population properties for 23 highly secure host galaxies of fast radio bursts (FRBs). Our sample comprises 6 repeating FRBs and ...17 apparent nonrepeaters. We present 82 new photometric and 8 new spectroscopic observations of these hosts. Using stellar population synthesis modeling and employing nonparametric star formation histories (SFHs), we find that FRB hosts have a median stellar mass of ≈10
9.9
M
⊙
, mass-weighted age ≈5.1 Gyr, and ongoing star formation rate ≈1.3
M
⊙
yr
−1
but span wide ranges in all properties. Classifying the hosts by degree of star formation, we find that 87% (20 of 23 hosts) are star-forming, two are transitioning, and one is quiescent. The majority trace the star-forming main sequence of galaxies, but at least three FRBs in our sample originate in less-active environments (two nonrepeaters and one repeater). Across all modeled properties, we find no statistically significant distinction between the hosts of repeaters and nonrepeaters. However, the hosts of repeating FRBs generally extend to lower stellar masses, and the hosts of nonrepeaters arise in more optically luminous galaxies. While four of the galaxies with the clearest and most prolonged rises in their SFHs all host repeating FRBs, demonstrating heightened star formation activity in the last ≲100 Myr, one nonrepeating host shows this SFH as well. Our results support progenitor models with short delay channels (i.e., magnetars formed via core-collapse supernova) for most FRBs, but the presence of some FRBs in less-active environments suggests a fraction form through more delayed channels.
Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have ...defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers.
Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity.
Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002).
Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
Abstract
We present a comprehensive optical and near-infrared census of the fields of 90 short gamma-ray bursts (GRBs) discovered in 2005–2021, constituting all short GRBs for which host galaxy ...associations are feasible (≈60% of the total Swift short GRB population). We contribute 274 new multi-band imaging observations across 58 distinct GRBs and 26 spectra of their host galaxies. Supplemented by literature and archival survey data, the catalog contains 542 photometric and 42 spectroscopic data sets. The photometric catalog reaches 3
σ
depths of ≳24–27 mag and ≳23–26 mag for the optical and near-infrared bands, respectively. We identify host galaxies for 84 bursts, in which the most robust associations make up 56% (50/90) of events, while only a small fraction, 6.7%, have inconclusive host associations. Based on new spectroscopy, we determine 18 host spectroscopic redshifts with a range of
z
≈ 0.15–1.5 and find that ≈23%–41% of Swift short GRBs originate from
z
> 1. We also present the galactocentric offset catalog for 84 short GRBs. Taking into account the large range of individual measurement uncertainties, we find a median of projected offset of ≈7.7 kpc, for which the bursts with the most robust associations have a smaller median of ≈4.8 kpc. Our catalog captures more high-redshift and low-luminosity hosts, and more highly offset bursts than previously found, thereby diversifying the population of known short GRB hosts and properties. In terms of locations and host luminosities, the populations of short GRBs with and without detectable extended emission are statistically indistinguishable. This suggests that they arise from the same progenitors, or from multiple progenitors, which form and evolve in similar environments. All of the data products are available on the Broadband Repository for Investigating Gamma-Ray Burst Host Traits website.
Current influenza vaccines predominantly induce immunity to the hypervariable hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, the immunosubdominant yet conserved HA ...stem harbors a supersite that is targeted by broadly neutralizing antibodies (bnAbs), representing a prime target for universal vaccines. Here, we showed that the co-immunization of two HA stem immunogens derived from group 1 and 2 influenza A viruses elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum-neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and protected against diverse viruses, including H5N1 and H7N9. Genetic and structural analyses revealed strong homology between macaque and human bnAbs, illustrating common biophysical constraints for acquiring cross-group specificity. Vaccine elicitation of stem-directed cross-group-protective immunity represents a step toward the development of broadly protective influenza vaccines.
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•Broad group 2 protective immunity was induced by H10-based group 2 HA stem immunogen•Co-immunization with group 1 and 2 HA stem immunogens elicits cross-protective antibodies•A bnAb isolated from an immunized NHP neutralizes both group 1 and 2 influenza A viruses•A common mode of HA recognition via the DH gene-encoded motif among NHP and human bnAbs
Current vaccine-induced influenza immunity targets the hypervariable HA head, requiring frequent vaccine reformulation. Moin et al. show that co-immunization with HA stem immunogens of group 1 and group 2 influenza A viruses broadly elicits cross-protective antibodies in animals and leads to the discovery of a cross-group protective monoclonal antibody in a macaque, offering a blueprint for broadly protective influenza vaccines.
Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this ...trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma.
In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete.
Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 35% patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 35% patients) in the placebo group (hazard ratio 0·23 95% CI 0·16–0·34; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 63% vs 118 62%), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 0·24–0·42; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 0·30–0·45; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 99% patients in the rucaparib group vs 189 100% in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 19% vs one 1%) and increased alanine or aspartate aminotransferase concentration (39 10% vs none).
Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy.
Clovis Oncology.
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