Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within ...resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition ...to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.
In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223.
At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval CI, 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events.
In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).
This book is a major English-language introduction to the earliest manuscripts of the New Testament. An essential handbook for scholars and students, it provides a thorough grounding in the study and ...editing of the New Testament text combined with an emphasis on the dramatic current developments in the field. Covering ancient sources in Greek, Syriac, Latin and Coptic, it:
• Describes the manuscripts and other ancient textual evidence, and the tools needed to study them
• Deals with textual criticism and textual editing, describing modern approaches and techniques, with guidance on the use of editions
• Introduces the witnesses and textual study of each of the main sections of the New Testament, discussing typical variants and their significance.
A companion website with full-colour images provides generous amounts of illustrative material, bringing the subject alive for the reader.
Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate ...cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP versus SOC+DocP.
Recruitment to SOC+DocP and SOC+AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for≥2years and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly×6+prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg+prednisolone 5mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC+AAP, and HR>1 favours SOC+DocP.
A total of 566 consenting patients were contemporaneously randomised: 189 SOC+DocP and 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8–10; 449 (79%) WHO performance status 0; median age 66years and median PSA 56ng/ml. With median follow-up 4years, 149 deaths were reported. For overall survival, HR=1.16 (95% CI 0.82–1.65); failure-free survival HR=0.51 (95% CI 0.39–0.67); progression-free survival HR=0.65 (95% CI 0.48–0.88); metastasis-free survival HR=0.77 (95% CI 0.57–1.03); prostate cancer-specific survival HR=1.02 (0.70–1.49); and symptomatic skeletal events HR=0.83 (95% CI 0.55–1.25). In the safety population, the proportion reporting≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, and 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm.
This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs.
Clinicaltrials.gov: NCT00268476.
The key component of a microstructural diffusion MRI ‘super-scanner’ is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional ...gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of ‘super-scanners’.
•Improved estimation of axon diameter in vivo.•Better fitting of complex microstructure models.•Improved characterisation of tumours.•Facilitation of multi-contrast MRI experiments.
The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan
. Caloric ...restriction (CR), defined as lessening caloric intake without depriving essential nutrients
, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)
, and is established to increase healthy lifespan in multiple species
. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref.
). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health
. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies
and contrasting with reports that biological aging may not be modifiable
. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality
.
Summary Background The alpha-emitter radium-223 (223 Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed ...to study mature outcomes from a randomised, multicentre, phase II study of223 Ra. Methods Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of223 Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat. Findings Median relative change in bone-ALP during treatment was −65·6% (95% CI −69·5 to −57·7) and 9·3% (3·8–60·9) in the223 Ra group and placebo groups, respectively (p<0·0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1·75 (0·96–3·19, p=0·065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued223 Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16–39) versus 8 weeks (4–12; p=0·048) for223 Ra versus placebo, respectively. Median overall survival was 65·3 weeks (48·7–∞) for223 Ra and 46·4 weeks (32·1–77·4) for placebo (p=0·066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2·12 (1·13–3·98, p=0·020, Cox regression). Interpretation223 Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study223 Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of223 Ra could also potentially be used for treating skeletal metastasis from other primary cancers.
We present the Runaways and Isolated O-Type Star Spectroscopic Survey of the SMC (RIOTS4), a spatially complete survey of uniformly selected field OB stars that covers the entire star-forming body of ...the Small Magellanic Cloud (SMC). Using the IMACS (Inamori-Magellan Areal Camera and Spectrograph) multislit spectrograph and MIKE (Magellan Inamori Kyocera Echelle) echelle spectrograph on the Magellan telescopes, we obtained spectra of 374 early-type field stars that are at least 28 pc from any other OB candidates. We also obtained spectra of an additional 23 field stars in the SMC bar identified from slightly different photometric criteria. RIOTS4 confirmed a steep upper initial mass function in the field, apparently caused by the inability of the most massive stars to form in the smallest clusters. Our survey also yields evidence for in situ field OB star formation, and properties of field emission-line star populations, including sgBe stars and classical Oe/Be stars. We also discuss the radial velocity distribution and its relation to SMC kinematics and runaway stars.
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