Showing papers by "Boston University published in 2015"

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer

Abstract: BACKGROUND Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.)

A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease

Abstract: Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Combined Measurement of the Higgs Boson Mass in pp Collisions at √s=7 and 8 TeV with the ATLAS and CMS Experiments

Abstract: A measurement of the Higgs boson mass is presented based on the combined data samples of the ATLAS and CMS experiments at the CERN LHC in the H→γγ and H→ZZ→4l decay channels. The results are obtained from a simultaneous fit to the reconstructed invariant mass peaks in the two channels and for the two experiments. The measured masses from the individual channels and the two experiments are found to be consistent among themselves. The combined measured mass of the Higgs boson is mH=125.09±0.21 (stat)±0.11 (syst) GeV.

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

Abstract: The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

Optical communications using orbital angular momentum beams

Abstract: Orbital angular momentum (OAM), which describes the “phase twist” (helical phase pattern) of light beams, has recently gained interest due to its potential applications in many diverse areas. Particularly promising is the use of OAM for optical communications since: (i) coaxially propagating OAM beams with different azimuthal OAM states are mutually orthogonal, (ii) inter-beam crosstalk can be minimized, and (iii) the beams can be efficiently multiplexed and demultiplexed. As a result, multiple OAM states could be used as different carriers for multiplexing and transmitting multiple data streams, thereby potentially increasing the system capacity. In this paper, we review recent progress in OAM beam generation/detection, multiplexing/demultiplexing, and its potential applications in different scenarios including free-space optical communications, fiber-optic communications, and RF communications. Technical challenges and perspectives of OAM beams are also discussed.

Idarucizumab for Dabigatran Reversal

Abstract: BACKGROUND Specific reversal agents for non–vitamin K antagonist oral anticoagulants are lacking Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran METHODS We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B) The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time A key secondary end point was the restoration of hemostasis RESULTS This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B) Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100) Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 114 hours Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated CONCLUSIONS Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrialsgov number, NCT02104947)

Fracture healing: mechanisms and interventions

Abstract: Fractures are the most common large-organ, traumatic injuries to humans. The repair of bone fractures is a postnatal regenerative process that recapitulates many of the ontological events of embryonic skeletal development. Although fracture repair usually restores the damaged skeletal organ to its pre-injury cellular composition, structure and biomechanical function, about 10% of fractures will not heal normally. This article reviews the developmental progression of fracture healing at the tissue, cellular and molecular levels. Innate and adaptive immune processes are discussed as a component of the injury response, as are environmental factors, such as the extent of injury to the bone and surrounding tissue, fixation and the contribution of vascular tissues. We also present strategies for fracture treatment that have been tested in animal models and in clinical trials or case series. The biophysical and biological basis of the molecular actions of various therapeutic approaches, including recombinant human bone morphogenetic proteins and parathyroid hormone therapy, are also discussed.

Depletion of microglia and inhibition of exosome synthesis halt tau propagation

Abstract: In this study, the authors show that microglia play an important role in the propagation of pathogenic tau protein. In addition, the authors find that spread of the tau protein occurs via exosome secretion from these microglial cells.

From Quantum Chaos and Eigenstate Thermalization to Statistical Mechanics and Thermodynamics

Abstract: This review gives a pedagogical introduction to the eigenstate thermalization hypothesis (ETH), its basis, and its implications to statistical mechanics and thermodynamics. In the first part, ETH is introduced as a natural extension of ideas from quantum chaos and random matrix theory (RMT). To this end, we present a brief overview of classical and quantum chaos, as well as RMT and some of its most important predictions. The latter include the statistics of energy levels, eigenstate components, and matrix elements of observables. Building on these, we introduce the ETH and show that it allows one to describe thermalization in isolated chaotic systems without invoking the notion of an external bath. We examine numerical evidence of eigenstate thermalization from studies of many-body lattice systems. We also introduce the concept of a quench as a means of taking isolated systems out of equilibrium, and discuss results of numerical experiments on quantum quenches. The second part of the review explores the implications of quantum chaos and ETH to thermodynamics. Basic thermodynamic relations are derived, including the second law of thermodynamics, the fundamental thermodynamic relation, fluctuation theorems, and the Einstein and Onsager relations. In particular, it is shown that quantum chaos allows one to prove these relations for individual Hamiltonian eigenstates and thus extend them to arbitrary stationary statistical ensembles. We then show how one can use these relations to obtain nontrivial universal energy distributions in continuously driven systems. At the end of the review, we briefly discuss the relaxation dynamics and description after relaxation of integrable quantum systems, for which ETH is violated. We introduce the concept of the generalized Gibbs ensemble, and discuss its connection with ideas of prethermalization in weakly interacting systems.

Universal high-frequency behavior of periodically driven systems: from dynamical stabilization to Floquet engineering

Abstract: We give a general overview of the high-frequency regime in periodically driven systems and identify three distinct classes of driving protocols in which the infinite-frequency Floquet Hamiltonian is not equal to the time-averaged Hamiltonian. These classes cover systems, such as the Kapitza pendulum, the Harper–Hofstadter model of neutral atoms in a magnetic field, the Haldane Floquet Chern insulator and others. In all setups considered, we discuss both the infinite-frequency limit and the leading finite-frequency corrections to the Floquet Hamiltonian. We provide a short overview of Floquet theory focusing on the gauge structure associated with the choice of stroboscopic frame and the differences between stroboscopic and non-stroboscopic dynamics. In the latter case, one has to work with dressed operators representing observables and a dressed density matrix. We also comment on the application of Floquet Theory to systems described by static Hamiltonians with well-separated energy scales and, in particul...

DNA methylation age of blood predicts all-cause mortality in later life.

Abstract: Background: DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age. Results: Here we test whether differences between people’s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43. Conclusions: DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.

Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline

Abstract: Objective: To formulate clinical practice guidelines for the pharmacological management of obesity. Participants: An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. This guideline was co-sponsored by the European Society of Endocrinology and The Obesity Society. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the European Society of Endocrinology, and The Obesity Society reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize some of the supporting evidence. Conclusions: Weight loss is a pathway to health improvement for patients with obesity-associated risk factors and comorbidit...

The Economics of Reproducibility in Preclinical Research

Abstract: Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total) prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B)/year spent on preclinical research that is not reproducible—in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures.

The effects of physical activity on sleep: a meta-analytic review

Abstract: A significant body of research has investigated the effects of physical activity on sleep, yet this research has not been systematically aggregated in over a decade. As a result, the magnitude and moderators of these effects are unclear. This meta-analytical review examines the effects of acute and regular exercise on sleep, incorporating a range of outcome and moderator variables. PubMed and PsycINFO were used to identify 66 studies for inclusion in the analysis that were published through May 2013. Analyses reveal that acute exercise has small beneficial effects on total sleep time, sleep onset latency, sleep efficiency, stage 1 sleep, and slow wave sleep, a moderate beneficial effect on wake time after sleep onset, and a small effect on rapid eye movement sleep. Regular exercise has small beneficial effects on total sleep time and sleep efficiency, small-to-medium beneficial effects on sleep onset latency, and moderate beneficial effects on sleep quality. Effects were moderated by sex, age, baseline physical activity level of participants, as well as exercise type, time of day, duration, and adherence. Significant moderation was not found for exercise intensity, aerobic/anaerobic classification, or publication date. Results were discussed with regards to future avenues of research and clinical application to the treatment of insomnia.

Common genetic variants influence human subcortical brain structures.

Abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Precise determination of the mass of the Higgs boson and tests of compatibility of its couplings with the standard model predictions using proton collisions at 7 and 8 TeV

Abstract: Properties of the Higgs boson with mass near 125 GeV are measured in proton-proton collisions with the CMS experiment at the LHC. Comprehensive sets of production and decay measurements are combined. The decay channels include gamma gamma, ZZ, WW, tau tau, bb, and mu mu pairs. The data samples were collected in 2011 and 2012 and correspond to integrated luminosities of up to 5.1 inverse femtobarns at 7 TeV and up to 19.7 inverse femtobarns at 8 TeV. From the high-resolution gamma gamma and ZZ channels, the mass of the Higgs boson is determined to be 125.02 +0.26 -0.27 (stat) +0.14 -0.15 (syst) GeV. For this mass value, the event yields obtained in the different analyses tagging specific decay channels and production mechanisms are consistent with those expected for the standard model Higgs boson. The combined best-fit signal relative to the standard model expectation is 1.00 +/- 0.09 (stat) +0.08 -0.07 (theo) +/- 0.07 (syst) at the measured mass. The couplings of the Higgs boson are probed for deviations in magnitude from the standard model predictions in multiple ways, including searches for invisible and undetected decays. No significant deviations are found.

Psychotherapy for Military-Related PTSD: A Review of Randomized Clinical Trials.

Abstract: Importance Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder common among military personnel and veterans. First-line psychotherapies most often recommended for PTSD consist mainly of “trauma-focused” psychotherapies that involve focusing on details of the trauma or associated cognitive and emotional effects. Objective To examine the effectiveness of psychotherapies for PTSD in military and veteran populations. Evidence Review PubMed, PsycINFO, and PILOTS were searched for randomized clinical trials (RCTs) of individual and group psychotherapies for PTSD in military personnel and veterans, published from January 1980 to March 1, 2015. We also searched reference lists of articles, selected reviews, and meta-analyses. Of 891 publications initially identified, 36 were included. Findings Two trauma-focused therapies, cognitive processing therapy (CPT) and prolonged exposure, have been the most frequently studied psychotherapies for military-related PTSD. Five RCTs of CPT (that included 481 patients) and 4 RCTs of prolonged exposure (that included 402 patients) met inclusion criteria. Focusing on intent-to-treat outcomes, within-group posttreatment effect sizes for CPT and prolonged exposure were large (Cohen d range, 0.78-1.10). CPT and prolonged exposure also outperformed waitlist and treatment-as-usual control conditions. Forty-nine percent to 70% of participants receiving CPT and prolonged exposure attained clinically meaningful symptom improvement (defined as a 10- to 12-point decrease in interviewer-assessed or self-reported symptoms). However, mean posttreatment scores for CPT and prolonged exposure remained at or above clinical criteria for PTSD, and approximately two-thirds of patients receiving CPT or prolonged exposure retained their PTSD diagnosis after treatment (range, 60%-72%). CPT and prolonged exposure were marginally superior compared with non–trauma-focused psychotherapy comparison conditions. Conclusions and Relevance In military and veteran populations, trials of the first-line trauma-focused interventions CPT and prolonged exposure have shown clinically meaningful improvements for many patients with PTSD. However, nonresponse rates have been high, many patients continue to have symptoms, and trauma-focused interventions show marginally superior results compared with active control conditions. There is a need for improvement in existing PTSD treatments and for development and testing of novel evidence-based treatments, both trauma-focused and non–trauma-focused.

Thresholds for the cost-effectiveness of interventions: alternative approaches.

Abstract: Many countries use the cost–effectiveness thresholds recommended by the World Health Organization’s Choosing Interventions that are Cost–Effective project (WHO-CHOICE) when evaluating health interventions. This project sets the threshold for cost–effectiveness as the cost of the intervention per disability-adjusted life-year (DALY) averted less than three times the country’s annual gross domestic product (GDP) per capita. Highly cost–effective interventions are defined as meeting a threshold per DALY averted of once the annual GDP per capita. We argue that reliance on these thresholds reduces the value of cost–effectiveness analyses and makes such analyses too blunt to be useful for most decision-making in the field of public health. Use of these thresholds has little theoretical justification, skirts the difficult but necessary ranking of the relative values of locally-applicable interventions and omits any consideration of what is truly affordable. The WHO-CHOICE thresholds set such a low bar for cost–effectiveness that very few interventions with evidence of efficacy can be ruled out. The thresholds have little value in assessing the trade-offs that decision-makers must confront. We present alternative approaches for applying cost–effectiveness criteria to choices in the allocation of health-care resources.

How to constrain your m dwarf: measuring effective temperature, bolometric luminosity, mass, and radius

Abstract: Precise and accurate parameters for late-type (late K and M) dwarf stars are important for characterization of any orbiting planets, but such determinations have been hampered by these stars' compl ...

The Mars Atmosphere and Volatile Evolution (MAVEN) Mission

Abstract: The MAVEN spacecraft launched in November 2013, arrived at Mars in September 2014, and completed commissioning and began its one-Earth-year primary science mission in November 2014 The orbiter’s science objectives are to explore the interactions of the Sun and the solar wind with the Mars magnetosphere and upper atmosphere, to determine the structure of the upper atmosphere and ionosphere and the processes controlling it, to determine the escape rates from the upper atmosphere to space at the present epoch, and to measure properties that allow us to extrapolate these escape rates into the past to determine the total loss of atmospheric gas to space through time These results will allow us to determine the importance of loss to space in changing the Mars climate and atmosphere through time, thereby providing important boundary conditions on the history of the habitability of Mars The MAVEN spacecraft contains eight science instruments (with nine sensors) that measure the energy and particle input from the Sun into the Mars upper atmosphere, the response of the upper atmosphere to that input, and the resulting escape of gas to space In addition, it contains an Electra relay that will allow it to relay commands and data between spacecraft on the surface and Earth

Attentional Selection in a Cocktail Party Environment Can Be Decoded from Single-Trial EEG

Abstract: How humans solve the cocktail party problem remains unknown. However, progress has been made recently thanks to the realization that cortical activity tracks the amplitude envelope of speech. This has led to the development of regression methods for studying the neurophysiology of continuous speech. One such method, known as stimulus-reconstruction, has been successfully utilized with cortical surface recordings and magnetoencephalography (MEG). However, the former is invasive and gives a relatively restricted view of processing along the auditory hierarchy, whereas the latter is expensive and rare. Thus it would be extremely useful for research in many populations if stimulus-reconstruction was effective using electroencephalography (EEG), a widely available and inexpensive technology. Here we show that single-trial (≈60 s) unaveraged EEG data can be decoded to determine attentional selection in a naturalistic multispeaker environment. Furthermore, we show a significant correlation between our EEG-based measure of attention and performance on a high-level attention task. In addition, by attempting to decode attention at individual latencies, we identify neural processing at ∼200 ms as being critical for solving the cocktail party problem. These findings open up new avenues for studying the ongoing dynamics of cognition using EEG and for developing effective and natural brain– computer interfaces.