We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small ...lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio HR 95% CI, 0.206 0.159-0.265; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.
We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We ...present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors.
We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 95% confidence interval 3.3-26 for PP and 9.7 95% confidence interval 3.2-29.6 for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females.
ICD therapy is indicated for PP in postpubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.
A reduction in plasma membrane cholesterol is one of the early events that either triggers or is closely associated with capacitation
of mammalian spermatozoa. In this investigation, we have examined ...the effects of cholesterol efflux on tyrosine phosphorylation,
lipid diffusion, and raft organization in boar spermatozoa. Results show that a low level of cholesterol efflux, mediated
by 5 mM methyl-β-cyclodextrin (MBCD), enhances capacitation and induces phosphorylation of two proteins at 26 and 15 kDa without
affecting sperm viability. Lipid diffusion rates under these conditions are largely unaffected except when cholesterol efflux
is excessive. Low-density Triton X100-insoluble complexes (lipid rafts) were isolated from spermatozoa and found to have a
restricted profile of proteins. Capacitation-associated cholesterol efflux has no effect on raft composition, but cholesterol
depletion destabilizes them completely and phosphorylation is suppressed. During MBCD-mediated capacitation, the distribution
of GM1 gangliosides on spermatozoa changes in a sequential manner from overlying the sperm tail to clustering on the sperm
head. It is concluded that there is a safe window for removal of plasma membrane cholesterol from spermatozoa within which
protein phosphorylation and polarized migration of lipid rafts take place. A preferential loss of cholesterol from the nonraft
pool may be the stimulus that promotes raft clustering over the anterior sperm head.
Advanced glycation end products (AGE) exacerbate disease progression through two general mechanisms: modifying molecules and forming nondegradable aggregates, thus impairing normal cellular/tissue ...functions, and altering cellular function directly through receptor-mediated activation. In the present study receptor for AGE (RAGE)-mediated cellular activation was evaluated in the etiology of human retinal aging and disease.
The maculas of human donor retinas from normal eyes and eyes with early age-related macular degeneration (AMD) and advanced AMD with geographic atrophy (GA) were assayed for AGE and RAGE by immunocytochemistry. Cultured ARPE-19 cells were challenged with known ligands for RAGE, AGE, and S100B, to test for activation capacity. Immunocytochemistry, real-time RT-PCR, immunoblot analysis, and the TUNEL assay were used to determine the consequences of RPE cellular activation.
Little to no immunolabeling for AGE or RAGE was found in photoreceptor and RPE cell layers in normal retinas. However, when small drusen were present, AGE and RAGE were identified in the RPE or both the RPE and photoreceptors. In early AMD and GA, the RPE and remnant photoreceptor cells showed intense AGE and RAGE immunolabeling. Both AGE and S100B activated cultured RPE cells, as revealed by upregulated expression of RAGE, NFkappaB nuclear translocation, and apoptotic cell death.
Immunolocalization of RAGE in RPE and photoreceptors coincided with AGE deposits and macular disease in aged, early AMD, and GA retinas. Further, AGE stimulated RAGE-mediated activation of cultured ARPE-19 cells in a dose-dependent fashion. AGE accumulation, as occurs with normal aging and in disease, may induce receptor-mediated activation of RPE/photoreceptor cells, contributing to disease progression in the aging human retinas.
A history of the extraordinary society that has touched all aspects of British life From its beginnings in a coffee house in the mid-eighteenth century, the Royal Society for the Encouragement of ...Arts, Manufactures and Commerce has tried to improve British life in every way imaginable. It has sought to influence how Britons work, how they are educated, the music they listen to, the food they eat, the items in their homes, and even how they remember their own history. Arts and Minds is the remarkable story of an institution unlike any other—a society for the improvement of everything and anything.Drawing on exclusive access to a wealth of rare papers and artefacts from the Society's own archives, Anton Howes shows how this vibrant and singularly ambitious organisation has evolved and adapted, constantly having to reinvent itself to keep in step with changing times. The Society has served as a platform for Victorian utilitarian reformers, purchased and restored an entire village, encouraged the planting of more than sixty million trees, and sought technological alternatives to child labour. But this is more than just a story about unusual public initiatives. It is an engaging and authoritative history of almost three centuries of social reform and competing visions of a better world—the Society's members have been drawn from across the political spectrum, including Adam Smith, Edmund Burke, and Karl Marx.Informative and entertaining, Arts and Minds reveals how a society of public-spirited individuals tried to make their country a better place, and draws vital lessons from their triumphs and failures for all would-be reformers today.
To review new incidental findings detected on low-resolution CT attenuation correction (CTAC) images acquired during single-photon emission CT (SPECT-CT) myocardial perfusion imaging (MPI) and to ...determine whether the CTAC images had diagnostic value and warrant reporting.
A multicentre study was performed in four UK nuclear medicine departments. CTAC images acquired as part of MPI performed using SPECT were evaluated to identify incidental findings. New findings considered to be clinically significant were evaluated further. Positive predictive value (PPV) was determined at the time of definitive diagnosis.
Of 1819 patients studied, 497 (27.3%) had a positive CTAC finding. 51 (2.8%) patients had findings that were clinically significant at the time of the CTAC report and had not been previously diagnosed. Only four (0.2%) of these were potentially detrimental to patient outcome.
One centre had a PPV of 0%, and the study suggests that these CTAC images should not be reported. Two centres with more modern equipment had low PPVs of 0% and 6%, respectively, and further research is suggested prior to drawing a conclusion. The centre with best quality CT had a PPV of 67%, and the study suggests that CTAC images from this equipment should be reported.
This study is unique compared with previous studies that have reported only the potential to identify incidental findings on low-resolution CT images. This study both identifies and evaluates new clinically significant incidental findings, and it demonstrates that the benefit of reporting the CTAC images depends on the type of equipment used.
We compare the rise times of nearby and distant Type Ia supernovae (SNe Ia) as a test for evolution using 73 high-redshift spectroscopically confirmed SNe Ia from the first 2 years of the 5 year ...Supernova Legacy Survey (SNLS) and published observations of nearby SNe. Because of the 'rolling' search nature of the SNLS, our measurement is approximately 6 times more precise than previous studies, allowing for a more sensitive test of evolution between nearby and distant SNe. Adopting a simple t2 early-time model (as in previous studies), we find that the rest-frame B rise times for a fiducial SN Ia at high and low redshift are consistent, with values 19.10 ± 0.2 and 19.58 days, respectively; the statistical significance of this difference is only 1.4 s. The errors represent the uncertainty in the mean rather than any variation between individual SNe. We also compare subsets of our high-redshift data set based on decline rate, host galaxy star formation rate, and redshift, finding no substantive evidence for any subsample dependence.
We present Monte Carlo simulations of nonionic surfactant adsorption at the liquid/vapor interface of a monatomic solvent. All molecules in the system, solvent and surfactant, are characterized by ...the Lennard-Jones (LJ) potential using differing interaction parameters. Surfactant molecules consist of an amphiphilic chain with a solvophilic head and a solvophobic tail. Adjacent atoms along the surfactant chain are connected by finitely extensible harmonic springs. Solvent molecules move via the Metropolis random-walk algorithm, whereas surfactant molecules move according to the continuum configurational bias Monte Carlo (CBMC) method. We generate quantitative thermodynamic adsorption and surface tension isotherms in addition to surfactant radius of gyration, tilt angles, and potentials of mean force. Surface tension simulations compared to those calculated from the simulated adsorbed amounts and the Gibbs adsorption isotherm agree confirming equilibrium in our simulations. We find that the classical Langmuir isotherm is obeyed for our LJ surfactants over the range of head and tail lengths studied. Although simulated surfactant chains in the bulk solution exhibit random orientations, surfactant chains at the interface orient roughly perpendicular and the tails elongate compared to bulk chains even in the submonolayer adsorption regime. At a critical surfactant concentration, designated as the critical aggregation concentration (CAC), we find aggregates in the solution away from the interface. At higher concentrations, simulated surface tensions remain practically constant. Using the simulated potential of mean force in the submonolayer regime and an estimate of the surfactant footprint at the CAC, we predict a priori the Langmuir adsorption constant, K L, and the maximum monolayer adsorption, Γm. Adsorption is driven not by proclivity of the surfactant for the interface, but by the dislike of the surfactant tails for the solvent, that is by a “solvophobic” effect. Accordingly, we establish that a coarse-grained LJ surfactant system mimics well the expected equilibrium behavior of aqueous nonionic surfactants adsorbing at the air/water interface.
An understanding of the solid electrolyte interphase (SEI) that forms on the lithium-metal surface is essential to the further development of rechargeable lithium-metal batteries. Currently, the ...formation of dendrites during cycling, which can lead to catastrophic failure of the cell, has mostly halted research on these power sources. The discovery of ionic liquids as electrolytes has rekindled the possibility of safe, rechargeable, lithium-metal batteries. The current limitation of ionic liquid electrolytes, however, is that when compared with conventional non-aqueous electrolytes the device rate capability is limited. Recently, we have shown that the addition of a zwitterion such as
N-methyl-
N-(butyl sulfonate) pyrrolidinium resulted in enhancement of the achievable current densities by 100%. It was also found that the resistance of the SEI layer in the presence of a zwitterion is 50% lower. In this study, a detailed chemical and electrochemical analysis of the SEI that forms in both the presence and absence of a zwitterion has been conducted. Clear differences in the chemical nature and also the thickness of the SEI are observed and these may account for the enhancement of operating current densities.
The equatorial subsegment (EqSS) was originally identified by atomic force microscopy as a discrete region within the equatorial segment of Artiodactyl spermatozoa. In this investigation, we show ...that the EqSS is enriched in tyrosine phosphorylated proteins and present preliminary evidence for its presence in mouse and rat spermatozoa. The anti-phosphotyrosine monoclonal antibody (McAb) 4G10 bound strongly and discretely to the EqSS of permeabilized boar, ram, and bull spermatozoa. It also bound to a small patch on the posterior acrosomal region of permeabilized mouse and rat spermatozoa, suggesting that the EqSS is not restricted to the order Artiodactyla. An anti-HSPA1A (formerly Hsp70) antibody recognized the EqSS in boar spermatozoa. Immunogold labeling with McAb 4G10 localized the tyrosine phosphorylated proteins to the outer acrosomal membrane. This was verified by freeze-fracture electron microscopy, which identified the EqSS in three overlying membranes, the plasma membrane, outer acrosomal membrane, and inner acrosomal membrane. In all five species, tyrosine phosphorylated proteins became restricted to the EqSS during sperm maturation in the epididymis. The major tyrosine phosphorylated proteins in the EqSS of boar and ram spermatozoa were identified by mass spectrometry as orthologs of human SPACA1 (formerly SAMP32). Immunofluorescence with a specific polyclonal antibody localized SPACA1 to the equatorial segment in boar spermatozoa. We speculate that the EqSS is an organizing center for assembly of multimolecular complexes that initiate fusion competence in this area of the plasma membrane following the acrosome reaction.
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