High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the ...use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation.
We randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival.
Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P=0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P<0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy.
Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches. (Supported by Celgene and others; IFM 2009 Study ClinicalTrials.gov number, NCT01191060 .).
Comprehensive cancer genome studies have revealed genetically-defined subtypes of prostate cancer with distinct truncal driver mutations. Because prostate cancer has been largely seen as a rather ...uniform disease, the clinical significance of this discovery remained largely obscure. However, recent findings imply distinct biological features and therapeutic vulnerabilities linked to specific truncal mutations. Here we review our current understanding of prostate cancers harboring recurrent point mutations in the ubiquitin ligase adaptor protein SPOP and discuss opportunities for future clinical translation. More specifically, activation of the androgen receptor (AR) signaling emerges as the key oncogenic pathway. SPOP-mutant prostate cancer patients respond to AR inhibition in various clinical settings. Molecular insights on how mutant SPOP promotes tumorigenesis may open more specific therapeutic avenues which, in combination with conventional AR-targeting agents, could improve the outcome of patients with SPOP-mutant prostate cancer.
•SPOP represents a genetically and biologically distinct class of prostate cancer.•SPOP and ERG mutant prostate cancer may have distinct therapeutic opportunities.•Activation of androgen receptor signaling is a key component of SPOP mutant cancer.•SPOP mutant cancer is particularly sensitive to inhibition of androgen receptor signaling.•Co-targeting additional SPOP mutant specific vulnerabilities may further improve outcomes.
Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating ...protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.
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•USP7 is part of the MAGE-L2-TRIM27 ubiquitin ligase and enables endosomal recycling•USP7 protects TRIM27 from auto-ubiquitination and proteasomal degradation•USP7 buffers WASH ubiquitination levels to maintain proper endosomal actin levels•Mutation of USP7 causes a human neurodevelopmental syndrome, including autism
Hao et al. describe a function of the USP7 deubiquitinating enzyme in regulation of WASH/retromer-mediated endosomal protein recycling. USP7 functions as a molecular rheostat to prevent auto-ubiquitination and proteasomal degradation of TRIM27 E3 ubiquitin ligase, but also deubiquitinates WASH. Genetic studies identify cases of USP7 mutation/deletion resulting in a human neurodevelopmental disorder that overlaps with MAGE-L2 mutation.
One of the most important stability concepts for network formation is pairwise stability. We develop a homotopy algorithm that is effective in computing pairwise stable networks for a generic network ...formation problem. To do so, we reformulate the concept of pairwise stability as a Nash equilibrium of a non-cooperative game played by the links in the network and adapt the linear tracing procedure for non-cooperative games to the network formation problem. As a by-product of our main result, we obtain that the number of pairwise stable networks is generically odd. We apply the algorithm to the connections model and obtain a number of novel insights.
ABSTRACT
Ultra-diffuse galaxies (UDGs) reveal extreme properties. Here, we compile the largest study to date of 85 globular cluster (GC) systems around UDGs in the Coma cluster, using new deep ...ground-based imaging of the known UDGs and existing imaging from the Hubble Space Telescope of their GC systems. We find that the richness of GC systems in UDGs generally exceeds that found in normal dwarf galaxies of the same stellar mass. These GC-rich UDGs imply haloes more massive than expected from the standard stellar mass–halo mass relation. The presence of such overly massive haloes presents a significant challenge to the latest simulations of UDGs in cluster environments. In some exceptional cases, the mass in the GC system is a significant fraction of the stellar content of the host galaxy. We find that rich GC systems tend to be hosted in UDGs of lower luminosity, smaller size, and fainter surface brightness. Similar trends are seen for normal dwarf galaxies in the Coma cluster. A toy model is presented in which the GC-rich UDGs are assumed to be ‘failed’ galaxies within massive haloes that have largely old, metal-poor, alpha-element-enhanced stellar populations. On the other hand, GC-poor UDGs are more akin to normal, low surface brightness dwarfs that occupy less massive dark matter haloes. Additional data on the stellar populations of UDGs with GC systems will help to further refine and test this simplistic model.
Persuading sincere and strategic voters Kerman, Toygar T.; Herings, P. Jean‐Jacques; Karos, Dominik
Journal of public economic theory,
February 2024, Letnik:
26, Številka:
1
Journal Article
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A sender wants to persuade multiple homogeneous receivers to vote in favor of a proposal. Before the vote sender commits to a signal which sends private, potentially correlated, messages to receivers ...that are contingent on the true state of the world. The best equilibrium for sender in the resulting incomplete information game is unappealing: all receivers vote in favor of sender's preferred outcome, irrespective of their message. We therefore focus on the equilibrium where receivers vote sincerely, that is they vote in favor of the outcome that is optimal given their posterior. We characterize the optimal public and the optimal private signal, both for the case where receivers are behavioral and vote sincerely as well as the case where such behavior is a Bayes–Nash equilibrium (BNE). For the optimal public signal, sincere voting is a BNE, but the optimal private signal is subject to the swing voter's curse. Imposing the constraint that sincere voting be a BNE leads to an optimal signal where receivers are never pivotal.
Context. Gamma-ray emission at energies ≥100 MeV has been detected from nine novae using the Fermi Large Area Telescope (LAT), and can be explained by particle acceleration at shocks in these ...systems. Eight out of these nine objects are classical novae in which interaction of the ejecta with a tenuous circumbinary material is not expected to generate detectable gamma-ray emission. Aim. We examine whether particle acceleration at internal shocks can account for the gamma-ray emission from these novae. The shocks result from the interaction of a fast wind radiatively-driven by nuclear burning on the white dwarf with material ejected in the initial runaway stage of the nova outburst. Methods. We present a one-dimensional model for the dynamics of a forward and reverse shock system in a nova ejecta, and for the associated time-dependent particle acceleration and high-energy gamma-ray emission. Non-thermal proton and electron spectra are calculated by solving a time-dependent transport equation for particle injection, acceleration, losses, and escape from the shock region. The predicted emission is compared to LAT observations of V407 Cyg, V1324 Sco, V959 Mon, V339 Del, V1369 Cen, and V5668 Sgr. Results. The ≥100 MeV gamma-ray emission arises predominantly from particles accelerated up to ~100 GeV at the reverse shock and undergoing hadronic interactions in the dense cooling layer downstream of the shock. The emission rises within days after the onset of the wind, quickly reaches a maximum, and its subsequent decrease reflects mostly the time evolution of the wind properties. Comparison to gamma-ray data points to a typical scenario where an ejecta of mass 10−5–10−4 M⊙ expands in a homologous way with a maximum velocity of 1000–2000 km s−1, followed within a day by a wind with a velocity <2000 km s−1 and a mass-loss rate of 10−4–10−3 M⊙ yr−1 declining over a time scale of a few days. Because of the large uncertainties in the measurements, many parameters of the problem are degenerate and/or poorly constrained except for the wind velocity, the relatively low values of which result in the majority of best-fit models having gamma-ray spectra with a high-energy turnover below ~10 GeV. Our typical model is able to account for the main features in the observations of the recent gamma-ray nova ASASSN-16ma. Conclusions. The internal shock model can account for the gamma-ray emission of the novae detected by Fermi LAT. Gamma-ray observations hold potential for probing the mechanism of mass ejection in novae, but should be combined to diagnostics of the thermal emission at lower energies to be more constraining.
Continuous production of biologics, a growing trend in the biopharmaceutical industry, requires a reliable and efficient cell retention device that also maintains cell viability. Current filtration ...methods, such as tangential flow filtration using hollow-fiber membranes, suffer from membrane fouling, leading to significant reliability and productivity issues such as low cell viability, product retention, and an increased contamination risk associated with filter replacement. We introduce a novel cell retention device based on inertial sorting for perfusion culture of suspended mammalian cells. The device was characterized in terms of cell retention capacity, biocompatibility, scalability, and long-term reliability. This technology was demonstrated using a high concentration (>20 million cells/mL) perfusion culture of an IgG
-producing Chinese hamster ovary (CHO) cell line for 18-25 days. The device demonstrated reliable and clog-free cell retention, high IgG
recovery (>99%) and cell viability (>97%). Lab-scale perfusion cultures (350 mL) were used to demonstrate the technology, which can be scaled-out with parallel devices to enable larger scale operation. The new cell retention device is thus ideal for rapid perfusion process development in a biomanufacturing workflow.
: Inflammation is a physiological response to aggression of pathogenic agents aimed at eliminating the aggressor agent and promoting healing. Excessive inflammation, however, may contribute to tissue ...damage and an alteration of arterial structure and function. Increased arterial stiffness is a well recognized cardiovascular risk factor independent of blood pressure levels and an intermediate endpoint for cardiovascular events. In the present review, we discuss immune-mediated mechanisms by which inflammation can influence arterial physiology and lead to vascular dysfunction such as atherosclerosis and arterial stiffening. We also show that acute inflammation predisposes the vasculature to arterial dysfunction and stiffening, and alteration of endothelial function and that chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis are accompanied by profound arterial dysfunction which is proportional to the severity of inflammation. Current findings suggest that treatment of inflammation by targeted drugs leads to regression of arterial dysfunction. There is hope that these treatments will improve outcomes for patients.
The yeast-encapsulated orange oil (YEOO) is a novel larvicide under development against vector mosquitoes. Despite its efficiency against Aedes aegypti (L.) in small scale experiments, its ...applicability in vector control can be influenced by other effects on mosquito behaviour or physiology. For this reason, the impact of YEOO particles in mosquito oviposition was evaluated in laboratory and semi-field conditions. Oviposition assays with one gravid Aedes aegypti female were carried under laboratory and semi-field conditions with natural light and temperature fluctuation. For all ovitraps, the number of eggs was manually counted in the wooden paddle and in the solution of each ovitrap. The proportion of eggs between substrates (wooden paddle and solution) varied between conditions, with females in laboratory presenting a lower preference to lay eggs in paddles when compared with studies in semi-field. This behaviour shifts in laboratory can create challenges to extrapolate results from laboratory to the field. Here, studies in both conditions indicate a similar impact of YEOO particles in Aedes aegypti oviposition. The potential treatment concentration of YEOO particles presents a strong repellent/deterrent effect (-0.559 > OAI > -0.760) within the initial 72h of application when compared with water, and weak repellent/deterrent signal (OAI = -0.220) when compared against inactivated yeast. Control ovitraps with water were more positive for egg presence than treated ovitraps, while ovitraps with YEOO particles and inactivated yeast present similar number of positive ovitraps. It is possible that the repellent/deterrent action is partially driven by the delivery system, since most times Citrus sinensis EO oviposition repellent/deterrent signal is weak, and it seem influenced by solvent/delivery used. However, it is unclear how the yeast wall that protect/surrounds the orange oil will negatively affect oviposition since live yeast are normally consider an attractant for mosquito oviposition.
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