Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for ...patients with relapsed, EGFRvIII-positive glioblastoma.
In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.
Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (
= 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank
= 0.01, a higher ORR 30% (9/30) vs. 18% (6/34;
= 0.38), median duration of response 7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4), and ability to discontinue steroids for ≥6 months 33% (6/18) vs. 0% (0/19). Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45;
< 0.0001).
Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.
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Low electron/proton conductivities of electrochemical catalysts, especially earth‐abundant nonprecious metal catalysts, severely limit their ability to satisfy the triple‐phase boundary (TPB) theory, ...resulting in extremely low catalyst utilization and insufficient efficiency in energy devices. Here, an innovative electrode design strategy is proposed to build electron/proton transport nanohighways to ensure that the whole electrode meets the TPB, therefore significantly promoting enhance oxygen evolution reactions and catalyst utilizations. It is discovered that easily accessible/tunable mesoporous Au nanolayers (AuNLs) not only increase the electrode conductivity by more than 4000 times but also enable the proton transport through straight mesopores within the Debye length. The catalyst layer design with AuNLs and ultralow catalyst loading (≈0.1 mg cm−2) augments reaction sites from 1D to 2D, resulting in an 18‐fold improvement in mass activities. Furthermore, using microscale visualization and unique coplanar‐electrode electrolyzers, the relationship between the conductivity and the reaction site is revealed, allowing for the discovery of the conductivity‐determining and Debye‐length‐determining regions for water splitting. These findings and strategies provide a novel electrode design (catalyst layer + functional sublayer + ion exchange membrane) with a sufficient electron/proton transport path for high‐efficiency electrochemical energy conversion devices.
Easily accessible gold nanolayers with straight mesopores are discovered to build electron/proton highways for novel multiple‐layer (catalyst layer + functional sublayer + proton exchange membrane) water splitting electrodes. A new coplanar‐electrode proton exchange membrane water electrolyzer bridges the gap between catalyst development and real electrolyzer applications. Two reaction‐determining regions are proposed to guide electrode development in practical electrochemical devices.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We investigate differences in labour market transition rates between high and low minimum wage regimes using Canadian data spanning 1979-2008. We find that higher minimum wages result in lower hiring ...rates but also lower job separation rates. Importantly, the reduced separation rates are due mainly to reductions in layoffs, occur in the first six months of a job and are present for unskilled workers of all ages. Thus, jobs in higher minimum wage regimes are more stable but harder to get. For older workers, these effects are almost exactly offsetting, resulting in little impact on the employment rate.
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BFBNIB, FZAB, GIS, IJS, INZLJ, IZUM, KILJ, NLZOH, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
Better understanding of true electrochemical reaction behaviors in electrochemical energy devices has long been desired. It has been assumed so far that the reactions occur across the entire catalyst ...layer (CL), which is designed and fabricated uniformly with catalysts, conductors of protons and electrons, and pathways for reactants and products. By introducing a state-of-the-art characterization system, a thin, highly tunable liquid/gas diffusion layer (LGDL), and an innovative design of electrochemical proton exchange membrane electrolyzer cells (PEMECs), the electrochemical reactions on both microspatial and microtemporal scales are revealed for the first time. Surprisingly, reactions occur only on the CL adjacent to good electrical conductors. On the basis of these findings, new CL fabrications on the novel LGDLs exhibit more than 50 times higher mass activity than conventional catalyst-coated membranes in PEMECs. This discovery presents an opportunity to enhance the multiphase interfacial effects, maximizing the use of the catalysts and significantly reducing the cost of these devices.
For educational developers (also called academic or faculty developers) to facilitate change toward effective teaching and learning practices at any level, they must build trust and communicate ...credible expertise, often while conveying 'second-hand' educational knowledge to academics who then act on that knowledge in their own work. In this conceptual article, we propose a new credibility framework, drawing on the intertwined literature on trust and trustworthiness, non-positional leadership, cognitive authority, and educational development. Our framework delineates six interrelated dimensions that developers employ to build trust and promote evidence-informed change in their local contexts.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Since amphibian declines were first proposed as a global phenomenon over a quarter century ago, the conservation community has made little progress in halting or reversing these trends. The early ...search for a "smoking gun" was replaced with the expectation that declines are caused by multiple drivers. While field observations and experiments have identified factors leading to increased local extinction risk, evidence for effects of these drivers is lacking at large spatial scales. Here, we use observations of 389 time-series of 83 species and complexes from 61 study areas across North America to test the effects of 4 of the major hypothesized drivers of declines. While we find that local amphibian populations are being lost from metapopulations at an average rate of 3.79% per year, these declines are not related to any particular threat at the continental scale; likewise the effect of each stressor is variable at regional scales. This result - that exposure to threats varies spatially, and populations vary in their response - provides little generality in the development of conservation strategies. Greater emphasis on local solutions to this globally shared phenomenon is needed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
TCR-gene-transfer is an efficient strategy to produce therapeutic T cells of defined antigen specificity. However, there are substantial variations in the cell surface expression levels of human ...TCRs, which can impair the function of engineered T cells. Here we demonstrate that substitutions of 3 amino acid residues in the framework of the TCR variable domains consistently increase the expression of human TCRs on the surface of engineered T cells.The modified TCRs mediate enhanced T cell proliferation, cytokine production and cytotoxicity, while reducing the peptide concentration required for triggering effector function up to 3000-fold. Adoptive transfer experiments in mice show that modified TCRs control tumor growth more efficiently than wild-type TCRs. Our data indicate that simple variable domain modifications at a distance from the antigen-binding loops lead to increased TCR expression and improved effector function. This finding provides a generic platform to optimize the efficacy of TCR gene therapy in humans.
Most recent analyses of US penality describe and explain the exceptional harshening of punishment over the previous three decades. This article challenges and qualifies these accounts by identifying ...10 cultural, moral, and practical drivers of a bipartisan reconsideration of the discourses and policies responsible for mass incarceration. These penal-reform catalysts and drivers include: (1) the crime decline; (2) the Great Recession; (3) the prisoner-reentry movement and attendant changes in the moral status of prisoners; (4) apparent shifts in public attitudes about punishment; (5) ‘punitive saturation’ and the cyclical nature of penal thinking and policy; (6) changing dominant conceptions of the criminal offender; (7) the return of human dignity to US jurisprudence; (8) the ideational influence of Christian reformers who assail the morality of excessive punishment; (9) the conservative ‘Right on Crime’ initiative that promotes a range of reforms formerly associated with the Left; and (10) the American Legislative Exchange Council (ALEC), whose model legislation once drove mass incarceration but now aims to curtail it. The article also invites theoretical analysis of whether ongoing shifts represent a structural reordering of the penal field akin to the punitive turn or merely a set of benevolent tendencies within the same carceral paradigm.
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NUK, OILJ, PRFLJ, SAZU, UKNU, UL, UM, UPUK
•Ultracentrifugation with a sucrose cushion allowed sensitive detection of SARS-CoV-2 wastewater RNA.•Per capita levels of crAssphage were consistent across sites supporting its use as a surrogate ...for SARS-CoV-2.•Limits of quantification corresponded to daily positive tests as low as 0.37 per 10,000 people, depending on the area.•SARS-CoV-2 RNA signal strength is associated with increased COVID-19 cases in the following 7 days.•SARS-CoV-2:crAssphage ratios were significantly associated with COVID-19 cases.
Wastewater surveillance of SARS-CoV-2 RNA is increasingly being incorporated into public health efforts to respond to the COVID-19 pandemic. In order to obtain the maximum benefit from these efforts, approaches to wastewater monitoring need to be rapid, sensitive, and relatable to relevant epidemiological parameters. In this study, we present an ultracentrifugation-based method for the concentration of SARS-CoV-2 wastewater RNA and use crAssphage, a bacteriophage specific to the human gut, to help account for RNA loss during transit in the wastewater system and sample processing. With these methods, we were able to detect, and sometimes quantify, SARS-CoV-2 RNA from 20 mL wastewater samples within as little as 4.5 hours. Using known concentrations of bovine coronavirus RNA and deactivated SARS-CoV-2, we estimate recovery rates of approximately 7-12% of viral RNA using our method. Results from 24 sewersheds across Upstate New York during the spring and summer of 2020 suggested that stronger signals of SARS-CoV-2 RNA from wastewater may be indicative of greater COVID-19 incidence in the represented service area approximately one week in advance. SARS-CoV-2 wastewater RNA was quantifiable in some service areas with daily positives tests of less than 1 per 10,000 people or when weekly positive test rates within a sewershed were as low as 1.7%. crAssphage DNA concentrations were significantly lower during periods of high flow in almost all areas studied. After accounting for flow rate and population served, crAssphage levels per capita were estimated to be about 1.35 × 1011 and 2.42 × 108 genome copies per day for DNA and RNA, respectively. A negative relationship between per capita crAssphage RNA and service area size was also observed likely reflecting degradation of RNA over long transit times. Our results reinforce the potential for wastewater surveillance to be used as a tool to supplement understanding of infectious disease transmission obtained by traditional testing and highlight the potential for crAssphage co-detection to improve interpretations of wastewater surveillance data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In Search of Labor Demand Beaudry, Paul; Green, David A.; Sand, Ben M.
The American economic review,
09/2018, Volume:
108, Issue:
9
Journal Article
Peer reviewed
Open access
We propose and estimate a novel specification of labor demand which encompasses search frictions and the role of entrepreneurs in new firm creation. Using city-industry variation over four decades, ...we estimate the wage elasticity of employment demand to be close to −1 at the industry-city level and −0.3 at the city level. We argue that the difference between these estimates reflects the congestion externalities predicted by the search literature. Our estimates also indicate that entrepreneurship should be treated as a scarce factor in the determination of labor demand. We use our estimates to evaluate the impact of large changes in the minimum wage on employment.
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BFBNIB, CEKLJ, INZLJ, IZUM, KILJ, NMLJ, NUK, ODKLJ, PILJ, PNG, SAZU, UL, UM, UPUK, ZRSKP
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