785 research outputs found
The Across-shelf larval, postlarval, and juvenile fish communities associated with offshore oil and gas platforms west of the Mississippi River Delta
A new experimental technique for the analysis of cake filtration
An electrical conductivity technique for determining cake heights, and hence average
concentrations, during stepped-up pressure filtrations is described. Experimental data are
presented which compare the results from individual constant pressure filtrations and a filtration
employing a sequence of corresponding pressures. The data are analysed in a variety of ways
that show the accuracy of the time saving step-up technique when the solids concentration is
measured in-situ
Do low-salinity, rock jetty habitats serve as nursery areas for presettlement larval and juvenile reef fish?
Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells
Background
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with multiple roles in tumour growth, cell invasion and metastasis. We have previously established GSK-3 as an upstream regulator of PD-1 gene expression in CD8 + T cells and demonstrated that GSK-3 inhibition is as effective as anti-PD-1 mAb blockade in controlling tumour growth. Elraglusib (9-ING-41) is a specific small-molecule inhibitor of GSK-3β with clinical activity in patients with advanced cancers, including a patient with refractory melanoma whose response provided the rationale for the current study.
Methods
The B16 melanoma mouse model was used to observe the effect of elraglusib on tumour growth either as a single agent or in combination (simultaneously and sequentially) with anti-PD-1 mAb treatment. B16 tumour cells were implanted in either the flank, brain or both locations, and Kaplan–Meier plots were used to depict survival and significance determined using log rank tests. Expression of the immune checkpoint molecules, TIGIT, LAG-3 and PD-1, was evaluated using flow cytometry alongside expression of the chemokine receptor, CXCR3. Further evaluation of PD-1 expression was determined through RT-qPCR and immunohistochemistry.
Results
We demonstrated that elraglusib has a suppressive effect against melanoma as a single agent and enhanced anti-PD-1 therapy. There was a synergistic effect when elraglusib was used in combination with anti-PD-1 mAb, and an even greater effect when used as sequential therapy. Suppression of tumour growth was associated with a reduced expression of immune checkpoint molecules, PD-1, TIGIT and LAG-3 with upregulation of CXCR3 expression.
Conclusions
These data highlight the potential of elraglusib as an immune-modulatory agent and demonstrate the benefit of a sequential approach with immune checkpoint inhibition followed by GSK-3β inhibition in melanoma and provide a rationale for clinical investigation of elraglusib combined with immune checkpoint inhibitory molecules, including those targeting PD-1, TIGIT and LAG-3. This has several potential implications for current immunotherapy regimes, including possibly reducing the intensity of anti-PD-1 mAb treatment needed for response in patients receiving elraglusib, especially given the benign adverse event profile of elraglusib observed to date. Based on these data, a clinical study of elraglusib, an anti-PD-1 mAb and chemotherapy is ongoing (NCT NCT05239182)
Low temperature expansion of the gonihedric Ising model
We investigate a model of closed -dimensional soft-self-avoiding
random surfaces on a -dimensional cubic lattice. The energy of a surface
configuration is given by , where is the number of
edges, where two plaquettes meet at a right angle and is the number of
edges, where 4 plaquettes meet. This model can be represented as a
-spin system with ferromagnetic nearest-neighbour-, antiferromagnetic
next-nearest-neighbour- and plaquette-interaction. It corresponds to a special
case of a general class of spin systems introduced by Wegner and Savvidy. Since
there is no term proportional to the surface area, the bare surface tension of
the model vanishes, in contrast to the ordinary Ising model. By a suitable
adaption of Peierls argument, we prove the existence of infinitely many ordered
low temperature phases for the case . A low temperature expansion of the
free energy in 3 dimensions up to order () shows,
that for only the ferromagnetic low temperature phases remain stable. An
analysis of low temperature expansions up to order for the
magnetization, susceptibility and specific heat in 3 dimensions yields critical
exponents, which are in agreement with previous results.Comment: 27 pages, Postscript figures include
Alpha-1 antitrypsin mitigates the inhibition of airway epithelial cell repair by neutrophil elastase
Copyright © 2016 by the American Thoracic Society. Neutrophil elastase (NE) activity is associated with many destructive lung diseases and is a predictor for structural lung damage in early cystic fibrosis (CF), which suggests normal maintenance of airway epitheliumis prevented byuninhibitedNE.However, limited data exist on how the NE activity in airways of very young children with CF affects function of the epithelia. The aimof this studywas to determine if NE activity could inhibit epithelial homeostasis and repair and whether any functional effect was reversible by antiprotease alpha-1 antitrypsin (a1AT) treatment. Viability, inflammation, apoptosis, and proliferation were assessed in healthy non-CF and CF pediatric primary airway epithelial cells (pAEC non-CF and pAEC CF , respectively) during exposure to physiologically relevant NE. The effect of NE activity on pAEC CF wound repair was also assessed.We report that viability after 48 hours was significantly decreased by 100 nM NE in pAEC non-CF and pAEC CF owing to rapid cellular detachment that was accompanied by inflammatory cytokine release. Furthermore, both phenotypes initiated an apoptotic response to 100 nM NE, whereas ≥50 nM NE activity significantly inhibited the proliferative capacity of cultures. Similar concentrations of NE also significantly inhibited wound repair of pAEC CF , but this effect was reversed by the addition of a1AT. Collectively, our results demonstrate free NE activity is deleterious for epithelial homeostasis and support the hypothesis that proteases inthe airway contribute directly toCF structural lung disease. Our results also highlight the need to investigate antiprotease therapies in early CF disease in more detail
Twenty five years after KLS: A celebration of non-equilibrium statistical mechanics
When Lenz proposed a simple model for phase transitions in magnetism, he
couldn't have imagined that the "Ising model" was to become a jewel in field of
equilibrium statistical mechanics. Its role spans the spectrum, from a good
pedagogical example to a universality class in critical phenomena. A quarter
century ago, Katz, Lebowitz and Spohn found a similar treasure. By introducing
a seemingly trivial modification to the Ising lattice gas, they took it into
the vast realms of non-equilibrium statistical mechanics. An abundant variety
of unexpected behavior emerged and caught many of us by surprise. We present a
brief review of some of the new insights garnered and some of the outstanding
puzzles, as well as speculate on the model's role in the future of
non-equilibrium statistical physics.Comment: 3 figures. Proceedings of 100th Statistical Mechanics Meeting,
Rutgers, NJ (December, 2008
Rare Charm Decays in the Standard Model and Beyond
We perform a comprehensive study of a number of rare charm decays,
incorporating the first evaluation of the QCD corrections to the short distance
contributions, as well as examining the long range effects. For processes
mediated by the transitions, we show that sensitivity to
short distance physics exists in kinematic regions away from the vector meson
resonances that dominate the total rate. In particular, we find that
and are sensitive to non-universal
soft-breaking effects in the Minimal Supersymmetric Standard Model with
R-parity conservation. We separately study the sensitivity of these modes to
R-parity violating effects and derive new bounds on R-parity violating
couplings. We also obtain predictions for these decays within extensions of the
Standard Model, including extensions of the Higgs, gauge and fermion sectors,
as well as models of dynamical electroweak symmetry breaking.Comment: 45 pages, typos fixed, discussions adde
Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.
BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research
Observation of exclusive DVCS in polarized electron beam asymmetry measurements
We report the first results of the beam spin asymmetry measured in the
reaction e + p -> e + p + gamma at a beam energy of 4.25 GeV. A large asymmetry
with a sin(phi) modulation is observed, as predicted for the interference term
of Deeply Virtual Compton Scattering and the Bethe-Heitler process. The
amplitude of this modulation is alpha = 0.202 +/- 0.028. In leading-order and
leading-twist pQCD, the alpha is directly proportional to the imaginary part of
the DVCS amplitude.Comment: 6 pages, 5 figure
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