618 research outputs found
Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K Ī³-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3KĪ³-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner
New type of microengine using internal combustion of hydrogen and oxygen
Microsystems become part of everyday life but their application is restricted
by lack of strong and fast motors (actuators) converting energy into motion.
For example, widespread internal combustion engines cannot be scaled down
because combustion reactions are quenched in a small space. Here we present an
actuator with the dimensions 100x100x5 um^3 that is using internal combustion
of hydrogen and oxygen as part of its working cycle. Water electrolysis driven
by short voltage pulses creates an extra pressure of 0.5-4 bar for a time of
100-400 us in a chamber closed by a flexible membrane. When the pulses are
switched off this pressure is released even faster allowing production of
mechanical work in short cycles. We provide arguments that this unexpectedly
fast pressure decrease is due to spontaneous combustion of the gases in the
chamber. This actuator is the first step to truly microscopic combustion
engines.Comment: Paper and Supplementary Information (to appear in Scientific Reports
Versatile thiol-based reactions for micrometer- and nanometer-scale photopatterning of polymers and biomolecules
Thiol-based chemistry provides a mild and versatile tool for surface functionalization. In the present work, mercaptosilane films were patterned by utilizing UV-induced photo-oxidation of the thiol to yield sulfonate groups via contact and interferometric lithography (IL). These photo-generated sulfonic acid groups were used for selective immobilization of amino-functionalized molecules after activation with triphenylphosphine ditriflate (TPPDF). Moreover, protein-resistant poly(oligoethyleneglycolmethacrylate) (POEGMA) brushes were grown from the intact thiol groups by a surface-induced polymerization reaction. Exploiting both reactions it is possible to couple amino-labelled nitrilotriacetic acid (NH2-NTA) to sulfonate-functionalized regions, enabling the site-specific binding of green fluorescent protein (GFP) to regions defined lithographically, while exploiting the protein-resistant character of POEGMA brushes to prevent non-specific protein adsorption to previously masked areas. The outstanding reactivity of thiol groups paves the way towards novel strategies for the fabrication of complex protein nanopatterns beyond thiolāene chemistry
No Rise in Incidence but Geographical Heterogeneity in the Occurrence of Primary Biliary Cirrhosis in North East England
In this study, we examined temporal changes in the incidence of primary biliary cirrhosis (PBC) and investigated associations between PBC incidence and sociodemographic factors and spatial clustering. We included 982 patients aged ā„40 years from North East England with incident PBC diagnosed during 1987ā2003. Age-standardized incidence rates with 95% confidence intervals were calculated. Negative binomial regression was used to analyze incidence and socioeconomic deprivation. Clustering analysis was performed using point process methods, testing the null hypothesis that disease risk does not vary spatially and that PBC cases occur independently. The age-standardized incidence rate was 53.50 per million persons per year (95% confidence interval: 48.65, 58.35) in 1987ā1994 and 45.09 per million persons per year (95% confidence interval: 41.10, 49.07) in 1995ā2003. Risk of PBC increased in areas with higher levels of socioeconomic deprivation (P = 0.035). More specifically, risk increased in areas with higher levels of overcrowded homes (P = 0.040), higher levels of households without cars (P < 0.001), and higher levels of non-owner-occupied homes (P < 0.001). Overall, there was evidence of spatial clustering (P = 0.001). The findings confirm that overall incidence of PBC did not rise over time, but sociodemographic variations suggest that certain aspects of deprivation are involved in its etiology
Design catalogue for eco-engineering of coastal artificial structures:a multifunctional approach for stakeholders and end-users
Coastal urbanisation, energy extraction, food production, shipping and transportation have led to the global proliferation of artificial structures within the coastal and marine environments (sensu āocean sprawlā), with subsequent loss of natural habitats and biodiversity. To mitigate and compensate impacts of ocean sprawl, the practice of ecoengineering of artificial structures has been developed over the past decade. Eco-engineering aims to create sustainable ecosystems that integrate human society with the natural environment for the benefit of both. The science of eco-engineering has grown markedly, yet synthesis of research into a user-friendly and practitioner-focused format is lacking. Feedback from stakeholders has repeatedly stated that a āphoto user guideā or āmanualā covering the range of eco-engineering options available for artificial structures would be beneficial. However, a detailed and structured āuser guideā for eco-engineering in coastal and marine environments is not yet possible; therefore we present an accessible review and catalogue of trialled eco-engineering options and a summary of guidance for a range of
different structures tailored for stakeholders and end-users as the first step towards a structured manual. This work
can thus serve as a potential template for future eco-engineering guides. Here we provide suggestions for potential eco-engineering designs to enhance biodiversity and ecosystem functioning and services of coastal artificial structures with the following structures covered: (1) rock revetment, breakwaters and groynes composed of armour stones or concrete units; (2) vertical and sloping seawalls; (3) over-water structures (i.e., piers) and associated support structures; and (4) tidal river walls
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Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors
The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and is strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant or sensitive to new ATP-competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of over 600 human cancer cell lines to identify markers of resistance and sensitivity to the mTOR inhibitor PP242. RAS and PIK3CA mutations were the most significant genetic markers for resistance and sensitivity to PP242, respectively; colon origin was the most significant marker for resistance based on tissue type. Among colon cancer cell lines, those with KRAS mutations were most resistant to PP242, while those without KRAS mutations most sensitive. Surprisingly, cell lines with co-mutation of PIK3CA and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling targets downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was correlated with inhibition of phosphorylation of the translational repressor 4E-BP1, but not ribosomal protein S6. In a tumor growth inhibition trial of PP242 in patient-derived colon cancer xenografts, resistance to PP242 induced inhibition of 4E-BP1 phosphorylation and xenograft growth was again observed in KRAS mutant tumors without PIK3CA co-mutation, compared to KRAS WT controls. We show that, in the absence of PIK3CA co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the level of phosphorylation of 4E-BP1
Team resilience emergence: Perspectives and experiences of military personnel selected for elite military training
We conducted a longitudinal (3-month) qualitative study to examine elite military personnel's (NĀ =Ā 32) experiences and perspectives of team resilience emergence following two team-oriented training courses within an 18-month high-stakes training programme where personnel are required to operate in newly formed tactical teams for extended periods. Our thematically informed interpretations of the participantsā subjective experiences of reality were constructed according to five key themes: (i) adversity is an enduring, shared experience of an event; (ii) individuals recognise adversity through physiological and/or behavioural states; (iii) social resources bind together individual self-regulatory capacities when confronted with adversity to support team functioning; (iv) shared experiences of adversity and collective structures strengthen social bonds and mental models needed for resilience emergence; and (v) behavioural processes and shared states are how collectives turn individual and team capacities into performance under adversity. These findings provide novel insights that supplement our current understanding of team resilience emergence, including the varying means by which adversity may be collectively experienced, synergies between specific forms of adversity and resilience processes or protective factors, and the unique influence of performance context (e.g., task type)
Casimir Forces between Spherical Particles in a Critical Fluid and Conformal Invariance
Mesoscopic particles immersed in a critical fluid experience long-range
Casimir forces due to critical fluctuations. Using field theoretical methods,
we investigate the Casimir interaction between two spherical particles and
between a single particle and a planar boundary of the fluid. We exploit the
conformal symmetry at the critical point to map both cases onto a highly
symmetric geometry where the fluid is bounded by two concentric spheres with
radii R_- and R_+. In this geometry the singular part of the free energy F only
depends upon the ratio R_-/R_+, and the stress tensor, which we use to
calculate F, has a particularly simple form. Different boundary conditions
(surface universality classes) are considered, which either break or preserve
the order-parameter symmetry. We also consider profiles of thermodynamic
densities in the presence of two spheres. Explicit results are presented for an
ordinary critical point to leading order in epsilon=4-d and, in the case of
preserved symmetry, for the Gaussian model in arbitrary spatial dimension d.
Fundamental short-distance properties, such as profile behavior near a surface
or the behavior if a sphere has a `small' radius, are discussed and verified.
The relevance for colloidal solutions is pointed out.Comment: 37 pages, 2 postscript figures, REVTEX 3.0, published in Phys. Rev. B
51, 13717 (1995
Statistical analysis plan for the LAKANA trial: a cluster-randomized, placebo-controlled, double-blinded, parallel group, three-arm clinical trial testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1ā11-month-old infants in Mali
BACKGROUND:The Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin (LAKANA) trial in Mali aims to evaluate the efficacy and safety of azithromycin (AZI) mass drug administration (MDA) to 1ā11-month-old infants as well as the impact of the intervention on antimicrobial resistance (AMR) and mechanisms of action of azithromycin. To improve the transparency and quality of this clinical trial, we prepared this statistical analysis plan (SAP). METHODS/DESIGN: LAKANA is a cluster randomized trial that aims to address the mortality and health impacts of biannual and quarterly AZI MDA. AZI is given to 1ā11-month-old infants in a high-mortality setting where a seasonal malaria chemoprevention (SMC) program is in place. The participating villages are randomly assigned to placebo (control), two-dose AZI (biannual azithromycin-MDA), and four-dose AZI (quarterly azithromycin-MDA) in a 3:4:2 ratio. The primary outcome of the study is mortality among the intention-to-treat population of 1ā11-month-old infants. We will evaluate relative risk reduction between the study arms using a mixed-effects Poisson model with random intercepts for villages, using log link function with person-years as an offset variable. We will model outcomes related to secondary objectives of the study using generalized linear models with considerations on clustering. CONCLUSION: The SAP written prior to data collection completion will help avoid reporting bias and data-driven analysis for the primary and secondary aims of the trial. If there are deviations from the analysis methods described here, they will be described and justified in the publications of the trial results. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT04424511. Registered on 11 June 2020
Theory of Coexistence of Superconductivity and Ferroelectricity : A Dynamical Symmetry Model
We propose and investigate a model for the coexistence of Superconductivity
(SC) and Ferroelectricity (FE) based on the dynamical symmetries for
the pseudo-spin SC sector, for the displaced oscillator FE sector, and
for the composite system. We assume a minimal
symmetry-allowed coupling, and simplify the hamiltonian using a double mean
field approximation (DMFA). A variational coherent state (VCS) trial
wave-function is used for the ground state: the energy, and the relevant order
parameters for SC and FE are obtained. For positive sign of the SC-FE coupling
coefficient, a non-zero value of either order parameter can suppress the other
(FE polarization suppresses SC and vice versa). This gives some support to
"Matthias' Conjecture" [1964], that SC and FE tend to be mutually exclusive.
For such a Ferroelectric Superconductor we predict: a) the SC gap
(and ) will increase with increasing applied pressure when pressure
quenches FE as in many ferroelectrics, and b) the FE polarization will increase
with increaesing magnetic field up to . The last result is equivalent to
the prediction of a new type of Magneto-Electric Effect in a coexistent SC-FE
material. Some discussion will be given of the relation of these results to the
cuprate superconductors.Comment: 46 page
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