PTEN, more than the AKT pathway Blanco-Aparicio, Carmen; Renner, Oliver; Leal, Juan F.M. ...
Carcinogenesis (New York),
07/2007, Letnik:
28, Številka:
7
Journal Article
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Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT constitute an important pathway regulating the signaling of multiple biological processes such ...as apoptosis, metabolism, cell proliferation and cell growth. PTEN is a dual protein/lipid phosphatase and its main substrate phosphatidyl-inositol 3,4,5 triphosphate (PIP3) is the product of PI3K. Increase in PIP3 recruits AKT to the membrane where is activated by other kinases also dependent on PIP3. Many components of this pathway have been described as causal forces in cancer. PTEN activity is lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers. Germ line mutations of PTEN are found in several familial cancer predisposition syndromes. Recently, many activating mutations in the PI3KCA gene (coding for the p110α catalytic subunit of PI3K) have been described in human tumors. Activation of PI3K and AKT are reported to occur in breast, ovarian, pancreatic, esophageal and other cancers. Genetically modified mice confirm these PTEN activities. Tissue-specific deletions of PTEN usually provoke cancer. Moreover, an absence of PTEN cooperates with an absence of p53 to promote cancer. However, we have observed very different results with the expression of activated versions of AKT in several tissues. Activated AKT transgenic lines do not develop tumors in breast or prostate tissues and do not cooperate with an absence of p53. This data suggest that an AKT-independent mechanism contributes to PTEN tumorigenesis. Crosses with transgenic mice expressing possible PTEN targets indicate that neither cyclin D1 nor p53 are these AKT-independent targets. However, AKT is more than a passive bridge toward PTEN tumorigenesis, since its expression not only allows but also enforces and accelerates the tumorigenic process in combination with other oncogenes.
The evolution of glyphosate resistance (GR) in weeds is an increasing problem. Glyphosate has been used intensively on wild poinsettia (Euphorbia heterophylla L.) populations for at least 20 years in ...GR crops within South America. We investigated the GR mechanisms in a wild poinsettia population from a soybean field in southern Brazil. The GR population required higher glyphosate doses to achieve 50% control (LD50) and 50% dry mass reduction (MR50) compared to a glyphosate susceptible (GS) population. The ratio between the LD50 and MR50 of GR and GS resulted in resistance factors (RF) of 6.9-fold and 6.1-fold, respectively. Shikimate accumulated 6.7 times more in GS than in GR when leaf-discs were incubated with increasing glyphosate concentrations. No differences were found between GR and GS regarding non-target-site mechanisms. Neither population metabolized glyphosate to significant levels following treatment with 850 g ha-1 glyphosate. Similar levels of 14C-glyphosate uptake and translocation were observed between the two populations. No differences in EPSPS expression were found between GS and GR. Two target site mutations were found in all EPSPS alleles of homozygous resistant plants: Thr102Ile + Pro106Thr (TIPT-mutation). Heterozygous individuals harbored both alleles, wild-type and TIPT. Half of GR individuals were heterozygous, suggesting that resistance is still evolving in the population. A genotyping assay was developed based on the Pro106Thr mutation, demonstrating high efficiency to identify homozygous, heterozygous or wild-type EPSPS sequences across different plants. This is the first report of glyphosate-resistant wild-poinsettia harboring an EPSPS double mutation (TIPT) in the same plant.
An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On ...the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma.
The aim of this paper is to study the controllability and stabilization for the Benjamin equation on a periodic domain T. We show that the Benjamin equation is globally exactly controllable and ...globally exponentially stabilizable in Hps(T), with s≥0. The global exponential stabilizability corresponding to a natural feedback law is first established with the aid of certain properties of solution, viz., propagation of compactness and propagation of regularity in Bourgain's spaces. The global exponential stability of the system combined with a local controllability result yields the global controllability as well. Using a different feedback law, the resulting closed-loop system is shown to be locally exponentially stable with an arbitrarily large decay rate. A time-varying feedback law is further designed to ensure a global exponential stability with an arbitrary large decay rate. The results obtained here extend the ones we proved for the linearized Benjamin equation in 32.
Systemic treatment with the active transcription inhibitor lurbinectedin aims at inducing tumor cell death in hyperproliferative neoplasms. Here we show that cell death induced by lurbinectedin ...reinstates and enhances systemic anticancer immune responses. Lurbinectedin treatment showed traits of immunogenic cell death, including the exposure of calreticulin, the release of ATP, the exodus of high mobility group box 1 (HMGB1) and type 1 interferon responses in vitro. Lurbinectedin treated cells induced antitumor immunity when injected into immunocompetent animals and treatment of transplanted fibrosarcomas reduced tumor growth in immunocompetent yet not in immunodeficient hosts. Anticancer effects resulting from lurbinectedin treatment were boosted in combination with PD-1 and CTLA-4 double immune checkpoint blockade (ICB), and lurbinectedin combined with double ICB exhibited strong antineoplastic effects. Cured animals exhibited long term immune memory effects that rendered them resistant to rechallenge with syngeneic tumors underlining the potency of combination therapy with lurbinectedin.
Red blood cells (RBCs) generate microvesicles to remove damaged cell constituents such as oxidized hemoglobin and damaged membrane constituents, and thereby prolong their lifespan. Damage to ...hemoglobin, in combination with altered phosphorylation of membrane proteins such as band 3, lead to a weakening of the binding between the lipid bilayer and the cytoskeleton, and thereby to membrane budding and microparticle shedding. Microvesicle generation is disturbed in patients with RBC-centered diseases, such as sickle cell disease, glucose 6-phosphate dehydrogenase deficiency, spherocytosis or malaria. A disturbance of the membrane-cytoskeleton interaction is likely to be the main underlying mechanism, as is supported by data obtained from RBCs stored in blood bank conditions. A detailed proteomic, lipidomic and immunogenic comparison of microvesicles derived from different sources is essential in the identification of the processes that trigger vesicle generation. The contribution of RBC-derived microvesicles to inflammation, thrombosis and autoimmune reactions emphasizes the need for a better understanding of the mechanisms and consequences of microvesicle generation.
Background fermion condensates in a landscape dominated by global supersymmetry are reassessed in connection with a scenario where Lorentz symmetry is violated in the bosonic sector (actually, the ...photon sector) by a CPT-even
k
F
term. An effective photonic action is discussed that originates from the supersymmetric background fermion condensates. Also, the photino mass emerges in terms of a particular condensate contrary to what happens in the case of
k
A
F
-violation. Finally, the interparticle potential induced by the effective photonic action is investigated and a confining profile is identified.
Abstract
The center of mass motion of trapped ions and neutral atoms is suitable for approximation by a time-dependent driven quantum harmonic oscillator whose frequency and driving strength may be ...controlled with high precision. We show the time evolution for these systems with continuous differentiable time-dependent parameters in terms of the three basic operations provided by its underlying symmetry, rotation, displacement, and squeezing, using a Lie algebraic approach. Our factorization of the dynamics allows for the intuitive construction of protocols for state engineering, for example, creating and removing displacement and squeezing, as well as their combinations, optimizing squeezing, or more complex protocols that work for slow and fast rates of change in the oscillator parameters.
Small microplastics (SMPs) in the gulf of Cadiz was sampled at 5 m depth by pumping it through the ship's pipe system and filtered through a 45 μm mesh size net. Our study reveals that higher ...densities have been found (130 mg·m−3) compared to other regions worldwide and these densities decreased from the coastline to the outer stations, showing a general coastal gradient influenced by estuarine outflows. SMPs with a size range between 45 and 193 μm were predominant and most of them composed by polyethylene and polypropylene. The metals associated with the MPs were mainly Na (21.1%), K (11.3%), Fe (8.5%), Ca (2.1%), Cr (1.8%), Zr (13.3%) and Hf (0.7%). The high proportion of Zr compared to Fe, which is different from what can be found in the environment, suggests that this metal is intrinsic to the materials used in catalytic processes during plastic production.
•Subsurface waters contain high small microplastics (SMPs) abundances•SMPs clear pattern in relation to the distance from the coast•SMPs composed mainly by polyethylene and polypropylene•Metals associated with the MPs intrinsic to plastic production
Dependence of lightning electric field waveform parameters on distance between the lightning channel and the field measuring point is examined. The analyses are performed based on representative ...wideband electric field waveforms that were obtained by averaging individual waveforms produced by negative return strokes at distances ranging from 10 to 500 km. The methodology employed for finding the representative waveforms using a large database is described in the companion paper. In this article, we present evolution with distance of the following waveform parameters: zero-to-peak rise time, zero-crossing time, ratio of the initial electric field peak to the opposite polarity overshoot, all for the ground wave, and the ratio of the ground wave initial electric field peak to the peak of the first skywave. We also present a catalog of representative waveforms for different distances, time of day, and stroke order. Additionally, we examine the peak-to-peak and zero-to-zero time intervals between the ground wave and the first skywave that are often used for estimating the apparent ionospheric reflection height.
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