1,721,494 research outputs found
Targeting redox alterations and sensors in colorectal cancer
Full text linkBiguanides are a class of antidiabetic drugs known for their anticancer properties, but their mechanism of action is still poorly understood. The most widely accepted model links biguanides antitumoral activity to the inhibition of Complex I of mitochondrial respiratory chain and consequent activation of the AMP Kinase, a sensor of energy stress. However, this model has raised several concerns since inhibition of Complex I requires millimolar concentrations of the drugs, which cannot be reached in patients or animal models, where the maximum tolerated doses are in the range of low micromolar range. This observation suggests that at physiologic doses alternate mechanisms of action may contribute to the antitumor effects of biguanides.
In this study, we have investigated the mechanism of action of biguanides, using as a model colorectal cancer (CRC), a disease where biguanides have shown promising therapeutic properties.
Oral administration of biguanides to APC-mutated mice revealed that phenformin, but not metformin, causes a significant reduction of intestinal tumorigenesis and its maximum concentration in the gut is within the low micromolar range.
Treatment of CRC cell lines with low micromolar concentrations result in a significant inhibitory effect of cell proliferation, mediated by an increase of cytoplasmic NADH/NAD+ levels.
This redox imbalance is due to inhibition of mitochondrial Glycerol-3-Phosphate Dehydrogenase (mGPD), a component of the glycerophosphate shuttle (GPS), that is inhibited by biguanides.
The anti-proliferative effect of redox imbalance is reproduced by alterations of lactate/pyruvate ratio and can be rescued by specific NADH oxidases. We show that the redox dependent inhibitory effect is mediated by the corepressor C-terminal Binding Protein 2 (CtBP2), that senses redox alterations through its NADH-binding domain. Relevantly, we demonstrate that dietary limitation through short-term starvation (STS) significantly enhances the redox-dependent inhibition of cancer cells growth after phenformin treatment, both in in vitro and in vivo CRC models.
Collectively we demonstrate that therapeutic concentrations of phenformin exert a robust anticancer activity in CRC cells by a coupled metabolic-corepressor mechanism and that a combination of calorie restricted diet and phenformin may represent a promising novel therapeutic opportunity to treat colorectal cancer
A Morse Lemma for Degenerate Critical Points of Solutions of Nonlinear Equations in R 2
No full textIn this paper we prove a Morse Lemma for degenerate critical points of a function u which satisfies - Δ u = f (u) in B1, where u ∈ C2 (B1), B1 is the unit ball of R2 and f is a smooth nonlinearity. Other results on the nondegeneracy of the critical points and the shape of the level sets are proved
On the critical points of solutions of PDE in non-convex settings: the case of concentrating solutions
No full textIn this paper we are concerned with the number of critical
points of solutions of nonlinear elliptic equations. We will deal
with the case of non-convex, contractile and non-contractile
planar domains. We will prove results on the estimate of their
number as well as their index. In some cases we will provide
the exact calculation. The toy problem concerns the multi-
peak solutions of the Gel’fand problem, namely
−Δu = λeu
u=0 on ∂Ω,
where Ω ⊂ R2 is a bounded smooth domain and λ > 0 is a
small parameter
Investigation of the Impact of BTI Aging Phenomenon on Analog Amplifiers
Full text linkCMOS technology scaling allows the design of even more complex system but, at the same time, introduces some reliability problems. In particular, aggressively scaled microelectronic technologies are affected by the Bias Temperature Instability (BTI) aging phenomenon that results in an increase of the absolute value of the transistor threshold voltage with aging time and a consequent reduction for the microelectronic circuit reliability. In this paper we estimate the performance degradation caused by BTI on an operational amplifier (OPAMP) in open loop configuration as well as on three other analog amplifiers based on OPAMPs. The results have shown that BTI can seriously impact the performance of the investigated circuits, and that such performance degradation worsens as operating temperature increases. We also briefly describe a possible low-cost monitoring scheme to detect the performance degradation of the OPAMPs caused by BTI. The effectiveness of our monitor has been validated by means of pre-layout electrical simulations, and the results have shown that it can be reliably used to evaluate the OPAMPs aging degradation
Peserico, A. Germani, P. Sanese, V. Di Virgilio, V. Grossi, M. Nicola, A.J.M. Barbosa, A. Del Rio, C. Simone
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
On the number of critical points of the second eigenfunction of the Laplacian in convex planar domains
Full text linkIn questo lavoro consideriamo la seconda autofunzione del Laplaciano con condizioni al contorno di Dirichlet in domini convessi. Se il dominio ha una grande eccentricità, l'autofunzione ha esattamente due punti critici non degenerati (ovviamente sono un massimo e un minimo). La dimostrazione utilizza alcune stime dimostrate da Jerison ([13]) e Grieser-Jerison ([10]) congiuntamente con un argomento di grado topologico. Risultati analoghi per autofunzioni di ordine superiore sono dimostrati in domini di tipo rettangolare considerati in [11].In this paper we consider the second eigenfunction of the Laplacian with Dirichlet boundary conditions in convex domains. If the domain has large eccentricity then the eigenfunction has exactly two nondegenerate critical points (of course they are one maximum and one minimum). The proof uses some estimates proved by Jerison ([13]) and Grieser-Jerison ([10]) jointly with a topological degree argument. Analogous results for higher order eigenfunctions are proved in rectangular-like domains considered in [11]
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