Enhanced glucose and lipid metabolism is one of the most common properties of malignant cells. ATP citrate lyase (ACLY) is a key enzyme of de novo fatty acid synthesis responsible for generating cytosolic acetyl-CoA and oxaloacetate. To evaluate its role in lung cancer progression, we here analyzed ACLY expression in a subset of human lung adenocarcinoma cell lines and showed a relationship with the phosphatidyl-inositol-3 kinase-Akt pathway. The introduction of constitutively active Akt into cells enhanced the phosphorylation of ACLY, whereas dominant-negative Akt caused attenuation. In human lung adenocarcinoma samples, ACLY activity was found to be significantly higher than in normal lung tissue. Immunohistochemical analysis further showed phosphorylated ACLY overexpression in 162 tumors, well-correlating with stage, differentiation grade, and a poorer prognosis. Finally, to show the therapeutic potential and mechanism of ACLY inhibition for lung cancer treatment, we assessed the effect of RNA interference targeting ACLY on lipogenesis and cell proliferation in A549 cells. ACLY inhibition resulted in growth arrest in vitro and in vivo. Interestingly, increased intracellular lipids were found in ACLY knockdown cells, whereas de novo lipogenesis was inhibited. Supplementation of insulin could rescue the proliferative arrest elicited by ACLY inhibition; however, in contrast, fatty acid palmitate induced cell death. Taken together, these findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target. [Cancer Res 2008;68(20):8547-54]

Recent experiments have shown that hydrogels with enhanced toughness can be synthesized by incorporating self-healing physical cross-links in a chemically cross-linked gel network. These gels exhibit rate dependent mechanical behavior, suggesting that improved mechanical properties are closely tied to the breaking and reattaching of temporary crosslinks in the gel network. In this work, the connection between rate dependent mechanical behavior and kinetics of breaking and reattachment of temporary cross-links is quantified using a three-dimensional finite strain constitutive model. The parameters of the model are fitted using relaxation and constant strain rate tests in uniaxial tension of a model dualcross-link gel. The stress versus time curves of more complex strain histories, involving loading followed by unloading at different rates, is successfully and quantitatively predicted by our model. Such modeling strategy combining physically based kinetics and three-dimensional large strain mechanics shows great promise for quantitative modeling of soft biological tissues and synthetic counterparts containing dynamic bonds.

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We studied the stress–strain relation of model dual cross-link gels having permanent cross-links and transient cross-links over an unusually wide range of extension ratios λ and strain rates ϵ̇ (or time t = (λ – 1)/ϵ̇). We propose a new analysis method and separate the stress into strain- and time-dependent terms. The strain-dependent term is derived from rubber elasticity, while the time-dependent term is due to the failure of transient cross-links and can be represented as a time-dependent shear modulus which shows the same relaxation as in small strain. The separability is applicable except for the strain stiffening regimes resulting from the finite extensibility of polymer chains. This new analysis method should have a wide applicability not only for hydrogels but also for other highly viscoelastic soft solids such as soft adhesives or living tissues.

Dynamics of poly(vinyl alcohol) (PVA) hydrogels having chemical and physical transient cross-links simultaneously (dual cross-link PVA gels) were studied by microrheology based on diffusing-wave spectroscopy (DWS), classical rheology and single dynamic light scattering (DLS), and compared with those of corresponding chemical and physical PVA gels. Three different relaxation modes (fast, intermediate and slow modes) are observed for physical gels, while one mode (fast mode) is found for chemical gels, and two (fast and intermediate) for dual cross-link gels. The three modes are attributed respectively to Brownian diffusion of PVA polymer or collective diffusion of the network or gel mode (fast mode), macroscopic stress relaxation (intermediate mode whose characteristic time shows q 0 dependence) and Brownian diffusion of aggregates (slow mode). Microrheological measurements are in good agreement with macrorheological showing segmental Rouse mode dynamics in the high frequency range. For physical gels, we found Maxwell type viscoelasticity characterized by a crossover frequency (maximum of G″) and G′ ∼ ω 2 and G″ ∼ ω 1 in the lower frequency range. The chemical gels displayed an elastic plateau with low G″ at low frequency. For the dual cross-link gel a maximum of G″ was observed, and its characteristic time agrees with that of the intermediate mode measured by DLS. We show that this relaxation mode corresponds to the associative Rouse mode characterized by G′ = G″ ∼ ω 0.5 , depending on the dissociation rate of the reversible transient cross-links. We propose a stress relaxation mechanism of the PVA chains in the presence of elastically inactive but associative transient cross-links which induces incomplete stress relaxation.

The strain rate effect on large strain dissipation and behavior recovery are presented to understand the toughening effect of silica nanoparticles in nanohybrid hydrogels. Such nanohybrid gels combine a poly(N,N-dimethylacrylamide) (PDMA) covalent network and physical interactions by adsorption of polymer chains at the silica nanoparticle surface. A series of model nanohybrid gels has been designed to obtain a well-controlled architecture. First insights on the structure (SANS) demonstrated that silica nanoparticles were welldispersed in the gel, including after cyclic mechanical loading. The characteristic times involved in the nanoparticle/polymer association were investigated by large strain mechanical cycling varying the strain rate from 3 × 10 −4 s −1 to 0.6 s −1 . The mechanical behavior of the hybrid hydrogel varies tremendously over a relatively small range of strain rates, ranging from almost non dissipative (at slow strain rates) to highly dissipative at high strain rates. However, upon cycling over time-scales of tens of seconds, the strong physical interactions taking place between nanosilica particles and PDMA network chains enabled the hydrogel to recover its initial mechanical properties. The main feature of this work is the remarkable role played by silica nanoparticles in the network to promote transient and recoverable connectivity by reversible adsorption/desorption processes. The strong strain rate dependence suggests that toughening mechanisms operating at standard strain rates as often reported, maybe quite different at slower or larger strain rates.

Abstract. , a novel noncleavable, complexstabilizing type topoisomerase (topo) II inhibitor, has been shown to target topo II in mammalian cells (Ishida, R., T. Miki, T. Narita, R. Yui, S. Sato, K. R. Utsumi, K. Tanabe, and T. Andoh. 1991. Cancer Res. 51:4909--4916). With the aim of elucidating the roles of topo II in mammalian cells, we examined the effects of ICRF-193 on the transition through the S phase, when the genome is replicated, and through the M phase, when the replicated genome is condensed and segregated. Replication of the genome did not appear to be affected by the drug because the scheduled synthesis of DNA and activation of cdc2 kinase followed by increase in mitotic index occurred normally, while VP-16, a cleavable, complex-stabilizing type topo II inhibitor, inhibited all these processes. In the M phase, however, late stages of chromosome condensation and segregation were clearly blocked by . Inhibition at the stage of compaction of 300-nm diameter chromatin fibers to 600-nm diameter chromatids was demonstrated using the drug during premature chromosome condensation (PCC) induced in tsBN2 baby hamster kidney cells in early S and G2 phases. In spite of interference with M phase chromosome dynamics, other mitotic events such as activation of ode2 kinase, spindle apparatus reorganization and disassembly and re, assembly of nuclear envelopes occurred, and the cells traversed an unusual M phase termed "absence of chromosome segregation" (ACS)-M phase. Cells then continued through further cell cycle rounds, becoming polyploid and losing viability. This effect of ICRF-193 on the cell cycle was shown to parallel that of inactivation of topo II on the cell cycle of the ts top2 mutant yeast. The results strongly suggest that the essential roles of topo II are confined to the M phase, when the enzyme decatenates intertwined replicated chromosomes. In other phases of the cycle, including the S phase, topo II may thus play a complementary role with topo I in controlling the torsional strain accumulated in various genetic processes. topoisomerases (topo) t have been implicated in e maintenance of genetic processes such as repliation, transcription, and recombination by controlling the higher order chromosomal structure through the cell cycle (for review, see Wang, , 1987Cozzarelli and Address all correspondence to Ryoji Ishida,

International audienceWe studied the dynamics of water sessile droplets advancing on hydrophobic and visco-elasticpoly(styrene-butadiene-styrene)(SBS)–paraffin gel substrates at various inflation rates. During theadvancing process, the droplet contact line exhibits three different regimes of motions. When thecontact line advances at a high velocity, it moves continuously with a constant contact angle. As thecontact line slows down, it starts a stick-slip motion: the contact line is pinned at a certain position andthen suddenly slips forward. With further decrease of the velocity, the contact line stops the stick-slipmotion and continuously advances again. The observed threshold values for the transitions of thecontact line motions (continuous–stick-slip–continuous) indicate that the rheology of the gel drasticallyaffects the dynamics of liquid on its surface. We suggest that on visco-elastic gels, the moving contactline exhibits both aspects of wetting on elastic solids and wetting on viscous liquids depending on thecharacteristic frequency of the gel surface deformation. At an intermediate regime, the stick-slip motionof the contact line appears. We also propose a simple geometrical model in the stick-slip regime whichallows us to relate the jumps of the droplet radius to the jumps of the apparent contact angl