Evaluation of bioactive sphingolipids in 4-HPR-resistant leukemia cells

Background -- N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) is a synthetic retinoid with potent pro-apoptotic activity against several types of cancer, but little is known regarding mechanisms leading to chemoresistance. Ceramide and, more recently, other sphingolipid species (e.g., dihydroceramide and dihydrosphingosine) have been implicated in 4-HPR-mediated tumor cell death. Because sphingolipid metabolism has been reported to be altered in drug-resistant tumor cells, we studied the implication of sphingolipids in acquired resistance to 4-HPR based on an acute lymphoblastic leukemia model. Methods -- CCRF-CEM cell lines resistant to 4-HPR were obtained by gradual selection. Endogenous sphingolipid profiles and in situ enzymatic activities were determined by LC/MS, and resistance to 4-HPR or to alternative treatments was measured using the XTT viability assay and annexin V-FITC/propidium iodide labeling. Results -- No major crossresistance was observed against other antitumoral compounds (i.e. paclitaxel, cisplatin, doxorubicin hydrochloride) or agents (i.e. ultra violet C, hydrogen peroxide) also described as sphingolipid modulators. CCRF-CEM cell lines resistant to 4-HPR exhibited a distinctive endogenous sphingolipid profile that correlated with inhibition of dihydroceramide desaturase. Cells maintained acquired resistance to 4-HPR after the removal of 4-HPR though the sphingolipid profile returned to control levels. On the other hand, combined treatment with sphingosine kinase inhibitors (unnatural (dihydro)sphingosines ((dh)Sph)) and glucosylceramide synthase inhibitor (PPMP) in the presence or absence of 4-HPR increased cellular (dh)Sph (but not ceramide) levels and were highly toxic for both parental and resistant cells. Conclusions -- In the leukemia model, acquired resistance to 4-HPR is selective and persists in the absence of sphingolipid profile alteration. Therapeutically, the data demonstrate that alternative sphingolipid-modulating antitumoral strategies are suitable for both 4-HPR-resistant and sensitive leukemia cells. Thus, whereas sphingolipids may not be critical for maintaining resistance to 4-HPR, manipulation of cytotoxic sphingolipids should be considered a viable approach for overcoming resistance.

Numeric Calculation for Transient Thermal Stress Field in Wall-Shape Metal Part During Laser Direct Forming

In order to investigate the transient thermal stress field in wall-shape metal part during laser direct forming, a FEM model basing on ANSYS is established, and its algorithm is also dealt with. Calculation results show that while the wall-shape metal part is being deposited, in X direction, the thermal stress in the top layer of the wall-shape metal part is tensile stress and in the inner of the wall-shape metal part is compressive stress. The reason causing above-mentioned thermal stress status in the wall-shape metal part is illustrated, and the influence of the time and the processing parameters on the thermal stress field in wall-shape metal part is also studied. The calculation results are consistent with experimental results in tendency.

Effects and impacts of physical stress on entrained organisms.

Environmental studies of power plants have recently shifted their emphasis from examination of the effects of heated discharges to studies of the impacts of entire cooling systems. One of the major impacts arises when planktonic organisms are carried into and through a plant with the cooling water. Because of their relatively immobile, free-floating character, planktonic organisms are highly vulnerable to being "entrained" or passively drawn into the cooling water condenser systems of power plants. More than 70% of estuarine animals have planktonic eggs and larvae. The environmental impact of entrainment is related to the composition and abundance of affected organisms, the numbers of organisms in the adjacent waters, survival rates during entrainment as related to natural survival, the ecological roles of entrained organisms, and their reproductive strategies.

Modeling Environmental Stress

The word stress when applied to ecosystems is ambiguous. Stress may be low-level, with accompanying near-linear strain, or it may be of finite magnitude, with nonlinear response and possible disintegration of the system. Since there are practically no widely accepted definitions of ecosystem strain, classification of models of stressed systems is tenuous. Despite appearances, most ecosystem models seem to fall into the low-level linear response category. Although they sometimes simulate systems behavior well, they do not provide necessary and sufficient information about sudden structural changes nor structure after transition. Dynamic models of finiteamplitude response to stress are rare because of analytical difficulties. Some idea as to future transition states can be obtained by regarding the behavior of unperturbed functions under limiting strain conditions. Preliminary work shows that, since community variables do respond in a coherent manner to stress, macroscopic analyses of stressed ecosystems offer possible alternatives to compartmental models.