Treatment Strategies that Enhance the Efficacy and Selectivity of Mitochondria-Targeted Anticancer Agents

Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been written about the role of mitochondria in the initiation and/or progression of various forms of cancer, and the possibility of exploiting differences in mitochondrial structure and function between normal and malignant cells as targets for cancer chemotherapy. A number of mitochondria-targeted compounds have shown efficacy in selective cancer cell killing in pre-clinical and early clinical testing, including those that induce mitochondria permeability transition and apoptosis, metabolic inhibitors, and ROS regulators. To date, however, none has exhibited the standards for high selectivity and efficacy and low toxicity necessary to progress beyond phase III clinical trials and be used as a viable, single modality treatment option for human cancers. This review explores alternative treatment strategies that have been shown to enhance the efficacy and selectivity of mitochondria-targeted anticancer agents in vitro and in vivo, and may yet fulfill the clinical promise of exploiting the mitochondrion as a target for cancer chemotherapy.     

Nucleotide and nucleotide sugar analysis by liquid chromatography-electrospray ionization-mass spectrometry on surface-conditioned porous graphitic carbon

We examined the analysis of nucleotides and nucleotide sugars by chromatography on porous graphitic carbon with mass spectrometric detection, a method that evades contamination of the MS instrument with ion pairing reagent. At first, adenosine triphosphate (ATP) and other triphosphate nucleotides exhibited very poor chromatographic behavior on new columns and could hardly be eluted from columns previously cleaned with trifluoroacetic acid. Satisfactory performance of both new and older columns could, however, be achieved by treatment with reducing agent and, unexpectedly, hydrochloric acid. Over 40 nucleotides could be detected in cell extracts including many isobaric compounds such as ATP, deoxyguanosine diphosphate (dGTP), and phospho-adenosine-5'-phosphosulfate or 3',5'-cyclic adenosine 5'-monophosphate (AMP) and its much more abundant isomer 2',3'-cyclic AMP. A fast sample preparation procedure based on solid-phase extraction on carbon allowed detection of very short-lived analytes such as cytidine 5'-monophosphate (CMP)-2-keto-deoxy-octulosonic acid. In animal cells and plant tissues, about 35 nucleotide sugars were detected, among them rarely considered metabolites such as uridine 5'-diphosphate (UDP)-l-arabinopyranose, UDP-L-arabinofuranose, guanosine 5'-diphosphate (GDP)-L-galactofuranose, UDP-L-rhamnose, and adenosine diphosphate (ADP)-sugars. Surprisingly, UDP-arabinopyranose was also found in Chinese hamster ovary (CHO) cells. Due to the unique structural selectivity of graphitic carbon, the method described herein distinguishes more nucleotides and nucleotide sugars than previously reported approaches.     

Projection-based two-phase minimum and maximum length scale control in topology optimization

The objective of this paper is a tradeoff between changing design and controlling sampling uncertainty in reliability-based design optimization (RBDO). The former is referred to as ‘living with uncertainty’, while the latter is called ‘shaping uncertainty’. In RBDO, a conservative estimate of the failure probability is defined using the mean and the upper confidence limit, which are obtained from samples and from the normality assumption. Then, the sensitivity of the conservative probability of failure is derived with respect to design variables as well as the number of samples. It is shown that the proposed sensitivity is much more accurate than that of the finite difference method and close to the analytical sensitivity. A simple RBDO example showed that once the design variables reach near the optimum point, the number of samples is adjusted to satisfy the conservative reliability constraints. This example showed that not only shifting design but also shaping uncertainty plays a critical role in the optimization process.     

Public attitudes toward air pollution as a motivational factor in taking action

The public will probably play a major role in determining future programs to combat air pollution. Thus, a major task in any community is to stimulate public acceptance of the responsibility to take some kind of action. This study was conducted to investigate the attitudes of a metropolitan population toward air pollution and to attempt to measure in a crude way that public's willingness to take action.Data were collected by personal interview from 562 adult respondents living in Salt Lake City, Utah, which is surrounded by lofty mountains. High pressure areas frequently form an inversion which holds the air on the valley floor. The air quickly becomes polluted when it cannot escape.A health behavior model, formulated by Irwin Rosenstock, was used as a frame of reference in determining how residents perceive the pollution problem and its probable consequences in relation to their health.Willingness to donate money from one's own resources in an effort to reduce the problem was used as a measure of concern. Those most willing to donate money to combat air pollution were residents who perceived air pollution to be a serious problem in this community; who were personally bothered by it; who were concerned for their family's health, and who had confidence that the problem could be eliminated, or at least reduced by our technical expertise. Demographically, they were the more highly educated males working in high status occupations.The findings of this study suggest the potential usefulness of the model in designing community programs to reduce air pollution.This research was supported by a grant from the Air Pollution Control Office, No. 1 RO1 APO1345-01, Environmental Protection Agency, Department of Health, Education, and Welfare.     

Textural Features for Radar Image Analysis

Texture is an important spatial feature useful for identifying objects or regions of interest in an image. While textural features have been widely used in the analysis of a variety of photographic images, they have not been used for processing radar images. In this paper, we present a procedure for extracting a set of textural features for characterizing small areas in radar images and show that these features can be used for classifying segments of radar images corresponding to different geological formations.     

<Emphasis Type="Italic">Trans</Emphasis>-Fatty Acid-Stimulated Mammary Gland Growth in Ovariectomized Mice is Fatty Acid Type and Isomer Specific

We previously reported that the trans-18:2 fatty acid trans-10, cis-12 conjugated linoleic acid (t10,c12-CLA) stimulates mammary gland development independent of estrogen and its receptor. Given the negative consequences of dietary trans-fatty acids on various aspects of human health, we sought to establish whether other trans-fatty acids could similarly induce ovary-independent mammary gland growth in mice. Prepubertal BALB/cJ mice were ovariectomized at 21 days of age then were fed diets enriched with cis-9, trans-11 CLA (c9,t11-CLA), or mixtures of trans-18:1 fatty acids supplied by partially hydrogenated sunflower, safflower, or linseed oil. The resultant mammary phenotype was evaluated 3 weeks later and compared to the growth response elicited by t10,c12-CLA, or the defined control diet. Whereas partially hydrogenated safflower oil increased mammary gland weight, none of the partially hydrogenated vegetable oils promoted mammary ductal growth. Similarly, the c9,t11-CLA supplemented diet was without effect on mammary development. Taken together, our data emphasize a unique effect of t10,c12-CLA in stimulating estrogen-independent mammary gland growth manifest as increased mammary ductal area and elongation that was not recapitulated by c9,t11-CLA or the partially hydrogenated vegetable oil diets.     

The desorption of chemisorbed oxygen from activated carbons and its relationship to ageing and methyl iodide retention efficiency

KI impregnated carbons are used to prevent emission of traces of radioactive iodine compounds from British gas-cooled nuclear reactors. Commercial activated carbons, both with and without potassium iodide impregnant, have been compared in terms of the carbon dioxide and monoxide evolved when they are subjected to a linear temperature rise under inert gas. The desorption patterns obtained have been related to the type of carbon, the effect of aqueous impregnation and the effect of increasing surface oxidation with time (ageing). A strong relationship between the level of combined surface oxygen and methyl iodide retention efficiency is proposed and it is shown that those surface groups which decompose to carbon dioxide have the most deleterious effect on the retention efficiency of methyl iodide. Carboxylic acid and anhydride groups are the most likely source of carbon dioxide and prevention or reduction of the rate of formation of these groups is a necessary step in maintaining carbon performance.     

High Temperature Alters Secondary Metabolites and Photosynthetic Efficiency in Heracleum sosnowskyi

Due to global warming, invasive species have spread across the world. We therefore studied the impact of short-term (1 day or 2 days) and longer (7 days) heat stress on photosynthesis and secondary metabolites in Heracleum sosnowskyi, one of the important invasive species in the European Union. H. sosnowskyi leaves exposed to short-term heat stress (35 °C/1 d) showed a decrease in chlorophyll and maximum potential quantum efficiency of photosystem II (Fv/Fm) compared to control, 35 °C/2 d, or 30 °C/7 d treatments. In turn, the high level of lipid peroxidation and increased H₂O₂ accumulation indicated that the 30 °C/7 d stress induced oxidative damage. The contents of xanthotoxin and bergapten were elevated in the 2 d and 7 d treatments, while isopimpinellin was detected only in the heat-stressed plants. Additionally, the levels of free proline and anthocyanins significantly increased in response to high temperature, with a substantially higher increase in the 7 d (30 °C) treatment. The results indicate that the accumulation of proline, anthocyanins, and furanocoumarins, but not of phenolic acids or flavonols, contributes to protection of H. sosnowskyi plants against heat stress. Further studies could focus on the suppression of these metabolites to suppress the spread of this invasive species.     

Thermo mechanical behaviour of unsaturated polyester toughened epoxy–clay hybrid nanocomposites

The intercrosslinked networks of unsaturated polyester (UP) toughened epoxy–clay hybrid nanocomposites have been developed. Epoxy resin (DGEBA) was toughened with 5, 10 and 15% (by wt) of unsaturated polyester using benzoyl peroxide as radical initiator and 4,4′-diaminodiphenylmethane as a curing agent at appropriate conditions. The chemical reaction of unsaturated polyester with the epoxy resin was carried out thermally in presence of benzoyl peroxide-radical initiator and the resulting product was analyzed by FT-IR spectra. Epoxy and unsaturated polyester toughened epoxy systems were further modified with 1, 3 and 5% (by wt) of organophilic montmorillonite (MMT) clay. Clay filled hybrid UP-epoxy matrices, developed in the form of castings were characterized for their thermal and mechanical properties. Thermal behaviour of the matrices was characterized by differential scanning calorimetry (DSC), thermo gravimetric analysis (TGA) and dynamic mechanical analysis (DMA). Mechanical properties were studied as per ASTM standards. Data resulted from mechanical and thermal studies indicated that the introduction of unsaturated polyester into epoxy resin improved the thermal stability and impact strength to an appreciable extent. The impact strength of 3% clay filled epoxy system was increased by 19.2% compared to that of unmodified epoxy resin system. However, the introduction of both UP and organophilic MMT clay into epoxy resin enhanced the values of mechanical properties and thermal stability according to their percentage content. The impact strength of 3% clay filled 10% UP toughened epoxy system was increased by 26.3% compared to that of unmodified epoxy system. The intercalated nanocomposites exhibited higher dynamic modulus (from 3,072 to 3,820 MPa) than unmodified epoxy resin. From the X-ray diffraction (XRD) analysis, it was observed that the presence of d ₀₀₁ reflections of the organophilic MMT clay in the cured product indicated the development of intercalated clay structure which in turn confirmed the formation of intercalated nanocomposites. The homogeneous morphologies of the UP toughened epoxy and UP toughened epoxy–clay hybrid systems were ascertained from scanning electron microscope (SEM).