Synthesis and Characterization of Novel n-9 Fatty Acid Conjugates Possessing Antineoplastic Properties

The present study enumerates the synthesis, spectroscopic characterization, and evaluation of anticancer potential of esters of two n-9 fatty acids viz., oleic acid (OLA) and ricinoleic acid (RCA) with 2,4- or 2,6-diisopropylphenol. The synthesis strategy involved esterification of the hydroxyl group of diisopropylphenol (propofol) to the terminal carboxyl group of n-9 fatty acid. The synthesized propofol-n-9 conjugates having greater lipophilic character were tested initially for cytotoxicity in-vitro. The conjugates showed specific growth inhibition of cancer cell lines whereas no effect was observed in normal cells. In general, pronounced growth inhibition was found against the human skin malignant melanoma cell line (SK-MEL-1). The anticancer potential was also determined by testing the effect of these conjugates on cell migration, cell adhesion and induction of apoptosis in SK-MEL-1 cancer cells. Propofol-OLA conjugates significantly induced apoptosis in contrast to propofol-RCA conjugates which showed only weak signals for cytochrome c. Conclusively, the synthesized novel ester conjugates showed considerable moderation of anti-tumor activity. This preliminary study places in-house synthesized conjugates into the new class of anticancer agents that possess selectivity toward cancer cells over normal cells.     

Multifunctional and thermoresponsive unimolecular micelles for tumor-targeted delivery and site-specifically release of anticancer drugs

Considering the fact that tumors have a lower pH value and a higher temperature than a normal tissue, a new type of thermoresponsive and biodegradable micelles, based on the H40-poly(?-caprolactone)-b-poly(N-isopropylacrylamide-co-acrylamide)-fluorescein methyl ester/b′-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate (i.e., H40-PCL-b-P(NIPAAm-co-AAm)-FL/b′-MPEG/PEG-FA (HPPNAP-FA)) with imaging and targeting moieties on the periphery were developed for the tumor-targeted delivery and temperature-induced site-specifically release of hydrophobic anticancer drugs. The amphiphilic HPPNAP-FA copolymer was able to self-assemble into unimolecular micelles in aqueous solution with an average diameter of 65 nm. The lower critical solution temperature (LCST) of micelles was around 39.5 °C. The anticancer drug, paclitaxel (PTX), was encapsulated into the multifunctional micelles. In vitro release studies demonstrated that the drug-loaded delivery system is relatively stable at physiologic conditions but susceptible to mild acidic environments and temperatures above LCST which would trigger the release of encapsulated drugs. Both flow cytometry and fluorescent microscopy showed that the cellular uptake of the PTX-loaded HPPNAP-FA micelles is higher than that of the PTX-loaded HPPNAP because of the folate receptor mediated endocytosis. The efficacy of this thermoresponsive drug delivery system was also evaluated at temperatures above the LCST (40 °C); the results demonstrated that the cellular uptake and the cytotoxicity of PTX-loaded micelles increase prominently. These results indicate that these multifunctional and thermoresponsive unimolecular micelles are promising biomaterials to improve the delivery efficiency and cancer specificity of hydrophobic chemotherapeutic drugs.     

Matching IR-MALDI-o-TOF mass spectrometry with the TLC overlay binding assay and its clinical application for tracing tumor-associated glycosphingolipids in hepatocellular and pancreatic cancer

Glycosphingolipids (GSLs), composed of a hydrophilic carbohydrate chain and a lipophilic ceramide anchor, play pivotal roles in countless biological processes, including the development of cancer. As part of the investigation of the vertebrate glycome, GSL analysis is undergoing rapid expansion owing to the application of modern mass spectrometry. Here we introduce direct coupling of IR-MALDI-o-TOF mass spectrometry with the TLC overlay binding assay for the structural characterization of GSLs. We matched three complementary methods including (i) TLC separation of GSLs, (ii) their detection with oligosaccharide-specific proteins, and (iii) in situ MS analysis of protein-detected GSLs. The high specificity and sensitivity is demonstrated by use of antibodies, bacterial toxins, and a plant lectin. The procedure works on a nanogram scale, and detection limits of less than 1 ng at its best of immunostained GSLs were obtained. Furthermore, only crude lipid extracts of biological sources are required for TLC-IR-MALDI-MS, omitting any laborious GSL downstream purification procedures. This strategy was successfully applied to the identification of cancer-associated GSLs in human hepatocellular and pancreatic tumors. Thus, the in situ TLC-IR-MALDI-MS of immunolabeled GSLs opens new doors by delivering specific structural information of trace quantities of GSLs with only a limited investment in sample preparation.     

Cell formation with alternative process routings and machine reliability consideration

Cell formation is the first step in the design of cellular manufacturing systems. The main objective of this step is to cluster machines and parts into machine cells and part families respectively so that the minimum of intercellular part movements will be achieved. In this paper, we will focus on the configuration of machine cells considering production volumes and process sequences of parts. Also, we will study alternative process routings for part types and machine reliability considerations. A pure linear integer program will be developed to formulate this situation. The results of solving numerical examples show that the reliability consideration has significant impacts on the final block diagonal form of machine-part matrixes.     

Factors Controlling Gully Advancement and Models Evaluation (Hableh Rood Basin,Iran)

Gully erosion is one of the most complicated and destructive forms of water erosion. In order to prevent this erosion, the important factors controlling gully heads must be understood. This paper examines gully head advancement in the Hableh Rood Basin, Iran by (1) observing gully head advance between 1957 and 2005 using field studies, aerial photography and GIS analysis and: (2) applying and evaluating widely used experimental models including the, Thompson (Trans ASAE 7(1):54–55, 1964), SCS (I) and SCS (II) models, for estimating migrating headcuts over the study period. The results showed that the highest mean gully advancement (0.26 m year^− 1) took place during the 1956–1967 period, with most gullies having lower and steady headcut retreat rates between 1967–2000 (0.21 m year^− 1) and 2000–2005 (0.15 m year^− 1). This suggests that the majority of gullies in the study area were still in the early stages of formation in the first study period and their formation may be linked to land use or climatic changes pre 1956. Analysis of the correlation between environmental characteristics of the study area and gully advancement indicated that the upslope area of head cuts and soluble mineral content of the soil were the two most important factors influencing the spatial and temporal variation of gully longitudinal development. Results of multiple regression revealed that the simple relation including upslope area and soluble minerals can explain 93% of total variance and relatively reflects the effects of runoff and waterfall process for headcut retreat. Application of statistical error analysis to evaluate the four gully advancement models showed that in comparison to other models, the second model of SCS has more reliable results for predicting longitudinal gully advancement in this study area and other similar regions. However, this study indicates that future modelling in the region should consider the role of soil soluble mineral content in predicting gully advancement.     

Control of Listeria monocytogenes in goat's milk and goat's jben by the bacteriocinogenic Enterococcus faecium F58 strain

The bacteriocinogenic Enterococcus faecium F58 strain, a natural goat's jben cheese isolate, lacks decarboxylase activity involved in most biogenic amine formation. It was also sensitive to 13 antibiotics assayed and free of virulence and vancomycin resistance genes. The F58 strain reached the stationary phase after 12 h of growth in sterile goat's milk, and the production of enterocin F-58 (Ent L50) was first detected after 48 h (400 AU/ml), thereafter remaining stable up to 5 days. The effectiveness of the F58 strain in controlling Listeria monocytogenes serovar 4b in reduced fat and whole goat's milk, and in goat's jben has been examined. Coculture experiments of F58-L. monocytogenes in both types of milk demonstrated that listeriae were not eliminated, although reductions by 1 to 4 log units were found. Nevertheless, when the F58 strain was previously inoculated in whole milk and left to grow for 12 h before contamination, the pathogen was completely eliminated after 130 h of coculture. Production of jben cheese contaminated with L. monocytogenes prior to packaging, using preparations of F58-producer strain, caused a significant decrease in the number of viable listeriae, which were undetectable after 1 week of cheese storage at 22 degrees C. Altogether, results from this study suggest that E. faecium F58 strain may be used as an adjunct culture in cheese to control contamination and growth of L. monocytogenes by in situ enterocin production, thus providing an additional hurdle to enhance control of this pathogen.     

Oxadiazoline and Ketoimine Palladium(II) Complexes as Highly Efficient Catalysts for Suzuki–Miyaura Cross‐Coupling Reactions in Supercritical Carbon Dioxide

The [2+3] cycloaddition of nitriles (RCN) with 2,2‐dimethyl‐3,4‐dihydro‐2H‐pyrrole 1‐oxide, in the presence of palladium dichloride (PdCl₂) gives the corresponding 2,3‐dihydro[1.2.4]oxadiazole (Δ⁴‐1,2,4‐oxadiazoline) palladium(II) complexes 1 – 4 in good yields. However, the Pd(II)‐assisted reaction of pentafluorobenzonitrile with the same pyrroline N‐oxide gives a mixture of oxadiazoline 5 , ketoimine 6 and pyrrolylbenzamide‐ketoimine 7 Pd(II) complexes, which affords upon heating in refluxing acetone the unprecedented fused tricyclic ketoimine complex 8 as the exclusive product. Under heating, compounds 5 and 7 transform to 6 , the latter undergoing intramolecular cyclization by nucleophilic attack of the amino moiety to the ortho carbon of the pentafluorophenyl ring leading ultimately to 8 . The compounds were characterized by IR, ¹H and ¹³C NMR, ESI⁺‐MS, elemental analyses and, in the cases of 3 , 6 , 7 and 8 , also by X‐ray diffraction analyses. The catalytic properties of the Pd complexes were evaluated in Suzuki–Miyaura cross‐coupling reactions, using supercritical carbon dioxide (scCO₂) as a green solvent. Cross‐couplings of aryl halides with phenylboronic acid give the desired biaryl products in quantitative yields, in a short reaction time, for substrate‐to‐catalyst molar ratios as high as 4.0⋅10⁴.     

Occurrence and Safety Evaluation of Ochratoxin A in Cereal‐based Baby Foods Collected from Iranian Retail Market

Contamination of agricultural commodities with ochratoxin A (OTA) is a worldwide concern in recent decades. Consumption of OTA‐contaminated baby foods exerts health implications especially in children as the most vulnerable subpopulations. In the current study, for the first time in Iran, 64 baby foods (rice, wheat, and multigrain) samples from five different brands available in the Iranian market were analyzed to determine OTA level, using a HPLC with fluorescence detector. Overall, OTA was observed in 41% of analyzed samples with a mean and maximum level of 0.42 ± 0.27 and 1.1 μg/kg, respectively. OTA levels in five of 64 samples (7.8 %) were higher than the permissible limit recommended by European Commission (permissible limit: 0.5 μg/kg) and OTA levels in two of 64 samples (3.1%) were higher than the standard set by Iranian standard organization (1 μg/kg). The highest OTA contamination was observed in rice‐based baby food cereals (1.1 μg/kg; 57% of the samples), followed by wheat‐based (23%) and multigrain (20%) samples. OTA intake in infants (≥9 months old) was more than established provisional tolerable weekly intake by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Food Safety Authority (EFSA) (100 and 120 ng OTA per kg of body weight, respectively). OTA content in baby food and cereals, as well as other raw foodstuff should be investigated comprehensively to reduce the exposure rate of young children to OTA.     

Weight function for an external circumferential semielliptical crack in a cylinder

In this paper, the weight function was extracted at the deepest point of a semielliptical circumferential crack. The crack is assumed to exist on the outer surface of the cylinder. For this purpose, the three‐dimensional finite element method was accomplished to specify two reference loads, which are indispensable for determining the weight function. The verification study confirms the accuracy of the derived weight function under prescribed mechanical loading on the crack surfaces. There is consistency among the solution results compared with those in the literature. The second part describes the application of the weight function for the thermal boundary conditions. Steady‐state thermal stress intensity factors are demonstrated using the weight function and presented as a closed‐form solution. The results were compared with the finite element data on the special case of thermal loading, and good agreement is obtained.     

A survey on bug prioritization

Daily large number of bug reports are received in large open and close source bug tracking systems. Dealing with these reports manually utilizes time and resources which leads to delaying the resolution of important bugs. As an important process in software maintenance, bug triaging process carefully analyze these bug reports to determine, for example, whether the bugs are duplicate or unique, important or unimportant, and who will resolve them. Assigning bug reports based on their priority or importance may play an important role in enhancing the bug triaging process. The accurate and timely prioritization and hence resolution of these bug reports not only improves the quality of software maintenance task but also provides the basis to keep particular software alive. In the past decade, various studies have been conducted to prioritize bug reports using data mining techniques like classification, information retrieval and clustering that can overcome incorrect prioritization. Due to their popularity and importance, we survey the automated bug prioritization processes in a systematic way. In particular, this paper gives a small theoretical study for bug reports to motivate the necessity for work on bug prioritization. The existing work on bug prioritization and some possible problems in working with bug prioritization are summarized.