Betulin Sulfonamides as Carbonic Anhydrase Inhibitors and Anticancer Agents in Breast Cancer Cells

Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.     

Mycosporine-like amino acid composition of the edible red alga, Palmaria palmata (dulse) harvested from the west and east coasts of Grand Manan Island,New Brunswick

The oxygen radical absorbance capacity (ORAC), antiproliferative activities and mycosporine-like amino acid (MAA) profiles of methanol extracts from two grades of dulse harvested from locations varying in UV-exposure (west vs east coasts of Grand Manan Island, NB) were determined in the present study. MAAs confirmed by LC/MS in both grades 1 (low-UV) and 2 (high-UV) dulse were palythine, shinorine, asterina-330, palythinol and porphyra-334; usujirene was present only in grade 2 dulse. ORAC values of grade 1 and 2 dulse extracts were 36.42 and 38.78 μmol Trolox/g extract. B16-F1 murine skin melanoma cell proliferation was inhibited (p < .05) by 68.5% and 91.9% by grade 1 and 2 dulse extracts at 6.0 mg/mL. The antiproliferative efficacy of grade 2 dulse was greater (p < .05) than grade 1 from 0.375 to 6.0 mg/mL. MAA differences between the grade 1 and 2 dulse extracts likely influenced the antiproliferative efficacies, despite the similar ORAC values.     

In vitro digestion kinetics of excipients for lipid-based drug delivery and introduction of a relative lipolysis half life

Background: Lipid-based drug delivery systems are widely used for enhancing the solubility of poorly water soluble drugs in the gastro-intestinal tract. Following oral intake, lipid systems undergo digestion in the stomach as well as the intestine. Lipolysis is here a complex process at the oil/water interface, influenced by numerous factors. Purpose: To study the digestibility of nine excipients often used in lipid-based drug delivery systems. In addition, we introduced a mathematical model to describe in vitro lipolysis kinetics. A relative lipolysis half life was defined using the reference excipient medium-chain triglycerides. Methods: Using pH-stat equipment, the NaOH consumption was determined in an in vitro lipolysis assay. Results: We identified two classes of excipients. Some additives were partially hydrolysed, whereas other excipients displayed complete lipolysis. For the latter class, a simplified mathematical model provided a good first approximation of initial lipolysis kinetics. Conclusions: Digestion characterization of excipients is important for the development of lipid-based delivery systems. The applied kinetic model and the concept of a relative lipolysis half life seemed to be promising tools for comparing in vitro lipolysis results.     

Biofuel or excavation? - Life cycle assessment (LCA) of soil remediation options

The environmental consequences of soil remediation through biofuel or through dig-and-dump were compared using life cycle assessment (LCA). Willow (Salix viminalis) was actually grown in-situ on a discontinued oil depot, as a phytoremediation treatment. These data were used for the biofuel remediation, while excavation-and-refill data were estimated from experience. The biofuel remediation had great environmental advantages compared to the ex situ excavation remediation. With the ReCiPe impact assessment method, which included biodiversity, the net environmental effect was even positive, in spite of the fact that the wood harvest was not utilised for biofuel production, but left on the contaminated site. Impact from the Salix viminalis cultivation was mainly through land use for the short rotation coppice, and through journeys of control personnel. The latter may be reduced when familiarity with biofuel as a soil treatment method increases. The excavation-and-refill remediation was dominated by the landfill and the transport of contaminated soil and backfill.     

Enabling controlled dispersion in polyethylene nanocomposites using small‐angle scattering

In this article, we present some key results that demonstrate the useful application of light scattering to characterize the dispersion of nanoparticles in polymer matrix, using polyethylene nanocomposite as an example. Our results show that the dispersions of nanoparticles in polyethylene nanocomposite, that influence the thermomechanical properties of polyethylene nanocomposites, can be characterized by using small angle light scattering. This proposition is motivated by recent synthetic and morphological characterization progress towards achieving ideally dispersed polyethylene nanocomposites. Our results are significant because it is shown that using light, size and shape features that correlate well with the scanning electron microscopy observations of nanoparticle dispersion can be obtained using our unique vertical light scattering set‐up. POLYM. COMPOS., 2009. © 2008 Society of Plastics Engineers     

The impact of supply base complexity on disruptions and performance: the moderating effects of slack and visibility

In the face of increasing supply base complexity, organisations have to develop new ways to manage or mitigate risk. This paper investigates the impact of four dimensions of complexity on the frequency of disruptions and plant performance. We apply insights from organisational information processing theory to understand how organisations can mitigate against the impact of more frequent disruptions. We test the moderating effects of slack resources as a means to absorb the effects of disruptions and supply visibility as a means to improve the ability to handle disruptions. The model is tested with data from 264 supply chain management professionals. Our findings broadly support the original hypotheses and suggest that supply base complexity can increase the frequency of disruptions and reduce plant performance but that slack resources and visibility can help to mitigate the effects. The study offers valuable insights into the management of supply base complexity.     

Profiling of bioactive compounds in cultivars of Runner and Valencia peanut market-types using liquid chromatography/APCI mass spectrometry

Peanuts are classified into four market-types (Runners, Spanish, Virginia and Valencia). Studies on their phytochemical composition have focused mainly on market-types other than Valencia. The objectives of this study are to evaluate the phytochemical composition of cultivars of Valencia and Runner market-types. Extracts of 25 peanut cultivars of Runner and Valencia market-types were analysed using HPLC-DAD-MS analysis. Results showed major differences in UV profile of the market-types. A major peak with m/z 317 identified as isorhamnetin was present only in Valencia cultivars while its glycoside (isorhamnetin-3-O-rutinoside) having m/z 625 was identified in both market-types. Genistein, daidzein, rutin, quercetin and trans-resveratrol were also identified and quantified. Genistein and daidzein concentrations (0.03 mg/100 g) were similar in both market-types. trans-Resveratrol and rutin were significantly (p < 0.05) higher in Runner cultivars while quercetin was 10-fold higher (0.60 ± 0.04 mg/100 g) in Valencia cultivars making them a better source of this phytochemical.     

In vitro stability and compatibility of tenecteplase in central venous access devices

Central venous access devices (CVADs) aid in the delivery of nutritional support, infusion therapy, and hemodialysis. Maintaining continuous flow through these devices is challenging, because they are susceptible to complications such as thrombi occlusion. Therefore, CVADs may require treatment with anticoagulant or thrombolytic agents. Using these agents as locking solutions has been widely investigated; however, few publications have described the compatibility of the therapeutic with the CVAD itself. The objective of this investigation was to evaluate the in vitro stability and compatibility of a thrombolytic biologic agent, tenecteplase, with various CVAD materials. Tenecteplase was reconstituted to 1 mg/mL with either sterile water for injection or bacteriostatic water for injection (0.9% benzyl alcohol) then incubated in glass vials, polysulfone/silicone vascular access ports, and polyurethane or silicone catheters for up to 96 hours. Biochemical assays including protein monomer, protein one-chain, and in vitro bioactivity were used to assess tenecteplase's compatibility with the investigated diluents and materials every 24 hours. Antimicrobial testing was also performed for up to 28 days on bacteriostatic water for injection-reconstituted samples only. Our results showed tenecteplase to be compatible with both types of diluents (in glass vials) and catheters for up to 72 hours. Furthermore, tenecteplase was compatible with the polysulfone/silicone vascular access ports for up to 24 hours. Finally, bacteriostatic water for injection-reconstituted tenecteplase effectively met USP criteria for the inhibition of growth of micro-organisms. This study serves as an example of a best practice to evaluate the in vitro stability and compatibility of a biologic agent with CVAD materials.