Quantitative Analysis of the Potency of Equimolar Two-Drug Combinations and Combi-Molecules Involving Kinase Inhibitors In Vitro: The Concept of Balanced Targeting

The median-effect principle proposed by Chou and Talalay is the most effective approach to parameterize interactions between several agents in combination. However, this method cannot be used to evaluate the effectiveness of equimolar drug combinations, which are comparative references for dual-targeting molecular design. Here, using data acquired through the development of “combi-molecules” blocking two kinases (e.g., EGFR-c-Src and EGFR-c-Met), we established potency indices for equimolar and dual-targeted inhibitors. If the fold difference (κ) between the IC50 of the two individual kinase inhibitors was >6, the IC50 of their equimolar combination resembled that of the more potent inhibitor. Hence, the “combi-targeting” of the two kinases was considered “imbalanced” and the combination ineffective. However, if κ ≤ 6, the IC50 of the combination fell below that of each individual drug and the combi-targeting was considered “balanced” and the combination effective. We also showed that combi-molecules should be compared with equimolar combinations only under balanced conditions and propose a new parameter Ω for validating their effectiveness. A multi-targeted drug is effective if Ω < 1, where Ω is defined as the IC50 of the drug divided by that of the corresponding equimolar combination. Our study provides a methodology to determine the in vitro potency of equimolar two-drug combinations as well as combi-/hybrid molecules inhibiting two different kinase targets.     

Microfluidic-Based Technologies for CTC Isolation: A Review of 10 Years of Intense Efforts towards Liquid Biopsy

The selection of circulating tumor cells (CTCs) directly from blood as a real-time liquid biopsy has received increasing attention over the past ten years, and further analysis of these cells may greatly aid in both research and clinical applications. CTC analysis could advance understandings of metastatic cascade, tumor evolution, and patient heterogeneity, as well as drug resistance. Until now, the rarity and heterogeneity of CTCs have been technical challenges to their wider use in clinical studies, but microfluidic-based isolation technologies have emerged as promising tools to address these limitations. This review provides a detailed overview of latest and leading microfluidic devices implemented for CTC isolation. In particular, this study details must-have device performances and highlights the tradeoff between recovery and purity. Finally, the review gives a report of CTC potential clinical applications that can be conducted after CTC isolation. Widespread microfluidic devices, which aim to support liquid-biopsy-based applications, will represent a paradigm shift for cancer clinical care in the near future.     

Effect of fruit load on maturity and carotenoid content of clementine (Citrus clementina Hort. ex Tan.) fruits

BACKGROUND: Citrus fruits contain many secondary metabolites displaying valuable health properties. There is a lot of interest in enhancing citrus quality traits, especially carotenoid contents, by agronomic approaches. In this study the influence of carbohydrate availability on maturity and quality criteria was investigated in clementine fruits during ripening. Fruiting branches were girdled and defoliated after fruit set to obtain three levels of fruit load: high (five leaves per fruit), medium (15) and low (30). RESULTS: Considering the soluble solid content/titratable acidity (SSC/TA) ratio, it was found that fruits of the high and medium fruit load treatments reached maturity 1.5 months later than fruits of the control. At the time of maturity the SSC/TA ratio of fruits of all treatments was about 13.6. At harvest, fruits were 23% smaller and total sugar concentration of the endocarp was 12.6% lower in the high fruit load treatment than in the control. In contrast, the concentrations of organic acids and total carotenoids were 55.4 and 93.0% higher respectively. Total carotenoids were not positively correlated with either soluble sugars or total carbohydrates. CONCLUSION: Taken together, the results do not support the common view that carbohydrate availability directly determines carotenoid synthesis by influencing precursor availability. Copyright © 2012 Society of Chemical Industry     

Back to the future: Fatty acids,the green genie to design smart soft materials

Fatty acids are widely used in industries for various applications as soaps or in their crystalline form. Fatty acid soaps are used as surface-active agent to stabilize foams and emulsions, for detergency, and surface wetting. Fatty acid molecules in organic solvents are used as low-molecular-mass organic gelators. Currently, there is a renewed interest in using fatty acids in industrial applications instead of petrochemical surfactants since fatty acid soaps are green surfactants. Fatty acids exhibit also many advantages, including the design of responsive soft-materials. Fatty acid soaps are natural pH and thermoresponsive surfactants, which can lead to responsive foams and emulsions. In their crystalline form, fatty acid crystals in both aqueous and non-aqueous solvents stabilize liquid foams. These crystals are also efficient in the production of liquid marbles. Fatty acids are solvosurfactants with the ability to form microemulsions and capillary suspensions. In this review, we illustrate how fatty acid molecules can be used in the manufacture of multiresponsive soft-materials ranging from aqueous and non-aqueous foams, emulsions, nanoemulsions, microemulsions, liquid marbles and capillary suspensions.     

Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy

Nanoscale drug delivery vehicles have been extensively studied as carriers for cancer chemotherapeutics. However, the formulation of platinum chemotherapeutics in nanoparticles has been a challenge arising from their physicochemical properties. There are only a few reports describing oxaliplatin nanoparticles. In this study, we derivatized the monomeric units of a polyisobutylene maleic acid copolymer with glucosamine, which chelates trans-1,2-diaminocyclohexane (DACH) platinum (II) through a novel monocarboxylato and O --> Pt coordination linkage. At a specific polymer to platinum ratio, the complex self-assembled into a nanoparticle, where the polymeric units act as the leaving group, releasing DACH-platinum in a sustained pH-dependent manner. Sizing was done using dynamic light scatter and electron microscopy. The nanoparticles were evaluated for efficacy in vitro and in vivo. Biodistribution was quantified using inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The PIMA-GA-DACH-platinum nanoparticle was found to be more active than free oxaliplatin in vitro. In vivo, the nanoparticles resulted in greater tumor inhibition than oxaliplatin (equivalent to 5 mg kg?1 platinum dose) with minimal nephrotoxicity or body weight loss. ICP-AAS revealed significant preferential tumor accumulation of platinum with reduced biodistribution to the kidney or liver following PIMA-GA-DACH-platinum nanoparticle administration as compared with free oxaliplatin. These results indicate that the rational engineering of a novel polymeric nanoparticle inspired by the bioactivation of oxaliplatin results in increased antitumor potency with reduced systemic toxicity compared with the parent cytotoxic. Rational design can emerge as an exciting strategy in the synthesis of nanomedicines for cancer chemotherapy.     

Effect of temperature on the processing of a magnesium alloy by high-pressure torsion

It is now well known that processing by SPD can significantly increase the strength of metallic materials by refining the grain structure and increasing the density of defects. The rapid increase in strength observed in the early stages of deformation is expected to slow down and saturate at large strains because of an increasing recovery of the material. Therefore, a saturation strength is anticipated that will depend on the processing temperature. This investigation analyses this parameter by determining the evolution of hardness of a magnesium alloy processed by high-pressure torsion at different temperatures.     

Comparison of theoretical and measured P1dB of a photonic microwave link: influence of some physical parameters of the DFB laser

This paper studies a microwave photonic link built as an IM/DD or intensity modulation–direct detection semiconductor laser system. The radiofrequency gain and 1 dB compression point of the link are both simulated with a modelling approach and compared to measurements. The electrical model of the electro-optic transducer, a distributed feedback laser, is first presented. Taking into account the nonlinearities and noise sources, it is developed on the commercial electrical software Advanced Design System. Owing to this accurate model, the impact of the relaxation oscillation frequency is presented on the system nonlinearity characteristic as for example the input 1 dB compression point. The comparison of simulated results to measured ones confirms the accuracy of this model.     

Impact of industrial processing and storage on major polyphenols and the antioxidant capacity of tropical highland blackberry (Rubus adenotrichus)

Critical steps of a typical industrial line for processing a blackberry-based beverage in glass bottles have been studied, together with the effects of storage of final product at four different temperatures. For the steps, contents of total phenolics, anthocyanins, ellagitannins, and minor phenolic compounds were assessed by HPLC-DAD and antioxidant capacity by H-ORAC and DPPH. Thermal processes, especially blanching, drastically reduced anthocyanins, whereas hot-filling degraded ellagitannins. The final product showed reduced values for the anthocyanins cyanidin-3-glucoside (by 52%) and cyanidin-3-malonyl glucoside (64%), and ellagitannins lambertianin C (80%), and sanguiin H-6 (50%). Antioxidant capacity (H-ORAC) dropped by almost 47%. The anthocyanins and ellagitannins continued degrading during storage, especially if temperatures were high. Reduction kinetic parameters during storage were estimated for anthocyanins and, for the first time, for both lambertianin C and sanguiin H-6.