Circumventing Doxorubicin Resistance Using Elastin-like Polypeptide Biopolymer-Mediated Drug Delivery

Although doxorubicin (dox), an anthracycline antibiotic, is widely used and effective in treating cancer, its treatment efficiency is limited by low blood plasma solubility, poor pharmacokinetics, and adverse side effects, including irreversible cardiotoxicity. Moreover, cancer cells often develop drug resistance over time, which decreases the efficacy of anti-cancer drugs, including dox. In this study, we examine a macromolecular drug delivery system for its ability to specifically deliver doxorubicin to cancer cells with and without drug resistance. This drug delivery system consists of a multi-part macromolecule, which includes the following: elastin-like polypeptide (ELP), cell penetrating peptide (CPP), a cleavable linker (releasing at low pH), and a derivative of doxorubicin. ELP is thermally responsive and improves drug solubility, while the CPP mediates cellular uptake of macromolecules. We compared cytotoxicity of two doxorubicin derivatives, where one is cleavable (DOXO) and contains a pH-sensitive linker and releases dox in an acidic environment, and the other is non-cleavable (ncDox) doxorubicin. Cytotoxicity, apoptosis, cell cycle distribution and mechanism of action of these constructs were tested and compared between dox-responsive MCF-7 and dox-resistant NCI/ADR cell lines. Dox delivered by the ELP construct is comparably toxic to both sensitive and drug resistant cell lines, compared to unconjugated doxorubicin, and given the pharmacokinetic and targeting benefits conveyed by conjugation to ELP, these biopolymers have potential to overcome dox resistance in vivo.     

Low-noise and low-sensitivity filters using current-mode coupled biquads

In this paper, it is shown that by adding coupling to biquad pairs to obtain a fourth-order band-pass filter, the output thermal noise is reduced. It is shown analytically that minimum output thermal noise is obtained when the biquads are identical and the negative-feedback factor used for coupling is the same as for the minimum sensitivity to component tolerances and ambient changes. Furthermore, by optimizing the coupled biquads for maximum dynamic range, the output noise is further decreased.     

Pesticide Residues in Strawberries sampled from the Market of the Federal State of Baden-Württemberg in the Period between 2002 and 2005

Within the framework of food surveillance a total number of 593 conventionally grown strawberry samples mainly originating from Germany, Spain, Italy and Morocco were analysed for pesticide residues at the Chemisches und Veterin?runtersuchungsamt Stuttgart between 2002 and 2005 using the QuEChERS multiresidue method. Pesticide residues were detected in 98% of the samples and 93% of all strawberry samples were found to contain multiple pesticide residues. The German or EU-harmonised MRLs were exceeded by 54 strawberry samples (9%) with mepanipyrim being the most frequently violative compound. The average total concentration of pesticides per sample was 0.41 mg/kg which is similar to the average value for fruits in general, with Italian products containing the highest and the German ones the lowest residue concentrations. A general trend observed was the decline of the total pesticide residue concentration as the harvest season is progressing. For more efficient analysis, the spectrum of pesticides to be targeted in instrumental analysis was regularly being adjusted to include compounds that are relevant for strawberry samples. The information was extracted from the internet database Pesticides- Online. In total, 105 different pesticide compounds were identi- fied with 65% of the positive residue findings being < 0.05 mg/kg and 96 of them being < 0.5 mg/kg. Fungicides were much more often detected than insecticides and herbicides with cyprodinil, fludioxonil, fenhexamid, tolylfluanid and azoxystrobin being the most frequently detected compounds together accounting for 50% of the total detections. A toxicological risk assessment with the emphasis on multiple residues was performed using the results obtained for the strawberry samples.

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Zusammenfassung (Redaktion). Für den Zeitraum von 2002 bis 2005 wurden im Rahmen der Lebensmittelüberwachung insgesamt 593 Proben von konventionell angebauten Erdbeeren mit Herkunft aus Deutschland, Spanien, Italien und Marokko am Chemischen und Veterin?runtersuchungsamt Stuttgart mit Hilfe der QuEChERS-Methode auf Pestizid-Rückst?nde untersucht. Pestizid- Rückst?nde wurden in 98% dieser Proben nachgewiesen und in 93% aller Erdbeerproben wurden mehr als ein Pestizid nachgewiesen. Die von Deutschland oder der EU festgelegten H?chstmengen wurden von 54 Erdbeerproben (9%) überschritten, wobei es sich meist um das Pestizid Mepanipyrim handelte. Die durchschnittliche Konzentration an Pestiziden in den Erdbeerproben lag bei 0,41 mg/kg; grunds?tzlich entspricht dieser Pestizidgehalt den Durchschnittswerten von Obst, wobei Erdbeeren italienischer Herkunft die h?chsten und die deutscher Herkunft die niedrigsten Konzentrationen an Pestizidrückst?nden aufwiesen. Au?erdem konnte festgestellt werden, dass generell im Verlauf der Erntesaison die Konzentration an Pestizidrückst?nden in den Erdbeerproben abnimmt. Das Analyseverfahren für den Nachweis der Pestizidrückst?nde wurde auf das für die Erdbeerproben relevante Pestizidspektrum optimiert. Dazu wurden Informationen aus der Internet- Datenbank „ „Pesticides-Online“ herangezogen. Insgesamt wurden 105 verschiedene Pestizidrückst?nde in den Erdbeerproben nachgewiesen; bei 65% dieser Rückst?nde lag die Konzentration unter 0,05 mg/kg und bei 96% von ihnen unter 0,5 mg/kg. Fungizide wurden weit h?ufiger nachgewiesen als Insektizide und Herbizide; dabei waren Cyprodinil, Fludioxonil, Fenhexamid, Tolylfluanid und Azoxystrobin die am h?ufigsten nachgewiesenen Substanzen, die damit insgesamt 50% der nachgewiesenen Rückst?nde stellten. Auf der Grundlage dieser Ergebnisse wurde in Bezug auf die nachgewiesene Mehrfachbelastung der Erdbeerproben eine toxikologische Risikobewertung unternommen.

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FEM-based prediction of heat partition in dry metal cutting of AISI 1045

Thermal effects often limit the performance of cutting processes. The energy spent in cutting is almost completely converted into heat which partly flows to workpiece, chip, and tool during the process. Therefore, knowledge about this partition is valuable for the process, tool, and coolant system design or for the compensation of thermal deformations of the workpiece and machine tool. For this reason, a simulation model based on the finite element method was developed to analyze the heat partition in dry metal cutting. The model utilizes the coupled Eulerian-Lagrangian method to simulate the chip formation in orthogonal cutting and to calculate the temperature distribution within workpiece, chip, and tool. This distribution was used to compute the heat partition between workpiece, chip, and tool in dependence of relevant process parameters. Furthermore, the results were validated by orthogonal cutting experiments and summarized in a formula to calculate the rate of heat flow into the workpiece as a function of those parameters.     

Localization of airway constriction using gases of varying density and viscosity

Paired pulse stimulation increases the contractile strength of mammalian myocardium. If stimulation is discontinued the "potentiated state" takes several minutes to decay, as shown by the first contraction following resumption of stimulation. From earlier experiments it has been inferred that contractile force depends on Ca2+ released from intracellular stores rather than on an influx of Ca2+ associated with a given action potential. This view now receives support from the following findings: (1) Ni2+ and Co2+, known to inhibit Ca2+ influx during the action potential, when applied during a 2-minute rest period, are practically without effect on the strength of the first beat but strongly depress steady state contractions. (2) Caffeine, known to enhance Ca2+ efflux from and inhibit Ca2+ uptake into intracellular stores, greatly accelerates the decay of the potentiated state during a rest period. (3) Na+ -poor solution, known to inhibit Ca2+ efflux, has a strong positive inotropic effect. Paired pulse stimulation fails to increase contractile strength in Na+ -poor solution, and a rest period of many minutes is practically without effect on the amplitude of the first beat after resumption of stimulation. The results indicate that contraction is due to Ca2+ released from internal stores whose degree of filling can be altered.     

Influence of Tool Coating,Tool Material,and Cutting Speed on the Machinability of Low-Leaded Brass Alloys in Turning

The influence of tool coating and material on the machinability of low-leaded brass alloys (Pb < 0.2%) was analyzed in external turning. Carbide tools with various coatings as well as polycrystalline diamond (PCD) tools were applied. As workpiece materials, three low-leaded brass alloys CuZn38As, CuZn42, and CuZn21Si3P were used. Their machining behavior was compared to the leaded (Pb < 3.32%) brass CuZn39Pb3. CuZn38As showed the worst machinability in terms of process forces, chip formation, and workpiece quality. This is due to the high volume fraction of α-phase with face-centered cubic lattice structure. The machining problems were reduced by the use of tool coatings, in particular by a diamond-like carbon coating. The latter is characterized by high hardness, diamond-like cubic-crystalline lattice structure, and low chemical affinity to brass, which reduced friction in the secondary shear zone. CuZn42 exhibited an improved machinability compared to CuZn38As due to the lower volume fraction of α-phase. The positive influence of the tool coating was similar to CuZn38As. Main machining problem of CuZn21Si3P is tool wear because of the hard silicon-rich κ-phase. In tool life tests, PCD showed higher performance than uncoated and coated carbide tools due to its high abrasive wear resistance and low adhesion tendency.     

Recurrent network with large representational capacity

A recurrent network is proposed with the ability to bind image features into a unified surface representation within a single layer and without capacity limitations or border effects. A group of cells belonging to the same object or surface is labeled with the same activity amplitude, while cells in different groups are kept segregated due to lateral inhibition. Labeling is achieved by activity spreading through local excitatory connections. In order to prevent uncontrolled spreading, a separate network computes the intensity difference between neighboring locations and signals the presence of the surface boundary, which constrains local excitation. The quality of surface representation is not compromised due to the self-excitation. The model is also applied on gray-level images. In order to remove small, noisy regions, a feedforward network is proposed that computes the size of surfaces. Size estimation is based on the difference of dendritic inhibition in lateral excitatory and inhibitory pathways, which allows the network to selectively integrate signals only from cells with the same activity amplitude. When the output of the size estimation network is combined with the recurrent network, good segmentation results are obtained. Both networks are based on biophysically realistic mechanisms such as dendritic inhibition and multiplicative integration among different dendritic branches.     

Agonist-induced lipoxin A4 generation: Detection by a novel lipoxin A4-ELISA

Lipoxin A₄ (LXA₄) possesses potent bioactions. To facilitate its detection, an enzyme-linked immunosorbent assay (ELISA) was developed that proved sensitive and selective. Quantitation by ELISA of LXA₄ generated from cellular sources strongly correlated (r=0.99) with values obtained by high-pressure liquid chromatography (HPLC). We used this LXA₄-ELISA to examine parameters influencing LXA₄ generation from endogenous substrates during human platelet-neutrophil (PLT-PMN) interactionsin vitro. Agonist-induced LXA₄ production was clearly evident at a PLT-PMN ratio of 10∶1, and recombinant human granulocyte/monocyte colony stimulating factor-priming of PMN augmented LXA₄ generation 5–6 fold. The chemotactic peptide formylmethionyl-leucyl-phenylalanine, platelet-derived growth factor and arachidonic acid (20∶4n−6) each stimulated formation of immunoreactive LXA₄ (iLXA₄) in these co-incubations. The presence of iLXA₄ was also evaluatedin vivo in aspirin-sensitive asthmatic patients who, in a randomized, double-blind crossover design, underwent nasal lavage after they each ingested a predetermined threshold dose of aspirin or placebo. Aspirin challenge provoked statistically significant increases in iLXA₄ in each patient (P<0.005). These results validate the use of a solid-phase ELISA for detection of LXA₄. Furthermore, the use of this ELISA has allowed the first documentation of iLXA₄ formation in human subjects with aspirin-sensitive asthma following specific antigenic challenge.     

Low‐noise,low‐sensitivity,active‐RC allpole filters using impedance tapering

In this paper it is shown that active‐RC filters whose sensitivity to component tolerances can be minimized by impedance tapering, will also have low output thermal noise. It is shown that impedance tapering will also reduce output thermal noise in OTA‐C filters. Copyright © 2010 John Wiley & Sons, Ltd.