Polymeric prodrugs of mitomycin C designed for tumour tropism and sustained activation

Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.     

Lithographic and pattern transfer of a novel deep-UV photoresist: ARCH2

We have developed a novel chemically amplified deep-UV photoresist called ARCH2. ARCH2 displays a resolution of<0.23μm with a DOF of 1.0μm at 0.25μm. This material also displays superior time delay stability (>8 hours). The post exposure bake (PEB) temperature was varied from 100°C to 120°C and the PEB time was varied from 60s to 180s. This had very little effect on the CD of the resist profiles. Preliminary etching experiments in a conventional reactive ion etcher were then carried out using CF₄ to etch TiN. In these experiments the ARCH2 etched at a similar rate as conventional Novolac.     

In vitro displacement by rat serum of adsorbed radiolabeled poloxamer and poloxamine copolymers from model and biodegradable nanospheres

Poloxamer 407 and poloxamine 908 have been used by many research groups to modify the surface of both model latex and biodegradable nanospheres, thereby producing nanospheres that have shown reduced protein adsorption in vitro and extended circulation times in vivo. A potential limitation of such systems is the desorption of the copolymer coating layer. We describe a two-stage process to radiolabel poloxamer 407 and poloxamine 908 that has facilitated an investigation into this potential desorption, in vitro. The first stage of the labeling procedure involved the substitution of the terminal hydroxyl groups in each poly(ethylene oxide) (PEO) chain of poloxamer 407 and poloxamine 908 with an amino group. The aminated copolymers were then radiolabeled with 125Iodine Bolton-Hunter reagent. The efficiency of labeling was calculated to be approximately 20% for the tetramine poloxamine 908 and approximately 33% for the diamine poloxamer 407. Remaining free amino groups were then either acetylated, using acetic anhydride, or left in the free amino form. Covalent linkage of the radiolabel to the copolymer was confirmed by nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. The stability of the link between radiolabel and copolymer to hydrolysis was also confirmed; <4% loss of radiolabel occurred from poloxamine 908 after incubation in phosphate-buffered saline (PBS) at 37 degrees C for 8 days. The radiolabeled copolymers (with the free amino groups acetylated) were then used in experiments that have given the first direct evidence that adsorbed copolymers can be displaced by serum proteins in significant amounts from the surface of model and biodegradable nanospheres. The displacement was highly dependent on copolymer-nanosphere compatibility, with up to 78% of 125I tetramine poloxamine 908 being displaced from poly(lactide-co-glycolide) (PLGA) nanospheres in 24 h, compared with 20% displacement of 125I tetramine poloxamine 908 in 24 h from polystyrene nanospheres. These results have direct implication for the future design of drug delivery systems based on coated nanospheres.     

Is subject selection a source of subtle artifact in psychotherapy research?

Identifies and discusses some subtle experimental artifacts that may be generated by common procedures for the selection of patients to serve as Ss in psychotherapy research. Clinical observations derived from a project investigating Time-Limited Dynamic Psychotherapy are used as examples of potential artifacts in both the recruitment and screening phases of the selection process. It is proposed that the activities of patient recruitment and screening ought to become separate foci of research attention in their own right, so that questions of extratherapeutic motives, expectancies, and role can be addressed more systematically than is possible with informal clinical observation. Investigators should eschew any avoidable intrusions upon the naturalistic help-seeking and help-giving activities of patients and therapists. It is concluded that there should be some attempt to standardize recruitment and screening activities across research projects and settings. (35 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ausmauerungen in chemisch beanspruchten Behältern und Apparaten

Brick-lining of Vessels and Process Units for Chemical Service. Bricklinings are used as an internal protection in chemically attacked vessels and process units. They generally consist of an impermeable membrane and the masonry itself. Materials of the single parts of the lining are described and guidelines for chosing materials and designing the lining are given. After some details of installing the lining typical examples of bricklined vessels and process units are given.     

Geschichtliche Entwicklung und aktuelle Praxis der Probebelastung — Teil 2: Entwicklung von Normen und heutige Anwendung

Im Zuge des massenhaften Einsatzes von Probebelastungen im 19. und zu Beginn des 20. Jahrhunderts zeigte sich die Notwendigkeit, deren Planung, Durchführung und Auswertung durch allgemeine Richtlinien und Normen zu stützen. Im Beitrag wird das Ringen um erste zaghafte Festlegungen beschrieben, die im Laufe der Jahre immer konkreter zu einer verwendbaren Handlungsgrundlage ausgearbeitet wurden. Unter Kritikern blieb jedoch immer die Frage über die Sicherheit und vor allem die Aussagekraft von Belastungsversuchen auf der Grundlage der verwendeten Bewertungskriterien offen. Mit der Weiterentwicklung der Berechnungsverfahren auch durch den Einsatz von Computertechnik wurden Probebelastungen von Neubauten ab den 1970‐er Jahren entbehrlich. Für auffällig gewordene bestehende Tragwerke stellt die Probebelastung jedoch auch heute noch eine — und manchmal die einzige — Methode zum Nachweis einer ausreichenden Tragfähigkeit dar. Die hierfür angewendete moderne Belastungs‐ und Messtechnologie bietet jedoch im Unterschied zur traditionellen Vorgehensweise ein hohes Maß an Sicherheit und Informationsgewinn. Historical Development and current practise of load tests in situ — Part 2: Development of standards and current practise. Because of the large demand and use of load testing in the 19th and at the beginning of the 20th century, there was the necessity to standardise the planning, execution and analysis in general guidelines and codes. This article describes the struggling and first tentative specification, which were more and more specified to an useful basis in the following years. The used criterions for the assessment have often been a reason for critics on the value and the safety of loading tests. The further development of calculation methods especially the computer technology made the load testing of new structures superfluous in the 1970s. But for existing structures loading tests are today often a — and sometimes the only — method to proof a sufficient load bearing capacity. The today used modern loading‐ and measuring technology provides, in contrast to the traditional method, a high degree of safety and structural information.     

Attenuation of cochlear damage from noise trauma by an iron chelator, a free radical scavenger and glial cell line-derived neurotrophic factor in vivo

Tissue injury by reactive oxygen species (ROS) may play a role in noise-induced hearing loss (NIHL). Since iron is involved in ROS generation, we studied if an iron chelator, deferoxamine mesylate (DFO), alone or in combination with mannitol, a hydroxyl scavenger and weak iron chelator, attenuates NIHL. Further, we investigated if glial cell line-derived neurotrophic factor (GDNF) provides additive or synergistic protection of the cochlea from acoustic trauma when given together with DFO and mannitol. Pigmented female guinea pigs were exposed to noise (4 kHz octave band, 115 dB SPL, 5 h). One hour before, immediately after, and 5 h after noise exposure, subjects received an injection of 5 ml saline/kg (control, group I), 100 mg DFO/kg (group II), 15 mg mannitol/kg (group III), or both DFO and mannitol (group IV and V). Animals in group V underwent implantation of an osmotic pump filled with GDNF (100 ng/ml) in the left ear 4 days before noise. Each treatment afforded some protection from noise damage. Group I showed significantly greater outer hair cell loss and threshold shifts at two or more frequencies compared to groups II through V. GDNF provided an additive functional, but not morphological, protection with DFO and mannitol. These findings indicate that iron chelators can attenuate NIHL, as do ROS scavengers, supporting the notion that ROS generation plays a role in NIHL. Additional functional protection provided with GDNF suggests that GDNF may attenuate noise-induced cochlear damage through a mechanism that is additive with antioxidants.     

Surface condition monitoring of unalloyed steel sheet by measuring ferromagnetic properties and using multi-parameter data analysis

Initial investigations into coated steel sheets were conductted to verify whether sample- and batch-independent classification of surface condition can be achieved with multi-inductive data acquisition and multivariate data analysis without using a priori information. Using an ‘integrated sensor’ - a multi-inductive sensor - it is possible to obtain parameters of eddy currents, hysteresis and noise voltage with PC control. These parameters are the input values of multivariate data analysis.     

Energy metabolism in cochlear outer hair cells in vitro

ATP levels in outer hair cells in vitro were measured using the luciferin/luciferase method. Hair cells were isolated from the guinea pig cochlea and maintained for 2 h in a balanced salt solution with 5.5 mM glucose. Ten to 20 cells sufficed for a robust and reproducible luminescence signal, indicating an ATP content of 6.2 +/- 0.4 fmol/cell. This ATP concentration is similar to that found in cultures of other cell types and agrees well with the classical measurements in freeze-dried preparations. The ATP levels were reduced by the following treatments: (1) the omission of glucose in the culture medium lowered ATP levels by 28%; (2) the inhibition of glycolysis by 2-deoxyglucose lowered ATP levels by 66%; (3) the inhibition of oxidative phosphorylation by carbonyl cyanide m-chlorophenylhydrazine (CCCP) lowered ATP levels by 75%, and (4) the inhibition of both pathways reduced the ATP content to non-detectable levels. Acetoacetate was able to restore ATP levels partially when glycolysis was inhibited. These results suggest that (1) the major pathway of ATP synthesis in outer hair cells is the aerobic metabolism of glucose; (2) endogenous energy stores (e.g. glycogen) can maintain ATP levels in the absence of glucose; and (3) ketone bodies may be alternative energy sources.