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.     

Ventricular arrhythmias in myocardial hypertrophy of various origins

BACKGROUND: Elevated serum sialic acids are associated with increased cardiovascular mortality, but sialic acid levels have not been studied in cardiac tissue. METHODS: Myocardial samples were obtained at the time of transplantation from 23 patients (age 54 +/- 12 years) with heart failure secondary to ischemic heart disease and 16 patients (age 51 +/- 7 years) with idiopathic dilated cardiomyopathy (DCM). A control group comprised postmortem samples obtained from 14 patients (age 70 +/- 5 years) who died of non-cardiovascular causes. Ventricular sialylation was quantitated using the sialic acid-specific lectins Maackia amurensis agglutinin (MAA) and Sambucus nigra agglutinin (SNA) using a chemiluminescence assay. Results are expressed as the percentage (+/-standard error of the mean) of the binding of lectin to a standardized control sample of human myocardium. RESULTS: Ventricular sialylation recognized by MAA was 55 +/- 7% in patients with heart failure secondary to ischemic heart disease compared with 26 +/- 7% for DCM (p = 0.006) and 32 +/- 8% for controls (p = 0.04), and that recognized by SNA was 69 +/- 7% in patients with heart failure secondary to ischemic heart disease compared with 42 +/- 6% for DCM (p = 0.006) and 38 +/- 7% for controls (p = 0.006). No significant difference in ventricular sialylation was observed between patients with DCM and controls. CONCLUSION: Myocardial levels of sialic acids are significantly increased in patients with heart failure secondary to ischemic heart disease compared with patients with idiopathic dilated cardiomyopathy and controls. Our findings are important in view of recent reports of an association between serum sialic acid concentration and cardiovascular mortality and require further investigation.     

Acrylonitrile-based copolymers: Synthesis,characterization, and formation of ultrafiltration membranes utilized for the immobilization of proteins

Various high molecular weight copolymers of acrylonitrile and a vinyl comonomer containing an aryl amine, a pyridine, or an aliphatic hydroxyl group were synthesized via slurry polymerization techniques so as to contain from 1 to 15 mol % functional comonomer. The comonomer content was quantitated by ultraviolet absorbance, base titration of acid polymer salts, and/or relative chemical reactivity with trichloro-s-triazine. Thin films were cast from copolymer solutions, coagulated into unsupported ultrafiltration membrances, and characterized with respect to both water permeability and pore size distribution. Analysis by size exclusion chromatography of the membrane permeate of a pool of dextran fractions yielded a continuous distribution curve for membrane pore size over the range 1.5 to 70 nm. The ultrafiltration membranes were used for protein immobilization after appropriate chemical activation. The three distinct types of functional copolymers gave comparable results for α-chymotrypsin, with protein weight loadings of 6–12% and 40–65% retention of enzymatic specific activity.     

Myxomas of the mandible and maxilla

Two cases of congenital absence of a cervical vertebral pedicle are reported. This condition includes hypoplasia of the ipsilateral posterior arch and may predispose to spinal cord injury. The radiographic and computed tomography (CT) findings are reviewed, and the importance of the ipsilateral oblique radiographic view and of CT in diagnosis is stressed.     

Convolutional solutions of partial difference equations

A significant part of the theory of one-dimensional linear shift-invariant systems is based on the concept of weighting function (or impulse response): the output is the convolution of the weighting function with the input. This paper introduces the concept of linear translation-invariant systems and uses this notion in studying impulse response, z-transforms, and transfer functions for multidimensional systems.     

Categorical scaling of time: Implications for clock-counter models.

Pigeons partitioned time into three intervals. Responses to one key could be reinforced after a short time, to a second key after an intermediate time, and to a third key after a long time. The values of the short, intermediate, and long times and the proportion of trials ending with reinforcement were varied. Absolute and relative response rates on each key were an orderly function of time and showed approximately proportional changes with changes in the interval values, consistent with Weber's law, Gibbon's (1977) scalar expectancy theory, and Killeen and Fetterman's (1988) behavioral theory of timing (BeT). Standard deviations of the times at which subjects switched between successive keys increased more slowly within a condition than across conditions, as predicted by BeT. Increases and decreases in reinforcement probability produced both transient and longer lasting changes in timing behavior, once again, in accord with predictions of BeT. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Porphyrin fluorescence in plasma of various types of porphyria

Fluorescence spectra of plasma porphyrin were measured in 6 patients with the acute intermittent porphyria (AIP), 30 patients with variegate porphyria (PV), 2 patients with hereditary coproporphyria, 2 patients with porphyria cutanea tarda, and in 6 patients with erythropoietic protoporphyria (EPP). It was found that the excitation and emission wavelengths at which maximum fluorescence is seen may help to diagnose and differentiate PV and EPP. In patients with AIP spectrum characteristic for porphyria of such a type was noted in all patients during the attack of disease and in only 33% of patients in remission. Fluorescence spectrum was normal in asymptomatic family members. In variegate porphyria spectrum with a characteristic maximum of fluorescence was noted in all patients during an attack and remission, and 62% of the asymptomatic family members.     

Self-calibration based on invariant view recognition: Dynamic approach to navigation

We extend a dynamic approach of behavior generation to the representation of spatial information. Two levels of dynamics integrate dead-reckoning, dominant far from home bases, and piloting, dominant near home bases. When the view-based piloting system recognizes a home base, visual place information recalibrates the dead-reckoning system, inverting the hierarchical ordering of the two dynamic levels by time scale inversion. Reference views taken at discrete home bases are recognized invariantly under rotation of views. This process yields compass information. Continuous translational information is obtained as a neural place representation built from view correlations with a scattered set of local views. This self-calibrating cognitive map couples into a dynamics of heading direction integrating the behaviors of obstacle avoidance and target acquisition. Targets can be designated in terms of the cognitive map. We demonstrate the dynamical model in simulation.