Phase I evaluation of low-dose suramin as chemosensitizer of doxorubicin in dogs with naturally occurring cancers

BACKGROUND: Low and nontoxic concentrations (10-50 microM) of suramin, which is a nonspecific inhibitor of multiple growth factors, including fibroblast growth factors, enhances the activities of cytotoxic chemotherapeutic agents, such as doxorubicin and paclitaxel, both in vitro and in vivo. Suramin has not been evaluated as a chemosensitizing agent in dogs with cancer. HYPOTHESIS: Nontoxic suramin can be used safely as a chemosensitizer in dogs. ANIMALS: Sixteen dogs of various breeds with measurable tumors were treated; 1 dog that had undergone amputation for osteosarcoma received adjuvant therapy. METHODS: The dogs received 53 courses of treatment with suramin in combination with doxorubicin. The suramin dosage was 6.75 mg/kg IV 3 h before standard doxorubicin administration every 2 weeks. The pharmacokinetics and clinical efficacy were determined. RESULTS: The pharmacokinetics of low-dose suramin followed a 2-compartment model with half-lives of 2 h and 6 days. The distribution volume was a 0.34 +/- 0.12 L/kg, and clearance was 1.86 +/- 0.76 mL/kg/h. During the time interval that doxorubicin was present at therapeutically active concentrations (ie, from the start of infusion to 24 hours), the plasma concentrations were maintained within 20% of the target range (8-60 microM) in 72% of the treatments. The toxicity of the suramin/doxorubicin combination was mild and comparable to the toxicity expected for doxorubicin monotherapy. Objective partial responses were observed in 2 out of 16 evaluable dogs (13%). All 5 dogs that previously received doxorubicin showed improved responses to the suramin/doxorubicin combination. CONCLUSIONS AND CLINICAL IMPORTANCE: A fixed, low-dose suramin regimen yields the desired target plasma concentrations in most dogs, and appears to enhance the activity of doxorubicin without enhancing toxicity.     

Hierarchical Tendencies of Capital Markets Among International Financial Centers

Abstract The dramatic evolution of global finance in the last three decades has seen intensified competition among the world's major cities to become prominent control centers of global financial flows. This paper examines the spatial organization and evolution of capital markets in forty‐three world cities from 1980 to 1998. It finds evidence of the strengthening of hierarchical tendencies among world financial and capital cities as they search for ways to differentiate between themselves through financial concentration and productivity. The results also indicate a trend towards the dominance of London and New York in this financial hierarchy, and that top tier cities tend to be characterized by significantly lower levels of market and share concentrations, share trading value, and risks. Finally, important differences in ownership patterns between the capital markets are detected for the top cities of the hierarchy.     

Effect of steel-making slag as a soil amendment on arsenic uptake by radish (Raphanus sativa L.) in an upland soil

The steel-making slag (SMS), a by-product of steel manufacturing process with an alkaline pH (11–12) and high amount of iron (Fe) and calcium (Ca) oxides, was used to reduce arsenic (As) phytoextractability. The by-product was selected as an alternative to commercial Fe oxides, which can decrease plant uptake, but they are expensive if used as amendments of contaminated arable soils. SMS was applied at rates 0, 2, 4, and 8 Mg ha⁻¹ to an As (1 N HCl-extractable As 25 mg kg⁻¹) contaminated soil prepared by mixing non-contaminated soil and mine tailings and cropped to radish (Raphanus sativa L.) seeding. Calcium hydroxide (Ca(OH)₂), a common liming material in Korea, was applied at the same rates for comparison. Steel-making slag more effectively suppressed radish As uptake and increased yield than Ca(OH)₂ due to stronger As immobilization because it significantly increased extractable Fe concentration and decreased extractable As. The SMS-treated soil showed an apparent increase in As chemisorbed by Fe and Al oxides and hydroxides of surface soil, As associated at the Fe and Al oxides and hydroxides of internal surfaces of soil aggregates, and Ca-associated As. The steel-making slag can be a good soil amendment to suppress As phytoextractability and improve nutrient balance in As-contaminated soil.     

Prognostic value of mitral annular systolic plane excursion and tricuspid annular plane systolic excursion in cats with hypertrophic cardiomyopathy

Introduction

Hypertrophic cardiomyopathy (HCM) has a variable prognosis; left atrial size, presence of clinical signs and left ventricular systolic function have been shown to predict outcomes. Mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) assess longitudinal ventricular systolic function and are decreased in cats with HCM. The aim of the study was to ascertain whether MAPSE and TAPSE have prognostic value in HCM and if cats with pleural effusion have lower MAPSE and TAPSE than cats with pulmonary oedema.

A practical method for creating a digital topographic surface for ecological plots using ground-based measurements

Context

Digital elevation models (DEMs) are widely used in landscape ecology to link topographic features with biotic and abiotic factors. However, to date, high-resolution, affordable, and easy to process elevation data are not available for many regions.

Objectives

Here we propose a field-based method for efficiently and inexpensively collecting or analysing already existing slope data. We compare the field approach to two commonly used remote sensing techniques to test the similarly of the DEMs using different methods.

Methods

To provide an ecological example of the method, we selected four 1-ha forest plots and compared the DEM generated by using our field method with those derived from: (i) coarse (~ 30 m pixel) data from the Shuttle Radar Topography Mission and (ii) high-resolution (~ 1 m) data from Light Detection and Ranging devices (LiDAR).

Results

Field- and LiDAR-based DEMs showed strong concordance in two of the four sites. The sites where field-based and LiDAR DEMs substantially differed, suffered from relatively few LiDAR sampling points. Diagnostic tests suggested that the field–LiDAR discrepancy was due to dense over-storey vegetation, which reduced LiDAR’s accuracy due to a failure to penetrate the forest canopy adequately in some areas.

Conclusions

Our method has the advantage of being quick and cheap to collect yet able to produce small-scale (plot-scale) DEMs of high quality. By using the R-code we have provided, ecologists will be able to use slope data (collected using any means) to generate a DEM without the need of specific skills in spatial sciences.

     

Electron diffraction of frozen, hydrated protein crystals

High-resolution electron diffraction patterns have been obtained from frozen, hydrated catalase crystals to demonstrate the feasibility of using a frozen specimen hydration technique. The use of frozen specimens to maintain the hydration of complex biological structures has certain advantages over previously developed liquid hydration techniques.     

Targeted Large-Scale Genome Mining and Candidate Prioritization for Natural Product Discovery

Large-scale genome-mining analyses have identified an enormous number of cryptic biosynthetic gene clusters (BGCs) as a great source of novel bioactive natural products. Given the sheer number of natural product (NP) candidates, effective strategies and computational methods are keys to choosing appropriate BGCs for further NP characterization and production. This review discusses genomics-based approaches for prioritizing candidate BGCs extracted from large-scale genomic data, by highlighting studies that have successfully produced compounds with high chemical novelty, novel biosynthesis pathway, and potent bioactivities. We group these studies based on their BGC-prioritization logics: detecting presence of resistance genes, use of phylogenomics analysis as a guide, and targeting for specific chemical structures. We also briefly comment on the different bioinformatics tools used in the field and examine practical considerations when employing a large-scale genome mining study.