Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy.

Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds (CPA-7 [trichloronitritodiammineplatinum(IV)], WP1066 [(S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, C17H14BrN3O], and ML116 [4-benzyl-1-{thieno[2,3-d]pyrimidin-4-yl}piperidine, C18H19N3S]) in cultured rodent and human glioma cells, including GBM cancer stem cells. Our results demonstrate a potent induction of growth arrest in GBM cells after drug treatment with a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor κ light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7-derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors.

Chlorine dioxide is a size-selective antimicrobial agent.

BACKGROUND / AIMS: ClO2, the so-called "ideal biocide", could also be applied as an antiseptic if it was understood why the solution killing microbes rapidly does not cause any harm to humans or to animals. Our aim was to find the source of that selectivity by studying its reaction-diffusion mechanism both theoretically and experimentally. METHODS: ClO2 permeation measurements through protein membranes were performed and the time delay of ClO2 transport due to reaction and diffusion was determined. To calculate ClO2 penetration depths and estimate bacterial killing times, approximate solutions of the reaction-diffusion equation were derived. In these calculations evaporation rates of ClO2 were also measured and taken into account. RESULTS: The rate law of the reaction-diffusion model predicts that the killing time is proportional to the square of the characteristic size (e.g. diameter) of a body, thus, small ones will be killed extremely fast. For example, the killing time for a bacterium is on the order of milliseconds in a 300 ppm ClO2 solution. Thus, a few minutes of contact time (limited by the volatility of ClO2) is quite enough to kill all bacteria, but short enough to keep ClO2 penetration into the living tissues of a greater organism safely below 0.1 mm, minimizing cytotoxic effects when applying it as an antiseptic. Additional properties of ClO2, advantageous for an antiseptic, are also discussed. Most importantly, that bacteria are not able to develop resistance against ClO2 as it reacts with biological thiols which play a vital role in all living organisms. CONCLUSION: Selectivity of ClO2 between humans and bacteria is based not on their different biochemistry, but on their different size. We hope initiating clinical applications of this promising local antiseptic.

Study on inactivation kinetics of hepatitis A virus and enteroviruses with peracetic acid and chlorine. New ICC/PCR method to assess disinfection effectiveness.

The virucidal activity of chlorine-compounds was studied using hepatitis A virus (HAV) and Poliovirus 2 and comparing the disinfectant efficiency of peracetic acid. HAV presented a higher resistance to HClO than Poliovirus did. With ClO2 the inactivation times of HAV were markedly shorter. A comparison between these data and those resulting from the kinetics with peracetic acid (PA) showed that PA is less effective than chlorine. As a preliminary to future research, the PCR-test integrated with cell-cultures was experimentally introduced for a quick evaluation of the HAV-infectiveness, with the aim of possible application in the field of disinfection and of viruses-isolation from environmental and food samples.

The safety and intraocular pressure-lowering efficacy of brimonidine tartrate 0.15% preserved with polyquaternium-1.

PURPOSE: The safety and intraocular pressure (IOP)-lowering efficacy of brimonidine tartrate 0.15% preserved with polyquaternium-1 were evaluated and compared with brimonidine tartrate 0.15% preserved with chlorine dioxide in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). DESIGN: Randomized, double-masked, parallel group, multicenter equivalence study. PARTICIPANTS: Eight hundred forty-two patients randomized to the study treatments. METHODS: Patients with OAG or OHT and with qualifying IOP (22-36 mmHg at 8 am on 2 eligibility visits after an appropriate washout period from previous treatment) were assigned randomly to either brimonidine tartrate 0.15% preserved with polyquaternium-1 (brimonidine PQ) or brimonidine tartrate 0.15% preserved with chlorine dioxide (brimonidine P) dosed 3 times daily and were followed up for 6 months. Approximately one half of the study sites continued to follow up their patients for an additional 6 months to obtain longer-term safety data. RESULTS: Brimonidine PQ produced statistically significant and clinically relevant reductions from baseline ranging from 4.3 to 6.5 mmHg, which were statistically and clinically equivalent to brimonidine P at all 18 visit days and times. No safety concerns were identified based on an assessment of ocular and cardiovascular parameters. Patient discontinuations resulting from adverse events were similar for both groups and most of these were a result of signs or symptoms of ocular allergic reaction. CONCLUSIONS: Brimonidine PQ is equivalent in IOP-lowering efficacy and safety to brimonidine P.

Hydroxylated PCBs and other chlorinated phenolic compounds in lake trout (Salvelinus namaycush) blood plasma from the Great Lakes region.

Recently, there has been an increase in studies focusing on an emerging class of organic contaminants, hydroxylated PCBs (OH-PCBs) and chlorinated phenolic compounds (CPCs) in the environment, particularly in northern regions of Europe and Canada. Since information for fish from the Great Lakes are scarce, we determined the blood plasma concentrations of OH-PCB congeners, pentachlorophenol (PCP), 2,3,4,5-tetrachlorophenol (TCP), and 4-hydroxyheptachlorostyrene (4-OH-HpCS) for lake trout (Savelinus namaycush) collected from two of the Great Lakes, Lake Ontario and Lake Superior, and two regional lakes, Lake Champlain and Lake Opeongo. PCP was the dominant CPC in lake trout (105-658 pg/g of plasma). Detectable concentrations of 2,3,4,5-TCP and 4-OH-HpCS were found in all lake trout (2.6-101 and 0.4-27 pg/g, respectively). Highest concentrations were found in trout from Lake Ontario and Lake Superior. Sixteen OH-PCBs were quantified, with 4-OH-CB187 having the highest concentration in all samples (10-173 pg/g of plasma). Unexpectedly, highly chlorinated OH-PCBs such as 4'-OH-CB199 (mean 21.4 and 74.4 pg/g), 4,4'-diOH-CB202 (18.3 and 27.7 pg/g), and 4'-OH-CB208 (24.5 and 34.7 pg/g) were found in lake trout from Lake Ontario and Lake Superior, respectively. Future studies to delineate the sources and impacts of CPCs in the Great Lakes catchment are needed.

The development and testing of a dermal exposure system for pharmacokinetic studies of administered and ambient water contaminants.

INTRODUCTION: In order to investigate the pharmacokinetics of water-borne chemicals while eliminating exposures by other routes, a dermal exposure system was developed to expose the hand and forearm of human subjects. METHODS: The goal was, primarily, to study the dermal pharmacokinetics of methyl tertiary butyl ether (MTBE), a water contaminant, and, secondarily, the ambient disinfection byproducts (DBPs). MTBE is used as a fuel oxygenate and DBPs result from chlorination of drinking water. The DBPs measured in the water and blood of the subjects were chloroform, bromodichloromethane, and dibromochloromethane. The dermal exposure system was constructed of inert and impervious materials. The interface between the glass and Teflon exposure tank and the subject was custom-made of clear Tedlar (polyvinylfluoride) so that the depth of the arm in the media could be monitored. RESULTS: Sampling of the water concentration of the test chemical, MTBE, demonstrated stability over the duration of the exposure. A temperature loss of about 1.5 degrees C occurred over the course of the 1-h exposure. Blood concentrations taken from 14 human subjects before, during, and after the 1-h exposure demonstrated that measurable MTBE and DBPs were absorbed. DISCUSSION: This system has the advantages of maintaining contaminant concentration and exposing an anatomically distinct body region, and the convenience of blood sampling.

Polychlorinated naphthalene levels, distribution, and biomagnification in a benthic food chain in the Baltic Sea.

The scientific literature contains little information regarding bioaccumulation and biomagnification of polychlorinated naphthalenes (PCNs) in food webs. Here we present new information on the food chain transfer of PCNs within a food chain in a subarctic environment PCNs (tetra- to hepta-chloro congeners) were measured in surface sediments and in a marine benthic food chain, comprising amphipods, isopods, and fourhorned sculpins. Samples were collected from five locations in the Gulf of Bothnia, northern Baltic Sea. PCN concentrations in the sediments were similar to background levels determined previously in sediments from the northern hemisphere. Measurement of the carbon content of the sediments allowed the calculation of biota to sediment accumulation factors (BSAFs). Tetra- and penta-CNs exhibited BSAF values greater than one, while BSAFs for the more chlorinated PCNs were less than one. This suggests more efficient assimilation, by amphipods, of the less chlorinated PCNs. A decrease in sigmaPCN concentrations from the lowest to the highest trophic level was demonstrated (amphipods: 10-69 ng/g lw, isopods: 3.9-16 ng/g lw; fourhorned sculpins: 0.54-1.5 ng/g lw). Biomagnification factors (BMFs) were calculated based on the concentrations of the congeners. These indicated that a few congeners biomagnified significantly: the highest BMFs (0.09-1.4) were found for 2,3,6,7-substituted congeners and those lacking adjacent hydrogen-substituted carbon atoms.

Levels of short and medium chain length polychlorinated n-alkanes in environmental samples from selected industrial areas in England and Wales.

Electron capture or negative ion chemical ionisation gas chromatography-mass spectrometry was employed to measure concentrations of short and medium chain length polychlorinated n-alkanes extracted from samples of water, river sediment, benthos, fish, soil, digested sewage and earthworms. Analysis of samples from 20 aquatic and eight agricultural sites indicated that short and medium chain length polychlorinated alkanes were present in the following concentration ranges: sediment < 0.2-65.1 mg/kg dry weight, water < 0.1-1.7 micrograms/l, fish < 0.1-5.2 mg/kg wet weight, benthos < 0.05-0.8 mg/kg wet weight, digested sewage 1.8-93.1 mg/kg dry weight, soil < 0.1 mg/kg dry weight, and earthworms < 0.1-1.7 mg/kg wet weight. It is clear from this study that these compounds are widely distributed in the UK environment, although it is not yet possible to fully assess the risks posed to either wildlife or humans by their continued use. Further study of these compounds is indicated.

Uptake of chlorination disinfection by-products; a review and a discussion of its implications for exposure assessment in epidemiological studies.

We have reviewed the relevant issues in the exposure assessment of disinfection by-products (DBPs) of chlorination for epidemiological and health risk assessment. Various DBPs can be detected in drinking water and swimming pools, and the reported levels show a considerable range, but were generally below the current health standard for total trihalomethanes (TTHMs) (100 microg/l). Relatively little information is available on the correlation between the various DBPs in drinking water and in swimming pools. Chloroform was generally, but not always, the most predominant DBP. In epidemiological studies, TTHM levels have been used as an indicator for total DBP load, even though TTHM levels do not always correlate well with individual DPBs. Factors such as residence time, temperature, pH, organic content, including humic and fulvic acid and bromide levels affect the composition and levels of DBPs. Although there are biomarkers of DBPs, mainly for chloroform and more recently for the other volatile trihalomethanes (THMs) and the nonvolatile haloacetic acids (HAAs) such as trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA), they have not been used in epidemiological studies. The THMs have been measured in exhaled breath and serum, while the HAAs have been measured in urine. These biomarkers have been useful to estimate the actual uptake of the DBPs and the relative contribution of various exposure routes. Physiologically based pharmacokinetic (PBPK) models exist for, e.g. chloroform, but their main target organs are the kidney and liver and they have not been used in epidemiological studies. Tap water ingestion, showering, bathing, swimming, boiling water and dishwashing are all activities that have been associated with the uptake of DBPs, and considerable variation in these activities has been observed between people. No studies have reported on the correlation between human uptake of DBPs and water-zone mean estimates, but various studies found a good correlation between THM concentrations in exhaled breath and THM concentrations in water during showering and swimming. In general exposure assessment in epidemiological studies has been limited which complicates the interpretation. These findings have implications for epidemiological studies, particularly with reference to Berkson and classical error type models, study power, attenuation and precision of health-risk estimates and study efficiency. Recommendations are made for further areas of study.