Rapid characterization of mutagenic aromatic amines in energy-related materials by short column liquid chromatography with electrochemical detection

A liquid Chromatograph equipped with a short (3 cm) reverse phase column and electrochemical detector was used to characterize aromatic amines in shale oil, synthetic oil, and coal gasification streams. Five major peaks were produced from each sample mixture. The composition of the peaks was determined by high performance liquid chromatography with a long (25 cm) reverse phase column and by gas chromatography/mass spectrometry. Amines in the various peaks included aminonaphthalenes, aminobiphenyls, aminofluorenes, and aminophenanthrenes plus aminoanthracenes. The concentration of aminofluorenes, and aminophenanthrenes plus aminoanthracenes correlated with relative mutagenicity of the base fraction from the oils or tars. The levels of 2- and 3-ringed aromatic amines from shale oil and oil from the Great Plains commercial coal gasification plan were 24 and 184 g/g tar, respectively, while the respective mutagenicities were 8 and 214 revertants/g base fraction. This technique has the advantages of high sensitivity and rapid analysis, and could be used to screen for the presence of mutagens in synthetic fuel samples.     

Medikamentöse Schmerztherapie—ein großes Repertoire an Möglichkeiten

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Effect of dipyridamole on fluorodeoxyuridine cytotoxicity in vitro and in cancer patients

Summary Dipyridamole (DP) has previously been studied both in vitro and in vivo in combination with various antimetabolites, including methotrexate and 5-fluorouracil (5FU). We evaluated in vitro and clinically the effects of adding DP to fluorodeoxyuridine (FUDR) in colorectal cancer. Using a human colony-forming assay, we observed that 0.05 M DP increased the cytotoxicity of FUDR by a median of 33.5-fold vs 1.5-fold for 5FU against human colon-cancer cell lines. The mechanism of the DP-enhanced antitumor activity of FUDR is not completely understood but appears to be related to a profound inhibition by DP of thymidine accumulation in and FUDR efflux from colon-cancer cell lines. On the basis of these in vitro results, 28 patients with metastatic colon cancer were entered in a clinical trial of monthly courses of 0.1 mg/kg FUDR daily for 14 days and 75 mg oral DP 5 times daily for 14 days starting on the 3rd day of continuous i.v. FUDR infusion. The pharmacokinetics of DP was studied in three patients; the results showed that 98% of total serum DP was protein-bound and that free DP levels were significantly lower than the concentrations necessary for the expected in vitro DP/FUDR modulation. Treatment was well tolerated, with only 12 patients developing mild to moderate toxicity. Of 27 evaluable patients, 4 achieved a partial response that lasted 2, 3, 5, and 6+ months. This relatively low response rate (15%), which is similar to that achieved with FUDR alone, may be explained by the low steady-state plasma concentrations of free DP achieved in our patients. Other means of DP administration, such as i.v., i.a., and i.p. injection, may be required to achieve free DP concentrations necessary for successful biochemical modulation of FUDR in patients.Supported in part by grants CA17094, CA23074, and CA39629 from the National Institutes of Health, Bethesda, Md 20205, and a grant from the Arizona Chronic Disease Commission. HSG is a recipient of an American Cancer Society Career Development Award     

Localization of SNARE proteins and secretory organelle proteins in astrocytes in vitro and in situ

Astrocytes are capable of regulated release of messenger molecules. Astrocytes cultured from new born rodent brain express a variety of classical presynaptic proteins. We investigated the question whether the capability to express synaptic proteins in culture was a feature only of immature astrocytes, and whether these proteins were also expressed by astrocytes in situ. Experiments were performed with transgenic mice expressing the enhanced green fluorescent protein under the control of the human glial fibrillary acidic protein promoter. Using double fluorescence and astrocytes cultured from 1 to 16 day-old animals we show that the astrocytic expression of synaptic proteins in culture is invariant of the age of donor animals. Culturing can induce the astrocytic expression of specific synaptic proteins such as SV2, synaptophysin and SNAP-25. Astrocytes in brain sections of 1-16 day-old animals revealed a punctuate immunofluorescence for secretory carrier membrane protein (SCAMP), SNAP-23, synaptobrevin II, and cellubrevin, to a minor extent for SNAP-25 and synaptophysin, and none for SV2. Our results demonstrate that cultured astrocytes express synaptic proteins not present in situ. Nevertheless, astrocytic organelles in situ are equipped with molecules that could be involved in regulated exocytosis of messenger substances.     

Detailed gene copy number and RNA expression analysis of the 17q12-23 region in primary breast cancers

Chromosome region 17q12-23 commonly shows an increase in DNA copy number in breast cancers, suggesting that several oncogenes are located at this site. We performed a high-resolution expression array and comparative genomic hybridization analysis of genes mapped to the entire 17q12-23 region, to identify novel candidate oncogenes. We identified 24 genes that showed significant overexpression in breast cancers with gain of 17q12-23, compared to cancers without gain. These genes included previously identified oncogenes, together with several novel candidate oncogenes. FISH analysis using specific gene probes hybridized to tissue arrays confirmed the underlying amplification of overexpressed genes. This high-resolution analysis of the 17q12-23 region indicates that several established and novel candidate oncogenes, including a Wnt-signaling pathway member, are amplified and overexpressed within individual primary breast cancer samples. We were also able to confirm the presence of two apparently separate and reciprocally amplified groups of genes within this region. Investigation of these genes and their functional interactions will facilitate our understanding of breast oncogenesis and optimal management of this disease.     

Role of RNA and protein in memory storage: A review

The literature on the possible role of RNA and protein in long-term memory is reviewed in terms of the following five criteria: (1) The molecule should have a defined role in normal brain function. (2) There should be a quantitative and/or qualitative change in the molecule as a function of learning. (3) The molecule should lead to some type of relatively permanent change in the functioning of the brain. (4) Altered synthesis or utilization of the molecule should lead to predictable consequences for memory. (5) The localization of the response should be consistent in terms of the utilization of that portion of the brain in the particular task.     

Enhanced cerebrovascular permeability by Metrazol: significance for brain metastases

Metrazol enhanced the penetration of two proteins (¹²⁵I human serum albumin and horseradish peroxidase), and the anticancer agent, razoxane, into the central nervous system of anaesthetized rats. Penetration was increased throughout the whole brain. With the exception of the bladder, no peripheral tissue was affected. The increase in brain permeability was temporary and reversed within 4 hours; brain levels of drug and protein were increased by up to three times.[/p]