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Biomedical subjects

A E Warren

Publications and source records attributed to A E Warren.

15 recordsLinked to original sources
PubMed2006

Dilatation of the ascending aorta in paediatric patients with bicuspid aortic valve: frequency, rate of progression and risk factors.

OBJECTIVES: To describe the incidence and rate of dilatation of the ascending aorta in children with bicuspid aortic valve (BAV) and to determine factors that predict rapid aortic dilatation. DESIGN: Retrospective cohort study. SETTING: Regional tertiary care children's hospital. PATIENTS: All children aged 0-18 years seen at the authors' institution between 1990 and 2003 with an "isolated" BAV. All patients had had more than one technically adequate echocardiogram, at least six months apart, with concomitant height and weight data. INTERVENTIONS: Offline echocardiographic measurements of multiple levels of the aortic root were completed for each participant at each serial echocardiogram. These measurements were then compared with expected measurements derived from a normal local control population. MAIN OUTCOME MEASURES: Rate of change of the ascending aorta size over time, where aortic size is expressed as the number of standard deviations above or below the mean size expected for a given body surface area (z score). RESULTS: 279 echocardiograms spanning a period of from 9 months to 13.3 years were analysed for 88 patients with BAV. The ascending aorta in the BAV group was larger than expected for body surface area at diagnosis and continued to increase in relative size at each of the four subsequent follow-up echocardiograms. Ascending aortic z score increased at an average rate of 0.4/year. A faster rate of increase in z score was predicted by both larger initial aortic valve gradient and non-use of beta blockers. CONCLUSIONS: Children with BAV are at risk of having a dilated ascending aorta. This risk increases with longer follow up.

Adolescent↗
PubMed2001

Tmolt4 leukemic type II isoform of IMP dehydrogenase as a target for 1,2,4-triazolidine-3,5-diones, 1-(1-(3-methylphenyl)ethylidineamino)-4,4-diethyl-3,5-azetidinediones, 3,5-isoxazolidinediones, and 4,4-disubstituted-3,5-pyrazolidinediones.

The 1,2,4-triazolidine-3,5-diones, 1-(1-(3-methylphenyl)ethylidineamino)-4,4-diethyl-3,5-azetidinediones, and 4,4-disubstituted-3,5-pyrazolidinediones proved to be potent competitive inhibitors of human Tmolt4 leukemia Type II IMP dehydrogenase [IMPDH] activity, an enzyme isoform which is induced in highly proliferating cells. On the other hand, the 3,5-isoxazolidinediones were shown to be uncompetitive inhibitors of Type II IMPDH activity. The correlation between inhibition of Type II IMPDH activity with the agents' ability to suppress DNA and purine syntheses in these Tmolt4 leukemia cell was positive. Type I IMPDH (i.e., the isoform that is present in normal cells) was not inhibited by these compounds suggesting that these agents would be less toxic to normal cells and have selective inhibition towards proliferating cells.

Antineoplastic Agents↗
PubMed2001

Targeting of human Tmolt4 leukemic type II IMP dehydrogenase by cyclic imide related derivatives.

2,3-Dihydrophthalazine-1,4-diones, indazolones, 3-imino-1-oxoisodolines, homophthalimides, napthalidimides, diphenamides, and 6,7-dihydro-5H-dibenz[c,e]azepines proved to be potent inhibitors of the activity of human Tmolt4 T cell leukemia Type II IMP dehydrogenase (IMPDH). This inhibition was competitive, yielding Ki values in the range of 1.96 to 48.9 microM. The inhibition of Type II IMPDH correlated positively with the inhibition of the growth of Tmolt4 cells, the syntheses of DNA and purine, and the activity of crude IMPDH. The Type II IMPDH isoform is found in rapidly proliferating cells. The isoform present in normal resting cells, Type I IMPDH, was elevated by the compounds at 100 microM. In addition, Compound 5 significantly increased the Type I enzyme activity in a concentration and time dependent manner. The selectivity of these derivatives towards Type II IMPDH will allow for the separation of cellular effects, which should reduce clinical toxicity when treating with antimetabolite IMPDH inhibitors.

DNA, Neoplasm↗
PubMed2000

Synthesis and cytotoxicity of 2,4-disubstituted and 2,3,4-trisubstituted brominated pyrroles in murine and human cultured tumor cells.

The 2,4-disubstituted and 2,3,4-trisubstituted brominated pyrroles were successfully prepared and demonstrated potent cytotoxicity against the growth of suspended murine and human tumors, i.e. leukemia and lymphomas, acute monocytic leukemia, and HeLa-S3 uterine carcinoma. The brominated compounds were more selective in inhibiting the growth of tumors derived from human solid tumors. Nevertheless, activity with some of the derivatives occurred in the human KB nasopharynx, SW-480 colon, and HCT ileum adenocarcinoma, and lung A549 carcinoma screens. In Tmolt4 T cell leukemia cells DNA synthesis was reduced over 60 min from 25 to 100 microM followed by RNA synthesis reduction. De novo purine synthesis was retarded with the regulatory enzyme PRPP-amido transferase being markedly inhibited with less effects on the activities of IMP dehydrogenase, dihydrofolate reductase,, and the nucleoside kinases. After 60 min incubations d[TTP] and d[GTP] pools were marginally reduced. In vitro ct-DNA studies suggest that the agents may affect the DNA molecule itself with increased DNA viscosity and the Tmolt4 studies suggest that DNA cross-linking of DNA strands may be present.

Antineoplastic Agents↗
PubMed1999

Hepatic vein to the azygous vein anastomosis for pulmonary arteriovenous fistulae.

Pulmonary arteriovenous fistulae after a cavopulmonary anastomosis have been reported to resolve after hepatic venous return is included in the pulmonary circulation. We report a case in which the hepatic veins were redirected to the pulmonary circulation by connecting them directly to the azygous continuation of the inferior vena cava that had previously been connected to the right pulmonary artery. The patient's arterial saturation of 71% increased to 92% after 6 months.

Adolescent↗
PubMed1999

The cytotoxicity and mode of action of 2,3,4-trisubstituted pyrroles and related derivatives in human Tmolt4 leukemia cells.

4-Carbethoxy-1-methyl-2-phenacyl-3-phenylpyrrole (9), 4-carbethoxy-2-(4-methoxybenzoyl)-3-(4-methoxyphenyl)pyrrole (10) and 2-(4-methoxybenzoyl)-3,4-bis-(4-methoxyphenyl)pyrrole (11) proved to be potent cytotoxic agents against the growth of murine and human leukemias and lymphomas. Selective toxicity was demonstrated against the growth of solid tumors, e.g., human adenocarcinoma of the colon SW480 and ileum HCT-8, glioma U-87-MG, and rat UMR-106 osteosarcoma. A mode of action study in Tmolt4 leukemia cells demonstrated that the agents inhibited de novo purine synthesis at the regulatory sites PRPP-amido transferase, IMP dehydrogenase as well as dihydrofolate reductase resulting in significant inhibition of DNA synthesis in 60 min. Other biochemical sites which were affected significantly were thymidylate synthetase, DNA polymerase alpha, RNA polymerases, nucleoside kinase and ribonucleoside reductase.

Animals↗
PubMed1998

Cytotoxicity of substituted alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates in L1210 lymphoid leukemia cells.

Two alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates proved to be potent cytotoxic agents in the murine L1210 lymphoid leukemia screen. DNA synthesis was preferentially inhibited with the major target of the agents being de novo purine biosynthesis at the regulatory enzyme sites of PRPP-amido transferase and IMP dehydrogenase. Other enzymatic activities which were suppressed by the drugs were DNA polymerase alpha, RNA polymerases, ribonucleoside reductase and dihydrofolate reductase. The d[NTP] pools, nucleoside kinase and the pyrimidine pathway were not affected by the presence of drugs. The DNA molecule itself was not the target of the agents, i.e. no alkylation of nucleotide bases, intercalation between bases or cross-linking of DNA strands occurred. The agents did cause L1210 DNA fragmentation after 24 h incubation at 100 microM.

Animals↗
PubMed1984

Specific [3H]-spiroperidol binding sites in human prefrontal cortex: potential site multiplicity and overall serotonin-like selectivity.

[3H]-Spiroperidol specifically binds at sites in human prefrontal cortex. The binding of this ligand is apparently anomalous at 37 degrees C, with a substantial loss of specific binding occurring between 5 and 40 min incubation. However, at 21 degrees C, this loss of binding is not observed even at 60 min. At 21 degrees C, [3H]-spiroperidol binding in human prefrontal cortex is apparently occurring at multiple sites or multiple affinity states of single classes of sites, or at a combination of both. The overall selectivity is predominantly serotonergic, rather than dopaminergic.

Adult↗
PubMedDate not supplied

Cytotoxicity and mode of action of aliphatic dicarboxylic acids in L1210 lymphocytic leukemia cells.

The aliphatic dicarboxylic acid surprisingly afforded potent cytotoxicity and in vivo antineoplastic activity. The agents were active against the growth of a variety of leukemias, lymphomas, and suspended HeLa uterine carcinoma. Suppression of growth of cell lines derived from human solid cancers, e.g. SW-480 colon adenocarcinoma, lung MB- 9812, glioma HS-683, and rat osteosarcoma UMR-106 was observed. A mode of action study in L1210 lymphoid leukemia demonstrated that DNA and RNA syntheses were inhibited at multiple sites including ribonucleoside reductase, purine de novo synthesis at PRPP-amidotransferase and IMP dehydrogenase and nucleic acid kinases. These studies could not exclude the possibility that the agents also interacted with the DNA molecule itself interfering with the utilization of the template.

Animals↗
PubMedDate not supplied

The cytotoxicity of 1-(1-phenylalkylideneamino)-2,4-azetidinediones and their mode of action in human and murine tumor cells.

The 1-(1-phenylalkylideneamino)-2,4-azetidinediones are potent cytotoxic agents against the growth of human and murine leukemias, lymphoma, and suspended HeLa uterine carcinoma. In cell lines cultured from solid human tumors, the agents were more selective with only a few agents demonstrating significant activity against the growth of HCT-8 ileum adenocarcinoma, Saos-2 osteosarcoma, KB nasopharynx, MCF-7 breast effusion, and ovary 1-A9 carcinoma A mode of action study in murine L1210 lymphoid leukemia cells showed that the agents inhibited DNA and RNA syntheses after 60 min. The compounds were potent inhibitors of the de novo purine synthesis suppressing the activity of both regulatory enzymes of the pathway, i.e., PRPP-amido transferase and IMP dehydrogenase. In addition, the agents reduced the activity of ribonucleotide reductase, dihydrofolate reductase, RNA polymerases, and thymidine kinases as well as the reduction of d[NTP] pools. All of these effects would contribute to the overall reduction of DNA and RNA syntheses. The DNA molecule itself was not a target for the agents in that alkylation of nucleoide bases, intercalation between base pairs, and cross-linking of DNA strands did not occur.

Animals↗
PubMedDate not supplied

Cytotoxicity of ferratricarbadecaboranyl complexes in murine and human tissue cultured cell lines.

The ferratricarbadecaboranyl salts [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9] + X-(X- = AsF6-, 1 and SbF6-, 2), as well as the neutral complex, 1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9, 4, are effective cytotoxic agents, causing cell death in a number of tissue culture lines, e.g. L-1210, Tmolt3, HL-60, and HeLa-S3. In general, these agents were not active against the solid cell growth, i.e. KB nasopharynx, A431 skin, HCT-8 ileum, SW480 colon, osteosarcoma, and glioma. However, they were active against the growth of lung bronchogenic MB-9812. The mode of action of the derivatives involves inhibition of de novo purine synthesis of L-1210 cells, which reduces DNA and RNA syntheses. Purine synthesis was reduced by complexes [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9]+ [SbF6]- 2 and ¿[1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9]+ [SbF6]- [1-(eta 5-C5H5)Fe-4-CH3-2,3,4-C3B7H9]+ [SbF6]-¿ [20:1] 3, at the regulatory enzyme, i.e. PRPP amido transferase. The agents lowered d[ATP] and d[CTP] pools, further reducing DNA synthesis. The salts 1, 2, and 3 were shown to be moderate inhibitors of isolated L-1210 DNA topoisomerase activity. DNA strand scission was evident after incubation with compounds 1-4 and [1-(eta 5-C5H5)Fe-2-CH3-2,3,4-C3B7H9 and 1-(eta 5-C5H5)Fe-4-CH3-2,3,4-C3B7H9] [20:1] 5, for 24 hours at 100 microM, lowering DNA synthesis, and causing cell death. The ferratricarbadecaboranes show activities and specificities different than those found for the analogous ferrocenium salts [(eta 5-C5H5)2Fe]+ [AsF6]- 6 and [(eta 5-C5H5)2Fe]+ [SbF6]- 7, and the neutral ferrocene compound (eta 5-C5H5)2Fe 8. The bioactivites of both the tricarbaboranyl and metallocenium salts are attributed to the cations, since Na+[AsF6]- 9, K+ [AsF6]- 10, Na+[SbF6]- 11, and K+[SbF6]- 12 were found to be inactive at equivalent ionic concentration.

Animals↗