Synthesis and anticancer activities of 4-oxobenzopyrano[2,3-d]pyrimidines

Several 2-aryl-4-oxoxbenzopyrano[2,3-d]pyrimidines have previously been shown to exhibit in vivo antitumor activity in mice with P388 lymphocytic leukemia. In the present study, a series of novel substituted benzopyrano[2,3-d]pyrimidines have been prepared and tested for cytotoxic activity against a panel of cancer cell lines including the P388 lymphocytic leukemia cell line. The unsubstituted parent compound, some methoxylated derivatives and a cyclohexyl derivative all exhibited potent cytotoxic activity (IC50 values 0.3-0.64 microM). A number of derivatives, including the unsubstituted parent pyrimidine, were shown to cause a significant perturbation in cell cycle kinetics with an observed 2- to 3-fold increase in cells in the G2/M phase of the cell cycle. Furthermore, a polymethoxylated derivative, 2-(3,4,5-trimethoxyphenyl)-9-methoxy-4-oxo-2,3-dihydrobenzopyrano[ 2,3-d]pyrimidine 13, was shown to be selectively active against a number of human ovarian cell lines.     

Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro.

There have been many reports that high soya-based diets reduce the risk of certain types of cancer. This effect may be due to the presence of high levels of isoflavones derived from the soya bean, particularly genistein which has been shown to be a protein tyrosine kinase (PTK) inhibitor and have both oestrogenic and anti-oestrogenic properties. We have examined the effect of genistein and a number of novel synthetic analogues on both normal (IEC6, IEC18) and transformed (SW620, HT29) intestinal epithelial cell lines. Responses were compared to those elicited by oestradiol, the anti-oestrogen tamoxifen, and the tyrosine kinase inhibitor tyrphostin. Genistein and tamoxifen were potent inhibitors of cell proliferation. Of seven novel isoflavones tested, none were more potent inhibitors than genistein, and all displayed similar relative activities across the different cell lines. In addition to inhibiting cell proliferation, cell death via apoptosis was observed when the cells were exposed to the isoflavones and all but one exhibited PTK inhibitory activity. These data suggest that by reducing proliferation and inducing apoptosis, possibly due in part to PTK inhibition, isoflavones may have a role in protecting normal intestinal epithelium from tumour development (reducing the risk) and may reduce colonic tumour growth.     

The interaction of chalcones with tubulin

The chalcone 3,4,3',4',5'-pentamethoxychalcone is a potent cytotoxic agent. A series of chalcones and (E)-4-(4'-hydroxyphenyl)but-3-en-2-one were prepared and assessed for their ability to inhibit cell growth in vitro. The cytotoxicity correlates with their ability to bind to tubulin as measured by immunofluorescence, cell cycle analysis and disruption of microtubule assembly. Some of the chalcones were shown to bind to the type II oestrogen receptor.     

Noncosmetic operations for benign breast disease

The operation of excision of the major duct system of the breast has remained unchanged since it was first designed by Adair and described by Hadfield [1–4], Urban [5], and recently by Preece [6] from Professor Hughes' unit in Cardiff.Operations for diseases for a single major duct or the whole major duct system, namely subareolar excision of the major ducts of the breast, are discussed. Technical problems are discussed and suggestions are made on ways to avoid these problems. An adequately performed operation should render the patient free from her disease with a good cosmetic result.Operations for excision of palpable and radiologically detected lesions are described. Since a histological examination is the final arbiter; methods ensuring that the whole lesion is demonstrated, excised, and fully examined are discussed. The medico-legal aspect of this is of obvious importance.

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Resumen La operación para resecar el sistema ductal principal del seno ha permanecido inmodificada desde su diseño original por Adair y su descripción por Hadfield [1–4], Urban [5], y, más recientemente, por Preece [6] del Servicio del Profesor Hughes en Cardiff.Las operaciones para el manejo de enfermedades que afectan a un ducto único o a la totalidad del sistema ductal principal, consistentes en la resección subareolar de los principales ductos o canalículos mamarios son analizadas. Se discuten los problemas técnicos y se hacen sugerencias sobre la manera de evitarlos. Una operación bien realizada debe dejar a la paciente libre de su enfermedad y con un buen resultado estético.Se describen las operaciones para resección de lesiones palpables o detectadas mediante radiología; el examen histológico representa el arbitraje final; se discuten los métodos que aseguran que la totalidad de la lesión ha sido demostrada, resecada, y completamente examinada. Los aspectos medicolegales pertinentes son de obvia importancia.

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Résumé La technique d'excision du système canalaire majeur du sein n'a guère changé depuis qu'elle a été imaginée pour la première fois par Adair et décrite successivement par Hadfield [1–4], Urban [5], et Preece [6] de Cardiff.Les interventions utilisées pour les maladies d'un canal galactophore majeur ou du système entier, c'est-à-dire l'excision sous aréolaire des canaux galactophores, sont exposées. Les écueils de la technique sont discutés et des suggestions sont formulées pour les éviter. Une intervention bien menée devrait libérer la patiente de sa maladie avec un bon résultat esthétique.On décrit ensuite des interventions pour excision des lésions détectables par la palpation et la radiologie. Comme finalement c'est l'examen histologique qui importe, des méthodes garantissant l'excision et l'examen de la pièce entière sont exposées et discutées. L'aspect médicolégal de ce détail est évident.

     

Peripheral arterial occlusive disease: P-31 MR spectroscopy of calf muscle

The effect of a graded exercise protocol on phosphorus-31 magnetic resonance (MR) spectroscopy of calf skeletal muscle in nine healthy (control) subjects and 16 patients with symptomatic peripheral arterial occlusive disease (PAOD) was assessed. Ankle-brachial pressure indexes were obtained in all 16 patients, and 10 patients underwent peripheral arteriography. Temporal profiles of pH and the inorganic phosphorus (Pi) index were calculated from the spectra. A Pi-index recovery rate constant was calculated for each subject. Arteriograms were graded by calculating the runoff resistance in the limb of interest. The pH profiles during exercise did not differ significantly between the PAOD patients and control subjects. The Pi-index recovery rate constant in the PAOD patients was significantly (P less than .01) smaller than in the control subjects. There was no significant correlation between recovery rate and the ankle-brachial pressure indexes, but there was a strong negative correlation between recovery rates and angiographic resistance grades, with smaller recovery rate constants in patients with increased arterial resistance. It is concluded that P-31 MR spectroscopy shows promise as a direct measure of tissue perfusion.     

Mycoses caused by Candida lusitaniae

Candida lusitaniae, a fungus with a low incidence of infection in immunocompetent people, is emerging as an opportunistic pathogen in immunocompromised hosts. This yeast is generally resistant to amphotericin B and may present therapeutic difficulties. C. lusitaniae may be misidentified as one of several other fungal species, including Candida tropicalis, Candida parapsilosis, and even Saccharomyces cerevisiae. As judged by in vitro antifungal susceptibility testing, minimal inhibitory concentrations of antifungal agents other than amphotericin B are achievable, but fungicidal levels are not. When encountered in blood or other body sites, C. lusitaniae should be carefully considered as a potential pathogen.     

Parkinsonism and extraocular motor abnormalities with unusual neuropathological findings

Parkinsonian patients with ocular motility abnormalities are usually considered to have progressive supranuclear palsy. However, a number of other conditions have been noted to have the combination of parkinsonism and ocular problems. We report a case of rigid akinetic parkinsonism, oculomotor palsy, and eyelid apraxia with postmortem examination. Our findings are unusual in that there was marked gliosis of the substantia nigra with a large amount of free extracellular neuromelanin despite a 3-year clinical course. Only rare hyaline inclusion bodies and no neurofibrillary tangles were seen in the brainstem. Excessive calcification of the vessels of the globus pallidus were also noted. This case represents another example of the diversity of conditions producing parkinsonism with extraocular motor abnormalities.