Phase I and pharmacological study of CI-980, a novel synthetic antimicrotubule agent

CI-980 (NSC 613862) is one of a novel class of 1,2-dihydropyrido[3, 4-b]pyrazines that inhibits tubulin polymerization, presumably by binding to the colchicine binding site of tubulin. In a Phase I and pharmacological study, 16 patients with advanced solid neoplasms were treated with CI-980 on a continuous 72-h infusion schedule at doses ranging from 3.0-5.4 mg/m2/day every 3 weeks. High rates of central nervous system (CNS) toxicity and neutropenia occurred in both minimally and heavily pretreated patients who were treated with CI-980 doses above 3.75 mg/m2/day, which is the maximum tolerated dose and the recommended dose for additional evaluations. CNS effects, characterized by neurocortical, mood, and cerebellar manifestations, were generally observed toward the end of the infusion and immediately posttreatment and usually resolved within 48 h after the completion of treatment. Toxicity was mild to modest at the 3.75 mg/m2/day dose level. Neither clinical nor pharmacological risk factors that may predispose patients to the development of CNS effects were evident. Although no objective antineoplastic activity was observed in this Phase I study, CI-980 steady-state plasma concentrations achieved at the recommended dose of 3.75 mg/m2/day (mean +/- SE, 5.74 +/- 0.54 nM) approached and exceeded concentrations that have been associated with significant activity in preclinical studies, indicating that additional disease-directed evaluations of CI-980 may be warranted.     

Decreased transforming growth factor beta type II receptor expression in intestinal adenomas from Min/+ mice is associated with increased cyclin D1 and cyclin-dependent kinase 4 expression

Two cases of cavitary lung cancer with pulmonary aspergillosis were experienced. Case 1 was a 45-year-old male. Chest X-ray and Chest CT revealed a round shadow in the thin-wall cavity of the upper lobe of the right lung. Upper lobectomy of the right lung was performed. Histologically large cell carcinoma was found to invade the entire cavity wall, and aspergillus was not detected in the intracavitary space. Case 2 was a 75-year-old male. Chest X-ray and Chest CT revealed a round shadow in the thin-wall cavity of the upper lobe S1 + 2 of the left lung. As a result of upper lobectomy of the left lung and S6 partial resection, large cell carcinoma was found to invade the entire cavity wall, and aspergillus was not detected in the intracavitary space. Only 19 cases including ours are reported about cases of lung cancer complicated by pulmonary aspergillosis at the same site in Japan. The mechanism of aspergillus infection had not been clarified in the discussions of the reported literature and nothing characteristic could be pointed out in our cases except for the assumption that the presence of cancer was a factor triggering Aspergillus implantation.     

An AP-2 binding sequence within exon 1 of human and porcine choline acetyltransferase genes enhances transcription in neural cells

It has been established that GABAA and GABAB receptors can exist separately and/or co-exist in the membrane of dorsal root ganglion neurons. In our previous investigation it has been shown that co-existence of these two kinds of receptors is about 80% of the neurons examined (20/25). The present study was aimed to explore whether the activation of these two kinds of receptors could interact with each other using intracellular and whole-cell patch-clamp recordings. Baclofen, a specific GABAB receptor agonist, was found to exert negative modulatory effects on the responses mediated by GABAA receptor. In experiments with intracellular recording, GABA (0.3-1000 microM)- and muscimol (100-1000 microM)-induced depolarization was attenuated markedly and reversibly by preapplication of baclofen (100 microM) (15/21 and 17/21, respectively). In whole-cell patch-clamp recordings GABA (100 microM) and two specific GABAA receptor agonists, muscimol (10 microM) and isoguvacine (50 microM), activated currents were inhibited markedly by preapplication of baclofen 30 s or more and the inhibition was concentration dependent (1-100 microM baclofen) and reversible. The possible mechanisms underlying the inhibition by baclofen of the responses mediated by GABAA receptor and the physiological significance implicated are discussed.     

Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system

Until fairly recently, investigations into the control of cell production (proliferation) have been the mainstay of studies into the maintenance of mucosal homeostasis and general integrity. However, in addition to proliferation, it is now increasingly evident that programmed cell death, specifically that form of programmed cell death known as apoptosis, is an equally, if not more important, mechanism of regulating mucosal cell number. This review will concentrate on the significance of damage (radiation) induced and spontaneous apoptosis in the maintenance of intestinal epithelial stem cell number and integrity, and its probable link to the level of cancer incidence in the small intestine and colon.     

A review of selected microstomia prevention appliances

This new technique uses helical computed tomography data and computer-aided design and manufacturing for preoperative fabrication of individual mandibular prostheses together with corresponding resection templates. Coherent 3D geometries for computer-based models are the basis for the construction of prostheses and provide data for a computerized numerical control fabrication. Fixation plates are fabricated with the titanium prostheses. The identical data of these plates are used for the computer-aided design and manufacturing of resection templates, which guide an oscillating saw in a precisely determined resection plane. This plane again is identical with the prostheses' margins for mandibular body replacement. The use of this technique in four patients is reported on: after temporary insertion of the templates for resection and after resection, the prostheses were stabilized with the same screws in the same screw-holes where the templates had been. Resection and reconstruction were thus highly precise, safe and fast and primarily led to excellent aesthetic and functional results. Wound-healing depends on a safe soft-tissue reconstruction over these large prostheses. Coverage with flaps seems obligatory. In spite of the superior technical aspects, the clinical long-term results of this new technique were poor.     

Ethical implications for early pregnancy of the fetus as patient: a basic ethical concept in fetal medicine

A new and rapid method is proposed for extraction of non-polar lipids from tissues where they are present as abundant components which can interfere with the usual procedures of lipid extraction and TLC separation, and hamper, in particular, sulphatide visualization. A solvent more hydrophobic than chloroform, i.e. n-hexane, was utilized to remove the neutral lipids from samples of female rabbit parotid gland, and the n-hexane phase was used for TLC which showed considerable amounts of cholesterol esters, in addition to triglycerides, diglycerides and monoglycerides. The methanol phase, now devoid of non-polar lipids, was utilized to prepare TLC plates in order to separate and visualize the polar lipid fractions, in particular the sulphatides.     

Gelatinase A (MMP-2) and cysteine proteinases are essential for the degradation of collagen in soft connective tissue

Epidermal growth factor (EGF) is a potent mitogen for normal mouse mammary epithelial cells grown in primary culture. EGF activation of the EGF-receptor (EGF-R) induces intrinsic tyrosine kinase activity which results in EGF-R autophosphorylation and tyrosine phosphorylation of other intracellular substrates involved in EGF-R signal transduction. Genistein and erbstatin are anticancer agents which have been shown to be potent tyrosine kinase inhibitors. However, the effects of these compounds in modulating EGF-dependent normal mammary epithelial cell proliferation is presently unknown. Therefore, studies were conducted to determine the effects of genistein and erbstatin on EGF-dependent proliferation, and EGF-R levels and autophosphorylation in normal mouse mammary epithelial cells grown in primary culture and maintained in serum-free media. Chronic treatment with 6.25-100 microM genistein or 1-16 microM erbstatin significantly decreased EGF-dependent mammary epithelial cell proliferation in a dose-responsive manner. However, the highest doses of genistein (100 microM) and erbstatin (16 microM) were found to be cytotoxic. Additional studies showed that acute treatment with 6.25-400 microM genistein did not affect EGF-R levels or EGF-induced EGF-R autophosphorylation, while acute treatment with 1-64 microM erbstatin caused a slight reduction in EGF-R levels, but had no effect on EGF-dependent EGF-R autophosphorylation in these cells. In contrast, chronic treatment with similar doses of genistein or erbstatin resulted in a large dose-responsive decrease in EGF-R levels, and a corresponding decrease in total cellular EGF-R autophosphorylation intensity. These results demonstrate that the inhibitory effects of chronic genistein and erbstatin treatment on EGF-dependent mammary epithelial cell proliferation is not due to a direct inhibition of EGF-R tyrosine kinase activity, but results primarily from a down-regulation in EGF-R levels and subsequent decrease in mammary epithelial cell mitogenic-responsiveness to EGF stimulation.     

Is milk production impaired by dieting during lactation?

To determine the feasibility of a weight-loss program during lactation, 33 healthy, well-nourished, breast-feeding women were enrolled. Twenty-two women completed the 10-wk study, losing a mean (+/- SD) of 4.8 +/- 1.2 kg. Mean energy intake during the study was nearly 2.25 MJ (538 kcal) below the mean daily baseline intake of 9.64 +/- 2.48 MJ (2303 +/- 592 kcal). The sum of three maternal skinfold thickness, waist, and hip measurements were significantly smaller (P = 0.0001) at study completion. Mean daily milk production was 759 +/- 142 mL/d at baseline and 802 +/- 189 mL/d at week 10. The infants gained an average of 21 g/d, or 1.48 +/- 0.40 kg overall. The mean percent fat of milk at baseline and 10 wk was 4.06 +/- 2.15 and 4.00 +/- 2.56, respectively. The mean daily nitrogen content of milk at baseline and study completion was 1.82 +/- 0.32 and 1.62 +/- 27 g/L. These findings suggest that modest weight loss by healthy breast-feeding women does not adversely affect either quantity or quality of milk consumed by their infants.