Effects of dietary retinoic acid on skin papilloma and carcinoma formation in female SENCAR mice

Previously we have shown that dietary retinoids are essential for papilloma formation induced by either an initiation-promotion or a complete skin carcinogenesis protocol. The present study was conducted to further determine the effect of dietary retinoic acid (RA) on papilloma formation and the conversion of papillomas to carcinomas. Skin tumors were induced in 3 week old female SENCAR mice by an initiation-promotion protocol with one application of 20 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA), followed by 20 weekly applications of 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice were fed RA at one of the three doses: 0.3 (nutritionally marginal dose), 3 (near physiological) and 30 (pharmacological) micrograms/g of diet. Mice fed 30 micrograms of RA/g of diet had the same survival rate as the other two groups despite a lower body weight and all three groups had similar papilloma incidence, which reached 100% at age 18 weeks. Mice fed 3 micrograms of RA/g of diet had the highest papilloma yield (approximately 14 papillomas/mouse) of all groups and it peaked between weeks 18 and 38 of age. These papillomas later regressed such that mice from all three groups had about the same papilloma yield at week 44 of age. Mice fed 30 micrograms of RA/g of diet failed to develop any visible carcinoma, while mice fed 0.3 or 3 micrograms/g showed 1.9% conversion of papillomas to carcinomas. Therefore, dietary RA at 30 micrograms/g of diet inhibited the conversion of papillomas to carcinomas without affecting papilloma incidence. In addition, dietary RA at 30 and 0.3 micrograms/g of diet lowered papilloma yield.     

Efficacy and toxicity of 9-beta-D-arabinofuranosylguanine (araG) as an agent to purge malignant T cells from murine bone marrow: application to an in vivo T-leukemia model

9-beta-D-Arabinofuranosylguanine (araG), an analog of deoxyguanosine which is not degraded by purine nucleoside phosphorylase, has been previously shown in in vitro studies by our laboratory to be effective in purging malignant T cells from human bone marrow (1). We now describe studies in a murine model of T-cell acute lymphoblastic leukemia (ALL) in which we tested whether bone marrow, contaminated with malignant T cells and purged ex vivo with araG, could reconstitute both the lymphoid and myeloerythroid lineages in the absence of leukemic relapse. The model utilized 6C3HED tumor cells, derived from a Thy 1.2+ malignant murine T-cell line, which were shown to cause lethal leukemia in C3H/HeN mice. Intravenous injection of 10(6) 6C3HED cells resulted in 100% mortality within 18 days, with autopsy revealing tumor infiltration of multiple organs. 100% of non-leukemia bearing lethally irradiated C3H/HeN mice transplanted with syngeneic bone marrow, treated ex vivo with 100 microM of araG for 18 hours, survived > 365 days post-transplant with full lymphohematopoietic reconstitution. Evidence of araG's ability to purge bone marrow of malignant tumor cells without causing significant toxicity to normal marrow derived hematopoietic progenitor cells was documented in experiments in which 75% of lethally irradiated mice transplanted with syngeneic bone marrow, contaminated with 6C3HED tumor cells and treated ex vivo with 100 microM araG for 18 hours, survived for > 250 to > 400 days. Death in 25% of mice was secondary to infection which developed before marrow reconstitution occurred. Reconstitution of the lymphoid, myeloid, and erythroid lineages with donor cells in surviving mice was documented. The data presented indicate that araG may effectively purge bone marrow of malignant T cells without irreversible toxicity to hematopoietic stem cells. This purging regimen is recommended for consideration for clinical trials in patients with T-cell malignancies undergoing autologous bone marrow transplantation and may also be a viable option for T-cell depletion as a strategy to prevent graft-versus-host disease.     

Comparative study of craniofacial morphology in Japanese and Australian aboriginal populations

A metric study of 71 Japanese and 106 Australian aboriginal precontemporary crania was undertaken using direct measurements and cephalograms. Compared with Australian aboriginals, the Japanese are characterized by smaller cranial length, cranial base length, nasal floor length, palatal length, mandibular dimensions (except symphysis height), facial depth, posterior face height, and facial profile angle and larger cranial breadth and height, maxillary breadth, palatal breadth, anterior face height, and occlusal and mandibular plane angles. These differences confirm the previously described brachycephalic tendency in aboriginals and the dolichocephalic form in the Japanese. The differences are also consistent with the expected functional differences between the Australian aboriginal hunter-gatherer group masticating more resistant food with larger, more anteriorly located, more powerful masseter muscles and the Japanese group masticating less resistant food with correspondingly less robust masticatory musculature. The results highlight the differences in craniofacial morphology between groups with different genetic backgrounds subjected to significantly different environmental influences.     

Effects of amino acids and gastric inhibitory polypeptide on insulin release in dogs

Insulin release following intravenous administration of an amino acid solution with and without a simultaneous infusion of varying amounts of porcine gastric inhibitory polypeptide (GIP) was studied in dogs. Group I received a 10-amino acid mixture (300 mosmol/kg iv) at 16.6 ml/min for 1 h; group II, amino acid mixture plus 0.5 micrograms.kg-1.h-1 porcine GIP; group III, amino acid mixture plus 1.0 micrograms.kg-1.h-1 of GIP; group IV (a and b) received either 0.5 or 1.0 micrograms.kg-1.h-1 of GIP alone. Compared to group I, groups II and III had a greater insulin response during the first 30 min of the infusion. Group] IV (a and b) showed no insulin release. Glucose concentrations showed no significant change in all groups. From these results, it is concluded that insulin release after intravenous infusion of an amino acid mixture plus GIP is greater than after amino acids or GIP alone. It appears that this effect is more pronounced in the early phase of insulin release.     

Safety and immunogenicity of capsular polysaccharide-tetanus toxoid conjugate vaccines for group B streptococcal types Ia and Ib

The translocation of spin-labeled analogues of phosphatidylcholine (4-doxylpentanoyl-PC, SL-PC), phosphatidylethanolamine (SL-PE), phosphatidylserine (SL-PS), and sphingomyelin (SL-SM) from the outer to the inner leaflet of the plasma membrane bilayer was investigated in dog kidney MDCK II and human colon Caco-2 cells. Disappearance from the outer leaflet was assayed using back-exchange to serum albumin. Experiments with cells in suspension as well as with polarized cells on filters were performed at reduced temperatures (10 and 20 degreesC) to suppress endocytosis and hydrolysis of spin-labeled lipids. For both epithelial cell lines, a fast ATP-dependent inward movement of the aminophospholipids SL-PS and SL-PE was found, while SL-SM was only slowly internalized without any effect of ATP depletion. The kinetics of redistribution of SL-PC were clearly different between the two cell lines. In MDCK II cells, SL-PC was rapidly internalized in an ATP-dependent and N-ethylmaleimide-sensitive manner and at a rate similar to that of the aminophospholipids. In contrast, in Caco-2 cells the inward movement of SL-PC was much slower than that of the aminophospholipids, did not depend on ATP, and was not N-ethylmaleimide-sensitive. Inhibitor studies indicated that the outward-translocating multidrug resistance P-glycoprotein present in these cells did not affect the kinetics of inward translocation. Internalization was always similar on the apical and basolateral cell surface, suggesting the presence of the same phospholipid translocator(s) on both surface domains of epithelial cells. We propose that Caco-2 cells contain the well-known aminophospholipid translocase, while MDCK II cells contain either two translocases, namely, the aminophospholipid translocase and a phosphatidylcholine-specific translocase, or one translocase of a new type, translocating aminophospholipids as well as phosphatidylcholine.     

The potential roles of intraovarian peptides in normal and abnormal mechanisms of reproductive physiology

Normal and abnormal follicular growth and steroidogenesis depend on gonadotropins as well as intraovarian peptide and polypeptide growth factors, which may mediate or potentiate gonadotropin action. Epidermal growth factor is mitogenic to ovarian granulosa and is a potent inhibitor of granulosa aromatase. It may be involved in the apparent arrest of follicular development commonly seen in women with polycystic ovarian syndrome as well as in the blunted response to gonadotropins seen in this syndrome. Insulin-like growth factors are also mitogenic to ovarian granulosa, but in contrast to epidermal growth factor, insulin-like growth factor-I, both alone and in synergy with gonadotropins, is a potent stimulus of aromatase and granulosa estradiol production. Insulin-like growth factor binding proteins-2 and -4, known inhibitors of insulin-like growth factor action, are higher in follicular fluid from atretic and polycystic ovarian syndrome follicles compared with estrogenic follicles and may be inhibitors of gonadotropin action in follicle selection and in polycystic ovarian syndrome. Cytokines including interleukins, tumor necrosis factor-alpha and interferon-gamma also appear to play a role in modulating ovarian steroidogenesis. Activins, inhibins, and follistatin (activin-binding protein) also affect follicular development and steroidogenesis and may play a role in dominant follicle selection and follicular atresia.     

Effects of indomethacin on intragastric pH and meal-stimulated serum gastrin secretion in rheumatoid arthritis patients

The effects of oral indomethacin on intragastric pH and serum gastrin were investigated in rheumatoid arthritis patients. Nine patients (1 male, 8 female) without a history of peptic ulcer disease and 6 patients with a history of peptic ulcer disease (5 male, 1 female) were studied. To obviate Helicobacter pylori infection as a confounding factor, only patients with positive H. pylori serology were included. After a 5-day period of placebo treatment and after a 5-day period of indomethacin (50 mg t.d.s.; total dose 750 mg), 24-h intragastric pH and basal and meal-stimulated serum gastrin levels were measured in a double-blind placebo controlled cross-over study. There were no differences in the median 24-h pH values between placebo and indomethacin users irrespective of peptic ulcer disease history. Indomethacin resulted in a higher basal and stimulated gastrin response than placebo in patients with a history of peptic ulcer disease. The basal and incremental responses were lower in patients with a history of peptic ulcer disease than in patients without a history of peptic ulcer disease, both during indomethacin and placebo. The same basal and stimulated incremental serum gastrin responses were found during placebo and indomethacin treatment in patients without a history of peptic ulcer disease. No correlation was established between median 2-h post-prandial intragastric pH and post-prandial incremental serum gastrin concentration. We conclude that indomethacin does not influence the intragastric pH of rheumatoid arthritis patients irrespective of history of peptic ulcer disease.