For some death certificates in England and Wales the cause information coded and published in national data is not that initially submitted by the certifier, but instead derives from a subsequent enquiry to the certifier for further information. These enquiries can lead to substantial artefacts in secular mortality data, and also to substantial non-comparability between mortality data for special study groups, such as subjects in cohort studies, and published mortality data. A description of current enquiry policy relevant to cancers, and changes in this policy over recent years is given to aid interpretation of mortality data. The effects on secular data of changes in enquiry policy are illustrated. At 4-digit level of the ICD, changes in enquiry policy can alter published mortality rates by several hundred per cent. At 3-digit level the greatest effects of enquiries at present are to increase the number of deaths coded to cancer of the eye by 35% and cancer of the body of the uterus by 31%; cancers of the thymus, heart and mediastinum are increased by 18%, and pleural cancer by 17%, while decreases of more than 10% are caused for several 'other' and 'unspecified' rubrics, and a decrease of 6% for deaths coded to melanoma.
Sodium stearate has no effect upon the bacteriological condition of a wound, but the addition of 4 parts per 1,000 of chloramine-T renders it antiseptic. Experiment I enabled us to compare the action of sodium stearate alone with that of sodium stearate containing 4 parts per 1,000 of chloramine-T. Wounds which had been previously sterilized could be maintained in an aseptic condition by 4 parts per 1,000 of chloramine-T, although in some cases reinfection occurred (Experiments 2, 3, and 5). For this reason the concentration of chloramine-T was increased. Surface wounds, deep-seated wounds, and osseous cavities, which had previously been either completely or almost completely sterilized, could be maintained for days and even weeks in a condition of surgical asepsis by the use of a paste containing 7 and 10 parts per 1,000 of chloramine-T. Experiments 7, 8, 9, 10, and 12 are examples of this. Slightly infected wounds (Experiments 9, II, and 12) were sterilized in the same manner. Next, it was attempted to sterilize wounds which were suppurating and more or less infected, and in some cases accompanied by fracture. This attempt was probably successful because the wounds used for the experiments showed but slight quantities of secretions and only a shallow layer of necrotic tissue. It is useless to attempt to sterilize severely infected wounds with a paste, for the volume of chloramine-T that can be applied is too limited. A large volume of an active substance is required to sterilize a wound which secretes great quantities of pus, for owing, on the one hand, to the dilution of this substance with the secretions, and, on the other, to its combination with the proteins contained in the pus, the concentration of the antiseptic is rapidly diminished. For these reasons it is essential that the antiseptic solution should be constantly renewed, so that the concentration may be sufficiently strong to effect the destruction of the bacteria. Therefore, the chloramine-T paste cannot sterilize a severely infected wound. The concentration of the active substance contained in a paste must at the same time be sufficiently weak to be innocuous to the tissues. We have seen that it should not exceed 15 parts per 1,000. Thus, it is evident that if the secretions from the wounds are abundant, the substance could exert its action upon the microorganisms for the space of only a few hours. For this reason the chloramine paste should only be applied under the conditions specified in our experiments; that is, in connection with moderately infected wounds which have been carefully washed with sodium oleate, and possess but slight quantities of secretion. Under these conditions, the chloramine paste effects the complete disappearance of the bacteria and maintains the sterility thus secured for as long a time as may be wished. If the technique followed in the dressing is not exactly as above described, reinfection will occur. If applied in this manner the chloramine paste is not injurious to the tissues, for the cicatrization curves of the wounds thus treated show but slight modification from the calculated curves. Chloramine paste makes it possible, therefore, to keep wounds sufficiently free from microorganisms so that the effect of substances which are believed to influence cicatrization can be studied.
Muscle biopsy samples were analysed from five control subjects, four patients with mild to moderate fibre atrophy and four patients with severe atrophy. Patchy increase in lipid was noted with oil red O staining but there was no consistent association of lipid with selective fibre types. Ultrastructural studies demonstrated lipid droplets both subjacent to the sarcolemma and between fibrils. Quantitative analysis showed that the increased lipid was solely due to excess triglyceride. GLC analysis of free and esterified acids was performed. The profiles were essentially similar for the phospholipid and free fatty acid fractions. The triglyceride fraction showed a decrease of myristate, stearate and linoleate with an increase in oleate and arachidate in the alcoholic tissue compared with control. The cholesteryl ester fraction showed an increase in palmitate with a decrease in stearate and oleate in the alcoholic muscle. The accumulation of lipid correlated with mean daily alcohol consumption but not with degree of atrophy suggesting that the two processes probably had different pathogenic mechanisms.
The 2010 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was held in Chicago, Illinois, in advance of the scientific symposium sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The goal of the annual NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for voting or discussion. Some topics covered during the symposium included a comparison of rat and mouse hepatocholangiocarcinoma, a comparison of cholangiofibrosis and cholangiocarcinoma in rats, a mixed pancreatic neoplasm with acinar and islet cell components, an unusual preputial gland tumor, renal hyaline glomerulopathy in rats and mice, eosinophilic substance in the nasal septum of mice, INHAND nomenclature for proliferative and nonproliferative lesions of the CNS/PNS, retinal gliosis in a rat, fibroadnexal hamartoma in rats, intramural plaque in a mouse, a treatment-related chloracne-like lesion in mice, and an overview of mouse ovarian tumors.
NTP Satellite Symposium; INHAND nomenclature; hepatocholangiocarcinoma; acinar-islet cell; preputial gland; hyaline glomerulopathy; eosinophilic substance; ependymoma; axonal degeneration; retinal gliosis; fibroadnexal hamartoma; intramural plaque; chloracne; ovary; cholangiocarcinoma
Careful study of reports prepared for the Confidential Enquiries into Maternal Deaths in England and Wales has made it clear that many maternal autopsy reports are not as informative as they might be. This is, in part at least, because no pathologist who does not work in a maternity unit can expect to see more than a handful of such deaths in a working lifetime. This paper describes briefly the particular features to look for at autopsy, stresses the importance of taking adequate material for histology and discusses some of the more significant histological findings, both of conditions which cause death and of those commonly associated with it.
The cells of tumours induced by many oncogenic DNA viruses, or cells transformed in vitro, contain virus-specific T and transplantation antigens; these have been described for SV40 virus, polyoma virus and adenoviruses. The investigation of viruses as causes of malignant disease in man has sought to establish whether tumour cells possess these virus-specific proteins; however, to date and with the limitations of present techniques, this enquiry has not demonstrated the above viruses as causal of human cancer. More recent studies with herpesvirus type 2 (HSV-2) have shown this virus to transform animal and human cells in culture, and induce cancer in experimental animals: for these reasons, many researchers have suggested that this agent may be an agent of some forms of cancer, in particular carcinoma of the cervix. The possible association of HSV-2 with human malignant disease is discussed.
The research presented in the toxicology session of the Symposium on the Health Effects of Acid Aerosols significantly advances our understanding of the health effects of acid aerosols and clearly illustrates the importance of animal inhalation toxicology to risk assessment. The description of the effects of acid on airway mucus buffering capacity and viscosity helps explain some of the mechanisms responsible for the effects of sulfuric acid on mucociliary clearance and pulmonary function observed in man and animals. Several of the papers illustrate that other pollutants interact with sulfuric acid (H2SO4), causing concern about exposure risks and helping in elucidating the effects observed in epidemiology studies that have not yet been duplicated in a laboratory. For example, H2SO4 absorbed in zinc oxide (ZnO) particles appears to be about a log more potent than H2SO4 alone in causing pulmonary function decrements. Low levels of H2SO4 and O3 were found to be synergistic in increasing collagen synthesis, implying a risk in development of lung fibrosis. More complex mixtures containing H2SO4 cause a variety of interactions, depending upon the end points examined and the chemistry of the mixture. Other reports indicate that dose rate and length of exposure issues are critical to toxicological outcomes. Animal data on mucociliary clearance, which parallels that of human data, was extended to show that concentration of exposure was more important than time of exposure in eliciting a response, although time played a significant role. A recent chronic study showed that H2SO4 caused effects that also can occur in the development of chronic bronchitis.(ABSTRACT TRUNCATED AT 250 WORDS)
A new method for the capping of colloidal CdS nanocrystals with ZnS shells is presented. A combination of the monomolecular precursor zinc ethylxanthate (Zn(ex)2) and zinc stearate was used to replace hazardous organometallic reagents usually applied in this procedure, i.e. bis(trimethylsilyl) sulfide and diethylzinc. Its simple preparation, air-stability and low decomposition temperature of 150 °C make Zn(ex)2a very suitable source for the ZnS shell growth. With this precursor, highly luminescent CdS/ZnS core/shell nanocrystals (Q.Y. 35–45%), exhibiting narrow emission linewidths of 15–18 nm (FWHM) in the blue spectral region, can reproducibly be obtained.
Semiconductor nanocrystals; CdS; ZnS; Fluorescence; Blue emission
The mechanisms of action of many environmental agents commonly involve oxidative stress resulting from mitochondrial dysfunction. Zinc is a common environmental metallic contaminant that has been implicated in a variety of oxidant-dependent toxicological responses. Unlike ions of other transition metals such as iron, copper, and vanadium, Zn2+ does not generate reactive oxygen species (ROS) through redox cycling.
To characterize the role of oxidative stress in zinc-induced toxicity.
We used an integrated imaging approach that employs the hydrogen peroxide (H2O2)-specific fluorophore Peroxy Green 1 (PG1), the mitochondrial potential sensor 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1), and the mitochondria-targeted form of the redox-sensitive genetically encoded fluorophore MTroGFP1 in living cells.
Zinc treatment in the presence of the Zn2+ ionophore pyrithione of A431 skin carcinoma cells preloaded with the H2O2-specific indicator PG1 resulted in a significant increase in H2O2 production that could be significantly inhibited with the mitochondrial inhibitor carbonyl cyanide 3-chlorophenylhydrazone. Mitochondria were further implicated as the source of zinc-induced H2O2 formation by the observation that exposure to zinc caused a loss of mitochondrial membrane potential. Using MTroGFP1, we showed that zinc exposure of A431 cells induces a rapid loss of reducing redox potential in mitochondria. We also demonstrated that zinc exposure results in rapid swelling of mitochondria isolated from mouse hearts.
Taken together, these findings show a disruption of mitochondrial integrity, H2O2 formation, and a shift toward positive redox potential in cells exposed to zinc. These data demonstrate the utility of real-time, live-cell imaging to study the role of oxidative stress in toxicological responses.
biosensors; confocal microscopy; hydrogen peroxide; mitochondrial dysfunction; oxidative stress; real-time imaging; ROS
This paper presents some of the significant milestones that were reached in the long struggle from rejection to acceptance. While it does not attempt to include all of the historical events which contributed to this evolutionary process, it does identify some of the key elements in the laying of a sound foundation upon which the profession could continue to build. It is hoped that other papers will be written to add to our understanding of this important era in chiropractic’s early development. The years from 1917-1958 deal mainly with medicine’s intransigent opposition; then the tide began to turn in chiropractic’s favour. Governments appointed commissions of enquiry to bring some order into the health care field. Our profession’s brief to the Royal Commission on Health Services was described by the Minister of National Health and Welfare as “a very powerful document”. The government enquiries, in addition to identifying professional weaknesses, also made favourable recommendations which encouraged the further growth and development of chiropractic. Commenting on his work as a Royal Commissioner, Mr. Justice Gerard Lacroix said that the medical opposition to chiropractic was:
“... based on bias and prejudice, ignorance and refusal to learn about chiropraxy. I thought it safer to know and understand before judging” (p. 13).8
The objective of this study was to determine if plasticized polyvinyl chloride film would support the growth of any of nine species of fungi. The film was suspended in distilled water with no nutrients or with glucose or ammonium sulfate. Spores of each of the test species were inoculated into the suspension medium, and the mixture was incubated at 30 degrees C for up to 18 weeks. Most species were found to be capable of utilizing the film for carbon or nitrogen when the other nutrient was supplied. Only two species, Aspergillus fischeri and Paecilomyces sp., were found to be capable of utilizing components of the film without added nutrients. Components of the polyvinyl chloride film were then incorporated into mineral salts medium to determine if these components could serve as carbon sources in the presence of ammonium nitrate. The only component found to be utilized by all the fungi as a carbon source was epoxidized oil, a plasticizer-stabilizer. Calcium-zinc stearate was an available carbon source for all except the Penicillium and Verticillium strains. The only other component utilized was a stearamide, which was metabolized solely by the Aspergillus sp. Only the stearamide contained enough nitrogen to serve as a primary source in the film. The compound, however, did not support growth of fungi in the presence of glucose. It was theorized that either the nitrogen of the stearamide was more readily available to the fungi in the whole film due to the presence of trace nutrients or the nitrogen was supplied by exogenous sources.
A clean-route synthesis of Zn-Al-hydrotalcites (Zn-Al-LDHs) using zinc oxide and sodium aluminate solution has been developed. The as-obtained materials were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). The effects of metal ions at different molar ratios on the performance of hydrotalcites were discussed. The results showed that the Zn-Al-hydrotalcites can be successfully synthesized at three different Zn/Al ratios of 3:1, 2:1 and 1:1. Thermal aging tests of polyvinyl chloride (PVC) mixed with Zn-Al-LDHs, calcium stearate (CaSt2) and β-diketone were carried out in a thermal aging test box by observing the color change. The results showed that Zn-Al-LDHs can not only enhance the stability of PVC significantly due to the improved capacity of HCl-adsorption but also increase the initial stability and ensure good-initial coloring due to the presence of the Zn element. The effects of various amounts of Zn-Al-LDHs, CaSt2 and β-diketone on the thermal stability of PVC were discussed. The optimum composition was determined to be 0.1 g Zn-Al-LDHs, 0.15 g CaSt2 and 0.25 g β-diketone in 5 g PVC.
Zn-Al-LDHs; polyvinyl chloride; stabilizer
A new simple method for synthesis of core/shell CdSe/ZnS nanocrystals (NCs) is present. By adapting the use of cadmium stearate, oleylamine, and paraffin liquid to a non-injection synthesis and by applying a subsequent ZnS shelling procedure to CdSe NCs cores using Zinc acetate dihydrate and sulfur powder, luminescent CdSe/ZnS NCs with quantum yields of up to 36% (FWHM 42–43 nm) were obtained. A seeding-growth technique was first applied to the controlled synthesis of ZnS shell. This method has several attractive features, such as the usage of low-cost, green, and environmentally friendlier reagents and elimination of the need for air-sensitive, toxic, and expensive phosphines solvent. Furthermore, due to one-pot synthetic route for CdSe/ZnS NCs, the approach presented herein is accessible to a mass production of these NCs.
Phosphine-free; CdSe/ZnS; One-pot; Non-injection
Animal experimentation arouses great emotion in many people, perhaps more especially in Britain, and this has increased as more sophisticated medical and non-medical animal experiments are demanded by modern research. The Cruelty to Animals Act of 1876 is the only legal regulation of experiments in animals, and many of its clauses are ambiguous. So in 1963 a committee of enquiry - the Littlewood Committee - was set up. Dr Lane-Petter examines the emotional and factual background to the enquiry, and discusses in an ethical context the usefulness and positive advantages of animal experiments compared with those of possible substitutes and in some detail three of the questions left unanswered by the Littlewood Committee.
The consequences of adventitious infectious agents upon the interpretation of toxicology studies performed in rats and mice are incompletely understood. Several prevalent murine pathogens cause alterations of the respiratory system that can confuse the assessment of chemically induced airway injury. In some instances the pathogenesis of infection with these agents has been relatively well studied in the lower respiratory tract. However, there are few well-controlled studies that have examined the upper respiratory region, which result in interpretive problems for toxicologic pathologists. The conduct and interpretation of both short-term and chronic rodent bioassays can be compromised by both the clinical and subclinical manifestations of infectious diseases. This paper reviews several important infectious diseases of the upper airway of rats and mice and discusses the potential influence of these conditions on the results of toxicology studies.
In addition to the usual toxicology studies necessary for the safe manufacture and use of polymers at room temperature, special studies are needed for polymers which will be used at elevated temperatures. This paper discusses various areas to be investigated and principles for deciding on test materials, tests, and test conditions, polytetrafluoroethylene (PTFE) and fluorinated polyethylene-propylene (PFEP) pyrolysis studies being used as an illustrative case history. Some limitations of animal testing also are mentioned. A toxicological spectrum relating toxicological determinants to PTFE temperature is developed.
For the past three decades, most attention in heavy metal toxicology has been paid to cadmium, mercury, lead, chromium, nickel, vanadium, and tin because these metals widely polluted the environment. However, with the development of new materials in the last decade, the need for toxicological studies on those new materials has been increasing. A group of rare earths (RE) is a good example. Although some RE have been used for superconductors, plastic magnets, and ceramics, few toxicological data are available compared to other heavy metals described above. Because chemical properties of RE are very similar, it is plausible that their binding affinities to biomolecules, metabolism, and toxicity in the living system are also very similar. In this report, we present an overview of the metabolism and health hazards of RE and related compounds, including our recent studies.
The 2011 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was held in Denver, Colorado in advance of the Society of Toxicologic Pathology’s 30th Annual Meeting. The goal of the NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers’ presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting or discussion. Some lesions and topics covered during the symposium include: proliferative lesions from various fish species including ameloblastoma, gas gland hyperplasia, nodular regenerative hepatocellular hyperplasia, and malignant granulosa cell tumor; spontaneous cystic hyperplasia in the stomach of CD1 mice and histiocytic aggregates in the duodenal villous tips of treated mice; an olfactory neuroblastoma in a cynomolgus monkey; various rodent skin lesions, including follicular parakeratotic hyperkeratosis, adnexal degeneration, and epithelial intracytoplasmic accumulations; oligodendroglioma and microgliomas in rats; a diagnostically challenging microcytic, hypochromic, responsive anemia in rats; a review of microcytes and microcytosis; nasal lesions associated with green tea extract and Ginkgo biloba in rats; corneal dystrophy in Dutch belted rabbits; valvulopathy in rats; and lymphoproliferative disease in a cynomolgus monkey.
NTP Satellite Symposium; ameloblastoma; gas gland hyperplasia; stomach cystic hyperplasia; sodium dichromate dihydrate; olfactory neuroblastoma; cynomolgus monkey; adnexal degeneration; parakeratotic hyperkeratosis; oligodendroglioma; microglioma; microcytic hypochromic anemia; microcytosis; spherocytosis; poikilocytosis; green tea; Ginkgo biloba; corneal dystrophy; Dutch belted rabbit valvulitis; valvulopathy; post-transplant lymphoproliferative disease
Stearic acid (stearate) is an 18-carbon saturated fatty acid that has been shown to inhibit invasion and proliferation and induce apoptosis in various human cell types. The specificity of stearate-induced apoptosis for cancerous versus non-cancerous breast cells has not been examined and the mechanism underlying stearate-induced apoptosis is unknown. Morphological analysis, cell viability and caspase-3 activity assays demonstrated that stearate activated apoptosis preferentially in cancerous breast cells in a time and dose dependent manner. Inhibition of de novo diacylgycerol synthesis or protein kinase C (PKC) blocked stearate-induced caspase-3 activity, indicating the involvement of a novel or classical PKC isozyme. To our knowledge this is the first study showing that stearate induces apoptosis preferentially in breast cancer cells and implicates protein kinase C in the signaling cascade. These results raise the possibility of dietary stearate having a beneficial role in the prevention or treatment of breast cancer.
stearate; apoptosis; protein kinase c; diacylglycerol
The objective of this study was to determine the effect of magnesium stearate on the physical stability of polydisperse powder mixtures. The effects of concentration of magnesium stearate and the time of lubrication of mixtures with magnesium stearate on the content uniformity of the active ingredient in the mixtures were evaluated in a model mixture of lactose and aspirin. These effects were compared in a random mixture of non-interacting components and a mixture based on particle interaction. A statistical model that adequately described the relationship between the factors examined and the response was generated. The model indicated the presence of an interaction between magnesium stearate concentration and lubrication time. At a given concentration of magnesium stearate, there was a significant reduction in the content uniformity of aspirin as the time of lubrication of the mixture with magnesium stearate was increased. This effect was larger in mixtures based on particle interaction than in random mixtures of non-interacting components.
magnesium stearate; content uniformity; powder mixtures
AIMS: To assess the efficacy of a bacteriology service in respect of the time interval between collection of specimen and receipt of final report using the number and type of incoming telephone enquiries as a proxy measure. METHODS: For three months, all incoming telephone enquiries regarding the results of bacteriology specimens were monitored. Specimen type, date of sampling, the sender's location and the reason for making the telephone enquiry were recorded. RESULTS: The number of telephone enquiries made during the study was 1170, about 5% of the total number of samples received. Most enquiries related to results of urine cultures. These accounted for 33.9% of the calls, but only 5% of the total number of urines cultured. Enquiries relating to blood cultures were the next largest group accounting for 14.9% of calls, but 11% of the blood cultures received resulted in a telephone enquiry. The most frequent reason for making the telephone call was that the sender had not received the final report. CONCLUSIONS: Clinicians may have unrealistic expectations of the time taken to examine a specimen. A requirement for reporting sterile blood cultures after a shorter incubation period was found, and the value to patient management of earlier reporting of negative urine samples was identified.
Stearate is an 18-carbon saturated fatty acid found in many foods in the western diet, including beef and chocolate. Stearate has been shown to have anti-cancer properties during early stages of neoplastic progression. However, previous studies have not investigated the effect of dietary stearate on breast cancer metastasis. In this study, we present evidence that exogenously supplied dietary stearate dramatically reduces the size of tumors that formed from injected human breast cancer cells within the mammary fat pads of athymic nude mice by approximately 50% and partially inhibits breast cancer cell metastasis burden in the lungs in this mouse model system. This metastatic inhibition appears to be independent of primary tumor size, as stearate fed animals that had primary tumors comparable in size to littermates fed either a safflower oil enriched diet or a low fat diet had reduced lung metastasis. Also stearate fed mice sub-groups had different primary tumor sizes but no difference in metastasis. This anti-metastasis effect may be due, at least in part, to the ability of stearate to induce apoptosis in these human breast cancer cells. Overall, this study suggests the possibility of dietary manipulation with selected long-chain saturated fatty acids such as stearate as a potential adjuvant therapeutic strategy for breast cancer patients wishing to maximize the suppression of metastatic disease.
Breast cancer; dietary fat; metastasis; linoleic acid; stearic acid; stearate
The objective of this study was to characterize the moisture sorption of magnesium stearate and the morphological changes, if any, resulting from moisture sorption. Six samples of commercial magnesium stearate USP were examined. Moisture sorption isotherms were obtained at 25°C and 5% to 98% relative humidity (RH) using a moisture balance. Changes in crystal form resulting from moisture sorption were determined by x-ray diffraction. There were differences in the shape of the isotherm, reversibility of moisture uptake, and shape of the hysteresis loop in the isotherms of crystalline and amorphous magnesium stearates. The isotherm of crystalline magnesium stearate was almost parallel to the pressure axis until and RH of ∼80%. The isotherm of the amorphous sample was characterized by continuous uptake of water over the entire range of RH. Exposure of amorphous magnesium stearate to RH greater than 70% resulted in the formation of the trihydrate. The trihydrate was converted into the anhydrous form when heated to a temperature of 100°C to 105°C. The trihydrate could be generated by exposing the anhydrate to RH higher than 70%.
Moisture sorption; magnesium stearate hydrates; crystalline; amorphous magnesium stearate
Previous studies have shown that stearate (C18:0), a dietary long-chain saturated fatty acid, inhibits breast cancer cell neoplastic progression; however, little is known about the mechanism modulating these processes. We demonstrate that stearate, at physiological concentrations, inhibits cell cycle progression in human breast cancer cells at both the G1 and G2 phases. Stearate also increases cell cycle inhibitor p21CIP1/WAF1 and p27KIP1 levels and concomitantly decreases cyclin-dependent kinase 2 (Cdk2) phosphorylation. Our data also show that stearate induces Ras– guanosine triphosphate formation and causes increased phosphorylation of extracellular signal-regulated kinase (pERK). The MEK1 inhibitor, PD98059, reversed stearate-induced p21CIP1/WAF1 upregulation, but only partially restored stearate-induced dephosphorylation of Cdk2. The Ras/mitogen-activated protein kinase/ERK pathway has been linked to cell cycle regulation but generally in a positive way. Interestingly, we found that stearate inhibits both Rho activation and expression in vitro. In addition, constitutively active RhoC reversed stearate-induced upregulation of p27KIP1, providing further evidence of Rho involvement. To test the effect of stearate in vivo, we used the N-Nitroso-N-methylurea rat breast cancer carcinogen model. We found that dietary stearate reduces the incidence of carcinogen-induced mammary cancer and reduces tumor burden. Importantly, mammary tumor cells from rats on a stearate diet had reduced expression of RhoA and B as well as total Rho compared with a low-fat diet. Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo.
It has been known for some time that zinc, as well as most transition metal ions, is capable of binding to the DNA bases. However, little is known about the presence and distribution of metal binding sites along naturally occurring genomic DNA molecules. In this paper, the interaction of zinc with the Xenopus 5S-RNA gene has been studied and several metal binding sites have been identified on the basis of the changes in chemical reactivity observed in the presence of the metal. The strongest zinc-binding sites of the Xenopus 5S-RNA gene correspond to GGG trinucleotide repeats. Some GG dinucleotides also show a significant affinity for zinc. Interestingly, the binding site for TFIIIA, a zinc-finger transcription factor, contains several sites with strong zinc affinity. In particular, a TGGGA sequence which is essential for the binding of TFIIIA shows the strongest affinity for zinc. The conformational properties of this DNA sequence, together with the high electronegative potential of GGG runs, is likely to determine its strong affinity for zinc. The possible biological relevance of these results is discussed.