The ceramide analog, B13, induces apoptosis in prostate cancer cell lines and inhibits tumor growth in prostate cancer xenografts

BACKGROUND: Apoptosis is a therapeutic target for the elimination of cancer cells. As elevations in ceramide levels induce apoptosis, there is much excitement about the use of agents that elevate ceramide levels as novel chemotherapeutic agents. Ceramidases are enzymes involved in degradation of ceramide and inhibition of ceramidase has been proposed as a mechanism to increase ceramide levels. This study provides the first insight into the effect of B13, an inhibitor of acid ceramidase, on human prostate cancer cell lines and xenografts. METHODS: Cell death was evaluated by the trypan blue assay; apoptosis by the Apo2.7 apoptosis assay; and glutathione levels by HPLC. Tumors were irradiated with a dose of 5 Gy of X-rays (250 kVp, 15 mA, 2 Gy/min) and tumor volume was measured during the course of the experiment. At the conclusion of the experiment, tumor weight was determined and the tumors were evaluated histologically. RESULTS: B13 is an inducer of cell death, by apoptosis, in cultured prostate cancer cells. LNCaP and PC3 cells have different responsiveness to the enantiomers of B13. In LNCaP cells, the R enantiomer of B13 (10 microM) was significantly more effective than the S enantiomer at inducing cell death as determined by the trypan blue assay, culminating in approximately 90% cell death at 48 hr. In contrast, the same concentration of B13S induced <20% cell death at 48 hr. In PC3 cells, the S enantiomer was a more effective inducer of cell death, culminating in approximately 30% cell death, relative to 14% for B13R in this model. Evaluation of induction of apoptosis by the Apo2.7 mitochondrial assay confirmed that this induction of cell death was by apoptosis. Concurrent with induction of apoptosis, glutathione levels drop in response to B13. Specifically, B13R caused a significant drop in glutathione levels in LNCaP cells, culminating in a reduction to 40% control values at 48 hr. In PC3 cells, in contrast, the drop in glutathione levels was more dramatic, culminating in a drop to 12% control values in response to B13S at 48 hr. The effects of B13R, however, were not significantly different from control values. In in vivo studies using a model of xenografted androgen-insensitive prostate cancer, B13 sensitized the tumors to the effects of radiation, resulting in a significant reduction in tumor volume and weight after treatment with the combination of B13 and radiation. Microscopic evaluation of the tumors indicated that apoptosis was the primary mechanism of this effect. CONCLUSIONS: Targeting ceramide pathways may be a novel treatment strategy for hormone refractory prostate cancer.     

Tuberculosis of the larynx and pharynx in hospitalized patients in ENT Department of Voivodeship Hospital in Kalisz

8 cases of tuberculosis were presented in this paper. Two patients had changes in the larynx and pharynx and one patient had pharyngeal tuberculosis and squamous carcinoma of epiglottis. Further specialty investigations e.g. MDL, biopsy, histopathological and bacteriological examinations were done and revealed proper diagnosis tuberculosis. Etiology, pathogenesis, diagnostic were described. Changes of tuberculosis were in unusual location. All patients were treated tuberculostatic drugs.     

Microstructure of tympanic membrane in chronic otitis media: immunohistochemical evaluation

Chronic otitis media (COM) is an inflammatory process involving the middle ear mucosa and the tympanic membrane. The healing and epidermization is mostly impaired by immunological response of the host. Investigating the activity and the function of immunological response elements one can learn the immunological mechanisms taking place in chronic otitis media. The ultrastructural investigations of the tympanic membrane were done on its fragments obtained from 19 patients with COM during middle ear surgery, performed at ENT Department of Medical University of Gdańsk in the years 1997-1999. Immunohistochemical investigations were performed using monoclonal antibodies against tenascin, S-100 protein, Ki 67, CD 31, F VIII, HLA-DR, TGFbeta1 and EGFR. The control group was 11 healthy tympanic membranes from cadavers. The presence of tenascin was proven in all COM tympanic membranes and in 45.5% of those from control group. S-100 protein was present in 88.9% of the patients with COM and absent in control group. Ki 67 was observed in 44.4% of the patients with COM and in 27.3% of the healthy tympanic membranes. Angiogenesis factors (CD 31 and FVIII) were present in 77.8% of the investigated COM tympanic membranes, in control group in 45.5%. HLA-DR expression was observed in 90% COM patients, in control group in 72.7%. Growth factor TGFbeta1 was present in the all cases in mucous and fibrous layer and in 54.5% of healthy tympanic membranes. EGF receptor was present in 60% of COM patients, mainly in epithelial layer of tympanic membrane and in 54.5% of those from control group. The presented investigations confirm the immunological activity of tympanic membrane in chronic otitis media.     

The giant osteoma of the ethmoid labyrinth in the patient cured in 1991 year

A 52-year-old female patient is described who was aperated upon for a giant osteoma involving the right side ethmoid labyrinth bulging into the orbit shifting the eyeball, passing into right of the frontal and sphenoidal sinuses. We obtained complete cure and good cosmetic result.     

Dietary secoisolariciresinol diglucoside and its oligomers with 3-hydroxy-3-methyl glutaric acid decrease vitamin E levels in rats

Secoisolariciresinol diglucoside (SDG) is an important dietary lignan that is found at very high levels in flaxseed (1-4 %, w/w). Flaxseed lignans have received much research interest in recent years because of reported phyto-oestrogenic, anticarcinogenic, and anti-atherogenic effects. Previously, flaxseed feeding has been shown to decrease vitamin E concentrations in rats despite the antioxidant potential of SDG in vitro. Sesamin, a sesame lignan, on the other hand has been shown to increase vitamin E concentrations in rats. The aim of the present study was to investigate the effect of dietary SDG and its oligomers on vitamin E and cholesterol concentrations in rats. SDG was extracted from defatted flaxseed flour with a dioxane-ethanol mixture and purified by silica column chromatography. The major oligomers with 3-hydroxy-3-methyl glutaric acid, containing a high ratio of SDG to p-coumaric and ferulic acid glucosides, were purified from the extracts by reversed-phase liquid chromatography. When fed to rats at 0.1 % in the diet for 27 d, both SDG and its oligomers had no effect on animal performance but caused an increase in liver cholesterol and a 2-fold reduction in the levels of alpha- and gamma-tocopherols in rat plasma and liver. It is notable that a phenolic antioxidant, such as SDG, causes a vitamin E-lowering effect in rats. This cannot be explained at present, but warrants further investigations with respect to the magnitude, mechanism, and significance of the observed effect for human nutrition.     

The validity of questionnaire-based micronutrient intake estimates is increased by including dietary supplement use in Swedish men

Although many validation studies of FFQ have been reported, only a few addressed the effect of inclusion of dietary supplement use on the validity of micronutrient estimates. The purpose of the present study was to assess reproducibility and validity of a self-administered FFQ, intended to measure total nutrient intake from diet and from dietary supplements, in a random population-based sample of 248 middle-aged and elderly men (40-74 y old) in central Sweden. Fourteen 24-h recall interviews were used as the reference method. Participants were telephoned about once a month for 1 y, covering every day of the week, twice in random order. Spearman correlation coefficients increased 13% (from 0.49 to 0.62), between FFQ-based micronutrient estimates and the fourteen 24-h recall interviews (reference method) when supplement use was included. Correct classification into highest quintiles was also improved by 14% (from 37 to 51%). There were no differences in mean intraclass correlation coefficients for 1-y reproducibility between total micronutrient intake and micronutrients from foods only. The increase in the validity of micronutrient estimates due to inclusion of supplements in nutrient intake assessment has important implications for sample size in epidemiologic studies. Because a dramatic increase in dietary supplement use has occurred in recent decades in many countries, the issue of including supplements in dietary assessment should be of highest priority in nutritional epidemiologic studies of chronic diseases.     

Drug evolution concept in drug design: 1. Hybridization method

A novel concept, "drug evolution", is proposed to develop chemical libraries that have a high probability of finding drugs or drug candidates. It converts biological evolution into chemical evolution. In this paper, we present "hybridization" drug evolution, which is the equivalent of sexual recombination of parental genomes in biological evolution. The hybridization essentially shuffles the building blocks of the parent drugs and ought to drug(s); no drug evolution can otherwise occur. We hybridized two drugs, benzocaine and metoclopramide and generated 16 molecules that include the parent drugs, four known drugs, and two molecules whose therapeutic activities are reported. The unusually high number of drugs and drug candidates in the library encourages high expectations of finding new drug(s) or drug candidate(s) within the remaining eight compounds. Interestingly, the therapeutic applications of the eight drugs or drug candidates in the library are fairly diverse as 38 therapeutic applications and 25 molecular targets are counted. Therefore, the library fits as a general chemical library for unspecified therapeutic activities. The hybridization of other two drugs, aspirin and cresotamide, is also described to demonstrate the generality of the method.     

Alcohol intake and risk of non-Hodgkin lymphoma in men and women

Objective: The effect of alcohol intake on risk of NHL is unclear. We therefore conducted a population-based case-control study to examine the association between alcohol and NHL risk. Methods: 613 NHL cases and 480 population controls in Sweden reported their average consumption of beer, wine, and liquor 2years before the study. Unconditional logistic regression was used to estimate the odds ratios (OR) and corresponding 95% confidence intervals (CI) for associations between alcohol intake and NHL risk. Results: Intake of total alcohol, beer, wine, or liquor was not associated with risk of overall NHL. There was no difference in risk of NHL among those who habitually consumed above 19.1g of ethanol per day, compared to those who consumed on average 0–2.2g of ethanol per day (OR = 1.2 (95% CI: 0.8, 1.7); p _trend = 0.29). However, the association was significantly positive among males (OR = 1.8 (95% CI: 1.1, 2.9); p _trend = 0.06). Total alcohol, beer, wine, or liquor intake was not associated with any major histopathologic subtype of NHL examined, apart from an association between high wine consumption and increased risk of chronic lymphocytic leukemia. Conclusions: Alcohol does not appear to be a major etiologic factor for overall NHL, nor its common subtypes.