Dietary phytochemicals in breast cancer research: anticancer effects and potential utility for effective chemoprevention.

Cancerous tissue transformation developing usually over years or even decades of life is a highly complex process involving strong stressors damaging DNA, chronic inflammation, comprehensive interaction between relevant molecular pathways, and cellular cross-talk within the neighboring tissues. Only the minor part of all cancer cases are caused by inborn predisposition; the absolute majority carry a sporadic character based on modifiable risk factors which play a central role in cancer prevention. Amongst most promising candidates for dietary supplements are bioactive phytochemicals demonstrating strong anticancer effects. Abundant evidence has been collected for beneficial effects of flavonoids, carotenoids, phenolic acids, and organosulfur compounds affecting a number of cancer-related pathways. Phytochemicals may positively affect processes of cell signaling, cell cycle regulation, oxidative stress response, and inflammation. They can modulate non-coding RNAs, upregulate tumor suppressive miRNAs, and downregulate oncogenic miRNAs that synergically inhibits cancer cell growth and cancer stem cell self-renewal. Potential clinical utility of the phytochemicals is discussed providing examples for chemoprevention against and therapy for human breast cancer. Expert recommendations are provided in the context of preventive medicine.

Anti-proliferative and anti-angiogenic effects of CB2R agonist (JWH-133) in non-small lung cancer cells (A549) and human umbilical vein endothelial cells: an in vitro investigation.

Non-small cell lung cancer has one of the highest mortality rates among cancer-suffering patients. It is well known that the unwanted psychotropic effects of cannabinoids (CBs) are mediated via the CB(1) receptor (R), and selective targeting of the CB(2)R would thus avoid side effects in cancer treatment. Therefore, the aim of our study was to evaluate the effect of selective CB(2)R agonist, JWH-133, on A549 cells (non-small lung cancer) and human umbilical vein endothelial cells (HUVECs). Cytotoxicity assay and DNA fragmentation assay were employed to evaluate the influence of JWH-133 (3-(1,1-dimethylbutyl)- 1-deoxy-Δ8-tetrahydrocannabinol) on investigated cancer cells. In addition, migration assay and gelatinase zymography were performed in HUVECs to asses JWH-133 anti-angiogenic activity. Our study showed that JWH-133 exerted cytotoxic effect only at the highest concentration used (10(-4) mol/l), while inhibition of colony formation was also detected at the non-toxic concentrations (10(-5)-10(-8) mol/l). JWH-133 was also found to be able to induce weak DNA fragmentation in A549 cells. Furthermore, JWH-133 at non-toxic concentrations inhibited some steps in the process of angiogenesis. It significantly inhibited endothelial cell migration after 17 h of incubation at concentrations of 10(-4)-10(-6) mol/l. In addition, JWH-133 inhibited MMP-2 secretion as assessed by gelatinase zymography. The present study demonstrates the in vitro anti-proliferative and anti-angiogenic potential of CB(2)R agonist, JWH-133, in nonsmall lung cancer cells and HUVECs. Our results generate a rationale for further in vivo efficacy studies with this compound in preclinical cancer models.

Gp96 and its different expression in breast carcinomas.

The aim of our work was to determine the expression of glycoprotein 96 (gp96; glucose-regulated protein 94 - GRP94) in 69 samples of breast carcinoma. Enzyme immunohistochemical method was chosen for the detection of gp96 protein and its expression was compared in breast cancer cells versus normal breast cells. We found higher expression of gp96 protein in breast carcinoma cells and low or no expression in normal breast cells. Furthermore, we demonstrate first time, that ductal invasive breast carcinomas showed higher expression of gp96 than lobular invasive breast carcinomas.

Multidrug resistance proteins in renal cell carcinoma.

A large number of renal cancer patients show poor or partial response to chemotherapy and the precise mechanism has not been understood yet. MDR is the principal mechanism by which many cancers develop resistance to chemotherapeutic drugs and is associated with the elevated expression of MDR proteins. These are divided into two groups: ABC transporters and non-ABC transporters. The aim of our study was to determine the expression of MDR1/Pgp, MRP1 and LRP in 47 samples of renal cell carcinomas using immunohistochemical assay. Our results were analysed in relation to nuclear grade and other clinical and pathological parameters to see the possible correlation between the expression of MDR proteins and factors mentioned above. The majority of renal carcinoma specimens showed positivity for MDR proteins. In this regard, 21 % of samples revealed positive results for MDR1, 62 % for MRP1 and 76.6 % for LRP protein. Furthermore, our study displayed significant differences between MDR1, LRP and nuclear grade. On the other hand, no association was found between MRP1 and nuclear grade, as well as between the expression of three MDR proteins and other clinically relevant parameters.

Hsp90 inhibitor geldanamycin increases the sensitivity of resistant ovarian adenocarcinoma cell line A2780cis to cisplatin.

Ovarian carcinoma is the leading cause of death among gynecological neoplasms in the world. The chemoresistance is a major obstacle in the effective treatment of ovarian and other cancers. We evaluated the effects of Hsp90 inhibitor geldanamycin (GEL) alone and in combination with cisplatin in cisplatin resistant ovarian adenocarcinoma cell line. Our results showed Akt depletion and S-phase arrest of A2780cis cells after GEL treatment. Combined exposure of A2780cis cells to GEL and cisplatin resulted in greater than additive cytotoxic effect.

RMS roughness-independent tuning of surface wettability by tailoring silver nanoparticles with a fluorocarbon plasma polymer.

A layer of 14 nm-sized Ag nanoparticles undergoes complex transformation when overcoated by thin films of a fluorocarbon plasma polymer. Two regimes of surface evolution are identified, both with invariable RMS roughness. In the early regime, the plasma polymer penetrates between and beneath the nanoparticles, raising them above the substrate and maintaining the multivalued character of the surface roughness. The growth (ß) and the dynamic (1/z) exponents are close to zero and the interface bears the features of self-affinity. The presence of inter-particle voids leads to heterogeneous wetting with an apparent water contact angle θa = 135°. The multivalued nanotopography results in two possible positions for the water droplet meniscus, yet strong water adhesion indicates that the meniscus is located at the lower part of the spherical nanofeatures. In the late regime, the inter-particle voids become filled and the interface acquires a single valued character. The plasma polymer proceeds to grow on the thus-roughened surface whereas the nanoparticles keep emerging away from the substrate. The RMS roughness remains invariable and lateral correlations propagate with 1/z = 0.27. The surface features multiaffinity which is given by different evolution of length scales associated with the nanoparticles and with the plasma polymer. The wettability turns to the homogeneous wetting state.

Influence of age and K, Mg aspartate (Cardilan) on murine haemopoiesis.

We have studied the effect of age as well as the effect of short-term and long-term intake of K and Mg salts of aspartic acid (Cardilan) on haemopoiesis in ICR mice strain. The cellularity of the bone marrow does not change with aging, but the number of granulocyte-macrophage colony-forming cells (GM-CFC) and also the number of spleen colony-forming units (CFU-S) and erythroid burst-forming units (BFU-E) in two-year-old mice increased in the bone marrow. In two-year-old mice the number of leukocytes decreased in the peripheral blood with aging, mainly as a result of a decrease in mononuclear cells. Short-term drinking (STD) of Cardilan caused increased numbers of CFU-S and BFU-E in bone marrow and increased numbers of reticulocytes in the peripheral blood of one-year old animals (STD/12 months old). In the oldest mice (STD/24) increased weight and cellularity of the spleen and rapid increase of leukocytes and reticulocytes in the peripheral blood was recorded. After long-term drinking (LTD) of Cardilan the number of spleen GM-CFC rose markedly in one-year-old mice (LTD/12) and in two-year-old mice (LTD/24) the number of reticulocytes in the peripheral blood rose. Our results indicate that K and Mg salts of aspartic acid influence erythropoietic activity most widely.

Very low sensitivity of Wistar:Han female rats to chemocarcinogens in mammary carcinogenesis induction.

Recently a great variability of various mouse and rat strains in the sensitivity for mammary tumors induction by means of physical (ionizing radiation) or chemical (mostly 7,12-dimethylbenz/a/anthracene, DMBA and N-methyl-N-nitrosourea, NMU) initiating agents was noted. The categorization into four groups was recommended in rats; the first group with high sensitivity (the incidence of tumors practically 100%, the frequency of tumors per entire treated group 2.0), the second with average type of sensitivity (incidence below 100%, frequency between 1.0-2.0), the third with low sensitivity (frequency 0.3-.4) and the fourth with zero sensitivity as the response to single standard dose of DMBA. After initial observations we decided to analyze the sensitivity to mammary carcinogenesis in the female rats of Wistar:Han strain, used frequently in central European region. Twenty mg of DMBA by gavage as single dose, or three-times 10 mg by gavage as repeated consecutive doses in three-day intervals, or 30 mg/kg b.w. of NMU intraperitoneally were administered, always between 50-55 postnatal days (single doses) or between 50-60 days (repeated doses of DMBA). The average incidence of mammary tumors did not exceed 10% and the entire group tumor frequency was about 0.1 for both carcinogens used. The data allowed us to indicate the female Wistar:Han rats as animals with "very low" sensitivity for the initiation of mammary tumors by single dose of DMBA or NMU; being in this way very close to the insensitive strains. The fact of "sensitivity" improvement to higher range after repeated doses of DMBA indicated a non-genetic background of the changed sensitivity. Our results support the need to use more then one rat strain for initiation of mammary carcinogenesis, and for assessing the bright range of the biological response. In this situation the concept of "multi-strain" assay seems to be the optimal.

The influence of melatonin on metabolic changes in female rats induced by continuous irradiation and/or administration of 7,12-dimethylbenz/a/anthracene.

Metabolic profile is an important biological marker of neoplastic processes not only in the tumor itself but also in the host organism. The neurohormone melatonin has been implicated in experiments as an oncostatic agent. Female Wistar:Han SPF rats (Velaz, Prague, Czech Republic) were irradiated continuously for 15 days using a daily gamma rays dose of 96 mGy. At the end of exposure one group of rats was administered 5 mg/kg b.w. of dimethylbenz/a/anthracene (DMBA) intragastrically. During the period of exposure to ionizing radiation a part of the animals was supplied with melatonin (M) at a concentration of 20 microliters/ml in drinking water. Selected parameters of lipid and carbohydrate metabolisms and levels of selected hormones were determined 2, 30 and 100 days post-irradiation. The irradiation itself caused only small changes in tissue lipids. The application of a single low dose (subthreshold from the point of view of induction of mammary tumors) of DMBA caused more pronounced changes in nonirradiated animals; of the changes observed an increase in lipids in the liver, triacylglycerols (TG) in the thymus and decrease in myocardial glycogen predominated. The intake (by drinking) of exogenous M prevented the biochemical pattern of fatty liver in animals administered DMBA in both groups, irradiated and nonirradiated. A prolonged effect of exogenous M, demonstrated by prevention of increase in TG in the thymus and of irradiated animals caused by administration of DMBA, was observed. The mechanism of metabolic effect of M is not known. Additional experiments are needed to explain the relationship between the beneficial effect of M on metabolic changes and its presumable oncostatic effect in rats.

Circadian oscillations of lipid peroxides in the rat pineal gland.

We studied the circadian oscillation of lipid peroxides (TBARS) in the pineal gland of rats adapted to light:dark 12:12 h regimen. The concentration of TBARS was determined at 3-h intervals during 24 hours. TBARS of pineal gland oscillated rhythmically during the 24 h period. The maximal concentration of lipoperoxidative products was found at 20.00 h and 02.00 h and the lowest values at 08.00 h and 23.00 h. The determination of antioxidant capacity is needed for explaining the mechanism of TBARS oscillations in the pineal gland.

Daily rhythm in rat pineal catecholamines.

A daily rhythm in the oscillations of pineal dopamine, norepinephrine and epinephrine content was found in male Wistar: Han rats. The acrophases of the oscillations were localized in the first half of the dark period and generally higher values were found in the dark part of the day.

Circadian and circaannual oscillations of tissue lipoperoxides in rats.

Circadian and circaannual oscillations of tissue lipid peroxides (LPO) were studied in young male Wistar rats. The concentration of malondialdehyde, one of LPO degradation products, was measured at 3-h intervals during 24 hours in rats, adapted to light:dark 12:12 h regimen in the course of the year. LPO in the liver, thymus and bone marrow oscillated rhythmically in the course of the day and year. Circadian oscillations in all tissues were two-peaked, with zeniths at various times of the light and dark parts of the day. In the liver and thymus, the highest mesors were found during the winter, in the bone marrow during the spring. The same holds for amplitude values, with the exception of the bone marrow which exhibited the highest values during the summer. The reason for the LPO oscillations is probably resulting from the changing ratio of pro- and anti-oxidative capacities in various tissues during the day and the year.

Incidence and suggested surgical management of septa in sinus-lift procedures.

A variable number of septa, also referred to as Underwood's septa, divide the floor of the maxillary sinus into several recesses and may thus cause various complications during sinus-lift procedures. The incidence of Underwood's septa was evaluated by examining 41 edentulous maxillas. In 13 of these maxillas (31.7% of the cases), sinus floors with at least one septum were observed. Most of the septa were located in the region between the second premolar and the first molar. A possible cause of septal formation could be the variable phases of maxillary sinus pneumatization of the empty alveolar process following tooth extraction.

Magnetic resonance in lesions of the parotid gland.

In a prospective study the relevance of magnetic resonance (MR) for the diagnoses of tumors of the parotid gland has been evaluated. Due to the excellent soft tissue contrast and also the possibility of imaging in various planes and sections and to the high resolution achieved by surface coils, it was possible to visualize the lesions and the surrounding anatomy in great detail. MR combines the advantages of ultrasound and computed tomography and is indicated if a tumor cannot be defined sharply by using ultrasound or CT.

The edentulous maxillary alveolar process in the region of the maxillary sinus--a study of physical dimension.

From 47 anatomic specimens, vertical sections were cut in the molar region, and computer-assisted measurements of both height and width of the alveolar ridge were made to assess the available bone volume for endosseous implant placement. The mean ridge heights ranged between 9.30 and 3.23 mm, the highest and lowest values being 13.8 and 0.8 mm, respectively. The ridge widths generally proved to be sufficient for placement of endosseous implants. Small knife-edge ridges are rarely found in the posterior maxilla. Reduction of the cancellous portion of the posterior maxilla seems to be influenced by the duration of edentulousness, as well as by osteoporotic changes, without being directly related to ridge configuration and bone volume.

Sonography of nonneoplastic disorders of the salivary glands.

We examined 637 patients with salivary gland disorders by real-time sonography. In 270 patients, the possibility of neoplasia of the salivary glands could not be excluded by ultrasound. In the remaining 367 patients, the following disorders were diagnosed sonographically: acute inflammation (72 patients), Sjögren's syndrome or chronic inflammation (81 patients), abscess (9 patients), sialolithiasis (192 patients), and cysts (13 patients). The present study discusses the ultrasound appearances of a variety of diseases and the indications and limits of sonography in the evaluation of salivary gland pathology.

Reproducibility of three-dimensional CT-assisted model production in the maxillofacial area.

In the mid-eighties, computerised tomography (CT) assisted three-dimensional imaging, and modelling of skull structures was introduced into preoperative diagnosis in maxillofacial surgery. This new method is already being used in the preoperative planning of corrections of post-traumatic defects and craniofacial deformities as well as in tumour surgery and implantology. The aim of the present study was to collect information on the reproducibility of a skull model milled from hardened polyurethane foam, and based on the CT data of a real skull. Thirty one measurements were carried out on the model and on the original skull, leading to the result that the model showed a mean inaccuracy of 1.5 mm. The deviations ranged between 0.0 and 3.6 mm. Generally, the model structures, however, tended to be larger than those of the original. As far as the total of all measurements is concerned, the model deviated from the original skull by 1.6%. A convincing aspect of the model, which cannot be obtained by any other method, is its plasticity and the possibility of 3-D orientation on a lifesize model. However, the study indicates that surgeons using this technique should consider the possible discrepancies between the model and the real skull when making preoperative assessments.

Location of the mandibular canal within the atrophic mandible.

In 43 edentulous, lower jaw halves, sections were carried out in the area between the mental foramen and the third molar. The relative changes in the location and course of the mandibular canal which are caused by atrophy were analysed. For this purpose, the mandibles were classified according to so-called residual ridge orders which describe the different stages of alveolar ridge resorption. The following findings were obtained: The distance between the mandibular canal and the lingual and buccal external border does not change in any stage of the atrophic process, i.e. it remains conspicuously constant. However, the distance between the mandibular canal and the cranial and caudal borders of the body of the mandible partly changes to a statistically highly-significant extent, the distance between the canal and the atrophic alveolar ridge being affected more strongly than that between the canal and the base of the mandible. These changes were most clearly pronounced in the area of the first molar.

Surgical criteria for endosseous implant placement: an overview.

This paper presents an overview of important criteria for successful endosseous implantation. It discusses implant-specific anatomy, preoperative planning, the influence of structure and quality of the available bone on implant prognosis, and the principles of mechanical implant site preparation. The presentation also considers the vitality of adjacent bone, implant surface integrity, local bone defect augmentation, implant selection, and immediate implantation. The learning objective of this article is to enhance the knowledge of surgical and implant site preparation protocol.