[Relationship between benign prostatic hyperplasia and prostate cancer: new opportunities for prostate cancer chemoprevention].

In a review article the relationship between benign prostatic hyperplasia (BPH) and prostate cancer (PC) has been conducted. Epidemiological data on increasing the risk of PC in patients with BPH are presented. There are discussed common for BPH and PC constitutional, food, and life style etiologic factors and also common for the both diseases pathogenetic factors such as androgens, inflammation, metabolic syndrome. Pharmaceutical drugs and natural agents that have unidirectional therapeutic and preventive effect on BPH and PC are presented. Results of experimental studies of the authors to prove the link between BPH and PC are presented. It is concluded that BPH is a risk factor for PC and, ideally, drugs for the treatment of BPH should have a chemo preventive effect on PC.

[Intraperitoneal chemotherapy--a method of improving treatment effectiveness in ovarian cancer].

The study or antitumor effects of dioxadet, cisplatin, melphalan, paclitaxel, mitomycin C, cyclophosphamide and gemcitabine at intraperitoneal (i.p.) and intravenous (i.v.) administration as monochemotherapy and polychemotherapy in a rat model of ascitic ovarian cancer was carried out in 244 female Wistar rats. Ovarian cancer was transplanted i.p. at a number of 1 x 10(7) tumor cells. The drugs were administered once in 48 hours after ovarian cancer transplantation i.p. or i.v. for monotherapy--in maximum tolerated doses, for i.p. polychemotherapy--in half doses from maximum tolerated doses. Antitumor effects of the treatment were estimated in increase in median survival time (MST) compared to control rats who were administered saline i.p. At i.p. administration dioxadet, cisplatin and melphalan increased MST by 79%, 88% and 144%, respectively, while at i.v. administration these drugs didn't affect MST. Mitomycin C and paclitaxel had stronger antitumor action at i.v. administration increasing MST by 152% and 81%, respectively, while at i.p. administration these drugs increased MST by 35 and 45%, respectively. Combinations dioxadet + cisplatin, dioxadet + cyclophosphamide and dioxadet + paclitaxel at i.p. administration increased MST by 305%, 277% and 133%, respectively, and had additive antitumor action compared to mono-effects of these drugs. Gemcitabine and combination dioxadet + gemcitabine at i.p. administration didn't significantly affect survival of rats with ovarian cancer. Intraperitoneal monochemotherapy and polychemotherapy could be more effective in the treatment of peritoneal carcinomatosis from ovarian cancer compared to systemic administration of the drugs.

[Therapeutic activity of gemcitabine in intracranial tumors].

Gemcitabine is known to exert a therapeutic effect on brain tumors despite the limited permeability of the blood-brain barrier (BBB). In our experimental research single intraperitoneal (i.p.) injection of gemcitabine 25 mg/kg provided increase in median survival of mice with intracranially transplanted Ehrlich carcinoma by 41-89% (p < 0.001). In this experimental model i.p. administration of gemcitabine (permeability of the BBB of less than 10%), carmustine (good permeability of the BBB), cyclophosphamide (poor permeability of the BBB) and cisplatin (doesn't penetrate through the BBB) increased median survival of mice by 88% (p < 0.001), 59% (p = 0.001), 35% (p = 0.005) and 18% (p = 0.302) respectively. Considering strong correlation between antitumor activity of the drugs (carmustine, cyclophosphamide and cisplatin) and their permeability of the BBB, efficacy of gemcitabine in intracranial tumors could be due to its wide range of therapeutic doses.

Confinement effects for ionic carriers in SrTiO3 ultrathin films: first-principles calculations of oxygen vacancies.

One-dimensional confinement effects are modelled within the hybrid HF-DFT LCAO approach considering neutral and single-charged oxygen vacancies in SrTiO(3) ultrathin films. The calculations reveal that confinement effects are surprisingly short-range in this partly covalent perovskite; already for film thickness of 2-3 nm (and we believe, similar size nanoparticles) only the surface-plane defect properties differ from those in the bulk. This includes a pronounced decrease of the defect formation energy (by ∼1 eV), a much deeper defect band level and a noticeable change in the electronic density redistribution at the near-surface vacancy site with respect to that in the bulk. The results also show that the size effect pertains to the interactions between the oxygen vacancy and two neighboring titanium atoms and orientation (parallel or perpendicular to the surface) of the Ti-V(O)-Ti complex. In particular, we predict considerable oxygen vacancy segregation towards the surface.

Ab initio modeling of spin and charge ordering and lattice dynamics in CaFeO(3) crystals.

Results of first-principles simulations on both orthorhombic and monoclinic phases of CaFeO(3) crystal are presented. The obtained atomic structures are consistent with x-ray diffraction data. The transition from a metallic orthorhombic to a narrow-gap semiconducting monoclinic phase is ascribed to the larger distortion of the Fe-O-Fe bond angle in the latter case. Calculations of Raman and optic active phonon modes at the Gamma point of the Brillouin zone are performed and discussed. The isotopic substitution technique is applied to analyze the vibration modes obtained. The found charge/spin disproportionation is analyzed and compared with available experimental estimates.

Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder.

To expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng's Shank3tm2Gfng model, hereafter Shank3/F, Jiang's Shank3tm1Yhj model, hereafter Shank3/J and the Cacna1c deletion model. The Shank3 models mimick gene mutations associated with Phelan-McDermid Syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. This study utilizes both standard and novel behavioral tests with the same methodology used in our previously published companion report on the Cntnap2 null and 16p11.2 deletion models. We found that some but not all behaviors replicated published findings and those that did replicate, such as social behavior and overgrooming in Shank3 models, tended to be milder than reported elsewhere. The Shank3/F model, and to a much lesser extent, the Shank3/J and Cacna1c models, showed hypoactivity and a general anxiety-like behavior triggered by external stimuli which pervaded social interactions. We did not detect deficits in a cognitive procedural learning test nor did we observe perseverative behavior in these models. We did, however, find differences in exploratory patterns of Cacna1c mutant mice suggestive of a behavioral effect in a social setting. In addition, only Shank3/F showed differences in sensory-gating. Both positive and negative results from this study will be useful in identifying the most robust and replicable behavioral signatures within and across mouse models of autism. Understanding these phenotypes may shed light of which features to study when screening compounds for potential therapeutic interventions.

Prefrontal control of respiration.

The aim of the present study was to test the hypothesis that different parts of the prefrontal cortex could be involved in respiratory control. This hypothesis was tested by examining the changes in respiratory pattern produced by low intensity electrical stimulation of the insular and infralimbic cortex. The experiments were performed on the anaesthetised rats. It was found that the sites capable of inducing different kinds of respiratory responses were localized to the insular and infralimbic cortices. Microstimulation of the anterior insular cortex produced responses which manifested themselves in a decrease of inspiratory flow and tidal volume, but the respiratory time remained stable. Responsive sites within caudal insular and infralimbic cortex produced other alterations in breathing which included an increase of inspiratory flow, and decreases of tidal volume and respiratory time. These observations support the hypothesis proposed and localize distinct patterns of respiratory responses to different parts of the prefrontal cortex in the rat.

PartsList: a web-based system for dynamically ranking protein folds based on disparate attributes, including whole-genome expression and interaction information.

As the number of protein folds is quite limited, a mode of analysis that will be increasingly common in the future, especially with the advent of structural genomics, is to survey and re-survey the finite parts list of folds from an expanding number of perspectives. We have developed a new resource, called PartsList, that lets one dynamically perform these comparative fold surveys. It is available on the web at http://bioinfo.mbb.yale.edu/partslist and http://www.partslist.org. The system is based on the existing fold classifications and functions as a form of companion annotation for them, providing 'global views' of many already completed fold surveys. The central idea in the system is that of comparison through ranking; PartsList will rank the approximately 420 folds based on more than 180 attributes. These include: (i) occurrence in a number of completely sequenced genomes (e.g. it will show the most common folds in the worm versus yeast); (ii) occurrence in the structure databank (e.g. most common folds in the PDB); (iii) both absolute and relative gene expression information (e.g. most changing folds in expression over the cell cycle); (iv) protein-protein interactions, based on experimental data in yeast and comprehensive PDB surveys (e.g. most interacting fold); (v) sensitivity to inserted transposons; (vi) the number of functions associated with the fold (e.g. most multi-functional folds); (vii) amino acid composition (e.g. most Cys-rich folds); (viii) protein motions (e.g. most mobile folds); and (ix) the level of similarity based on a comprehensive set of structural alignments (e.g. most structurally variable folds). The integration of whole-genome expression and protein-protein interaction data with structural information is a particularly novel feature of our system. We provide three ways of visualizing the rankings: a profiler emphasizing the progression of high and low ranks across many pre-selected attributes, a dynamic comparer for custom comparisons and a numerical rankings correlator. These allow one to directly compare very different attributes of a fold (e.g. expression level, genome occurrence and maximum motion) in the uniform numerical format of ranks. This uniform framework, in turn, highlights the way that the frequency of many of the attributes falls off with approximate power-law behavior (i.e. according to V(-b), for attribute value V and constant exponent b), with a few folds having large values and most having small values.

Phenozan, a Synthetic Phenolic Antioxidant, Inhibits the Development of Spontaneous Tumors in Rats and Mice.

Synthetic phenolic antioxidant ß-(4-hydroxy-3,5-di-tert-butylphenyl) propionic acid, named phenozan, is a potential antiepileptic drug. In pre-clinical trials this substance did not manifest any toxicity, and also inhibited the development of some spontaneous tumors in animals. The purpose of this study was to evaluate inhibiting effect of phenozan on spontaneous carcinogenesis in rats and mice. In experiments with rats LIO and mice SHR of local breeding, with high spontaneous tumor incidence, phenozan was dissolved in sunflower oil and administered by gavage in therapeutic dose 5 mg/kg 3 times per week for 18 months. There were no any signs of toxicity and differences in weight of animals during the phenozan treatment compared with the control (sunflower oil). Phenozan significantly reduced the overall incidence and multiplicity of all tumors but only multiplicity of malignant tumors, compared with the control. Moreover a significant decrease of overall incidence and multiplicity was observed in pituitary and breast tumors in females and only overall multiplicity of tumors of pituitary and lymphoid tissue in males. In mice phenozan reduced overall incidence and multiplicity of lung tumors (in females) and also overall multiplicity of all tumors (in females) and only malignant tumors (in males). These findings allow us to classify phenozan as anticarcinogenic agent. Anticarcinogenic activity of phenozan is important because clinical study of this drug as the possible antiepileptic drug goes along and it is known that such drugs are designed for long-term use.

Glucose consumption, newborn weight and nitrosomethylurea transplacental carcinogenesis in rats.

This study used rats bred at the Petrov Research Institute of Oncology. On the 21st day of pregnancy N-nitrosomethylurea (NMU) (20 mg/kg) was administered to the animals intraperitoneally. From the 7th day of pregnancy experimental rats were treated with 10% glucose solution instead of drinking water, and during 1.5 months after delivery the rats of this group and their progeny received 5% glucose solution. The present work has revealed an increase of fetal weight in pregnant rats treated with glucose. A significant increase of tumor frequency was detected in the progeny of these rats. In the male progeny, tumors of the nervous system and kidneys, typical for NMU, predominated and in females, tumors of other organs and tissues, particularly the mammary gland, pituitary body and hemopoietic system, predominated. This paper discusses a possible mechanism of the modifying effect of glucose on transplacental carcinogenic action of NMU.

Transplacental carcinogenic effect of n-nitrosoethylurea in dogs.

During the late period of pregnancy (on the 50th and 53rd days post coitum) 2 dogs were injected intraperitoneally with 100 mg/kg (a single administration) of nitrosoethylurea. Nine puppies were born. During the 9 year period of observation no tumours were detected in mother-dogs. Three of 9 offspring developed the following tumours: brain haemangioblastoma (on the 526th day after administration), nephroblastoma and spleen angioleiomyoma (on the 845th day after administration) and adenoma of thyroid gland (after 7 years). Among other lesions 3 offspring-dogs developed polycystic kidneys. The revealed tumours of brain, kidney and spleen could be connected with transplacental carcinogenic effect of N-nitrosoethylurea (NEU), while neoplasms of these localizations and types rarely occur in dogs spontaneously.

The stimulating effect of acetic acid, alcohol and thermal burn injury on esophagus and forestomach carcinogenesis induced by N-nitrososarcosin ethyl ester in rats.

Five groups of outbred white male rats were given N-nitrososarcosin ethyl ester (NSEE) i.g. for 4 or 6 months at a daily dose of 50 mg/kg of body wt. 5 days/week. Some groups of animals were given a 3% water solution of acetic acid or a 40% solution of ethanol i.g. for 8 months from the beginning of the experiment. The remaining groups of these rats received controlled local thermal burn injury of the esophageal mucosa 15 days before the beginning of the experiment. Acetic acid solution increased the multiplicity of benign and malignant tumors as well as carcinoma incidence in the esophagus. Ethanol in combination with NSEE did not influence carcinogenesis in the esophagus but increased the incidence of leukokeratosis and the multiplicity of forestomach papillomas. In rats treated with NSEE after thermal burn injury, a significant increase in the frequency and multiplicity of papillomas was found in the burn zone.

Study of postnatal effects of chemopreventive agents on offspring of ethylnitrosourea-induced transplacental carcinogenesis in rats. I. Influence of retinol acetate, alpha-tocopherol acetate, thiamine chloride, sodium selenite, and alpha-difluoromethylornithine.

We studied the influence of the vitamins retinol acetate, alpha-tocopherol acetate and thiamine chloride; the antioxidant sodium selenite and an inhibitor of polyamine biosynthesis, alpha-difluoromethylornithine, on the offspring of transplacental carcinogenesis by ethylnitrosourea in rats. Ethylnitrosourea was given to pregnant rats as a single i.v. injection, at a dose of 75 mg/kg body wt. or 5.5 mg/kg body wt., on the 21st day after conception. Retinol, tocopherol or thiamine was added to the diet, and selenite and alpha-difluoromethylornithine to drinking water of the offspring throughout their postnatal life at moderate doses. In control groups, ethylnitrosourea induced tumors of brain, spinal cord, peripheral nervous system and kidneys in the offspring. alpha-Difluoromethylornithine exerted a slight inhibitory effect; this agent decreased the total tumor multiplicity and the multiplicity of peripheral nervous system tumors and also prolonged survival time. Retinol, tocopherol, thiamine and selenite did not influence the development of the transplacentally-induced tumors.

Perioperative myocardial protection with the calcium antagonist diltiazem.

The effect of the calcium channel blocker, diltiazem, on cardiac performance was examined in 90 patients who underwent isolated aortic valve replacement for aortic valve diseases with marked left ventricular hypertrophy. The patients were randomly assigned to one of five groups dependent on the treatment plan with diltiazem: group 1, 5-day preoperative treatment with oral administration of 60 mg diltiazem 3 times daily, 10 mg diltiazem intravenously as a bolus dose before the beginning of the cardiopulmonary bypass, and 5 mg diltiazem intravenously 10 min before removal of aortic clamp; group 2, 5-day preoperative treatment with oral administration of 60 mg diltiazem 3 times daily; group 3, 10 mg diltiazem intravenously as a bolus dose before the beginning of CPB and 5 mg 10 min before removal of the aortic clamp; group 4, 15 mg diltiazem in 1000 ml cardioplegic solution, given as additive; group 5, control group not receiving diltiazem. All operative procedures were performed in an identical manner with an average cross-clamping time of 57.7 min and cooling the heart down to 16 degrees-17 degrees septal temperature by perfusion of the coronary arteries with 4 degrees C cold cardioplegic solution. In each patient the heart rate (HR), cardiac output and cardiac index (CO, CI), stroke volume index (SVI), left ventricular stroke work index (LVSWI) and systemic vascular resistance index (SVRI) were recorded and calculated before and after the ischemic period. Transmural samples were obtained three times by needle biopsy technique from the anterior free wall of the heart. Analysis of the variables revealed that: (1) complete cessation of electromechanical activity was achieved significantly more rapidly in groups 1 and 3 than in the other groups; (2) recovery of sinus rhythm and function of the conductive system required significantly longer in groups 1 and 3; (3) the time-related values of the important hemodynamic factors (CO, CI, LWSVI and SVRI) showed a significantly more effective postperfusion cardiac performance in groups 1 and 3 than in groups 2, 4 and 5. An oral dose of 180 mg diltiazem for 5 to 7 days preoperatively in combination with intravenous administration of 10 mg before the beginning of CPB and 5-10 mg during reperfusion can be recommended in patients undergoing open-heart surgery for isolated aortic valve diseases and left ventricular hypertrophy.

Some results and prospects of transplacental carcinogenesis studies.

Analysis of literary data and the author's findings have shown that the transplacental action of most of the compounds tested in experiments on rats manifested itself by a neurotropic carcinogenic effect. A marked neurotropism in transplacental carcinogenesis in rats is characteristic even for such drugs (e.g. dimethylbenzathracene) that have never induced neurogenic neoplasms in adult animals. To elucidate the relationship between teratogenesis and carcinogenesis the peculiarities of tumor development in brain against the background of malformations induced by combined transplacental treatment by methylnitrosourea (MNU) and ethylnitrosourea (ENU) in rats have been studied. Tumorigenesis was sharply inhibited by administration of ENU (on the 13th day) prior to MNU treatment (on the 15th day). There is reason to believe that the cytotoxic effect of MNU for microephaly results in the death of a considerable part of the cell population already transformed by ENU. In a special series of experiments characteristics of the permeability of polycyclic aromatic hydrocarbons through the placenta in rats have been specified.

Nephroblastoma and renal mesenchymal tumor induced in rats by N-nitrosoethyl- and N-nitrosomethylurea.

Rats treated prenatally with N-nitrosoethylurea or with N-nitrosomethylurea developed nephroblastomas, renal mesenchymal tumors and epithelial tumors (adenomas and carcinomas) of the kidneys. 15 nephroblastomas and 59 mesenchymal tumors were examined histologically. Nephroblastomas were encapsulated growths composed of dark cells, forming primitive tubules similar to those seen in the rat embryonal kidney and in human Wilms' tumor. Mesenchymal renal tumors showed an infiltrative growth and consisted of fibroblast-like cells, smooth muscles and angiomatous areas with the engulfed pre-existing tubules. These growths are similar to the mesenchymal renal tumors induced in the rat by N-nitrosodimethylamine. Nephroblastoma and mesenchymal renal tumor are considered to be separated entities, the first corresponsing to the epithelial variant of human Wilms' tumor and the second to congenital mesoblastic nephroma.

Modifying factors in prenatal carcinogenesis (review).

A description of the experimental approaches devised to control the growth of tumors induced by transplacental exposure to carcinogens is given. Due to the massive cell proliferation and differentiation taking place during embryogenesis, fetal tissues are believed to be privileged targets of neoplastic changes. As a consequence, trace amounts of environmental carcinogens capable of accumulating into the conceptuses may determine the appearance of tumors in the offspring, a possibility documented in several animal species including humans. Endogenous and exogenous factors counteracting this process have potential application as regulators of developmental carcinogenesis. Their identification is regarded as a means to chemoprevent pediatric tumors and can be instrumental in the analysis of the aetiopathogenesis of neoplastic phenotypes.