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The gestagenic and antiandrogenic drug cyproterone acetate (CPA is mitogenic, tumorigenic and induces DNA-adducts and DNA-repair synthesis in rat liver. Thus CPA is expected to be mutagenic. However in vitro mutagenicity test systems were negative. To examine whether CPA induces mutations in rat liver, the in vivo mutation assay based on Big Blue™ transgenic F344 rats was employed. Single oral doses of 25, 50, 75, 100 and 200 mg CPA/kg b.w. respectively were administered to female Big Blue™ rats. Six weeks after treatment, liver DNA was assayed for mutations. At the highest dose, 200 mg CPA/kg b.w., the frequency of (17 ± 4) x 10-6 spontaneous mutations was increased to a maximum of (80 ± 8) x 10-6 mutations. One-hundred and 75 mg CPA/kg b.w. resulted in mutation frequencies of (35 ± 5) and (27 ± 5) x 10-6, respectively. The mutation frequency at doses of 50 and 25 CPA/kg b.w. was similar to that of vehicle treated controls. Statistical analysis of the dose-effect relationship revealed that it was not possible to decide whether a threshold dose exists or not. DNA adducts were analyzed by the 32P-postlabelling technique. The total level of the major and the two minor adducts observed in the autoradiograms increased between doses of 25 to 75 mg CPA/kg b.w. to a maximum of 12 000 ± 3000 adducts per 109 nucleotides. The level did not further increase significantly with 100 and 200 mg CPA/kg b.w. After CPA treatment no preneoplastic liver foci were observed. However, single glutathione-S-transferase placental form (GST-P) positive hepatocytes were observed and the frequency was dependent on the dose. These cells are not supposed to represent initiated cells, since they occurred only transiently after 6 weeks and disappeared thereafter completely. In conclusion, our results demonstrate that CPA is mutagenic in vivo. The mutation frequency increased at high CPA doses, when the increase of the DNA adduct formation had already ceased. This suggests that the mitogenic activity of CPA is required to express the mutations. [ABSTRACT FROM PUBLISHER]

Three rat liver foci bioassays have been compared with respect to their sensitivity by the histochemical demonstration of preneoplastic foci, and by the biochemical determination of alterations in enzyme activities of serum indicating hepatotoxicity. We studied the initiation/promotion schedules according to Oesterle and Deml (A), and according to Pereira (B, Broad Spectrum Protocol), and the initiation/selection protocol according to Tatematsu . (C), with diethyl nitrosamine (DEN), given as a single initiating dose of 10 and 30 mg/kg body wt respectively. With all schedules Sprague-Dawley rats, either females, 3 weeks old (A), or males, 6 weeks old (B, C) were used. For promotion polychiorinated biphenyls (A) or phenobarbital (B) were administered. Selection was performed with 2-acetylaminofluorene (C). The rats in schemes (B) and (C) underwent partial hepatectomy one day prior to initiation. The number and total area of foci deficient in adenoslne-5'-triphosphatase (ATPase) and positive in γ-glutamyttranspeptidase (GGTase) was evaluated. In the complete schedule with 30mg of DEN in system (A) foci incidence exceeded that of the other systems by about 7-fold (ATPase) and 2-fold (G.GTase) respectively. The tower dose of DEN and all control experiments resulted In a respective lower foci yield. With scheme (C), but not with schemes (A) and (B), e.g. serum fructose-1.6-bisphosphatase and alkaline phosphatase were increased, suggesting liver cell damage. Thus tested with DEN, scheme (A) is most sensitive and causes a low impairment of animals' welfare. [ABSTRACT FROM PUBLISHER]

Objectives: The current study examined the association between alcohol use frequency (ie, days a week one consumes alcohol), sexual and gender identity, and bystander confidence to intervene in interpersonal violence (ie, bystander self-efficacy). Participants: Participants were 750 undergraduate students aged 18-25 (260 heterosexual men, 260 heterosexual women, 59 SM men [54 cisgender, 5 transgender men], and 171 SM women [169 cisgender, 2 transgender women]). Methods: Participants completed an online survey about alcohol and sexual behaviors. Results: Results indicated that (1) alcohol use frequency was positively associated with greater bystander self-efficacy, (2) heterosexual men, compared to heterosexual women, reported lower bystander self-efficacy, and (3) the association between alcohol use frequency and bystander self-efficacy was significant and positive among heterosexual, but not SM, women. Conclusions: Prevention efforts may benefit from targeting individuals who drink more frequently and ensuring that they have the skills to effectively intervene.

Sexual assault is a significant problem within the United States military. Bystander intervention skills training is recognized as a promising strategy for sexual assault prevention within both civilian and military populations. Sexual assault prevention programs which include training in bystander intervention teach individuals to notice situations that may pose a risk for harm and safely act to positively influence the outcome. This study examines correlates of bystander intervention attitudes and intentions among young adult active duty male soldiers (N = 282) between the ages of 18 and 24. Positive bystander intervention attitudes and intentions were associated with lower levels of rape myth acceptance, greater discomfort with sexism, lower likelihood of continuing an unwanted sexual advance after verbal resistance from a partner, greater likelihood of gaining verbal consent from a partner, and greater perceived peer approval for bystander intervention. In a multiple regression, perceived peer approval for bystander intervention and self-reported lower likelihood of continuing a sexual advance after verbal resistance from a partner emerged as significant predictors of positive bystander intervention attitudes and intentions (R 2 = .41). Given that perceptions of peer norms are modifiable, these findings highlight the importance of addressing peer norms in bystander intervention training programs for military personnel.

The present study examined the mediating role of sexual assertiveness in the relationship between psychological, physical, and sexual intimate partner violence (IPV) victimization and unprotected sex as a result of condom use resistance among sexually active young women attending community college. Women reported engagement in unprotected sex as a result of a partner's use of one of 32 forms of condom use resistance (e.g., physical force, deception, or other forms of coercion to avoid using a condom during intercourse). Women ages 18-24 years (N = 212) attending community college were recruited through paper advertisements to complete assessments of social and dating behavior in the campus computer laboratory. Only the women with a history of sexual intercourse (N = 178; 84% of the sample) were included in analyses. More frequent engagement in unprotected sex as a result of a partner's condom use resistance was associated with physical, psychological, and sexual IPV victimization. Sexual assertiveness mediated the relationship between physical IPV victimization and the frequency of unprotected sex as a result of condom use resistance. Efforts to prevent dating violence and enhance the sexual health of community college women may benefit from focusing on targeting sexual assertiveness as a protective factor.

Despite the prevalence of sexual assault on college campuses, few interventions aimed at decreasing college men's proclivity to perpetrate sexual aggression have been developed and tested. This article details the theoretical framework, content, and piloting of a sexual assault prevention program for college men who engage in heavy drinking, a high-risk group who may be particularly well positioned to intervene as proactive bystanders in drinking environments. In an open trial, male facilitators delivered the three-session Sexual Assault and Alcohol Feedback and Education (SAFE) program to 25 heavy drinking college men. Session 1 was a 90-min review of personalized normative feedback regarding alcohol use, sexual activity, alcohol-related sexual consequences, understanding of consent, and engagement in bystander intervention, delivered individually in a motivational interviewing style. Session 2 was a 2½-hr group-based sexual assault prevention workshop focusing on social norms, empathy, masculinity, consent, and bystander intervention. Session 3 was a 90-min booster group session that reviewed previous topics and included the active practice of bystander intervention skills. Analyses of postsession assessments of utility, therapeutic alliance, and satisfaction and examination of alcohol use and sexual assault-related outcomes from baseline to the 2-month assessment support the preliminary feasibility and acceptability of the SAFE program.

Current efforts to reduce sexual violence in college campuses underscore the role of engaging men in prosocial bystander behavior. The current study implemented an online survey to explore associations between engaging in heavy drinking and attitudes toward bystander intervention among a sample of college men (N = 242). Correlates of sexual aggression were also explored as mediators of the hypothesized relationship between engaging in heavy drinking and attitudes toward bystander intervention. Data indicated that men who engaged in two or more episodes of heavy drinking over the past month reported lower prosocial bystander attitudes compared with men who did not engage in such behavior. The association between engaging in heavy drinking and lower prosocial bystander attitudes was mediated by men's perception of their peers' approval for sexual aggression, their own comfort with sexism, and engagement in coercive sexual behavior. Implications for sexual assault prevention are discussed., (© The Author(s) 2015.)

Nitric oxide (NO) induces relaxation of colonic smooth muscle cells predominantly by cGMP/cGMP-dependent protein kinase I (cGKI)-induced phosphorylation of the inositol 1,4,5-trisphosphate receptor (IP(3)R)-associated cGMP kinase substrate (IRAG), to block store-dependent calcium signaling. In the present study we analyzed the structure and function of the human IRAG/MRVI1 gene. We describe four unique first exon variants transcribed from individual promoters in diverse human tissues. Tissue-specific alternative splicing with exon skipping and alternative splice donor and acceptor site usage further increases diversity of IRAG mRNA variants that encode for NH(2)- and COOH-terminally truncated proteins. At the functional level, COOH-terminally truncated IRAG variants lacking both the cGKI phosphorylation and the IP(3)RI interaction site counteract cGMP-mediated inhibition of calcium transients and relaxation of human colonic smooth muscle cells. Since COOH-terminally truncated IRAG mRNA isoforms are widely expressed in human tissues, our results point to an important role of IRAG variants as negative modulators of nitric oxide/cGKI-dependent signaling. The complexity of alternative splicing of the IRAG gene impressively demonstrates how posttranscriptional processing generates functionally distinct proteins from a single gene.

APC(min/+) mice, carrying a nonsense mutation in the adenomatous polyposis coli (APC) gene, appear as a perfect model to study development or therapy of intestinal neoplasia. We tested whether the flavonoid flavone is able to affect adenoma development in APC(min/+) mice. Tumor sizes were significantly increased by flavone selectively in small intestine. This was associated with reduced cell numbers displaying cleaved caspase-3 and enhanced expression of phosphoglycoprotein (P-gp). However, according to great variability in P-gp expression in all parts of mice intestines, an association between expression of P-gp and inhibition of apoptosis was demonstrated in human Caco-2 colorectal cancer cells.

The cholinergic neurotransmitter system and prolonged glucocorticoid-induced stress can affect cognitive functions in opposite ways. While pharmacological enhancement of cholinergic neurotransmission is known to induce neuroprotective effects, chronic glucocorticoids impair cognitive functions. Up to now, there is no consensus as to whether a subchronic stress period of several days would affect cognitive function. The goal of this study was to investigate whether or not repeated applications of physostigmine over 3 days lead to protective effects on rat spatial cognitive abilities in contrast to the deteriorating effect on rat cognitive function after corticosterone treatment. Furthermore, we wanted to investigate in what extent this cognition-modulating effect is associated with rat cerebral acetylcholinergic system. Male adult rats (n = 40) were randomly divided into four groups with n = 10 per group: (I) placebo-, (II) corticosterone- (15 mg/day), (III) physostigmine- (0.014 mg/day), and (IV) physostigmine + corticosterone-treated rats. Body mass and plasma corticosterone concentrations were measured. Psychometric investigations were conducted using a Morris water maze before and after a subchronic treatment. In cerebral tissue, ACh and acetylcholinesterase (AChE) content and ACh receptor density were determined. Tissue corticosterone concentration was measured in cerebral cortex, hippocampus, and adrenal glands. In corticosterone-treated rats, reduced spatial cognitive abilities were associated with a significant increase in plasma (+25%) and cerebral corticosterone levels (+350%) parallelled by a significant reduction in adrenal gland concentrations (-84%) as compared to placebo. Repeated physostigmine injections improved rats' spatial memory and increased cerebral ACh and AChE content (p < 0.05). When physostigmine was administered at the same time as corticosterone (group IV), it was not able to reverse the corticosterone effect. A significant correlation was detected between cerebral AChE and corticosterone concentrations as well as between AChE and psychometric parameters. We conclude that subchronic exogenous corticosterone administration induces memory dysfunction whereas physostigmine exerts cognitive-enhancing effects if given for 3 days. An apparently existing interaction between glucocorticoid excess and ACh metabolism is discussed.

Scope: Colorectal cancer is a major cause of cancer deaths worldwide with the need for improved therapeutics and adjuvants., Methods and Results: We here tested whether the secondary plant compound flavone affects the development of aberrant crypt foci and microadenomas triggered in C57BL/6J mice by 1,2-dimethylhydrazine. Ten weeks after the last 1,2-dimethylhydrazine injection, flavone was applied at 400 mg/kg body weight over 4 wk by gavage. Flavone was found to increase apoptosis and to reduce the rate of proliferation and aberrant crypt formation. More importantly, development of microadenomas was completely suppressed by flavone. Proteome analysis by 2-DE with mass spectrometric identification of regulated proteins suggests a downregulation of tricarboxylic acid cycle activity in colonocytes with compensation by increased FADH(2) production via a partial beta-oxidation of long-chain fatty acids to meet energy demands. Transcriptome analysis, using a Gene Chip expression array with 24,000 gene probes confirmed the proteome data and moreover revealed the increased expression of various solute transporters, suggesting increased substrate supply to be used for tricarboxylic acid cycle-independent energy production., Conclusion: In conclusion, changes in the levels of proteins from intermediary metabolism or their encoding mRNAs are linked to flavone-induced apoptosis and the prevention of microadenoma formation in transformed colonocytes of mice.

Colon cancer patients frequently show increased levels of serum insulin-like growth factor-binding protein-2 (IGFBP-2), however, the pathogenetic relevance of this phenomenon for colorectal cancer is unclear. Therefore, we have used IGFBP-2 transgenic animals which overexpress IGFBP-2 systemically and locally in the intestine to study its role in chemically induced colorectal carcinogenesis. Mice received intraperitoneal injections of 1,2-dimethylhydrazine (DMH) (40 mg/kg body weight) once a week for 6 weeks to selectively induce aberrant crypt foci (ACF) and tumors in the colon. While tumor incidence was comparable in transgenic and control mice, the volume of adenomas in IGFBP-2 transgenic mice was reduced more than 2-fold. Furthermore, serum IGFBP-2 levels negatively correlated with tumor volume in the IGFBP-2 transgenic group. Histological examination showed that IGFBP-2 transgenic mice developed significantly less dysplastic ACF with a high potential to progress to advanced stages. The reduced tumor volume in IGFBP-2 transgenic animals was due to significantly reduced proliferative capacity, evidenced by a lower proportion of cells positive for Ki67. Our results demonstrate for the first time in an experimental model that IGFBP-2 overabundance prior to the onset and during colorectal carcinogenesis reduces tumor growth by inhibition of cell proliferation., ((c) 2008 Wiley-Liss, Inc.)

Propylene oxide (PO) concentrations >or=300 ppm induced cell proliferation and tumors in rat nasal respiratory epithelium (NRE). Cell proliferation was suggested to result from depletion of glutathione (GSH) in NRE. In order to substantiate this hypothesis, cell proliferation - measured by bromodeoxyuridine incorporation into DNA of the epithelium lining middle septum, dorsal medial meatus, and medial and lateral surfaces of the nasoturbinate in transverse nasal sections taken immediately posterior to the upper incisor teeth - and water-soluble non-protein thiol (NPSH) in NRE were determined after exposing male Fischer 344 rats to 50 ppm, 100 ppm, 200 ppm, or 300 ppm PO (6 h/day, 3 days). Both parameters were also investigated after treating rats for 3 days with diethylmaleate (DEM; 2 x 250 mg/kg/day or 500 + 150 mg/kg/day) or buthionine sulfoximine (BSO; 500 mg/kg/day). Exposure to 50 ppm PO and treatment with 2 x2 50 mg/kg/day DEM resulted in NPSH levels approximating 50% and 80% of the level in untreated controls, respectively. Cell proliferation did not increase. After exposures to >or= 100 ppm PO or treatment with BSO or 500 + 150 mg/kg/day DEM, NPSH was depleted to