Physiological-induced conductive response evaluation in specific muscle compartments under hybrid of electrical muscle stimulation and voluntary resistance training by electrical impedance tomography.

Objective: The physiological-induced conductive response has been visualised for evaluation in specific muscle compartments under hybrid (hybridEMS) of electrical muscle stimulation (EMS) and voluntary resistance training (VRT) by electrical impedance tomography (EIT). Methods: In the experiments, tendency of conductivity distribution images σ over time was clearly detected for three specific muscle compartments, which are called AM 1 compartment composed of biceps brachii muscle, AM 2 compartment composed of triceps brachii muscle, and AM 3 compartment composed of brachialis muscle, under three training modalities. Results: From the experimental results, the tendency of physiological-induced conductive response are increased in all three training modalities with increasing training time. Correspondingly, the spatial-mean conductivity <σ>AM1,AM2,AM3 increased with the conductance value G and extracellular water ratio ß of right arm by bio-impedance analysis (BIA) method. In addition, hybridEMS has the greatest effect on physiological-induced conductive response in AM 1, AM 2, and AM 3. Under hybridEMS, the spatial-mean conductivity increased from <σ pre > AM1 = 0.154 to <σ 23mins > AM1 = 0.810 in AM 1 muscle compartment (n = 8, p < 0.001); <σ pre > AM2 = 0.040 to <σ 23mins > AM2 = 0.254 in AM 2 muscle compartment (n = 8, p < 0.05); <σ pre > AM3 = 0.078 to <σ 23mins > AM3 = 0.497 in AM 3 muscle compartment (n = 8, p < 0.05). Conclusion: The paired-samples t-test results of <σ>AM1,AM2,AM3 under all three training modalities suggest hybridEMS has the most efficient elicitation on physiological induced conductive response compared to VRT and EMS. The effect of EMS on deep muscle compartment (AM 3) is slower compared to VRT and hybridEMS, with a significant difference after 15 min of training.

Electrical-tomographic imaging of physiological-induced conductive response in calf muscle compartments during voltage intensity change of electrical muscle stimulation (vic-EMS).

Objectives. The electrical-tomographic imaging has been achieved for exploring differential tendency of physiological-induced conductive response in calf muscle compartments during voltage intensity change of electrical muscle stimulation (vic-EMS).Approach. In the experiments, the differential tendency of conductivity distribution imagesσduringvic-EMS were clearly imaged as three responsive muscle compartments, which are calledM1compartment composed of gastrocnemius muscle,M2compartment composed of tibialis anterior, extensor digitorum longus, and peroneus longus muscles, andM3compartment composed of soleus muscle.Main results. The differential tendency of spatial-mean conductivity 〈σ〉M1is the same as the differential tendency of venous blood flow velocityvbland blood lactate concentrationCblduringvic-EMS by the increased tendency of spatial-mean conductivity difference Δ〈σ〉M1, venous blood flow velocity difference Δvbland blood lactate concentration difference ΔCbl. The 〈σ〉M1is increased with the increase of voltage intensity from 〈σpre〉M1 = 0.142 [-] to 〈σl14 ã€‰ M1 = 0.442 [-] (pre: pre-training,l14: voltage level duringvic-EMSl = 14) by Δ〈σl14-pre〉M1 = 204.2% (n = 16,p < 0.01). Correspondingly, thevblandCblare increased with the increase of voltage intensity by Δvbll14-pre= 1480.5% (n = 16,p < 0.01) and ΔCbll14-pre= 230.1% (n = 16,p < 0.01) respectively.Significance: The reason for the differential tendency of increase in <σ>M1suggests an increase in muscle extracellular volumes duringvic-EMS due to the co-effect of venous blood flow velocity and blood lactate metabolism. Based on the conductivity second-order difference images∂2σM1φ∂φ2φand spatial-mean conductivity second-order difference∂2σM1φ∂φ2φ,optimum voltage intensityφOVIis discussed among sixteen volunteer subjects, which increased with a thicker subcutaneous fat layer.

Evaluation of the effectiveness of electrical muscle stimulation on human calf muscles via frequency difference electrical impedance tomography.

Objectives. The human skeletal muscle responds immediately under electrical muscle stimulation (EMS), and there is an immediate physiological response in human skeletal muscle. Non-invasive quantitative analysis is at the heart of our understanding of the physiological significance of human muscle changes under EMS. Response muscle areas of human calf muscles under EMS have been detected by frequency difference electrical impedance tomography (fd-EIT).Approach. The experimental protocol consists of four parts: pre-training (pre), training (tra), post-training (post), and relaxation (relax) parts. The relaxation part has three relaxation conditions, which are massage relaxation (MR), cold pack relaxation (CR), and hot pack relaxation (HR).Main results. From the experimental results, conductivity distribution imagesσp(pmeans protocol = pre,tra,post,or relax) are clearly reconstructed byfd-EIT as response muscle areas, which are called theM1response area (composed of gastrocnemius muscle) and theM2response area (composed of the tibialis anterior muscle, extensor digitorum longus muscle, and peroneus longus muscle). A paired samplest-test was conducted to elucidate the statistical significance of spatial-mean conductivities 〈σp〉M1and 〈σp〉M2inM1andM2with reference to the conventional extracellular water ratioßpby bioelectrical impedance analysis. Significance. From thet-test results, 〈σp〉M1and〈σp〉M2have good correlation withßp. In the post-training part, 〈σpost〉 andßpostwere significantly higher than in the pre-training part (n = 24,p < 0.001). The relax-pre difference ratios of spatial-mean conductivity Δ〈σrelax-pre〉 and the relax-pre difference ratios of extracellular water ratio Δßrelax-prein both MR and CR were lower; on the contrary, the Δ〈σrelax-pre〉 and Δßrelax-prein HR were significantly higher than those in post-pre difference ratios of spatial-mean conductivity Δ〈σpost-pre〉 (n = 8,p < 0.05). The reason for the changes in 〈σp〉M1and 〈σp〉M2are caused by the changes in muscle extracellular volumes. In conclusion,fd-EIT satisfactorily evaluates the effectiveness of human calf muscles under EMS.

No adverse effects detected for simultaneous whole-body exposure to multiple-frequency radiofrequency electromagnetic fields for rats in the intrauterine and pre- and post-weaning periods.

In everyday life, people are exposed to radiofrequency (RF) electromagnetic fields (EMFs) with multiple frequencies. To evaluate the possible adverse effects of multifrequency RF EMFs, we performed an experiment in which pregnant rats and their delivered offspring were simultaneously exposed to eight different communication signal EMFs (two of 800 MHz band, two of 2 GHz band, one of 2.4 GHz band, two of 2.5 GHz band and one of 5.2 GHz band). Thirty six pregnant Sprague-Dawley (SD) 10-week-old rats were divided into three groups of 12 rats: one control (sham exposure) group and two experimental (low- and high-level RF EMF exposure) groups. The whole body of the mother rats was exposed to the RF EMFs for 20 h per day from Gestational Day 7 to weaning, and F1 offspring rats (46-48 F1 pups per group) were then exposed up to 6 weeks of age also for 20 h per day. The parameters evaluated included the growth, gestational condition and organ weights of the dams; the survival rates, development, growth, physical and functional development, memory function, and reproductive ability of the F1 offspring; and the embryotoxicity and teratogenicity in the F2 rats. No abnormal findings were observed in the dams or F1 offspring exposed to the RF EMFs or to the F2 offspring for any of the parameters evaluated. Thus, under the conditions of the present experiment, simultaneous whole-body exposure to eight different communication signal EMFs at frequencies between 800 MHz and 5.2 GHz did not show any adverse effects on pregnancy or on the development of rats.

Establishment of a syngeneic orthotopic model of prostate cancer in immunocompetent rats.

We previously established 3 cell lines (PLS10, PLS20 and PLS30) from a chemically-induced prostate carcinoma in F344 rats, and demonstrated high potential for metastasis in nude mice. In the present study, we investigated the feasibility of establishing an orthotopic model using the 3 rat prostate cancer cell lines in immunocompetent rats with the aim of resolving species-mismatch problems and defects of immune systems. The PLS10, PLS20 and PLS30 cell lines were injected into the ventral prostates of 6-week-old rats, which were then sacrificed at experimental weeks 4 and 8. Tumor mass formation was found in rats with PLS10, but not in those with PLS20 or PLS30. Additionally, metastatic carcinomas could be detected in lymph nodes and lungs of PLS10-inoculated rats. Genetic analysis demonstrated K-ras gene mutations in PLS10 and PLS20, but not in PLS30 cells. There were no mutations in p53 and KLF6. In conclusion, we established a syngeneic orthotopic model for prostate cancer in immunocompetent rats simulating human castration-resistant prostate cancer (CRPC), which should prove useful for development and validation of therapeutic agents, especially with immunotherapy.

Dietary n-3/long-chain n-3 polyunsaturated fatty acids for prevention of sporadic colorectal tumors: a randomized controlled trial in polypectomized participants.

To address preventive effects of n-3 PUFAs/LC n-3 PUFAs on CRTs, a randomized controlled trial was conducted. One-hundred four experimental group participants were advised to increase intake of n-3 PUFAs, including fish/shell fish, fish oil supplements and perilla oils, and to decrease consumption of n-6 PUFAs and fats/oils as a whole for 24 months. One-hundred one control group participants were only cautioned to reduce consumption of fats/oils as a whole. Random allocation was satisfactorily attained, and participants sufficiently complied with our regimen. Intakes, plasma concentrations, and compositions of the RBC and sigmoid colon membranes of n-3 PUFAs, LC n-3 PUFAs, EPA and DHA increased, and the ratios of n-6 PUFAs/n-3 PUFAs and AA/LC n-3 PUFAs decreased without any adverse response. Twenty-four months after the intervention, the multivariate-adjusted hazard ratio (95% confidence intervals) was estimated to be 0.805 (0.536-1.209) with a signal towards the reduced CRT incidence.

Ellagic acid, a component of pomegranate fruit juice, suppresses androgen-dependent prostate carcinogenesis via induction of apoptosis.

BACKGROUND: Ellagic acid (EA), a component of pomegranate fruit juice (PFJ), is a plant-derived polyphenol and has antioxidant properties. PFJ and EA have been reported to suppress various cancers, including prostate cancer. However, their chemopreventive effects on development and progression of prostate cancer using in vivo models have not been established yet. METHODS: The transgenic rat for adenocarcinoma of prostate (TRAP) model was used to investigate the modulating effects of PFJ and EA on prostate carcinogenesis. Three-week-old male transgenic rats were treated with EA or PFJ for 10 weeks. In vitro assays for cell growth, apoptosis, and Western blot were performed using the human prostate cancer cell lines, LNCaP (androgen-dependent), PC-3 and DU145 (androgen-independent). RESULTS: PFJ decreased the incidence of adenocarcinoma in lateral prostate, and both EA and PFJ suppressed the progression of prostate carcinogenesis and induced apoptosis by caspase 3 activation in the TRAP model. In addition, the level of lipid peroxidation in ventral prostate was significantly decreased by EA treatment. EA was able to inhibit cell proliferation of LNCaP, whereas this effect was not observed in PC-3 and DU145. As with the in vivo data, EA induced apoptosis in LNCaP by increasing Bax/Bcl-2 ratio and caspase 3 activation. Cell-cycle related proteins, p21(WAF) , p27(Kip) , cdk2, and cyclin E, were increased while cyclin D1 and cdk1 were decreased by EA treatment. CONCLUSIONS: The results indicate that PFJ and EA are potential chemopreventive agents for prostate cancer, and EA may be the active component of PFJ that exerts these anti-cancer effects.

Multigenerational effects of whole body exposure to 2.14 GHz W-CDMA cellular phone signals on brain function in rats.

The present experimental study was carried out with rats to evaluate the effects of whole body exposure to 2.14 GHz band code division multiple access (W-CDMA) signals for 20 h a day, over three generations. The average specific absorption rate (SAR, in unit of W/kg) for dams was designed at three levels: high (<0.24 W/kg), low (<0.08 W/kg), and 0 (sham exposure). Pregnant mothers (4 rats/group) were exposed from gestational day (GD) 7 to weaning and then their offspring (F1 generation, 4 males and 4 females/dam, respectively) were continuously exposed until 6 weeks of age. The F1 females were mated with F1 males at 11 weeks old, and then starting from GD 7, they were exposed continuously to the electromagnetic field (EMF; one half of the F1 offspring was used for mating, that is, two of each sex per dam and 8 males and 8 females/group, except for all offspring for the functional development tests). This protocol was repeated in the same manner on pregnant F2 females and F3 pups; the latter were killed at 10 weeks of age. No abnormalities were observed in the mother rats (F0 , F1 , and F2 ) and in the offspring (F1 , F2 , and F3 ) in any biological parameters, including neurobehavioral function. Thus, it was concluded that under the experimental conditions applied, multigenerational whole body exposure to 2.14 GHz W-CDMA signals for 20 h/day did not cause any adverse effects on the F1 , F2 , and F3 offspring.

Establishment of an invasive prostate cancer model in transgenic rats by intermittent testosterone administration.

We have established a transgenic rat for adenocarcinoma of the prostate (TRAP) model that features uniform adenocarcinoma development in prostatic lobes at high incidence within a short experimental period. However, no invasive carcinomas with reactive stroma characteristics similar to those in man were observed. We therefore have focused on a new model for invasive carcinoma of the prostate using TRAP rats. In experiment 1, male TRAP rats in groups 1 and 2 were treated with orchiectomy at day 0 of the experiment. Rats in groups 1-3 underwent testosterone propionate (TP) implantation from weeks 1 to 4 and from weeks 6 to 16. Rats in groups 1 and 3 were given 3,2'-dimethyl-4-aminobiphenyl (DMAB) after TP implantation. The rats of group 4 served as controls. In experiment 2, the rats were divided into three groups, none of which received DMAB or orchiectomy, treated with TP continuously or with the treatment withdrawn once or twice. In experiment 1, invasive adenocarcinomas with abundant collagenous stroma were found in the dorsolateral and anterior prostate, some of which showed perineural space invasion at week 16. The number of invasive carcinoma foci was most frequent in group 3. In experiment 2, invasive adenocarcinoma development in the lateral prostates was correlated with the number of TP administration/withdrawal cycles. In conclusion, our newly established rat model for invasive adenocarcinoma of the prostate could serve as a useful preclinical model for evaluating the in vivo efficacy of preventive and therapeutic agents targeting of the tumor microenvironment.

Mutational analysis of FOXL2 p.C134W and expression of bone morphogenetic protein 2 in Japanese patients with granulosa cell tumor of ovary.

AIM: To assess whether FOXL2 p.C134W mutation may play a role in the development of human ovarian tumors in the Japanese, we investigated the FOXL2 codon 134 mutation and protein expression of inhibin-α, bone morphogenetic protein 2 (BMP2) and follistatin (FST) in Japanese patients with granulosa cell tumor (GCT) of the ovary and other ovarian tumors. METHODS: We analyzed 114 tumor tissues from ovarian tumors, including 44 adult-type and two juvenile-type GCT of the ovary and 68 ovarian tumors by DNA sequencing. Immunohistochemistry was also performed in the adult and juvenile GCT tissues by immunostaining inhibin-α, BMP2 and FST. RESULTS: We found the FOXL2 p.C134W mutation in 27 out of 44 (61.4%) adult-type GCT of the ovary, but none in other ovarian tumors. Histologically, all of the adult-type GCT sections were positive for inhibin-α, and the expression of BMP2 and FST was detected in 14 of 44 (31.8%) and zero of 47 (0%), respectively. No significant differences regarding the diagnosed age, preoperative serum carbohydrate antigen 125 levels, or BMP2 immunopositivity between the FOXL2 p.C134W mutation-positive and mutation-negative were found in the adult-type GCT patients. CONCLUSION: Our findings suggest that FOXL2 p.C134W mutation-positive adult-type GCT of the ovary may not be common in the Japanese as compared to the previous data.

GPX2 overexpression is involved in cell proliferation and prognosis of castration-resistant prostate cancer.

There is a need for exploration of new therapeutic strategies that target distinct molecular mechanisms of castration-resistant prostate cancer (CRPC) because its emergence following androgen deprivation therapy is a major clinical problem. In this report, we investigated the role of glutathione peroxidase 2 (GPX2) in CRPC. GPX2 expression was analyzed in rat and human CRPC cells. Next, we determined the proliferation rate and level of reactive oxygen species (ROS) in GPX2-small interfering RNA (siRNA)-transfected CRPC cells. For in vivo analysis, siRNA-transfected cells were subcutaneously implanted into normal and castrated nude mice. Further, immunohistochemical and prognostic analyses of GPX2 were performed using human specimens. Silencing of GPX2 caused significant growth inhibition and increased intracellular ROS in both rat (PCai1) and human (PC3) CRPC cells. Flow cytometry and western blot analyses revealed that the decrease in proliferation rate of the GPX2-silenced cells was due to cyclin B1-dependent G2/M arrest. Furthermore, knockdown of Gpx2 inhibited tumor growth of PCai1 cells in castrated mice. Immunohistochemical analyses indicated that expression of GPX2 was significantly higher in residual cancer foci after neoadjuvant hormonal therapy than in hormone naive cancer foci. Moreover, patients with high GPX2 expression in biopsy specimen had significantly lower prostate-specific antigen recurrence-free survival and overall survival than those with no GPX2 expression. These findings suggest that GPX2 is a prognostic marker in CRPC and affects proliferation of prostate cancer under androgen depletion partially through protection against ROS signaling.

Apocynin, an NADPH oxidase inhibitor, suppresses rat prostate carcinogenesis.

Recent evidence suggests that oxidative stress contributes to the pathogenesis of prostate cancer. The present study focused on the effect of apocynin, an inhibitor of NADPH oxidase, on prostate carcinogenesis using the transgenic rat for adenocarcinoma of prostate (TRAP) model. There were no toxic effects with apocynin treatment. The percentages and numbers of carcinomas in both the ventral and lateral prostate were significantly reduced by apocynin treatment, with dose dependence. Reduction of reactive oxygen species by apocynin was confirmed by immunohistochemistry of 8-OHdG and dihydroethidium staining. Positivity of Ki67 was significantly reduced by apocynin treatment, and downregulation of clusterin expression, as well as inactivation of the MEK-ERK1/2 pathway, was a feature of the apocynin treated groups. In human prostate cancer cell line LNCaP, apocynin also inhibited reactive oxygen species production and blocked cell growth by inducing G0/G1 arrest with downregulation of clusterin and cyclin D1. These data suggest that apocynin possesses chemopreventive potential against prostate cancer.

Elevated expression of coactivator-associated arginine methyltransferase 1 is associated with early hepatocarcinogenesis.

Aberrant expression of regulators for epigenetics is involved in tumorigenesis. There is an urgent need to identify and characterize regulators concerned with epigenetics in the early stages of hepatocarcinogenesis. In the present study, we found that the expression of coactivator-associated arginine methyltransferase 1 (CARM1), a histone methyltransferase that functions as a cofactor for nuclear hormone receptors and several transcription factors, was elevated in adenomas and aberrant in carcinomas during hepatocellular carcinogenesis. In addition to RNA expression, immunohistochemical staining of liver sections revealed that CARM1 was highly expressed in the nucleus of tumor marker glutathione S-transferase placental form (GST-P)-positive foci. Neoplastic transformation of GST-P-positive foci guides the formation of hepatocellular carcinomas. CARM1 expression was not elevated in GST-P-negative regions. Furthermore, a luciferase reporter analysis revealed that CARM1 activated the Gst-p promoter in H4IIE, a hepatocellular carcinoma cell line. This activation was mediated by the enhancer element responsible for the carcinogenic-specific expression of Gst-p and nuclear factor E2-related factor 2. Knockdown of Carm1 by shRNA in H4IIE cells inhibited cell proliferation. These findings suggest that aberrantly expressed CARM1 in tumor marker-positive cells promotes tumorigenesis in the early stages of hepatocarcinogenesis.

Expression of glutathione peroxidase 2 is associated with not only early hepatocarcinogenesis but also late stage metastasis.

Understanding of mechanisms of cancer progression is very important for reduction of cancer mortality. Of six rat hepatocellular carcinoma (HCC) cell lines, differing in their metastatic potential to the lung after inoculation into the tail vein of nude mice, the most metastatic featured particular overexpression of glutathione peroxidase 2 (GPX2). Therefore, we analyzed the influence of interference in highly metastatic L2 cells by siRNA transfection. Gpx2 siRNA significantly inhibited cell proliferation at 24 and 48h time points with induction of apoptosis but not cell cycle arrest. High expression of mutated p53 was detected in all HCC cell lines, with reduction in Gpx2 siRNA-transfected cells. Migration and invasion in vitro were also suppressed as compared to control siRNA-transfected cells and secretion of matrix metalloproteinase 9 was reduced. In vivo, the numbers and areas of metastatic nodules per area in the lungs were significantly reduced in the mice inoculated with Gpx2 siRNA-transfected cells as compared to control siRNA-transfected cells. In conclusion, expression of GPX2 is associated with cancer metastasis from rat HCCs both in vitro and in vivo. Together with immunohistochemical findings of elevated expression in rat and also human liver lesions, the results point to important roles in hepatocarcinogenesis.

Ellagic acid inhibits migration and invasion by prostate cancer cell lines.

Polyphenolic compounds from pomegranate fruit extracts (PFEs) have been reported to possess antiproliferative, pro-apoptotic, anti-inflammatory and anti-invasion effects in prostate and other cancers. However, the mechanisms responsible for the inhibition of cancer invasion remain to be clarified. In the present study, we investigated anti-invasive effects of ellagic acid (EA) in androgen-independent human (PC-3) and rat (PLS10) prostate cancer cell lines in vitro. The results indicated that non-toxic concentrations of EA significantly inhibited the motility and invasion of cells examined in migration and invasion assays. The EA treatment slightly decreased secretion of matrix metalloproteinase (MMP)-2 but not MMP-9 from both cell lines. We further found that EA significantly reduced proteolytic activity of collagenase/gelatinase secreted from the PLS-10 cell line. Collagenase IV activity was also concentration-dependently inhibited by EA. These results demonstrated that EA has an ability to inhibit invasive potential of prostate cancer cells through action on protease activity.

Apocynin, an NADPH oxidase inhibitor, suppresses progression of prostate cancer via Rac1 dephosphorylation.

Recently, considerable evidence has been generated that oxidative stress contributes to the etiology and pathogenesis of prostate cancer. The present study focused on the effects of apocynin, an inhibitor of the NADPH oxidase which generates intracellular superoxide, on a rat androgen-independent prostate cancer cell line (PLS10) in vitro and in vivo. Apocynin significantly inhibited cell proliferation of PLS10 cells via G1 arrest of the cell cycle in vitro. Surprisingly, it did not affect reactive oxygen species (ROS) but inhibited phosphorylation of Rac1, one component of the NADPH oxidase complex. A Rac1 inhibitor, NSC23766, also inhibited cell proliferation, and both apocynin and NSC23766 reduced phosphorylation of Rac1 and NF-κB, as well as cyclin D1. Furthermore, in a xenograft model of prostate cancer with PLS10, apocynin suppressed tumor growth and metastasis in a dose dependent manner in vivo, with reduction of cell proliferation and vessel number in the tumors. Expression and secretion of vascular endothelial growth factor (VEGF) were reduced by apocynin treatment in vivo and in vitro, respectively. In conclusion, despite no apparent direct relationship with oxidative stress, apocynin inhibited growth of androgen-independent prostate cancer in vitro and in vivo. Apocynin thus warrants further attention as a potential anti-tumor drug.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in benign prostate and subsequent risk for prostate cancer.

Despite convincing evidence that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)--a heterocyclic amine generated by cooking meats at high temperatures--is carcinogenic in animal models, it remains unclear whether PhIP exposure leads to increased cancer risk in humans. PhIP-DNA adduct levels were measured in specimens from 534 prostate cancer case-control pairs nested within a historical cohort of men with histopathologically benign prostate specimens. We estimated the overall and race-stratified risk of subsequent prostate cancer associated with higher adduct levels. PhIP-DNA adduct levels in benign prostate were significantly higher in Whites than African Americans (0.274 optical density units (OD) ±0.059 vs. 0.256 OD ±0.054; p<0.0001). Prostate cancer risk for men in the highest quartile of PhIP-DNA adduct levels was modestly increased [odds ratio (OR) = 1.25; 95% confidence interval (CI) = 0.76-2.07]. In subset analyses, the highest risk estimates were observed in White patients diagnosed more than 4 years after cohort entry (OR = 2.74; 95% CI = 1.01-7.42) or under age 65 (OR = 2.80; 95% CI = 0.87-8.97). In Whites, cancer risk associated with high-grade prostatic intraepithelial neoplasia combined with elevated PhIP-DNA adduct levels (OR = 3.89; 95% CI = 1.56-9.73) was greater than risk associated with either factor alone. Overall, elevated levels of PhIP-DNA adducts do not significantly increase prostate cancer risk. However, our data show that White men have higher PhIP-DNA adduct levels in benign prostate tissue than African American men, and suggest that in certain subgroups of White men high PhIP-DNA adduct levels may predispose to an increased risk for prostate cancer.

Organ differences in the impact of p27(kip1) deficiency on carcinogenesis induced by N-methyl-N-nitrosourea.

To evaluate the impact of p27 on carcinogenesis in various organs, N-methyl-N-nitrosourea (MNU), a direct-acting alkylating agent, was given to p27 knock-out mice. Groups of 20-40 male and female mice with null, hetero- or wild-type p27 alleles were given drinking water containing 240 ppm MNU or distilled water every other week for five cycles. The incidence and multiplicity of the induced proliferative lesions were then histologically evaluated at weeks 14 and 20. MNU treatment induced various lesions including squamous hyperplasia and squamous cell carcinoma in the forestomach, atypical hyperplasia and adenocarcinomas in the fundic and pyloric glands, adenomas and adenocarcinomas in the duodenum, malignant lymphomas in the thymus, liver, kidney and spleen and alveolar hyperplasia, adenomas, adenocarcinomas and malignant lymphomas in the lung. Although the incidences of the lesions in the forestomach, fundic and pyloric glands did not differ among the p27 genotypes, those of alveolar hyperplasia of the lung and malignant lymphoma of the thymus were significantly increased in p27-null males as compared with both wild- and hetero-type animals. Moreover, in both p27(+/+) and p27(+/-) cases, the rates for p27-positive cells were obviously increased in proliferative lesions of the pyloric gland and the lung. However, an increased rate of p27-positive cells was not observed in malignant lymphoma of the thymus. These findings suggest that p27 does not control the cell cycle equally in all organs affected by MNU-induced carcinogenesis.

Purple corn color inhibition of prostate carcinogenesis by targeting cell growth pathways.

Purple corn color is a widely used food colorant that was reported to have attenuating effects on hypertension, diabetes, and to have anti-cancer effects on colon and breast cancer. Our study is the first on its possible chemoprevention effects against prostate cancer. For this purpose an androgen-dependent prostate cancer cell line, LNCaP, was used to examine effects in vitro. Purple corn color inhibited the proliferation of LNCaP cells by decreasing the expression of Cyclin D1 and inhibiting the G1 stage of the cell cycle. Thirty-six male transgenic rats for adenocarcinoma of prostate were fed basic diet or diet with purple corn color for 8 weeks. Purple corn color decreased the incidence of adenocarcinoma in the lateral prostate and slowed down the progression of prostate cancer. A lower Ki67 positive rate, a decrease of the expression of Cyclin D1, and downregulation of the activation of Erk1/2 and p38 MAPK were observed in the group consuming purple corn color in the diet. Since purple corn color is a mixture, determining its active component should help in the understanding and usage of purple corn color for prostate cancer chemoprevention. Therefore, the three major anthocyanins in purple corn color, cyanidin-3-glucoside, pelargonidin-3-glucoside and peonidin-3-glucoside, were tested with LNCaP cells. The results suggested that cyanidin-3-glucoside and pelargonidin-3-glucoside are the active compounds.

Lack of Hepatocarcinogenicity of Combinations of Low Doses of 2-amino-3, 8-dimethylimidazo[4,5- f ]quinoxaline and Diethylnitrosamine in Rats: Indication for the Existence of a Threshold for Genotoxic Carcinogens.

The purposes of the present study were to evaluate the hepatocarcinogenicity of concurrent treatment of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and diethylnitrosamine (DEN) in rats and to determine whether no effect levels of combinations of these two different structural categories of genotoxic hepatocarcinogens exist. Two 16-week rat hepatocarcinogenesis assays were performed using a total of 790 male F344 rats. In experiment 1, we evaluated the effects of concurrent treatment of a subcarcinogenic dose of DEN on rat hepatocarcinogenesis induced by various doses of MeIQx. In experiment 2, we determined hepatocarcinogenicities of combinations of MeIQx and DEN at subcarcinogenic doses, low carcinogenic doses and high carcinogenic doses. Quantitative analyses of glutathione S-transferase placental form (GST-P)-positive foci, a preneoplastic lesion of the liver in rats, revealed that concurrent treatment with subcarcinogenic doses of DEN did not enhance MeIQx-induced rat hepatocarcinogenicity. We also found that concurrent treatment with combinations of subcarcinogenic doses of DEN and MeIQx was not hepatocarcinogenic, indicating that the combined effects of subcarcinogenic doses of DEN and MeIQx were neither additive nor synergistic. Moreover, concurrent treatment with low carcinogenic doses of these 2 carcinogens did not show additive or synergistic effects. Synergetic effects were observed only in rats coadministered high carcinogenic doses of the 2 carcinogens. These results demonstrate the existence of no effect levels of combinations of these 2 genotoxic hepatocarcinogens, and provide new evidence supporting our idea that there is a threshold, at least a practical threshold, that should be considered when evaluating the risk of genotoxic carcinogens. ( ; : -).