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AbstractObjective:Pen needles (PN) for subcutaneous insulin therapy have become smaller; 5mm PNs are now the shortest in use. We evaluated the safety, efficacy and patient ratings of a new 4mm×32 gauge (G) PN.Research design and methods:Subjects with type 1 and type 2 diabetes and HbA1c 5.5 to 9.5 participated in a randomized non-inferiority cross-over trial, at four U.S. centers. Subjects used 4mm×32G PNs and either 5mm×31G PNs (4/5mm) or 8mm×31G PNs (4/8mm) in two, 3-week treatment periods; order of needle use was controlled. Subjects were either low dose or regular dose users (highest single insulin dose≤20 units and 21–40 units, respectively). Percent absolute change in serum fructosamine ( |Δ Fru|) was the primary endpoint; unexplained, severe hypo- or hyperglycemia was a secondary measure. Leakage at injection sites and pain measured by visual analog scale were tertiary measures. Equivalent glycemic control was defined á priorias |Δ Fru| (including 95 CI) within 20; 40 subjects per subgroup provides 90 power at 0.05.Clinical trial registration:The study was registered on clinicaltrials.gov (identifier: NCT00928057).Results:Of 173 subjects randomized, 168 completed the study, and 163 were included in the fructosamine analyses – 83 and 80 in the 4/5mm and 4/8mm groups, respectively. Subjects were 56 male, mean 52.6 yrs, 63 type 2. Baseline HbA1c7.51.0 and fructosamine 30155.1 μmol/L. Mean |Δ Fru| was 4.9 (95 CI 3.8, 6.0) and 5.5 (4.5, 6.4), respectively, for the 4/5mm and 4/8mm groups, meeting glycemic equivalence criteria; results were similar in both dose groups. The median |Δ Fru| was 11.0 μmol/L (8.0, 13.0) and 13.5 μmol/L (9.8, 18.0) for the 4/5mm and 4/8mm groups, respectively. Unexplained, severe hypo- and hyperglycemic episodes were infrequent and not different between PNs. The 4mm PN was rated significantly less painful and preferred by approximately 2/3 of subjects (p<0.01). All three PNs had similar reported injection site leakage.Limitations:The study was of relatively short duration, in adults in the U.S. Further trials in other patients (e.g., GLP-1 users, pediatrics, obese) should be performed.Conclusions:The 4mm×32G PN provided equivalent glycemic control compared to 31G, 5mm and 8mm PNs with reduced pain, no difference in insulin leakage and was preferred by patients. [ABSTRACT FROM AUTHOR]

Abstract. Objective and design:  The aim of this study was to determine the effects of endotoxin on p38 MAPK activation in equine platelets and leukocytes in vivo and in vitro and its role in thromboxane (Tx) production with reference to equine endotoxaemia. Methods:  Six adult Thoroughbred horses were used for in vivo infusion studies and separate in vitro studies. For in vivo studies, following collection of a pre-infusion sample, horses were infused with E. Coli O55:B5 LPS (30 ng/kg; 30 min) during and after which platelets were harvested. For in vitro studies isolated platelets and leukocytes were exposed to LPS (10 pg/ml–1 μg/ml). p38 MAPK activity was assessed by SDS-PAGE followed by immunoblotting. TxA2 release was measured by radioimmunoassay. Results:  LPS infusion caused increased phospho-p38 MAPK in equine platelets and leukocytes (1492 486 % and 83 45 above basal, respectively) from 10 min after the start of the infusion, which returned to basal by 60 min. In vitro, platelets were 1,000 times more sensitive to LPS than leukocytes in terms of both TxA2 production (EC50 66 pg/ml versus 110 ng/ml, respectively) and p38 MAPK phosphorylation (EC50 11.1 2 pg/ml versus 14.8  4 ng/ml, respectively). p38 MAPK inhibitors SB203580 and PD169316 attenuated LPS-induced TxA2 release in platelets, but not leukocytes. Conclusions:  In vivo, LPS stimulates TxA2 production and p38 MAPK phosphorylation in equine platelets and leukocytes at a concentration within a similar range to those reported in clinical endotoxaemia. These data suggest that LPS-induced eicosanoid production in the early phase of clinical endotoxaemia may involve direct effects of LPS upon platelets, mediated via activation of p38 MAPK. [ABSTRACT FROM AUTHOR]

Chlorophyllin (CHL) is a potent antimutagen in vitro, an effective anti-carcinogen in several animal models, and significantly reduced urinary biomarkers of aflatoxin B1 (AFB1) exposure in a human population. Here we report an expanded analysis of CHL chemoprevention using the potent environmental hydrocarbon dibenzo[a,l]pyrene (DBP). A dose–dose matrix design employed over 12 000 rainbow trout to evaluate the interrelationships among dietary carcinogen dose, anti-carcinogen dose, carcinogen–DNA adduct levels at exposure and eventual tumor outcome in two target organs. Included was an evaluation of the pharmaceutical CHL preparation (Derifil), used previously in a study of individuals chronically exposed to AFB1. CHL was pre-, co- and post-fed at doses of 0–6000 p.p.m. and co-fed with DBP at doses of 0–371.5 p.p.m. for 4 weeks. This protocol generated a total of 21 dose–dose treatment groups, each evaluated with three or more replicates of 100 animals. The DBP-only treatment produced dose-responsive increases in liver and stomach DBP–DNA adducts, whereas increasing CHL co-treatment doses produced successive inhibition in liver (49–83%) and stomach (47–75%) adduct levels at each DBP dose examined. The remaining 8711 trout were necropsied, 10 months later. DBP treatment alone produced a logit incidence versus log [DBP] dose–response curve in stomach that was linear; CHL co-treatment provided dose-dependent tumor inhibition which ranged from 30 to 68% and was predictable from the adduct response. The Derifil CHL preparation was also found to effectively reduce DNA adduction and final tumor incidence in stomach (as well as liver), with a potency compatible with its total chlorin content. Liver tumor incidence in the DBP-only groups appeared to plateau near 60%. At DBP doses of ≤80 p.p.m., increasing CHL doses generally reduced tumor incidence and multiplicity consistent with early DNA adducts as biomarkers. At 225 p.p.m. DBP, however, very high CHL doses were required to reduce tumor incidence below the 60% plateau. Apparent tumor multiplicity in liver was neither linear nor monotonic with DBP dose, but peaked at 80 p.p.m. DBP and declined at 225 p.p.m., where it was increased by all but one CHL dose. Consequently, the effects of a given CHL dose and the predictivity of DNA adducts as biomarkers were highly dependent on carcinogen dose. These results underscore the critical importance of establishing carcinogen-end point dose–response relationships in chemoprevention studies, and the potential otherwise for misleading interpretations in chemoprevention studies carried out solely at high-carcinogen dose. (Supported by USPHS grants ES03850, ES00210, CA34732, ES07060, ES06052 and ES03819.) [ABSTRACT FROM AUTHOR]

The fetus and neonate are sensitive targets for chemically induced carcinogenesis. Few studies have examined the risk/benefit of chemoprotective phytochemicals, given in the maternal diet, against transplacental carcinogenesis. In this study, B6129 SF1/J (AHRb-1/d) and 129Sv/ImJ (AHRd/d) mice were cross-bred. The polycyclic aromatic hydrocarbon, dibenzo[a,l]pyrene (DBP), was administered to pregnant mice (15 mg/kg, gavage) on gestation day 17, and 2000 p.p.m. indole-3-carbinol (I3C), a chemoprotective phytochemical from cruciferous vegetables, was fed to half of the mice from gestation day 9 until weaning. Offspring born to dams fed I3C exhibited markedly fewer mortalities (P < 0.0001). Maternal dietary exposure to I3C also significantly lowered lung tumor multiplicity (P = 0.035) in offspring surviving to 10 months of age. The I3C chemoprotection was independent of either maternal or fetal AHR genotype. The bioavailability of DBP to fetal target tissue was demonstrated by assessing DNA covalent adduction with a 33P-post-labeling assay. The bioavailability of I3C was determined by dosing a subset of pregnant mice with [14C]-I3C. Addition of chemoprotective agents to the maternal diet during pregnancy and nursing may be an effective new approach in reducing the incidence of cancers in children and young adults. [ABSTRACT FROM AUTHOR]

In this work, certain peculiarities of the dynamics of pressure waves in a liquid containing bubbles are studied. The specification of a model of bubbly liquids with regard to acoustic damping of the bubbles is considered. Our theoretical results are compared with experimental ones. [ABSTRACT FROM AUTHOR]

Background. For adolescents, there is no specific needs assessment instrument that assesses significant problems that can benefit from specified interventions. A new instrument (S.NASA) was developed by incorporating and adapting three well established adult needs assessment instruments. The S.NASA covers 21 areas of functioning including social, psychiatric, educational and life skills. Method. Client and carer interviews were conducted by different researchers. A week later the interviews were repeated using a crossover design. Significant (cardinal) problems were generated from the clinical interviews using a pre-defined algorithm. Final need status (three categories) was made by clinicians assessing the cardinal problems against defined interventions. The interventions were generated from discussions with clinicians and a survey of appropriate professionals working with adolescents. Results. Pre-piloting led to the final version being administered to 40 adolescents from secure units, forensic psychiatric and adolescent psychiatric services. There were 25 males and 15 females, mean age 15·5 years. Overall there were moderate to good inter-rater and test–retest reliability coefficients, the test–retest reliability coefficients for the total scores on the needs assessment interviews ranged from 0·73 to 0·85. Consensual and face validity was good, the adolescents and staff finding the instrument useful and helpful. Conclusions. This new needs assessment instrument shows acceptable psychometric properties. It should be of use in research projects assessing the needs and the provision of services for adolescents with complex and chronic problems. [ABSTRACT FROM AUTHOR]

Introduction: Post-operative reflux (POR), sometimes due to ileus (POI), is a common complication of small intestinal (SI) surgery. Inflammation and production of nitric oxide from macrophages expressing the inducible form of nitric oxide synthase (iNOS) play important roles in POI in other species. We investigated the early inflammatory response in the SI associated with the subsequent development of POR. Materials and methods: Samples of jejunum or ileum were obtained from 25 horses undergoing small intestinal resection and/or anastomosis (AEC 1111993.1) and 7 normal horses euthanized at an abattoir. Surgical cases were divided into 3 groups: those that developed marked reflux (>20L reflux within 24h or ≥8L on any single occasion, not attributed to mechanical obstruction; ileus-group); less reflux and distention yet some decreased motility (mildileus- group); or no reflux. Histological sections were graded for inflammation and eosinophils, neutrophils, macrophages and iNOS-positive macrophages were counted. Results: Neutrophils were more numerous in the submucosa and muscularis externa of the ileusgroup compared with all other groups. Eosinophils were increased in the submucosa from all horses undergoing surgery. Macrophages were increased in the submucosa and muscularis externa from the ileus and mild-ileus groups, and iNOS-positive macrophages were increased in the ileus-group compared with the other groups. Relevance to Australian clinical equine practice: Increased numbers of iNOS-positive macrophages in the ileus group suggests that NO may play a role in the early stages of ileus in the horse, as is postulated in other species. This may present a therapeutic target for the future prevention [ABSTRACT FROM AUTHOR]

Background and Purpose: Effects of pulmonary disease could include decreased balance and muscle strength with resultant increased fall risk. Peripheral muscle weakness in participants in a pulmonary rehabilitation program(PRP) is also a contributing factor to exercise limitations ultimately affecting function. Including resistance training in PRP may improve peripheral muscle strength. Our purpose was to determine if the addition of leg press exercise (LPE) to a PRP would improve in function and balance in persons with chronic obstructive pulmonary disease (COPD). Case Description: Four persons with COPD enrolled in a PRP. Participant 1 (P1) was a 77 year old female with a BMI of 22.6 and FEV1 of 1.46. Participant 2 (P2) was a 46 year old male with a BMI of 42.4 and FEV1 of 4.48. Participant 3 (P3) was a 32 year old female with a BMI of 53.1 and FEV1 of 1.2. Participant 4 (P4) was a 66 year old male with a BMI of 30 and FEV1 of 1.57. All participants enrolled in a PRP and performed LPE of 1 set of 15 to 20 repetitions each session. The weight of the LPE was progressed if the participants perceived the LPE at ,13/20. Outcomes: Balance and function were evaluated before (PRE) and after 6 weeks (POST). P1 showed improvement in Timed Up and Go (TUG; PRE: 16.3 seconds; POST: 11.9 seconds), decrease in Activities-specific Balance Confidence (ABC) scale (PRE: 85%; POST: 79%), no change in gait speed (PRE and POST: 0.8 m/s), Short Physical Performance Battery (SPPB; PRE and POST: 9), and Falls Efficacy Scale (FES; PRE: 22; POST: 23). P2 showed improvement in TUG (PRE: 20.1 seconds; POST: 14.8 seconds), ABC scale (PRE: 60%; POST: 63.75%), gait speed (PRE: 0.5 m/s; POST: 0.8 m/s), SPPB (PRE: 4; POST: 7), and FES (PRE: 37; POST: 28). P3 showed decline in TUG (PRE: 9.4 seconds; POST: 11 seconds), no change in ABC scale (PRE and POST: 56%), SPPB (PRE and POST: 10), FES (PRE and POST: 44), and decrease in gait speed (PRE: 1 m/s; POST: 0.7 m/s). P4 showed no change in TUG (PRE and POST: 11.8 seconds) and gait speed (PRE: 0.8 m/s; POST: 0.7 m/s), improvement in ABC scale (PRE: 35%; POST: 72.5%), SPPB (PRE: 9; POST: 10), and decline in FES (PRE: 36; POST: 43). The leg press strength of participants increased 195% over 6 weeks. Adherence was .80% for all participants except for P3. Improvements in SPPB for P2 and P4, and gait speed for P2 were above the established MCID (SPPB: 0.54–1.54; gait speed: 8–11 cm/s). Discussion: After 6 weeks, leg press strength increased in participants. A majority of those with .80% adherence rate showed improvement in TUG, ABC and SPPB but mixed results were seen for gait speed and FES. The participant who had low adherence did not show improvement in any of the measures. The nature of pulmonary conditions can cause daily alterations in health, resulting in variable functional performance. Fatigue and illness seemed to be contributing factors to the inconsistency of the participants’ attendance and effort in the PRP and LPE program. It is possible that including the LPE for the entire 12 weeks of a typical PRP could yield additional benefits not seen after 6 weeks. [ABSTRACT FROM AUTHOR]

Purpose/Hypothesis: Balance deficits are common in individuals with pulmonary disease. Rehabilitation has been shown to improve balance deficits and reduce risk of falls in people with chronic obstructive pulmonary disease. To date there is no research addressing balance deficits and falls risks in candidates for lung transplantation. The purpose of this study was to examine the effects of rehabilitation prior to lung transplantation on balance, functional mobility and exercise capacity. Number of Subjects: Thirty-nine. Materials/Methods: Prospective study including 39 candidates for lung transplant at Duke Health between May 2016 and May 2017 (17 males, 22 females; age 50 ± 16 years). Individuals completed an outpatient physical therapy rehabilitation program prior to lung transplantation. Rehabilitation was 5 d/wk for an average of 21 sessions and consisted of: progressive ambulation, cycling, resistance training, flexibility exercise and balance training. The following assessments were completed at the start (PRE) and end (POST) of rehabilitation: Fullerton Advanced Balance Scale (FAB), 4 Square Step test (FSST), Short Physical Performance Battery (SPPB), and 6-minute walk test (6MWT). Two components of the SPPB, gait speed (GS) and 5 time sit to stand (5XSTS), were also analyzed separately. Paired samples t test was used to compare the outcome measures from PRE and POST. Results: Exercise capacity, balance and functional mobility improved significantly based on the following tests; 6MWT (PRE 392.2 ± 94.99 m; POST 435.15 ± 108.25 m; P = .002), FAB (PRE 34.08 ± 4.85; POST 36.31 ± 3.51; P < .001), FSST (PRE 7.94 ± 1.78; POST 7.44±1.72; P<.019) and SPPB (PRE 11.36±0.81; POST 11.74 ± 0.50; P < .005). The 5XSTS component of the SPPB improved significantly (PRE 9.24 ± 2.95; POST 7.93 ± 2.09; P < .001), 12 performed below age norms PRE and 3 performed below these norms POST. The GS component did not change significantly (PRE 0.95 ± 0.2; POST 0.96 ± 0.16; P =.735) and only 1 person scored less than a 4/4 on the PRE and POST balance portion of the SPPB. Prior to rehabilitation, 2 participants had increased falls risk based on cut-off scores for the FAB and GS. POST rehabilitation, no participants were at risk for falls according to FAB and GS. Conclusions: Participants had significant improvements on the 6MWT, indicating an improvement in exercise capacity. Functional mobility, measured by 5XSTS, was reduced in 30% of individuals PRE and improved POST. Prior to rehabilitation, a small number of individuals had mild balance deficits which improved POST, based on FAB and GS. Overall, there was a decline in risk of falls POST. Clinical Relevance: Rehabilitation prior to lung transplant can improve functional mobility, exercise capacity and balance. Individuals who complete rehabilitation prior to lung transplantation are at a lower risk of falling as well. The FAB and GS can be utilized clinically to assess risk of falls in the transplant population. Further research is needed to determine if improvements in functional balance tests leads to a reduction in actual falls. [ABSTRACT FROM AUTHOR]

SN Ia cosmology depends on the ability to fit and standardize observations of supernova magnitudes with an empirical model. We present here a series of new models of SN Ia spectral time series that capture a greater amount of supernova diversity than is possible with the models that are currently customary. These are entitled SuperNova Empirical MOdels (SNEMO; https://snfactory.lbl.gov/snemo). The models are constructed using spectrophotometric time series from 172 individual supernovae from the Nearby Supernova Factory, comprising more than 2000 spectra. Using the available observations, Gaussian processes are used to predict a full spectral time series for each supernova. A matrix is constructed from the spectral time series of all the supernovae, and Expectation Maximization Factor Analysis is used to calculate the principal components of the data. K-fold cross-validation then determines the selection of model parameters and accounts for color variation in the data. Based on this process, the final models are trained on supernovae that have been dereddened using the Fitzpatrick and Massa extinction relation. Three final models are presented here: SNEMO2, a two-component model for comparison with current Type Ia models; SNEMO7, a seven-component model chosen for standardizing supernova magnitudes, which results in a total dispersion of 0.100 mag for a validation set of supernovae, of which 0.087 mag is unexplained (a total dispersion of 0.113 mag with an unexplained dispersion of 0.097 mag is found for the total set of training and validation supernovae); and SNEMO15, a comprehensive 15-component model that maximizes the amount of spectral time-series behavior captured. [ABSTRACT FROM AUTHOR]

Purpose/Hypothesis: There is promising evidence to support the health and fitness benefits of high intensity interval training (HILT) in overweight adults, facilitating greater improvements in aerobic fitness and body composition than traditional exercise programs. However, there is limited research focusing on the effects of HILT training in overweight adolescents. The purpose of this study was to investigate the impact of HILT training on body composition and fitness levels in overweight adolescents. Number of Subjects: Intervention group n = 10; control group n = 6. Materials/Methods: Ten (4 male, 6 female; Age = 11.7 + 1.4 years) adolescents, referred from local pediatricians, completed 16 HILT sessions over an 8 week period. Each HILT session consisted of a 5 minute warm up, a 20 minute intervention period, and a 5 minute cool down. During the intervention period, subjects completed twenty 30 seconds "on," 30 seconds "off" intervals. During the initial session, the "on" workload was set equivalent to 90% of maximal workload recorded during the VO2max test, while the "off" workload was set equivalent to 50%. In subsequent sessions, workload was adjusted so that RPE during the last 5 "on" intervals was equivalent to at least 9 out of 10 on the Borg RPE scale. Workload, heart rate, and RPE were recorded at the end of each "on" interval. A control group (n = 6) (2 male, 4 female; Age = 12.7 + 0.9) was created from participants who enrolled in the program, but completed less than 33% of the scheduled sessions. Before (Pre) and after (Post) the intervention period, body composition was evaluated by a DXA Scan and the participants' enjoyment for exercise was determined using the Physical Activity Enjoyment Scale (PACES). Results: Maximal workload (pre = 146 ± 10 w, post = 263 ± 20 w; P = .0002) and Vo2max (pre = 27.4 mL•kg•min -1, post = 34.2 ± 4.0 mL•kg•min -1, P = .0009) increased as a result of HILT. In comparison, no changes were seen in maximal workload (pre = 133 ± 9 w, post = 163 ± 12 w) or Vo2max (pre = 25.5 ± 1.9 mL•kg•min -1, post = 23.9 ± 1 mL.kg.min 1) in the control group from the first to the last session. Similarly, a decrease in body fat was also seen in the intervention group (pre = 43.3 ± 3.3%, post = 41.5 ± 3.2%, P = .01) but not in the control group (pre = 45.7 ± 42 CSM 2018 Poster Presentation 3.8, post = 44.95 ± 4.0). Furthermore, the PACES score improved in the HILT group after the intervention (Pre = 63 ± 3, Post = 66 ± 3, P = .05). Conclusions: The results of this pilot study indicate that HILT may be an effective option for increasing both maximal workload and Vo2max, as well as improving % body fat in overweight adolescents. Clinical Relevance: HILT has been described as a more enjoyable and less time consuming approach to exercise in adults. With an increased number of adoles-cents falling into the overweight category, HILT can be used as a less time-intensive and more enjoyable approach to improving fitness and body composition in this adolescent population. [ABSTRACT FROM AUTHOR]

Correcting Type Ia Supernova brightnesses for extinction by dust has proven to be a vexing problem. Here we study the dust foreground to the highly reddened SN 2012cu, which is projected onto a dust lane in the galaxy NGC 4772. The analysis is based on multi-epoch, spectrophotometric observations spanning from 3300–9200 Å, obtained by the Nearby Supernova Factory. Phase-matched comparison of the spectroscopically twinned SN 2012cu and SN 2011fe across 10 epochs results in the best-fit color excess of (, RMS) = (1.00, 0.03) and total-to-selective extinction ratio of (RV, RMS) = (2.95, 0.08) toward SN 2012cu within its host galaxy. We further identify several diffuse interstellar bands and compare the 5780 Å band with the dust-to-band ratio for the Milky Way (MW). Overall, we find the foreground dust-extinction properties for SN 2012cu to be consistent with those of the MW. Furthermore, we find no evidence for significant time variation in any of these extinction tracers. We also compare the dust extinction curve models of Cardelli et al., O’Donnell, and Fitzpatrick, and find the predictions of Fitzpatrick fit SN 2012cu the best. Finally, the distance to NGC4772, the host of SN 2012cu, at a redshift of z = 0.0035, often assigned to the Virgo Southern Extension, is determined to be 16.6 ± 1.1 Mpc. We compare this result with distance measurements in the literature. [ABSTRACT FROM AUTHOR]

We introduce a method for identifying “twin” Type Ia supernovae (SNe Ia) and using them to improve distance measurements. This novel approach to SN Ia standardization is made possible by spectrophotometric time series observations from the Nearby Supernova Factory (SNfactory). We begin with a well-measured set of SNe, find pairs whose spectra match well across the entire optical window, and then test whether this leads to a smaller dispersion in their absolute brightnesses. This analysis is completed in a blinded fashion, ensuring that decisions made in implementing the method do not inadvertently bias the result. We find that pairs of SNe with more closely matched spectra indeed have reduced brightness dispersion. We are able to standardize this initial set of SNfactory SNe to 0.083 ± 0.012 mag, implying a dispersion of 0.072 ± 0.010 mag in the absence of peculiar velocities. We estimate that with larger numbers of comparison SNe, e.g., using the final SNfactory spectrophotometric data set as a reference, this method will be capable of standardizing high-redshift SNe to within 0.06–0.07 mag. These results imply that at least 3/4 of the variance in Hubble residuals in current SN cosmology analyses is due to previously unaccounted-for astrophysical differences among the SNe. [ABSTRACT FROM AUTHOR]

A 1 year carcinogenicity bioassay was conducted in rats treated with three short cycles of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)/high-fat (HF) diet, followed by 2% white tea (wt/vol), 0.05% epigallocatechin-3-gallate (EGCG) or 0.065% caffeine as sole source of fluid intake. Thirty-two percent of the PhIP/HF controls survived to 1 year, compared with 50, 48.7 and 18.2% in groups given white tea, EGCG and caffeine, respectively. After 1 year, PhIP/HF controls had tumors in the colon, skin, small intestine, Zymbal’s gland, salivary gland and pancreas. For all sites combined, excluding the colon, tumor incidence data were as follows: PhIP/HF 69.5%, PhIP/HF + EGCG 48.7%, PhIP/HF + white tea 46.9% and PhIP/HF + caffeine 13.3%. Unexpectedly, a higher incidence of colon tumors was detected in rats post-treated with white tea (69%) and caffeine (73%) compared with the 42% incidence in PhIP/HF controls. In the colon tumors, β-catenin mutations were detected at a higher frequency after caffeine posttreatment, and there was a shift toward more tumors harboring substitutions of Gly34 with correspondingly high protein and messenger RNA expression seen for both β-catenin and c-Myc. c-Myc expression exhibited concordance with tumor promotion, and there was a concomitant increase in cell proliferation versus apoptosis in colonic crypts. A prior report described suppression of PhIP-induced colonic aberrant crypts by the same test agents, but did not incorporate a HF diet. These findings are discussed in the context of epidemiological data which do not support an adverse effect of tea and coffee on colon tumor outcome—indeed, some such studies suggest a protective role for caffeinated beverages. [ABSTRACT FROM AUTHOR]

Indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM), a primary I3C derivative, are known dietary chemopreventive agents also available as supplements. However, I3C has been found to act as a tumor promoter in rat (multi-organ) and trout (liver) models. I3C and DIM were previously found to be estrogenic in trout liver based on toxicogenomic profiles. In this study, we compare the post-initiation effects of DIM and 17β-estradiol (E2) on aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in trout. Trout were initiated as embryos with AFB1 and juvenile fish were fed diets containing 0, 120 or 400 p.p.m. DIM or 5 p.p.m. E2 for 18 weeks. Tumor incidence was determined at 13 months and found to be significantly elevated in AFB1-initiated trout fed either 400 p.p.m. DIM or 5 p.p.m. E2 compared with control animals. To evaluate the mechanism of tumor enhancement, hepatic gene expression profiles were examined in animals fed promotional diets during the course of tumorigenesis and in hepatocellular carcinomas (HCCs) of initiated animals. We demonstrate that DIM alters gene expression profiles similar to E2 in liver samples during tumorigenesis and in HCC tumors. Further, HCCs from animals on DIM and E2 promotional diets had a transcriptional signature indicating decreased invasive or metastatic potential compared with HCCs from control animals. Overall, these findings are the first to demonstrate tumor promotion by DIM. They confirm the importance of estrogenic signaling in the mechanism of promotion by dietary indoles in trout liver and indicate a possible dual effect that enhances tumor incidence and decreases potential for metastasis. [ABSTRACT FROM AUTHOR]

Chemoprevention by chlorophyll (Chl) was investigated in a rat multi-organ carcinogenesis model. Twenty-one male F344 rats in three gavage groups (N = 7 rats each) received five daily doses of 250 μg/kg [3H]-aflatoxin B1 ([3H]-AFB1) alone, or with 250 mg/kg chlorophyllin (CHL), or an equimolar amount (300 mg/kg) of Chl. CHL and Chl reduced hepatic DNA adduction by 42% (P = 0.031) and 55% (P = 0.008), respectively, AFB1–albumin adducts by 65% (P P P = 0.0047) and 92% (P = 0.0029), respectively. To explore mechanisms, fluorescence quenching experiments established formation of a non-covalent complex in vitro between AFB1 and Chl (Kd = 1.22 ± 0.05 μM, stoichiometry = 1Chl:1AFB1) as well as CHL (Kd = 3.05 ± 0.04 μM; stoichiometry = 1CHL:1AFB1). The feces of CHL and Chl co-gavaged rats contained 137% (P = 0.0003) and 412% (P = 0.0048) more AFB1 equivalents, respectively, than control feces, indicating CHL and Chl inhibited AFB1 uptake. However, CHL or Chl treatment in vivo did not induce hepatic quinone reductase (NAD(P)H:quinone oxidoreductase) or glutathione S-transferase (GST) above control levels. These results are consistent with a mechanism involving complex-mediated reduction of carcinogen uptake, and do not support a role for phase II enzyme induction in vivo under these conditions. In a second study, 30 rats in three experimental groups were dosed as in study 1, but for 10 days. At 18 weeks, CHL and Chl had reduced the volume percent of liver occupied by GST placental form-positive foci by 74% (P P P = 0.0026) and 75% (P = 0.0004), respectively. These results show Chl and CHL provide potent chemoprotection against early biochemical and late pathophysiological biomarkers of AFB1 carcinogenesis in the rat liver and colon. [ABSTRACT FROM AUTHOR]