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Our objective was to evaluate the interaction of supplemental essential oils (EO) and monensin (MON) on performance and digestion. Two levels of EO (0 vs 0.011% Xtract®) and two levels of MON (0 vs 33 mg/kg) were evaluated in a 2 × 2 factorial arrangement. Treatment effects on 216-d growth performance were evaluated in 96 Holstein steers. Supplemental MON enhanced (P ≤ 0.05) ADG, DMI and gain efficiency. Without EO, MON improved (P < 0.05) gain efficiency and dietary NE. However, in diets with both EO and MON, gain efficiency and dietary NE were not different from non-supplemented diets (interaction, P < 0.10). Treatment effects on characteristics of digestion were evaluated using four cannulated steers. Ruminal digestion of OM and N were greater for MON alone. Ruminal digestion of OM and N were similar for EO-alone vs MON-alone, but not by the combination of the two (interaction P ≤ 0.02). Supplemental MON enhanced (P ≤ 0.02) total tract digestion of OM and N. We conclude that supplemental EO-alone or MON-alone may enhance gain efficiency and NE value of the diet. However, effects are negated when fed in combination. Treatment effects on performance are consistent with digestion measures. [ABSTRACT FROM AUTHOR]

One hundred and sixty-eight crossbred steers (133 ± 7 kg) were used in a 336-d experiment to evaluate the effects of enzymatically hydrolysed yeast cell wall plus yeast culture (EHY) supplementation on growth performance and carcass characteristics. Treatments consisted of steam-flaked corn-based diet supplemented with 0, 195, 390 or 585 mg/kg EHY. Supplemental EHY enhanced overall (336-d) dry matter intake (DMI, P < .01), averagde daily gain (ADG, P = .04), and final carcass weight (P = .04). Responses were maximal (quadratic effect, P ≤ .02) at the 195 mg/kg level of EHY supplementation. Feed intake enhancements were observed throughout each 112-d period of the study. Improvements in ADG were largely the result of increased DMI, as gain efficiency and estimated dietary net energy (NE) were not affected by EHY supplementation. Effects of supplemental EHY on other carcass measures were not appreciable (P > .20), except for a slight lowering (0.7%, P = .04) in carcass yield. We conclude that throughout the growing-finishing period, supplemental EHY will enhance ADG, resulting in marked increases in final carcass weight. This effect is due to consistent increases in DMI, as supplementation did not affect gain efficiency or estimated dietary NE. [ABSTRACT FROM AUTHOR]

Eight Holstein steers (216±48 kg body weight) fitted with ruminal and duodenal cannulas were used to evaluate effects of wheat straw processing (ground vs pelleted) at two straw inclusion rates (7% and 14%; dry matter basis) in dry rolled or steam-flaked cornbased finishing diets on characteristics of digestion. The experimental design was a split plot consisting of two simultaneous 4×4 Latin squares. Increasing straw level reduced ruminal (p<0.01) and total tract (p = 0.03) organic matter (OM) digestion. As expected, increasing wheat straw level from 7% to 14% decreased (p<0.05) ruminal and total tract digestion of OM. Digestion of neutral detergent fiber (NDF) and starch, per se, were not affected (p>0.10) by wheat straw level. Likewise, straw level did not influence ruminal acetate and propionate molar proportions or estimated methane production (p>0.10). Pelleting straw did not affect (p≥0.48) ruminal digestion of OM, NDF, and starch, or microbial efficiency. Ruminal feed N digestion was greater (7.4%; p = 0.02) for ground than for pelleted wheat straw diets. Although ruminal starch digestion was not affected by straw processing, post-ruminal (p<0.01), and total-tract starch (p = 0.05) digestion were greater for ground than for pelleted wheat straw diets, resulting in a tendency for increased post-ruminal (p = 0.06) and total tract (p = 0.07) OM digestion. Pelleting wheat straw decreased (p<0.01) ruminal pH, although ruminal volatile fatty acids (VFA) concentration and estimated methane were not affected (p=0.27). Ruminal digestion of OM and starch, and post-ruminal and total tract digestion of OM, starch and N were greater (p<0.01) for steamflaked than for dry rolled corn-based diets. Ruminal NDF digestion was greater (p = 0.02) for dry rolled than for steam-flaked corn, although total tract NDF digestion was unaffected (p = 0.94). Ruminal microbial efficiency and ruminal degradation of feed N were not affected (p>0.14) by corn processing. However, microbial N flow to the small intestine and ruminal N efficiency (non-ammonia N flow to the small intestine/N intake) were greater (p<0.01) for steam-flaked than for dry rolled corn-based diets. Ruminal pH and total VFA concentration were not affected (p= 0.16) by corn processing method. Compared with dry rolled corn, steam-flaked corn-based diets resulted in decreased acetate:propionate molar ratio (p = 0.02). It is concluded that at 7% or 14% straw inclusion rate, changes in physical characteristics of wheat straw brought about by pelleting negatively impact OM digestion of both steam-flaked and dry-rolled corn-based finishing diets. This effect is due to decreased postruminal starch digestion. Replacement of ground straw with pelleted straw also may decrease ruminal pH. [ABSTRACT FROM AUTHOR]

Fifty-four Holstein steer calves, divided in two weight groupings (141.2 ± 4.9 kg and 454.2 ± 7.0 kg respectively), were used in a 56-day study to evaluate the influence of supplemental vitamin E on growth performance and plasma vitamin concentrations. Steers were assigned within body weight groupings to 18 pens, 3 steers/pen. Dietary treatments consisted of a steam-flaked corn-based growing-finishing diet supplemented to provide 0, 250, or 500 IU/d of vitamin E as all racemicα-tocopherol. No morbidity was apparent during the course of the study. Calves in the heavier weight grouping had greater average daily gain (24.4%,P < .01), dry matter intake (54.3%,P < .01), and lower gain efficiency (40.7%,P < .01). Vitamin E supplementation did not affect (P > .10) feedlot growth performance. Initial and 56-day plasma tocopherol were not influenced (P > .10) by weight grouping. Final 56-day plasma tocopherol increased linearly (P < .01) with level of vitamin E supplementation. Plasma tocopherol of non-supplemented steers decreased (P = .01) from an average initial concentration of 1.66–1.16 ug/mL at day 56. It is concluded that vitamin E supplementation of calf-fed Holstein steers receiving a conventional steam-flaked corn-based growing-finishing diet is not expected to enhance growth performance. [ABSTRACT FROM PUBLISHER]

The effect of orally supplemented melatonin (MT) at 1 mg/kg bw for 4 weeks on feeding behavior of non-diabetic and diabetic male Wistar rats has been studied by computerized meal pattern analysis. Exogenous MT has a satiating effect in non-diabetic rats, but not in diabetic animals. The changes in feeding behavior induced by MT in non-diabetic animals are related to changes in meal frequency, size and duration leading to lower total food intake during the scotophase. MT administration to diabetic rats resulted in lower drinking time and higher faecal output, without further behavioral effects. We conclude that the notorious metabolic changes occurring in the streptozotocin-diabetic rat can overcome most of the underlying effects of MT supplementation. The possible MT usage for therapeutic purposes could benefit from the lack of behavioral alterations in diabetic animals. [ABSTRACT FROM AUTHOR]

We previously reported that antiestrogen-liganded estrogen receptor β (ERβ) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:quinone oxidoreductase). Further studies on the functional role of ERβ-mediated upregulation of antioxidative enzymes indicated protective effects against estrogen-induced oxidative DNA damage (ODD). We now report on in vivo and in vitro studies that show that ERβ-mediated upregulation of QR are involved in the protection against estrogen-induced mammary tumorigenesis. Using the August Copenhagen Irish (ACI) model of estrogen-induced carcinogenesis, we observed that increased ODD and decreased QR expression occur early in the process of estrogen-induced mammary tumorigenesis. Prevention of ACI mammary gland tumorigenesis by tamoxifen was accompanied by decreased ODD and increased QR levels. These correlative findings were supported by our findings that downregulation of QR levels led to increased levels of estrogen quinone metabolites and enhanced transformation potential of 17β-estradiol treated MCF10A non-tumorigenic breast epithelial cells. Concurrent expression of ERβ and treatment with 4-hydroxytamoxifen decreased tumorigenic potential of these MCF10A cells. We conclude that upregulation of QR, through induction by tamoxifen, can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a possible novel mechanism of tamoxifen prevention against breast cancer.Oncogene (2007) 26, 3587–3590. doi:10.1038/sj.onc.1210144; published online 11 December 2006 [ABSTRACT FROM AUTHOR]

Surface science studies of heterogeneous catalysis use model systems ranging from single crystals to monodispersed nanoparticles in the 1–10 nm range. Molecular studies reveal that bond activation (C–H, H–H, C–C, C≡O) occurs at 300 K or below as the active metal sites simultaneously restructure. The strongly adsorbed molecules must be mobile to free up these sites for continued turnover of reaction. Oxide–metal interfaces are also active for catalytic turnover. Examples using C–H and C = O activation are described to demonstrate these properties. Polymerization catalysis demonstrates a strong dependence upon catalyst surface structure, which allows for the selectivity to be tuned by the choice of Ziegler-Natta surface preparation. Novel preparation methods of model catalyst arrays in two and three dimensions are opening the door to a complete understanding of catalytic reaction selectivity. [ABSTRACT FROM AUTHOR]

Perinatal transmission of human immunodeficiency virus (HIV)-1 represents a major problem in many regions of the world, especially Southern Africa. With the exception of viral and proviral load, the role for maternal cofactors in perinatal transmission outcome is largely unknown. In this study, an assessment was made of peripheral blood mononuclear cells (PBMC) gene-expression profiles to better understand transcriptional changes associated with HIV-1 infection and perinatal transmission among young adult mothers with infants in Botswana. Peripheral blood mononuclear cells specimens were used from 25 HIV+ drug naive and 20 HIV− healthy mothers, similar in age and location, collected in 1999–2000 and 2003, and processed with the exact same methods, as previously described. Expression profiling of 22 277 microarray gene probes implicated a broad initiation of innate response gene-sets, including toll-like receptor, interferon-stimulated and antiviral RNA response pathways in association with maternal HIV-1 infection. Maternal transmission status was further associated with host genes that influence RNA processing and splicing patterns. In addition to real-time polymerase chain reaction validation of specific genes, enriched category validation of PBMC profiles was conducted using two independent data sets for either HIV-1 infection or an unrelated RNA virus, severe acute respiratory virus infection. HIV-1 pathogen-specific host profiles should prove a useful tool in infection and transmission intervention efforts worldwide.Genes and Immunity (2006) 7, 298–309. doi:10.1038/sj.gene.6364297; published online 4 May 2006 [ABSTRACT FROM AUTHOR]

Evaluates the influence of level of cottonseed meal (CSM) supplementation on its feeding value in finishing diets for feedlot cattle. Influence of CSM level on carcass characteristics; Treatment effects on growth performance and carcass characteristics; Average ruminal escape (REP) protein value of the diets.

A feedlot growth-performance trial was conducted to evaluate the relative response to tempering when flake density (FD) of corn is increased from 0.31 kg/L (24 lb/bushel) to 0.39 kg/L (30 lb/bushel). Treatments were (1) non-tempered, FD = 0.31 kg/L; (2) non-tempered, FD = 0.39 kg/L; (3) tempered, FD = 0.31 kg/L and (4) tempered, FD = 0.39 kg/L. Tempering prior to flaking increased (21%, P < .01) the moisture content of corn as it exited the rolls and decreased (14%, P = .02) the starch enzymatic reactivity. Increasing roll tension to reduce FD decreased flake thickness (24%, P < .01) and increased starch reactivity (43%, P < .01). Increasing FD decreased (P = .03) estimated dietary NEm and NEg, and the estimated NEm and NEg values of steam-flaked corn by 2.3% and 2.9%, respectively. We conclude that whereas tempering corn grain before steam flaking increases the moisture content of corn as it exits the roles, it has minimal influence on the feeding value for corn for feedlot cattle. Increasing FD from 0.31 to 0.39 kg/L decreases starch reactivity and the net energy value of corn, but does not affect daily weight gain or carcass characteristics. [ABSTRACT FROM AUTHOR]

Two experiments were conducted to evaluate the influence of dry-rolling (DRS) and tempering agent (TA) addition during the steam-flaking of grain sorghum (SFS) for feedlot cattle. Five dietary treatments were compared: 1) DRS; 2) SFS, no TA; 3) SFS, 0.275 mg/kg of TA; 4) SFS, 1.375 mg/kg of TA; and 5) SFS, 2.750 mg/kg of TA. Bulk densities of DRS and SFS were 0.48 and 0.36 kg/L, respectively. Diets contained 70.6% grain sorghum (DM basis). One hundred fifty crossbred steers (336 kg of BW) were used in a 115-d finishing experiment to evaluate treatment effects on feedlot performance. Body weight gain averaged 1.49 kg/d and was not affected (P = 0.47) by treatments. The SFS reduced (P < 0.01) DMI (9%) and enhanced (P < 0.01) G:F (13%) and the NEm and NEg value of the diet (9 and 11%, respectively). Use of a TA before flaking sorghum did not influence (P > 0.20) cattle growth performance or NEm or NEg value of the diet. Given that the NEm and NEg values of DRS are 2.00 and 1.35 Mcal/kg, respectively (NRC, 1996), the corresponding values for SFS were 2.28 and 1.59 Mcal/kg. Five steers (397 kg of BW) with ruminal and duodenal cannulas were used in a 5 × 5 Latin square design to evaluate treatment effects on digestive function. Ruminal digestion of OM and starch was greater (14 and 16%, respectively; P < 0.01) for SFS vs. DRS. Steamflaking sorghum increased (P < 0.01) postruminal digestion of OM (11%), N (10%), and starch (25%) and total tract digestion (P < 0.01) of OM (8.3%), N (8.2%), and starch (8.9%). Grain processing did not affect (P > 0.20) ruminal pH or VFA molar proportions. There was a cubic component (P < 0.10) to level of TA on ruminal pH and VFA molar proportions, with values being optimal at 1.375 mg/kg of tempering agent. It is concluded that steam-flaking grain sorghum will increase its NE value for maintenance and gain (14 and 18%, respectively) and enhance the MP value of the diet due to greater intestinal N digestion. The use of a TA to enhance the mechanical efficiency of the flaking process may not otherwise benefit the feeding value of sorghum. [ABSTRACT FROM AUTHOR]

Four Holstein steers (282 kg) with cannulas in the rumen and proximal duodenum were used in a 4 × 4 Latin square experiment to evaluate the influence of dietary urea level (0, 0.4, 0.8, and 1.2%, DM basis) in a steam-flaked barley-based finishing diet on digestive function. There were no treatment effects (P > 0.20) on ruminal digestion of OM and ADF. Increasing dietary urea level increased (linear, P < 0.01) ruminal starch digestion. Ruminal degradability of protein in the basal diet (no supplemental urea) was 60%. Increasing dietary urea level did not increase (P > 0.20) ruminal microbial protein synthesis or nonammonia N flow to the small intestine. There were no treatment effects (P > 0.20) on total-tract ADF digestion. Total tract digestion of OM (quadratic, P < 0.01) and starch (linear, P < 0.05) increased slightly with increasing urea level. Urea supplementation increased (linear, P < 0.01) ruminal pH 1 h after feeding; however, by 3 h after feeding, ruminal pH was lower (cubic, P < 0.05) with urea-supplemented diets. Urea supplementation did not affect (P > 0.20) ruminal molar proportions of acetate and propionate. One hundred twenty crossbred steers (252 kg; approximately 25% Brahman breeding) were used in an 84-d feeding trial (five pens per treatment) to evaluate treatment effects on growth performance. Daily weight gain increased (linear, P = 0.01) with increasing urea level, tending to be maximal (1.53 kg/d; quadratic, P = 0.13) at the 0.8% level of urea supplementation. Improvements in ADG were due to treatment effects (linear, P < 0.01) on DMI. Urea supplementation did not affect (P > 0.20) the NE value of the diet for maintenance and gain. Observed dietary NE values, based on growth performance, were in close agreement with expected based on tabular values for individual feed ingredients, averaging 100.4%. We conclude that with steam-flaked barely-based finishing diets, ruminal and total-tract digestion of OM and ruminal microbial protein synthesis may not be increased by urea supplementation. In contrast, ADG was optimized by dietary inclusion of 0.8% urea. Urea supplementation may not enhance the net energy value of steam-flaked barely-based finishing diets when degradable intake protein is greater than 85% of microbial protein synthesis. [ABSTRACT FROM AUTHOR]

Two experiments were conducted to examine the influence of protein and virginiamycin (VM) supplementation on feedlot growth performance, digestion, and metabolizable AA (MAA) supply of calf-fed Holstein steers. Growth performance and dietary energetics were evaluated in 120 Holstein steers (127 ± 9 kg). During the initial 112-d feeding period, a steam-flaked corn-based diet was balanced to meet either 100% (MAB) or 87% (UREA) of MAA requirements. Diets were supplemented with or without 22.5 mg/kg VM in a 2 x 2 factorial arrangement. Subsequently (d 112 to 308), all steers received the UREA diet with or without VM. During the initial 112-d, MAB increased ADG, G:F, and dietary NE (P < 0.01). Thereafter, when all steers received the UREA diet, ADG, G:F, and dietary NE were not different (P > 0.10) across initial supplementation treatments. Overall (d 1 to 308), MAB did not affect ADG (P > 0.10) but enhanced G:F efficiency (P = 0.03) and dietary NE (P = 0.05). During the initial 112-d period and through the remainder of the experiment, VM increased G:F (P < 0.01) and dietary NE (P < 0.01). Four Holstein steers (146 ± 4 kg) with cannulas in the rumen and proximal duodenum were used in a 4 x 4 Latin square design to evaluate initial 112-d treatment effects on digestive function. There were no treatment effects (P > 0.10) on ruminal digestion of OM, NDF, starch, microbial efficiency, or total tract digestion of OM and NDF. The MAB increased indispensable AA flow to the small intestine (P < 0.01) and total tract digestion of N (P < 0.01) and starch (P = 0.04). Observed AA supply to small intestine was in agreement with expected supply (r² = 0.96). Virginiamycin decreased (P = 0.04) nonammonia N flow to the small intestine and did not affect (P > 0.10) total tract N digestion. Extrapolating from AA supplies in the metabolism study, MAB satisfied indispensable AA requirements during the initial 112-d period, whereas the UREA diet met 73.5% and 79.2% of methionine and lysine requirements, respectively. During the subsequent periods (d 112 to 308) indispensable AA supplies exceeded theoretical requirements. We conclude that enhancements in energy utilization when diets are balanced to meet MAA requirements of calf-fed Holstein steers during the initial 112-d feedlot period remain appreciable throughout time on feed. Virginiamycin enhanced efficiency of energy utilization throughout the feedlot growing-finishing period. [ABSTRACT FROM AUTHOR]

We report on the role of hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) as an inhibitor of metastasis. HEXIM1 expression is decreased in human metastatic breast cancers when compared with matched primary breast tumors. Similarly we observed decreased expression of HEXIM1 in lung metastasis when compared with primary mammary tumors in a mouse model of metastatic breast cancer, the polyoma middle T antigen (PyMT) transgenic mouse. Re-expression of HEXIM1 (through transgene expression or localized delivery of a small molecule inducer of HEXIM1 expression, hexamethylene-bis-acetamide) in PyMT mice resulted in inhibition of metastasis to the lung. Our present studies indicate that HEXIM1 downregulation of HIF-1α protein allows not only for inhibition of vascular endothelial growth factor-regulated angiogenesis, but also for inhibition of compensatory pro-angiogenic pathways and recruitment of bone marrow-derived cells (BMDCs). Another novel finding is that HEXIM1 inhibits cell migration and invasion that can be partly attributed to decreased membrane localization of the 67 kDa laminin receptor, 67LR, and inhibition of the functional interaction of 67LR with laminin. Thus, HEXIM1 re-expression in breast cancer has therapeutic advantages by simultaneously targeting more than one pathway involved in angiogenesis and metastasis. Our results also support the potential for HEXIM1 to indirectly act on multiple cell types to suppress metastatic cancer. [ABSTRACT FROM AUTHOR]

Two experiments were conducted to evaluate the comparative feeding value of dried shredded sugarbeets (DSSB; 0, 20, and 40% of diet DM) as a replacement for steam-flaked corn (SFC) in finishing diets for feedlot cattle. In Exp. 1, 60 calf-fed Holstein steers (476 ± 6.3 kg) were used in a 97-d finishing trial. Substitution of SFC with DSSB did not affect ADG or DMI (P > 0.20). Increasing DSSB decreased gain efficiency (ADG:DMI; linear effect, P = 0.04) and dietary NE (linear effect, P = 0.03). Given that SFC has a NEm value of 2.38 Mcal/kg, the replacement NEm and NEg values for DSSB were 1.94 and 1.29 Mcal/kg, respectively. There were no treatment effects (P > 0.20) on carcass characteristics. In Exp. 2, 6 cannulated Holstein steers (205 kg) were used in a replicated 3 ×; 3 Latin square design to evaluate treatment effects on digestion. Ruminai digestion of starch, NDF, and feed N were not affected (P > 0.10) by DSSB, although ruminai OM digestion tended to increase (linear effect, P < 0.08). Replacing SFC with DSSB decreased flow of starch to the small intestine, but it increased flow of microbial N (linear effect, P = 0.05). There were no treatment effects (P > 0.14) on postruminal digestion of OM, NDF, starch, or feed N or total tract digestion of OM, starch, and N. Substitution of DSSB increased (linear effect, P = 0.05) total tract NDF digestion and decreased (linear effect, P = 0.05) dietary DE (Mcal/kg). Given that SFC has a DE value of 4.19 Mcal/kg, the replacement DE value of DSSB was 3.68 Mcal/kg. There were no treatment effects (P > 0.12) on ruminai pH or total VFA; however, DSSB decreased propionate (linear effect, P = 0.05) and increased acetate (linear effect, P = 0.07), butyrate (linear effect, P = 0.05), valerate (linear effect, P = 0.04), and estimated methane production (linear effect, P = 0.05). We concluded that DSSB may replace SFC in finishing diets at levels of up to 40% without detrimental effects on ADG and carcass characteristics. The NE value of DSSB is 82% that of SFC (DM basis). Partial replacement of SFC with DSSB alters ruminai VFA patterns, increasing estimated methane energy loss and slightly decreasing the efficiency of DE utilization. [ABSTRACT FROM AUTHOR]

In order to investigate the effects of distinct concurrent training sequences on serum leptin and cortisol levels, 10 subjects (27.1 ± 4.8 years, body mass index 25.38 ± 0.09) were submitted to a control session, concurrent training 1 and concurrent training 2. Samples of leptin and cortisol were collected. Concurrent training 1 consisted of indoor cycling followed by strength training and concurrent training 2 of strength training followed by indoor cycling. No exercises were performed at the control session. Blood was collected once again to verify the same variables. Shapiro-Wilk, 2-way ANOVA and Tukey post-hoc tests were used. There was a reduction in leptin levels after concurrent training 1 (Δ% = -16.04; p = 0.05) and concurrent training 2 (Δ% = -8.54; p = 0.02). Cortisol decreased after concurrent training 1 (Δ% = -26.32; p = 0.02) and concurrent training 2 (Δ% = -33.57; p = 0.05). There was a high and significant correlation between blood variables only in CS (lep PRE X cort PRE and cort POST: r = -0.80 and r = -0.81; lep POST X cort PRE and cort POST: r = -0.62 and r = -0.62). Concurrent training promoted a reduction in leptin and cortisol levels irrespective of sequence. [ABSTRACT FROM AUTHOR]

We have previously reported that the expression of antioxidative stress enzymes is upregulated by trans-hydroxytamoxifen (TOT) in breast epithelial cell lines providing protection against estrogen-induced DNA damage. This regulation involves Estrogen Receptor β (ERβ) recruitment to the Electrophile Response Element (EpRE) and a novel protein, human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2). We have also demonstrated that ERβ and hPMC2 are required for TOT-dependent recruitment of poly (ADP-ribose) polymerase 1 (PARP-1) and Topoisomerase IIβ (Topo IIβ) to the EpRE. Sequence analysis reveals that the C-terminus of hPMC2 encodes a putative exonuclease domain. Using in vitro kinetic assays, we found that hPMC2 is a 3′-5′ non-processive exonuclease that degrades both single-stranded and double-stranded substrates. Mutation of two conserved carboxylate residues drastically reduced the exonuclease activity of hPMC2, indicating the relative importance of the catalytic residues. Western blot analysis of breast cancer cell lines for Quinone Reductase (QR) levels revealed that the intrinsic exonuclease activity of hPMC2 was required for TOT-induced QR upregulation. Chromatin immunoprecipitation (ChIP) assays also indicated that hPMC2 was involved in the formation of strand breaks observed with TOT treatment and is specific for the EpRE-containing region of the QR gene. We also determined that the transcription factor NF-E2-related factor-2 (Nrf2) is involved in the specificity of hPMC2 for the EpRE. In addition, we determined that the catalytic activity of hPMC2 is required for repair of abasic sites that result from estrogen-induced DNA damage. Thus, our study provides a mechanistic basis for transcriptional regulation by hPMC2 and provides novel insights into its role in cancer prevention. [ABSTRACT FROM AUTHOR]

Abstract: Four Holstein steers (407±4kg) with cannulas in the rumen and proximal duodenum were used in a 4×4 Latin Square design experiment. Treatments consisted of a 755g/kg steam-flaked corn-based finishing diet in which fungal infested steam-flaked corn replaced 0, 150, 300, and 450g/kg of the control flaked corn. The yeast and mold counts averaged 2.9×102, and 1.2×104 CFU/g, respectively, for control flaked corn, and 7.0×105, and 6.2×106 CFU/g, respectively, for fungal infested flaked corn. There were no treatment effects (P>0.10) on ruminal pH or volatile fatty acids molar proportions. Ruminal digestion of organic matter (OM; linear component, P<0.10), and feed N (linear component, P<0.05) decreased with increasing levels of fungal infested flaked corn in the diet. There were no treatment effects (P>0.10) on net microbial N synthesis. Amino acid intake increased linearly (P<0.01) as fungal infested flaked corn was augmented, and amino acid flow to duodenum was increased (P<0.01) with the highest fungal infested flaked corn level. Total tract digestion of OM, N and energy decreased (linear component, P<0.05) with increasing SFM. Ruminal and total tract digestion of ADF and starch were not affected (P>0.10) by treatments. It is concluded that mold infestation diminishes the feeding value of steam-flaked corn. The consequence was not related to effects of fungal growth on characteristics of digestion, but rather, to loss of readily digestible nutrients (starch) through the spoilage process, and to a lesser extent, decreased N digestibility. On the other hand, the metabolizable protein value was greater for fungal infested flaked corn. [Copyright &y& Elsevier]

Tamoxifen resistance is a major problem in the treatment of estrogen receptor (ER)-positive patients. We have previously reported that hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) inhibits ERα activity by competing with ERα for binding to cyclin T1, a subunit of positive transcription elongation b (P-TEFb). This results in the inhibition of the phosphorylation of RNA polymerase II (RNAPII) at serine 2 and the inhibition of transcription elongation of ERα target genes. As HEXIM1 can inhibit ER activity, we examined whether it has a critical role in the inhibitory effects of tamoxifen on ER. We observed that tamoxifen-induced HEXIM1 recruitment to the promoter region of ER target genes and decreased the recruitment of cyclin T1 and serine 2 phosphorylated RNAPII to the coding regions of these genes. Conversely, in cells wherein HEXIM1 expression has been downregulated we observed attenuation of the inhibitory effects of tamoxifen on estrogen-induced cyclin T1 recruitment to coding regions of ER target genes. As a consequence, downregulation of HEXIM1 resulted in the attenuation of the repressive effects of tamoxifen on estrogen-induced gene expression and proliferation. Conferring clinical relevance to our studies is our analysis of human breast cancer tissue samples that indicated association of lower expression of HEXIM1 with tumor recurrence in patients who received tamoxifen. Our studies provide a better understanding of the mechanistic basis for the inhibitory effect of tamoxifen on ER activity and may suggest new therapeutic targets for the treatment of tamoxifen-resistant breast cancer. [ABSTRACT FROM AUTHOR]

Recently, we found that mutation of the C-terminus of transcription factor hexamethylene bisacetamide-inducible protein 1 (HEXIM1) in mice leads to abnormalities in cardiovascular development because of aberrant vascular endothelial growth factor (VEGF) expression. HEXIM1 regulation of some genes has also been shown to be positive transcription elongation factor b (P-TEFb) dependent. However, it is not known whether HEXIM1 regulates VEGF in the mammary gland. We demonstrate that HEXIM1 regulates estrogen-induced VEGF transcription through inhibition of estrogen receptor-α recruitment to the VEGF promoter in a P-TEFb-independent manner in MCF-7 cells. Under hypoxic conditions, HEXIM1 inhibits estrogen-induced hypoxia-inducible factor-1 alpha (HIF-1α) protein expression and recruitment of HIF-1α to the hypoxia-response element in the VEGF promoter. In the mouse mammary gland, increased HEXIM1 expression decreased estrogen-driven VEGF and HIF-1α expression. Conversely, a mutation in the C-terminus of HEXIM1 (HEXIM11−312) led to increased VEGF and HIF-1α expression and vascularization in mammary glands of heterozygous HEXIM11−312 mice when compared with their wild-type littermates. In addition, HEXIM11−312 mice have a higher incidence of carcinogen-induced mammary tumors with increased vascularization, suggesting an inhibitory role for HEXIM1 during angiogenesis. Taken together, our data provide evidence to suggest a novel role for HEXIM1 in cancer progression. [ABSTRACT FROM AUTHOR]

In the presence of ERβ, trans-hydroxytamoxifen (TOT) protects cells against 17β-estradiol (E2)-induced oxidative DNA damage (ODD) and this correlates with increased expression of the antioxidative enzyme quinone reductase (QR). Here, we investigate the molecular mechanism responsible for ERβ-mediated protection against ODD. We observe constitutive interaction between ERβ and the novel protein hPMC2. Using a combination of breast epithelial cell lines that are either positive or negative for ERα, we demonstrate TOT-dependent recruitment of both ERβ and hPMC2 to the EpRE (electrophile response element)-regulated antioxidative enzyme QR. We further demonstrate TOT-dependent corecruitment of the coactivators Nrf2, PARP-1 (poly (ADP-ribose) polymerase 1) and topoisomerase IIβ, both in the presence and absence of ERα. However, absence of either ERβ or hPMC2 results in nonrecruitment of PARP-1 and topoisomerase IIβ, loss of antioxidative enzyme induction and attenuated protection against ODD by TOT even in the presence of Nrf2 and ERα. These findings indicate minor role for Nrf2 and ERα in TOT-dependent antioxidative gene regulation. However, downregulation of PARP-1 attenuates TOT-dependent antioxidative gene induction. We conclude that ERβ and hPMC2 are required for TOT-dependent recruitment of coactivators such as PARP-1 to the EpRE resulting in the induction of antioxidative enzymes and subsequent protection against ODD.Oncogene (2008) 27, 6376–6384; doi:10.1038/onc.2008.235; published online 28 July 2008 [ABSTRACT FROM AUTHOR]