COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2).

Evidence is accumulating that nutritional exposures in utero can influence health outcomes in later life. Animal studies and human epidemiological studies have implicated epigenetic modifications as playing a key role in this process, but there are limited data from large well-controlled human intervention trials. This study utilized a large double-blind randomized placebo-controlled trial to test whether a defined nutritional exposure in utero, in this case docosahexaenoic acid (DHA), could alter the infant epigenome. Pregnant mothers consumed DHA-rich fish oil (800 mg DHA/day) or placebo supplements from 20 weeks' gestation to delivery. Blood spots were collected from the children at birth (n = 991) and blood leukocytes at 5 years (n = 667). Global DNA methylation was measured in all samples, and Illumina HumanMethylation450K BeadChip arrays were used for genome-wide methylation profiling in a subset of 369 children at birth and 65 children at 5 years.

Rheumatoid arthritis is a systemic, chronic disease which may increase the risk of osteoporosis. This study was carried out in order to examine the effect of conjugated linoleic acid (CLA) on bone markers in rheumatoid arthritis disease which is the most common autoimmune disease. The present study is a randomized double-blind clinical trial. Subjects included 52 patients with active rheumatoid arthritis who were divided into two groups. Group I received standard treatment plus 2 daily 1.25 g capsules (Containing about 2 g of 9-cis 11-trans isomer and 10-cis 12-trans isomer in ratio of 50 -50 CLA in glycerinated form), Group II received standard treatment plus 2 Placebo 1.25 g capsules containing sunflower oil with high oleic acid. Telopeptides C, osteocalcin, and MMP3 were analyzed by ELISA method, PGE2 was done by competitive enzymatic immunoassay method, and IGF-1 was analyzed by the IRMA method based on the sandwich method and ALK-P of bone. Before and after the intervention, the questionnaires about general information, nutrition assessment and medical history were filled out by the subjects. Nutritional assessment was done by a 24-h record questionnaire for the three-day diet. The results were analyzed using SPSS software (version 18).

Purpose: To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy.Experimental Design: A total of 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed one instead of two inductions and consolidations. To compensate for potential loss of efficacy of TT4-L, bortezomib and thalidomide were added to fractionated melphalan 50 mg/m2/d for 4 days.Results: Grade ≥3 toxicities and treatment-related mortalities were not reduced in TT4-L. Complete response (CR) rates were virtually identical (P = 0.2; TT4-S, 59%; TT4-L, 61% at 2 years), although CR duration was superior with TT4-S (P = 0.05; TT4-S, 87%; TT4-L, 81% at 2 years). With a median follow-up of 4.5 years, there was no difference in overall survival (OS) and progression-free survival (PFS). Whereas metaphase cytogenetic abnormalities (CAs) tended to be an adverse feature in TT4-S, as with predecessor TT trials, the reverse applied to TT4-L. Employing historical TT3a as training and TT3b as test set, 51 gene probes (GEP51) significantly differentiated the presence and absence of CA (q < 0.0001), seven of which function in DNA replication, recombination, and repair. Applying the GEP51 model to clinical outcomes, OS and PFS were significantly inferior with GEP51/CA in TT4-S; such a difference was not observed in TT4-L.Conclusions: We identified a prognostic CA-linked GEP51 signature, the adversity of which could be overcome by potentially synergizing anti-multiple myeloma effects of melphalan and bortezomib. These exploratory findings require confirmation in a prospective randomized trial. Clin Cancer Res; 23(11); 2665-72. ©2016 AACR.

Randomized experimental study.

Lymphocyte recruitment to the inflamed gut is increased in UC. Inhibition of this cell trafficking by vedolizumab (VDZ) was successful in inducing and maintaining remission and in induction of endoscopic mucosal healing. There are no data on histological healing with VDZ. We studied histological changes following VDZ therapy and compared gene expression in patients with UC before and after therapy.

Previous work demonstrated that a soy-dairy protein blend (PB) prolongs hyperaminoacidemia and muscle protein synthesis in young adults after resistance exercise.

During the periovulatory period, the cervix relaxes in response to changes in circulating concentrations of reproductive hormones. The present study investigated the role of gonadotrophins in cervical function by examining the expression of cyclooxygenase-2 (COX2) and COX2 mRNA and the concentration of hyaluronan (HA) in the cervix, after intracervical treatment with either FSH or LH. Eighteen ewes were assigned to four groups. They were then treated with commercial intravaginal progestagen sponges and eCG to synchronize their estrous cycles. Intracervical treatments were given 24 hours after removal of the sponges as follows: group 1: FSH, 2 mg; group 2: LH, 2 mg; group 3: vehicle; and group 4: control. Cervices were collected 54 hours after sponge removal and then divided into three regions. The expression of COX2 and COX2 mRNA was determined by immunohistochemistry and in situ hybridization and those of HA by ELISA. The levels of expression of COX2, COX2 mRNA, and HA were compared in six tissue layers (luminal epithelium, subepithelial stroma, circular, longitudinal and transverse muscle, and serosa) and in three cervical regions (vaginal, mid, and uterine). The results showed that both FSH and LH significantly increased the levels the COX2 mRNA and COX2 in the cervix, but the effects of the gonadotrophins were selective. The effects of both FSH and LH were most evident at the vaginal end of the cervix and least at the uterine end of the cervix. Furthermore, their effects were confined to the stroma and smooth muscle layers of the cervix in the case of FSH and to smooth muscle only in the case of LH. Neither FSH nor LH affected the concentration of HA in the cervix although FSH but not LH reduced the concentration of HA in cervical mucus. These findings suggest that the gonadotrophins regulate the expression of COX2 in the cervix and that they may have a role facilitating relaxation of the cervix during estrus in the ewe.

Posttranslational histone modifications (PTHMs) are altered by arsenic, an environmental carcinogen. PTHMs are also influenced by nutritional methyl donors involved in one-carbon metabolism (OCM), which may protect against epigenetic dysregulation.

This study was conducted to investigate the effects of benzoic acid (BA) on growth performance, intestinal development and intestinal barrier function in weaned pigs. Ninety weaned pigs were randomly assigned to one of three treatments: a basal diet (CON), the basal diet supplemented with 2000 mg/kg benzoic acid (BA1) and 5000 mg/kg benzoic acid (BA2). At the end of days 14 and 42, six pigs per treatment were randomly selected to collect plasma and intestinal samples. Results showed that BA supplementation not only improved final body weight, daily growth and feed conversion ratio from days 15 to 42 and days 1 to 42, but also decreased the activity of plasma diamine oxidase (day 42) and the pH values of jejunal contents (day 14) (p < 0.05). Ileal Bacillus populations (day 14) were increased by BA, while Escherichia coli counts in the ileum and caecum (day 42) were decreased (p < 0.05). Higher Lactobacillus counts occurred in the ileum (day 14, 42) of BA1-fed piglets as compared to CON and BA2-fed piglets (p < 0.05). In addition, BA supplementation increased the ratio of villus height to crypt depth (day 14, 42) and decreased the crypt depth (day 14) (p < 0.05). Growth-stimulating factors (insulin-like growth factor-1, day 42; insulin-like growth factor-1 receptor, day 14, 42) and tight junction protein (occludin, day 14, 42; zonula occludens-1, day 42)-related gene mRNA levels were upregulated in the jejunum of piglets fed BA diets (p < 0.05). In conclusion, this study provides the first evidence that BA has beneficial effects on intestinal development and intestinal barrier function of weaned pigs, which can partly explain why growth performance of pigs was improved by dietary BA supplementation.

Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV-1 infected treatment-naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP-glucuronosyltransferase (UGT) 1 A1-mediated glucuronidation pathway, co-administration of UGT1A1 inducers may alter plasma levels of raltegravir. Efavirenz, an UGT1A1 inducer, was used to assess the impact of altered UGT activity on a 1200 mg QD dose of raltegravir. An open label, randomized, 2-period fixed-sequence Phase 1 study was performed in adult healthy male and female subjects (non-childbearing potential) ≥ 19 and ≤55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤32.0 kg/m2 . Subjects (n = 21) received a single oral dose of 1200 mg raltegravir at bedtime on an empty stomach on Day 1 in Period 1. After a washout period of at least 7 days, subjects received oral doses of 600 mg efavirenz QD at bedtime for 14 consecutive days in Period 2. Subjects received a single oral dose of 1200 mg raltegravir co-administered with 600 mg efavirenz on Day 12 of Period 2. Pharmacokinetic (PK) samples were collected for 72 hours following raltegravir dosing and analyzed using a validated bioanalytical method to quantify raltegravir plasma concentrations. PK parameters were estimated using non-compartmental analysis. Administration of single 1200 mg oral doses of raltegravir alone and co-administered with multiple oral doses of efavirenz were generally well tolerated in healthy subjects. Co-administration with efavirenz yielded geometric mean ratios (GMRs) and their associated 90% confidence intervals (90% CIs) for raltegravir AUC0-∞, Cmax , and C24 of 0.86 (0.73, 1.01), 0.91 (0.70, 1.17), and 0.94 (0.76, 1.17), respectively. The results show that efavirenz modestly reduced the exposure of raltegravir. The reduction in raltegravir exposure is not considered clinically meaningful. Copyright © 2016 John Wiley & Sons, Ltd.

Exercise training induces adaptations in mitochondrial metabolism, dynamics, and oxidative protection. Omega-3 fatty acids change membrane lipid composition and modulate mitochondrial function. The aim was to investigate the effect of 8-week training and docosahexaenoic acid (DHA) supplementation (1.14 g/day) on the mitochondria dynamics and antioxidant status in peripheral blood mononuclear cells (PBMCs) from sportsmen. Subjects were assigned to an intervention (N = 9) or placebo groups (N = 7) in a randomized double-blind trial. Nutritional intervention significantly increased the DHA content in erythrocyte membranes from the experimental group. No significant differences were reported in terms of circulating PBMCs, Mn-superoxide dismutase protein levels, and their capability to produce reactive oxygen species. The proteins related to mitochondrial dynamics were, in general, increased after an 8-week training and this increase was enhanced by DHA supplementation. The content in mitofusins Mtf-1 and Mtf-2, optic atrophy protein-1 (Opa-1), and mitochondrial transcription factor A (Tfam) were significantly higher in the DHA-supplemented group after intervention. Cytochrome c oxidase (COX-IV) activity and uncoupling proteins UCP-2 and UCP-3 protein levels were increased after training, with higher UCP-3 levels in the supplemented group. In conclusion, training induced mitochondrial adaptations which may contribute to improved mitochondrial function. This mitochondrial response was modulated by DHA supplementation.

This study aimed to investigate the possible serum protein changes after endotoxin administration in healthy and choline-treated calves using proteomics. These results are expected to contribute to the understanding of the pathophysiological mechanisms of endotoxemia and the beneficial effect of choline administration in this clinical situation.

The aim of the study was to determine how supplementation with exogenous progesterone (P4) affects the expression of genes important for endometrial receptivity and conceptus development during the peri-implantation period in pigs. Gilts with PMSG/hCG-induced first estrus received daily injections of corn oil (CO; n=7) or P4 (n=7) on days 3 to 10 after insemination. The dose of P4 was 25mg/100kg BW on days 3 and 4 of gestation, then increased to 50mg/100kg BW on days 5 to 10. Blood samples were collected each day to monitor concentrations of circulating P4. Animals were slaughtered on day 12 of pregnancy to obtain endometrial tissue, conceptuses, and uterine luminal flushing (ULF). Gilts in the P4 group had consistently greater P4 concentrations in the blood compared with controls. Treatment of gilts with P4 increased uterine weight and enhanced total protein content and 6-keto PGF1α (a PGI2 metabolite) content in the uterine lumen. Moreover, injections of gilts with P4 increased the expression of prostaglandin endoperoxide synthase 2, microsomal PGE2 synthase and vascular endothelial growth factor A mRNA in the endometrium, but had no effect on gene expression in conceptuses. These results indicate that P4 supplementation stimulated the secretory activity of the endometrium and increased the expression of genes responsible for vascular function and luteotropic PGE2 synthesis, which are important components of successful pregnancy establishment in pigs. However, no effect of P4 treatment was detected in conceptuses.

This study was conducted to determine the effects of omega-3 fatty acids and vitamin E co-supplementation on gene expression of lipoprotein(a) (Lp[a]) and oxidized low-density lipoprotein (Ox-LDL), lipid profiles and biomarkers of oxidative stress in women with polycystic ovary syndrome (PCOS). This randomized double-blind, placebo-controlled trial was done on 68 women diagnosed with PCOS according to the Rotterdam criteria aged 18-40 years old. Participants were randomly assigned into two groups to receive either 1000 mg omega-3 fatty acids from flaxseed oil containing 400 mg α-Linolenic acid plus 400 IU vitamin E supplements (n = 34) or placebo (n = 34) for 12 weeks. Lp(a) and Ox-LDL mRNA levels were quantified in peripheral blood mononuclear cells of PCOS women with RT-PCR method. Lipid profiles and biomarkers of oxidative stress were quantified at the beginning of the study and after 12-week intervention. Quantitative results of RT-PCR demonstrated that compared with the placebo, omega-3 fatty acids and vitamin E co-supplementation downregulated expressed levels of Lp(a) mRNA (P < 0.001) and Ox-LDL mRNA (P < 0.001) in peripheral blood mononuclear cells of women with PCOS. In addition, compared to the placebo group, omega-3 fatty acids and vitamin E co-supplementation resulted in a significant decrease in serum triglycerides (-22.1 ± 22.3 vs. +7.7 ± 23.6 mg/dL, P < 0.001), VLDL- (-4.4 ± 4.5 vs. +1.5 ± 4.7 mg/dL, P < 0.001), total- (-20.3 ± 16.6 vs. +12.2 ± 26.1 mg/dL, P < 0.001), LDL- (-16.7 ± 15.3 vs. +11.9 ± 26.1 mg/dL, P < 0.001) and total-/HDL-cholesterol (-0.5 ± 0.6 vs. +0.4 ± 0.8, P < 0.001). There were a significant increase in plasma total antioxidant capacity (+89.4 ± 108.9 vs. +5.9 ± 116.2 mmol/L, P = 0.003) and a significant decrease in malondialdehyde levels (-0.3 ± 0.4 vs. -0.008 ± 0.6 μmol/L, P = 0.01) by combined omega-3 fatty acids and vitamin E intake compared with the placebo group. Overall, omega-3 fatty acids and vitamin E co-supplementation for 12 weeks in PCOS women significantly improved gene expression of Lp(a) and Ox-LDL, lipid profiles and biomarkers of oxidative stress.

The influence of induction of ovulation and superovulation with eCG and hCG on LH and FSH receptor levels in porcine oviducts on day 3 postcoitum was studied. In experiment I, gilts were assigned into cyclic (control; n = 5) and inseminated (n = 5) groups. In experiment II, there were 3 groups of animals: inseminated (n = 5), induced ovulation/inseminated (750 IU eCG, 500 IU hCG; n = 5) and superovulated/inseminated (1500 IU eCG, 1000 IU hCG; n = 5) gilts. Oviduct tissues were collected 3 d after insemination or PBS infusion. The messenger RNA (mRNA) expression of FSH receptor (FSHR) and luteinizing hormone/chorionic gonadotropin receptor (LH/CGR) was measured by real-time reverse transcription PCR and protein levels using Western blots. Localization of LH/CGR and FSHR-positive cells was studied by immunohistochemical staining. Insemination by itself did not influence mRNA and protein levels of LH/CGR. However, FSHR mRNA expression in the isthmus and ampulla of the oviduct was affected by insemination (P < 0.05). Similarly, insemination decreased FSHR protein level in the isthmus (P < 0.05). Stimulation with hCG and eCG did not affect LH/CGR and FSHR mRNA expression, either in the isthmus or in the ampulla. Nevertheless, superovulation decreased LH/CGR protein level in the oviductal ampulla (P < 0.05) in comparison with inseminated gilts. Similarly, protein levels of FSHR in the oviductal ampulla decreased after superovulation (P < 0.05). LH/CGR-positive cells were observed in the mucosa as well as in smooth muscle cells of both parts of the oviduct. Follicle-stimulating hormone receptor-positive cells were observed in smooth muscle cells and blood vessels of the isthmus. In the ampulla, FSHR-positive cells were observed in the smooth muscle as well as in the mucosa. Summarizing, the present study revealed for the first time that stimulation with eCG and hCG, especially in high doses, can change LH/CGR and FSHR levels in porcine oviducts. This may in turn alter many signaling pathways, eg, PGs or vascular endothelial growth factor synthesis, and consequently disturb the oviductal environment, with possible detrimental effects on fertilization and/or embryonic development.

Recent studies have shown that supplementation of plant products rich in polyphenols exerts anti-inflammatory effects in the small intestine and improves feed conversion in piglets. This study aimed to investigate whether dietary polyphenols have also anti-inflammatory and cytoprotective effects in the liver of piglets. For this end, relative mRNA concentrations of eight genes involved in proinflammatory pathways, eight genes involved in the antioxidative and cytoprotective system, six genes of phase I and phase II metabolism and 15 genes of the unfolded protein response (triggered by stress of the endoplasmic reticulum) in the liver of pigs fed diets supplemented with either 1% of grape seed and grape marc meal extract (GME) or 1% spent hops (SH) as sources of polyphenols were determined. Relative mRNA concentrations of almost all these genes, with few exceptions, in the liver of pigs supplemented with GME or SH did not differ from those in the liver of control piglets. Gene expression data were validated by consideration of concentrations of some selected proteins of these pathways which also did not differ between piglets supplemented with GME or SH and control piglets. Moreover, concentrations of thiobarbituric acid-reactive substances and tocopherols as well as the total antioxidant capacity in liver and plasma did not differ between pigs supplemented with either GME or SH and control piglets. Overall, this study shows that supplementation of GME or SH as sources of polyphenols does not influence hepatic pathways linked to inflammation, the antioxidant and cytoprotective system, stress of the endoplasmic reticulum and the xenobiotic system in healthy piglets.

The aim of the present study was to investigate whether changes in the tissue expression of human epididymis-specific protein 4 (HE4) could predict therapy resistance and relapse after progestin hormone therapy for medium- and low-risk endometrial hyperplasia.

Purpose: Anti-CD20 mAb therapies, including rituximab and obinutuzumab (GA101), are common treatments for follicular lymphoma. In an effort to better understand the role of complement in mAb action, we recently performed germline SNP profiling on 142 follicular lymphoma patients and found rs3766404 genotype correlated with patient response to rituximab. To assess the role of three SNP-associated complement-regulatory proteins (CFH, CFHR1, and CFHR3) in clinical response to anti-CD20 mAb, we studied two cohorts of patients treated with anti-CD20 mAb.Experimental Design: Cohorts included the Iowa/Mayo Lymphoma SPORE observational cohort of subjects with a new diagnosis of follicular lymphoma treated with rituximab and the GAUSS prospective randomized trial cohort of follicular lymphoma subjects randomized to receive single-agent rituximab or obinutuzumab. Circulating protein expression was measured for CFH, CFHR1, and CFHR3 and correlated to clinical outcome.Results: rs3766404 genotype correlated with expression of the related downstream genes CFHR1 and CFHR3 Loss of CFHR1 expression correlated with inferior patient outcome in the observational cohort, but not in the GAUSS cohort. Loss of CFHR3 correlated with superior event-free survival in GAUSS subjects treated with obinutuzumab, but not rituximab.Conclusions: We conclude that the relationship between complement-regulatory proteins CFHR1 and CFHR3 and response to anti-CD20 mAb therapy varies based on the specific anti-CD20 mAb used. We propose that CFHR3 is a candidate biomarker for obinutuzumab response. Further studies are needed to validate these findings and to better understand how complement pathways and complement-regulatory proteins impact on the efficacy of anti-CD20 mAb therapy. Clin Cancer Res; 23(4); 954-61. ©2016 AACR.

Gut microbes have a substantial influence on systemic immune function and allergic sensitisation. Manipulation of the gut microbiome through prebiotics may provide a potential strategy to influence the immunopathology of asthma. This study investigated the effects of prebiotic Bimuno-galactooligosaccharide (B-GOS) supplementation on hyperpnoea-induced bronchoconstriction (HIB), a surrogate for exercise-induced bronchoconstriction, and airway inflammation. A total of ten adults with asthma and HIB and eight controls without asthma were randomised to receive 5·5 g/d of either B-GOS or placebo for 3 weeks separated by a 2-week washout period. The peak fall in forced expiratory volume in 1 s (FEV1) following eucapnic voluntary hyperpnoea (EVH) defined HIB severity. Markers of airway inflammation were measured at baseline and after EVH. Pulmonary function remained unchanged in the control group. In the HIB group, the peak post-EVH fall in FEV1 at day 0 (-880 (sd 480) ml) was unchanged after placebo, but was attenuated by 40 % (-940 (sd 460) v. -570 (sd 310) ml, P=0·004) after B-GOS. In the HIB group, B-GOS reduced baseline chemokine CC ligand 17 (399 (sd 140) v. 323 (sd 144) pg/ml, P=0·005) and TNF-α (2·68 (sd 0·98) v. 2·18 (sd 0·59) pg/ml, P=0·040) and abolished the EVH-induced 29 % increase in TNF-α. Baseline C-reactive protein was reduced following B-GOS in HIB (2·46 (sd 1·14) v. 1·44 (sd 0·41) mg/l, P=0·015) and control (2·16 (sd 1·02) v. 1·47 (sd 0·33) mg/l, P=0·050) groups. Chemokine CC ligand 11 and fraction of exhaled nitric oxide remained unchanged. B-GOS supplementation attenuated airway hyper-responsiveness with concomitant reductions in markers of airway inflammation associated with HIB.