To investigate the mechanism underlying the regulatory effect of Met on broiler growth, the growth performance, organ development, serum profile, myogenic gene expression, and methylation of myostatin gene exon 1 region in response to dietary Met status were evaluated. A total of 192 one-day-old Arbor Acres broiler chicks were housed in 3-layer cages in a temperature-controlled room with continuous lighting. The temperature of the room was maintained at 32 to 34°C for the first 3 d and then reduced by 2 to 3°C per week to a final temperature of 20°C. Cages were randomly allocated to 2 dietary treatments with 6 replicate cages (8 males and 8 females/cage) per treatment. Control starter and finisher diets contained 0.50 and 0.43% Met, respectively. Corresponding values for a +Met treatment were 0.60 and 0.53% Met, respectively. The birds receiving the +Met diets had a greater (P < 0.05) G:F throughout the experiment. The +Met diets increased (P < 0.05) the relative weight of breast muscle and the concentrations of uric acid and triglyceride in serum at 42 d of age, whereas other serum measurements were not affected by treatments. Increased myogenic factor 5 (Myf5) and myocyte enhancer factor 2B (MEF2B) and decreased myostatin mRNA expression were observed in broilers fed the +Met diets (P < 0.05). However, methylation of myostatin gene exon 1 region was not different between groups. In conclusion, broilers fed the +Met diets increased breast muscle growth that was reflected in the expected expression of myostatin, Myf5, and MEF2B genes.

Previous studies have determined the effects of dietary selenium (Se) supplementation on selenoprotein N (SelN, SEPN1), selenophosphate synthetase-1 (SPS1), and selenocysteine-synthase (SecS) mRNA abundance in chicken skeletal and cardiac muscles. To investigate collective responses of these genes to dietary Se concentrations ranging from deficiency to moderately high level in muscle tissues of chicken, 1-day-old chickens were exposed to a diet of deficient Se and supplemented with Se (0.15 mg Se/kg and 1.50 mg Se/kg) as sodium selenite in the feed for 35 days. Muscle tissues (flight, breast, leg, and cardiac muscles) were collected and examined for Se content and mRNA levels of SelN on days 1, 15, 25, and 35 days, respectively. Moreover, SPS1 and SecS mRNA levels were analyzed. The results showed that the expression of SelN gene in cardiac muscle responded to dietary Se concentrations. SelN gene was downregulated in the Se deficiency group (L group), and upregulated in the Se excess group (H group) compared with the moderate Se group (M group) (P < 0.05) in cardiac muscle. Se deficiency mainly unregulated SelN mRNA level in skeletal muscles compared with M group. Excess dietary Se mainly resulted in the upregulation of SelN mRNA level in skeletal muscles compared with the M group. SecS mRNA levels responded to dietary Se concentrations showed a similar change compared with SelN in cardiac muscle. SPS1 mRNA levels responded to dietary Se concentrations showed a downregulation in L group and upregulation in H group. However, SelN mRNA levels displayed a different expression pattern in different skeletal and cardiac muscles. Moreover, Se also regulated the levels of SPS1 and SecS mRNAs. In summary, Se regulated the expression of SelN gene and affected the mRNA levels of SecS and SPS1. The level of Se in the feed may regulate SelN biosynthesis by affecting the levels of SPS1 and SecS mRNA.

Glucagon-like peptide-1 (GLP-1) and the insulin-like growth factor (IGF) system are important factors in metabolic regulation and cellular growth. Interactions between the systems exist but these are vaguely explored and only in vitro, where GLP-1 has been reported to stimulate IGF-binding protein 1 (IGFBP-1). This study, therefore, aimed to elucidate the effects of GLP-1 on IGF-I and the IGFBPs, which regulate IGF-I bioactivity.

Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co-administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib.

The present study was conducted to determine whether dietary threonine supplementation can improve immunity of weaned pigs challenged by swine Pseudorabies live vaccine (SPLV). Thirty crossbred piglets weaned at 21 days of age were randomly assigned to three groups receiving diets containing true ileal digestible threonine (TIDT) at 0.74, 0.89 and 1.11% for 14 days. On day 8, all pigs were injected intramuscularly with SPLV or sterile 0.9% NaCl solution. SPLV injection enhanced serum IgA, IgM, IgG, IFN-γ, IL-1β, TNF-α and IL-10 concentrations (p < 0.05) and stimulated the relative mRNA abundance of Toll-like receptors (TLR3, TLR7 or TLR9) in different tissues (p < 0.05). Under no challenge, increasing dietary TIDT levels enhanced serum IgG (p < 0.05), IgM (p = 0.07) and IFN-γ (p < 0.05) concentration, tended to decrease serum IL-1β, TNF-α and IL-10 concentration, and regulated relative mRNA abundance of TLR3, TLR7 or TLR9 in different tissues (p < 0.05). However, there was a synergistic role for increasing the serum IL-10 concentration between dietary TIDT levels and SPLV injection (p < 0.05). Under SPLV challenge, increasing dietary TIDT levels attenuated the increase of the serum IFN-γ concentration, and the increase of the relative mRNA abundance of TLR3, TLR7 and TLR9 in the different tissues (p < 0.05). These results suggest that an appropriate dietary threonine supplementation could improve the immune status of weaned pigs injected with SPLV by down-regulating the expression of TLR3, TLR7 and TLR9 in tissues, and thus regulating T-helper cytokine secretion.

Lapatinib is approved in combination with capecitabine for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who have progressed on prior trastuzumab in the metastatic setting. Vinorelbine is an important chemotherapy option for MBC. We evaluated efficacy and safety of lapatinib plus vinorelbine, compared with lapatinib plus capecitabine, in women with HER2-positive MBC. In this open-label, multicenter, phase II study, eligible patients (N = 112) were randomized 2:1 to lapatinib plus vinorelbine [(N = 75) 1,250 mg orally once daily (QD) continuously plus 20 mg/m(2)/day intravenously] or lapatinib plus capecitabine [(N = 37) 1,250 mg orally QD continuously plus 2,000 mg/m(2)/day orally, 2 doses]. The primary endpoint was progression-free survival (PFS). Other endpoints included overall survival (OS) and safety. Patients progressing within the study were given the option of crossover to the other treatment arm; time to second progression was an exploratory endpoint. Patient demographics, stratification, and prognostic factors were well balanced between treatments. Median PFS in both arms was 6.2 months [95 % confidence interval (CI) 4.2, 8.8 (lapatinib plus vinorelbine); 4.4, 8.3 (lapatinib plus capecitabine)]. Median OS on lapatinib plus vinorelbine was 24.3 months (95 % CI 16.4, NE) and 19.4 months (95 % CI 16.4, 27.2) on lapatinib plus capecitabine. In total, 42 patients opted to cross over; median PFS was 3.2 months (95 % CI 1.7, 5.1) on lapatinib plus vinorelbine and 4.0 months (95 % CI 2.1, 5.8) on lapatinib plus capecitabine. Lapatinib plus vinorelbine offers an effective treatment option for patients with HER2-overexpressing MBC, having displayed comparable efficacy and tolerability rates to lapatinib plus capecitabine.

Protein glycosylation via O-linked N-acetylglucosaminylation (O-GlcNAcylation) is an important post-translational regulatory mechanism mediated by O-GlcNAc transferase (OGT) and responsive to nutrients and stress. OGT attaches an O-GlcNAc moiety to proteins, while O-GlcNAcase (OGA) catalyzes O-GlcNAc removal. In skeletal muscle of experimental animals, prolonged increase in O-GlcNAcylation associates with age and muscle atrophy. Here we examined the effects of hormone replacement therapy (HRT) and power training (PT) on muscle OGT and OGA gene expression in postmenopausal women generally prone to age-related muscle weakness. In addition, the associations of OGT and OGA gene expressions with muscle phenotype were analyzed. Twenty-seven 50-57-year-old women participated in a yearlong randomized placebo-controlled trial: HRT (n=10), PT (n=8) and control (n=9). OGT and OGA mRNA levels were measured from muscle samples obtained at baseline and after one year. Knee extensor muscle cross-sectional area (CSA), knee extension force, running speed and vertical jumping height were measured. During the yearlong intervention, HRT suppressed the aging-associated upregulation of OGT mRNA that occurred in the controls. The effects of PT were similar but weaker. HRT also tended to increase the OGA mRNA level compared to the controls. The change in the ratio of OGT to OGA gene expressions correlated negatively with the change in muscle CSA. Our results suggest that OGT and OGA gene expressions are associated with muscle size during the critical postmenopausal period. HRT and PT influence muscle OGT and OGA gene expression, which may be one of the mechanisms by which HRT and PT prevent aging-related loss of muscle mass.

Disturbing maternal metabolism during the first pregnancy and postpartum period is associated with sub fertility in rabbit does. Nutritional strategies can be used during those periods and its effects to improve reproductive management may affect periconceptional events and early embryo development. Our goal was to elucidate if treatment with a glycogenic precursor such as propylene glycol (PG) could affect the maternal metabolic profile, follicular and oocyte quality and gene expression patterns in early embryos. Rabbit does were supplemented with 2.5% (v/v) PG from either mid-pregnancy and for 25 days of lactation (PG-GL group); only during lactation (PG-L group); or were not treated (control group). Ovarian parameters and embryos were studied at the end of treatment. At parturition serum non-esterified fatty acid concentrations increased whilst insulin decreased in all groups. Maternal feed intake was reduced in PG-supplemented does but glycaemia was maintained during the experimental period. When PG was suppressed, blood insulin immediately increased in PG-groups, but no differences in follicular population, follicular atresia, and nuclear and cytoplasmic oocyte maturation were observed compared with non-treated animals. Although embryo development was similar among groups, mRNA of SLC2A4, INSR, IGF1R, PLAC8, COX2 and IGF2R were up regulated in the blastocysts of PG-GL does. Transcripts of SOD1 were lower in PG-L embryos; but NOS3 and TP53 were similar among groups. PG did not affect the maternal metabolic profile during the postpartum period, nor the ovarian response or number of embryos developed. Nonetheless, PG supplied from mid-pregnancy modified mRNA transcripts involved in some important developmental and metabolic events in the blastocysts of those females. More experiments are needed to elucidate the physiological consequence of these results.

We explored the impact of early molecular response (EMR; BCR-ABL ≤10% on the international scale [BCR-ABL(IS)] at 3 or 6 months) on outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with nilotinib or imatinib based on 4 years of follow up in Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients. Patients (n = 846) received nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily. At 3 months, more patients had EMR failure (ie, BCR-ABL(IS) >10%) on imatinib (33%) than on nilotinib (9%-11%); similarly at 6 months, 16% of patients in the imatinib arm vs 3% and 7% in the nilotinib arms had EMR failure. In all arms, EMR failure was associated with lower rates of molecular response, an increased risk of progression, and lower overall survival compared with EMR achievement. We also analyzed patient and treatment characteristics associated with EMR and found distinct patterns in the nilotinib arms vs the imatinib arm. High Sokal risk score was associated with a high rate of EMR failure on imatinib, but not on nilotinib. In contrast, reduced dose intensity and dose interruptions were strongly associated with EMR failure in nilotinib-treated, but not imatinib-treated, patients. This study is registered at www.clinicaltrials.gov as #NCT00471497.

Little is known about the role insulin plays in regulating whole-body and muscle protein metabolism in horses. The objective of this study was to determine the effects of graded rates of insulin infusion on plasma amino acid concentrations and the activation of factors in the mechanistic target of rapamycin signaling pathway in the skeletal muscle of horses. Isoglycemic, hyperinsulinemic clamp procedures were conducted in 8 mature, thoroughbred mares receiving 4 rates of insulin infusion: 0 mU · kg(-1) · min(-1) (CON), 1.2 mU · kg(-1) · min(-1) (LOWINS), 3 mU · kg(-1) · min(-1) (MEDINS), and 6 mU · kg(-1) · min(-1) (HIGHINS). Blood samples were taken throughout the clamp procedures to measure plasma amino acid concentrations, and a biopsy from the gluteus medius muscle was collected at the end of the 2-h clamp to measure phosphorylation of protein kinase B, eukaryotic initiation factor 4E-binding protein 1, and riboprotein S6. Plasma concentrations of most of the essential amino acids decreased (P < 0.05) after 120 min of insulin infusion in horses receiving the LOWINS, MEDINS, and HIGHINS treatments, with the largest decreases occurring in horses receiving the MEDINS and HIGHINS treatments. Phosphorylation of protein kinase B, 4E-binding protein 1, and riboprotein S6 increased with all 3 rates of insulin infusion (P > 0.05), relative to CON, with maximum phosphorylation achieved with MEDINS and HIGHINS treatments. These results indicate that insulin stimulates whole-body and muscle protein synthesis in mature horses.

To define protein molecular characteristics of tumor cells prior to, and immediately following, preoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy that correlate with pathologic complete response (pCR) or non response (no pCR) to preoperative HER2-directed therapy and chemotherapy.

This cross-sectional study tested the hypothesis that treatment with the combination of Ezetimibe/Simvastatin (Vytorin) leads to broader changes in the expression levels of immunomodulatory genes as compared to Simvastatin monotherapy.

Our aim was to investigate the relationship between mutant p53 and the prognosis of malignant glioma treated with temozolomide, and the regulation of mutant TP53 induced drug resistance, by molecular experimentation and a clinical trial.

Severe traumas are associated with hypercortisolemia due to both disruption of cortisol secretion rhythm and increase in its total concentration. Understanding the effects of altered cortisol levels and rhythms on immune function is of great clinical interest, to prevent conditions such as sepsis from complicating the recovery. This in vivo study assesses the responses of circulating leukocytes to coupled dose and rhythm manipulation of cortisol, preceding an immune challenge induced by endotoxin administration. Through continuous infusion, plasma cortisol concentration was increased to and kept constant at a level associated with major physiologic stress. In response, transcriptional programming of leukocytes was altered to display a priming response before endotoxin exposure. Enhanced expression of a number of receptors and signaling proteins, as well as lowered protein translation and mitochondrial function indicated a sensitization against potential infectious threats. Despite these changes, response to endotoxin followed very similar patterns in both cortisol and saline pre-treated groups except one cluster including probe sets associated with major players regulating inflammatory response. In sum, altered dose and rhythm of plasma cortisol levels engendered priming of circulating leukocytes when preceded an immune challenge. This transcriptional program change associated with stimulated surveillance function and suppressed energy-intensive processes, emphasized permissive actions of cortisol on immune function.

Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent degradation of incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), whereas metformin may increase GLP-1 levels. We examined, in a four-period crossover trial, the influence of metformin (2,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly augmented insulin secretion, in monotherapy and as an add-on to metformin. The incretin effect was not changed numerically with any of the treatments. In conclusion, sitagliptin increased intact GLP-1 and GIP through DPP-4 inhibition but reduced total GLP-1 and GIP (feedback inhibition) without affecting the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic agents besides GLP mediating the antidiabetic effects of DPP-4 inhibition.

Hashimoto's thyroiditis is less prevalent in tobacco smokers. Anatabine, an alkaloid found in Solanaceae plants including tobacco, has been reported to ameliorate a mouse model of Hashimoto's thyroiditis.

To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program.

Recent trials with inhibition of the renin-angiotensin-aldosterone system (RAAS) in patients with established atherosclerosis have been equivocal. MicroRNAs (miRs) are known to affect multiple pathways relevant to atherosclerosis, including RAAS. We postulated that the use of a direct renin antagonist would result in differential regulation of miRs. We examined monocyte miR expression before and after treatment with renin antagonist, Aliskiren, in patients with established cardiovascular disease as part of a prospective, single-center, randomized, double-blind and placebo-controlled clinical trial (NCT01417104). After screening, patients (mean age 62±3 years) were randomized to placebo or Aliskiren. Three-dimensional dark-blood magnetic resonance imaging assessment of atherosclerosis in the thoracic and abdominal aorta was conducted at baseline and at study completion (19-36 weeks). MiR expression arrays were performed on RNA from peripheral blood mononuclear cells collected at baseline and 12 weeks following randomization to placebo or Aliskiren and showed that hsa-miR-106b-5p, 27a-3p and 18b-5p were significantly downregulated with Aliskiren. Baseline expression of these miRs positively correlated with normalized total wall volume in subjects taking Aliskiren (miR-106b, R=0.62; miR-27a, R=0.63; miR-18b, R=0.77; P<0.05). Hsa-miR-106b-5p, 27a-3p and 18b-5p may represent pathway-specific adaptations to renin inhibition relevant to atherosclerosis.

The HIV-TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) can complicate combined treatments for HIV-1 and TB. Little is known about tissue damage in TB-IRIS. Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix and consequently may play a role in such immunopathology. Here we investigated the involvement of MMPs in TB-IRIS. We determined MMP transcript abundance and secreted protein in Mycobacterium tuberculosis stimulated PBMCs from 22 TB-IRIS patients and 22 non-IRIS controls. We also measured MMP protein levels in corresponding serum and the effect of prednisone--which reduces the duration of symptoms in IRIS patients--or placebo treatment on MMP transcript and circulating MMP protein levels. PBMCs from TB-IRIS had increased MMP-1, -3, -7, and -10 transcript levels when compared with those of controls at either 6 or 24 h. Similarly, MMP-1, -3, -7, and -10 protein secretion in stimulated cultures was higher in TB-IRIS than in controls. Serum MMP-7 concentration was elevated in TB-IRIS and 2 weeks of corticosteroid therapy decreased this level, although not significantly. TB-IRIS is associated with a distinct pattern of MMP gene and protein activation. Modulation of dysregulated MMP activity may represent a novel therapeutic approach to alleviate TB-IRIS in HIV-TB patients undergoing treatment.

OBJECTIVE The extracellular matrix protein fibulin-1 is upregulated in the arterial wall in type 2 diabetes (T2D) and circulates in increased concentrations in diabetes. Metformin is an antidiabetic drug with beneficial cardiovascular disease effects in diabetes. We hypothesized that metformin would influence the increased level of plasma fibulin-1 in diabetes. RESEARCH DESIGN AND METHODS After a 4-week run-in period, 371 eligible patients with T2D were randomized to treatment groups in a factorial design including insulin alone (control), +metformin, +rosiglitazone, or +both metformin and rosiglitazone. Plasma fibulin-1 was analyzed at the beginning of the study and after 18 and 24 months. RESULTS Plasma fibulin-1 increased in all groups throughout the 2-year period; however, the increase was strongly attenuated among patients treated with metformin. A highly significant difference was observed when the mean change in plasma fibulin-1 was compared between metformin- and non-metformin-treated individuals both at 18 and 24 months of treatment, but rosiglitazone had no effect. Metformin and rosiglitazone alone reduced the HbA1c levels to comparable levels and in combination even further. CONCLUSIONS Metformin attenuates the increase in plasma fibulin-1 concentrations in T2D, independently of glycemic effects. Changes in fibulin-1 may reflect an important element in diabetic arteriopathy that can be influenced by metformin.