Dehorning is a painful husbandry procedure that is commonly performed in dairy calves. Parenteral meloxicam combined with local anesthesia mitigates the physiological and behavioral effects of dehorning in calves. The purpose of this study was to determine the influence of timing of oral meloxicam administration on physiological responses in calves after dehorning. Thirty Holstein bull calves, 8 to 10 wk of age (28-70 kg), were randomly assigned to 1 of 3 treatment groups: placebo-treated control group (n=10), calves receiving meloxicam administered orally (1 mg/kg) in powdered milk replacer 12h before cautery dehorning (MEL-PRE; n=10), and calves receiving meloxicam administered as an oral bolus (1 mg/kg) at the time of dehorning (MEL-POST; n=10). Following cautery dehorning, blood samples were collected to measure cortisol, substance P (SP), haptoglobin, ex vivo prostaglandin E2 (PgE2) production after lipopolysaccharide stimulation and meloxicam concentrations. Maximum ocular temperature and mechanical nociceptive threshold (MNT) were also assessed. Data were analyzed using noncompartmental pharmacokinetic analysis and repeated measures ANOVA models. Mean peak meloxicam concentrations were 3.61±0 0.21 and 3.27±0.14 μg/mL with average elimination half-lives of 38.62±5.87 and 35.81±6.26 h for MEL-PRE and MEL-POST, respectively. Serum cortisol concentrations were lower in meloxicam-treated calves compared with control calves at 4 h postdehorning. Substance P concentrations were significantly higher in control calves compared with meloxicam-treated calves at 120 h after dehorning. Prostaglandin E2 concentrations were lower in meloxicam-treated calves compared with control calves. Mechanical nociceptive threshold was higher in control calves at 1h after dehorning, but meloxicam-treated calves tended to have a higher MNT at 6h after dehorning. No effect of timing of meloxicam administration on serum cortisol concentrations, SP concentrations, haptoglobin concentrations, maximum ocular temperature, or MNT was observed. However, PgE2 concentrations in MEL-PRE calves were similar to control calves after 12h postdehorning, whereas MEL-POST calves had lower PgE2 concentrations for 3 d postdehorning. These findings support that meloxicam reduced cortisol, SP, and PgE2 after dehorning, but only PgE2 production was significantly affected by the timing of meloxicam administration.

No abstract

Proper control of the G 1 /S checkpoint is essential for normal proliferation. The activity of p53 must be kept at a very low level under unstressed conditions to allow growth. Here we provide evidence supporting a crucial role for TopBP1 in actively repressing p53. Depletion of TopBP1 upregulates p53 target genes involved in cell cycle arrest and apoptosis and enhances DNA damage-induced apoptosis. The regulation is mediated by an interaction between the seventh and eighth BRCT domains of TopBP1 and the DNA-binding domain of p53, leading to inhibition of p53 promoter binding activity. Importantly, TopBP1 overexpression is found in 46 of 79 primary breast cancer tissues and is associated with high tumor grade and shorter patient survival time. Overexpression of TopBP1 to a level comparable to that seen in breast tumors leads to inhibition of p53 target gene expression and DNA damage-induced apoptosis and G 1 arrest. Thus, a physiological level of TopBP1 is essential for normal G 1 /S transition, but a pathological level of TopBP1 in cancer may perturb p53 function and contribute to an aggressive tumor behavior.

The epidermal growth factor receptor (EGFR) plays an important role in cancer by activating downstream signals important in growth and survival. Inhibitors of EGFR are frequently selected as treatment for cancer including lung cancer. We performed an unbiased and comprehensive search for EGFR phosphorylation events related to somatic activating mutations and EGFR inhibitor (erlotinib) sensitivity. EGFR immunoprecipitation combined with high resolution liquid chromatography-mass spectrometry and label free quantitation characterized EGFR phosphorylation. Thirty (30) phosphorylation sites were identified including 12 tyrosine (pY), 12 serine (pS), and 6 threonine (pT). Site-specific phosphorylation was monitored by comparing ion signals from the corresponding unmodified peptide. Phosphorylation sites related to activating mutations in EGFR as well as sensitivity to erlotinib were identified using 31 lung cancer cell lines. We identified three sites (pY1092, pY1110, pY1172) correlating with activating mutations while three sites (pY1110, pY1172, pY1197) correlated with erlotinib sensitivity. Five sites (pT693, pY1092, pY1110, pY1172 and pY1197) were inhibited by erlotinib in concentrationdependent manner. Erlotinib sensitivity was confirmed using liquid chromatography coupled to multiple reaction monitoring (LC-MRM) and quantitative western blotting. This LC-MS/MS strategy can quantitatively assess site-specific EGFR phosphorylation and can identify relationships between somatic mutations or drug sensitivity and protein phosphorylation. § Correspondence should be addressed to: Eric B. Haura,

The polyethylene glycol (PEG) modified gold nanoparticle complex was synthesized by a one-solution synchrotron x-ray irradiation method. The impact on the structure and morphology of the gold nanoparticles of process parameters such as the PEG molecular weight, the PEG/gold molar ratio and the x-ray dosage were investigated. The size of PEG modified gold particles was found to decrease with increasing PEG addition and x-ray dosage. With the capability to monitor the absorption spectra in situ during the fast synthesis process, this opens the way to accurate control of the size and distribution. PEG chains with an intermediate length (MW6000) were found optimal for size control and colloidal stability in biologically relevant media. Our x-ray synthesized PEG-gold nanoparticles could find interesting applications in nanoparticle-enhanced x-ray tumour imaging and therapy.

In the present study, we successively extracted the pu-erh raw tea with methanol (PR-1), chloroform (PR-2), ethyl acetate (PR-3), n-butanol (PR-4), and water (PR-5). Among these extracts, PR-3 extract contained ingredients with the most effective hypolipidemic potential and was further purified by column chromatography. Moreover, chronic administration of PR-3 provoked a significant reduction in levels of serum triglyceride and low-density lipoprotein (LDL) in rats. Our study demonstrated that fraction 5 from the PR-3 extract (PR-3-5s) showed a hypolipidemic effect in human hepatoma HepG2 cells. PR-3-5s decreased the expression of fatty acid synthase (FASN) and inhibited the activity of acetyl-coenzyme A carboxylase (ACC) by stimulating AMP-activated protein kinase (AMPK) through the LKB1 pathway. Moreover, PR-3-5s blocked the progression of the cell cycle at the G1 phase by inducing p53 expression and in turn upregulating p21 expression.

No abstract

Human breast cancers cells overexpressing HER2/neu are more aggressive tumors with poor prognosis, and resistance to chemotherapy. This study investigates antiproliferation effects of anthraquinone derivatives of rhubarb root on human breast cancer cells. Of 7 anthraquinone derivatives, only rhein showed antiproliferative and apoptotic effects on both HER2-overexpressing MCF-7 (MCF-7/HER2) and control vector MCF-7 (MCF-7/VEC) cells. Rhein induced dose- and time-dependent manners increase in caspase-9-mediated apoptosis correlating with activation of ROS-mediated activation of NF-κB- and p53-signaling pathways in both cell types. Therefore, this study highlighted rhein as processing anti-proliferative activity against HER2 overexpression or HER2-basal expression in breast cancer cells and playing important roles in apoptotic induction of human breast cancer cells.