The zinc finger domain of Wilms' tumor 1 suppressor gene (WT1) behaves as a dominant negative, leading to abrogation of WT1 oncogenic potential in breast cancer cells

Abstract Introduction There is growing evidence that the Wilms' tumor 1 suppressor gene (WT1) behaves as an oncogene in some forms of breast cancer. Previous studies have demonstrated that the N-terminal domain of WT1 can act as a dominant negative through self-association. In the studies presented here we have explored the potential for the zinc finger domain (ZF) of WT1 to also have dominant-negative effects, and thus further our understanding of this protein. Methods Using full-length and ZF-only forms of WT1 we assessed their effect on the WT1 and c-myc promoter using luciferase and chromatin immunoprecipitation assays. The gene expression levels were determined by quantitative real-time RT-PCR, northern blot and western blot. We also assessed the effect of the ZF-only form on the growth of breast cancer cell lines in culture. Results Transfection with WT1–ZF plasmids resulted in a stronger inhibition of WT1 promoter than full-length WT1 in breast cancer cells. The WT1–ZF form lacking the lysine–threonine–serine (KTS) insert (ZF - KTS) can bind to the majority of WT1 consensus sites throughout the WT1 promoter region, while the ZF containing the insert (ZF + KTS) form only binds to sites in the proximal promoter. The abundances of endogenous WT1 mRNA and protein were markedly decreased following the stable expression of ZF - KTS in breast cancer cells. The expressions of WT1 target genes, including c-myc, Bcl-2, amphiregulin and TERT, were similarly suppressed by ZF - KTS. Moreover, WT1–ZF - KTS abrogated the transcriptional activation of c-myc mediated by all four predominant isoforms of WT1 (including or lacking alternatively spliced exons 5 and 9). Finally, WT1–ZF - KTS inhibited colony formation and cell division, but induced apoptosis in MCF-7 cells. Conclusion Our observations strongly argue that the WT1–ZF plasmid behaves as a dominant-negative regulator of the endogenous WT1 in breast cancer cells. The inhibition on proliferation of breast cancer cells by WT1–ZF - KTS provides a potential candidate of gene therapy for breast cancer

Sparticle mass spectra from SU(5) SUSY GUT models with b−τb-\tau Yukawa coupling unification

Supersymmetric grand unified models based on the gauge group SU(5) often require in addition to gauge coupling unification, the unification of b-quark and $\tau$-lepton Yukawa couplings. We examine SU(5) SUSY GUT parameter space under the condition of $b-\tau$ Yukawa coupling unification using 2-loop MSSM RGEs including full 1-loop threshold effects. The Yukawa-unified solutions break down into two classes. Solutions with low tan\beta ~3-11 are characterized by gluino mass ~1-4 TeV and squark mass ~1-5 TeV. Many of these solutions would be beyond LHC reach, although they contain a light Higgs scalar with mass <123 GeV and so may be excluded should the LHC Higgs hint persist. The second class of solutions occurs at large tan\beta ~35-60, and are a subset of $t-b-\tau$ unified solutions. Constraining only $b-\tau$ unification to ~5% favors a rather light gluino with mass ~0.5-2 TeV, which should ultimately be accessible to LHC searches. While our $b-\tau$ unified solutions can be consistent with a picture of neutralino-only cold dark matter, invoking additional moduli or Peccei-Quinn superfields can allow for all of our Yukawa-unified solutions to be consistent with the measured dark matter abundance.Comment: 19 pages, 5 figures, 1 table, PDFLate

Neutralino dark matter in mSUGRA/CMSSM with a 125 GeV light Higgs scalar

The minimal supergravity (mSUGRA or CMSSM) model is an oft-used framework for exhibiting the properties of neutralino (WIMP) cold dark matter (CDM). However, the recent evidence from Atlas and CMS on a light Higgs scalar with mass m_h\simeq 125 GeV highly constrains the superparticle mass spectrum, which in turn constrains the neutralino annihilation mechanisms in the early universe. We find that stau and stop co-annihilation mechanisms -- already highly stressed by the latest Atlas/CMS results on SUSY searches -- are nearly eliminated if indeed the light Higgs scalar has mass m_h\simeq 125 GeV. Furthermore, neutralino annihilation via the A-resonance is essentially ruled out in mSUGRA so that it is exceedingly difficult to generate thermally-produced neutralino-only dark matter at the measured abundance. The remaining possibility lies in the focus-point region which now moves out to m_0\sim 10-20 TeV range due to the required large trilinear soft SUSY breaking term A_0. The remaining HB/FP region is more fine-tuned than before owing to the typically large top squark masses. We present updated direct and indirect detection rates for neutralino dark matter, and show that ton scale noble liquid detectors will either discover mixed higgsino CDM or essentially rule out thermally-produced neutralino-only CDM in the mSUGRA model.Comment: 17 pages including 9 .eps figure

The botanical integrity of wheat products influences the gastric distention and satiety in healthy subjects

<p>Abstract</p> <p>Background</p> <p>Maintenance of the botanical integrity of cereal kernels and the addition of acetic acid (as vinegar) in the product or meal has been shown to lower the postprandial blood glucose and insulin response and to increase satiety. However, the mechanism behind the benefits of acetic acid on blood glucose and satiety is not clear. We hypothesized that the gastric emptying rate could be involved. Thus, the aim of this study was to evaluate the possible influence of maintained botanical integrity of cereals and the presence of acetic acid (vinegar) on gastric emptying rate (GER), postprandial blood glucose and satiety.</p> <p>Methods</p> <p>Fifteen healthy subjects were included in a blinded crossover trial, and thirteen of the subjects completed the study. Equicarbohydrate amounts of the following wheat-based meals were studied: white wheat bread, whole-kernel wheat bread or wholemeal wheat bread served with white wine vinegar. The results were compared with a reference meal consisting of white wheat bread without vinegar. The GER was measured with standardized real-time ultrasonography using normal fasting blood glucose <6.1 mmol/l or plasma glucose <7.0 mmol/l as an inclusion criterion. The GER was calculated as the percentage change in the antral cross-sectional area 15 and 90 minutes after ingestion of the various meals. Satiety scores were estimated and blood glucose was measured before and 15, 30, 45, 60, 90 and 120 min after the start of the meal.</p> <p>Results</p> <p>The whole-kernel wheat bread with vinegar resulted in significantly higher (<0.05) satiety than the wholemeal wheat bread and white wheat bread with vinegar and the reference bread. Wheat fiber present in the wholemeal wheat bread, or the presence of wheat kernels per se, did not affect the postprandial blood glucose or GER significantly compared with white wheat bread, neither did the addition of vinegar to white bread affect these variables. There was no correlation found between the satiety with antral areas or GER</p> <p>Conclusion</p> <p>The present study shows higher satiety after a whole-kernel wheat bread meal with vinegar. This may be explained by increased antral distension after ingestion of intact cereal kernels but, in this study, not by a lower gastric emptying rate or higher postprandial blood glucose response.</p> <p>Trial registration</p> <p>NTR1116</p

Does green tea affect postprandial glucose, insulin and satiety in healthy subjects: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Results of epidemiological studies have suggested that consumption of green tea could lower the risk of type 2 diabetes. Intervention studies show that green tea may decrease blood glucose levels, and also increase satiety. This study was conducted to examine the postprandial effects of green tea on glucose levels, glycemic index, insulin levels and satiety in healthy individuals after the consumption of a meal including green tea.</p> <p>Methods</p> <p>The study was conducted on 14 healthy volunteers, with a crossover design. Participants were randomized to either 300 ml of green tea or water. This was consumed together with a breakfast consisting of white bread and sliced turkey. Blood samples were drawn at 0, 15, 30, 45, 60, 90, and 120 minutes. Participants completed several different satiety score scales at the same times.</p> <p>Results</p> <p>Plasma glucose levels were higher 120 min after ingestion of the meal with green tea than after the ingestion of the meal with water. No significant differences were found in serum insulin levels, or the area under the curve for glucose or insulin. Subjects reported significantly higher satiety, having a less strong desire to eat their favorite food and finding it less pleasant to eat another mouthful of the same food after drinking green tea compared to water.</p> <p>Conclusions</p> <p>Green tea showed no glucose or insulin-lowering effect. However, increased satiety and fullness were reported by the participants after the consumption of green tea.</p> <p>Trial registration number</p> <p>NCT01086189</p

Modelling molecular interaction pathways using a two-stage identification algorithm

In systems biology, molecular interactions are typically modelled using white-box methods, usually based on mass action kinetics. Unfortunately, problems with dimensionality can arise when the number of molecular species in the system is very large, which makes the system modelling and behavior simulation extremely difficult or computationally too expensive. As an alternative, this paper investigates the identification of two molecular interaction pathways using a black-box approach. This type of method creates a simple linear-in-the-parameters model using regression of data, where the output of the model at any time is a function of previous system states of interest. One of the main objectives in building black-box models is to produce an optimal sparse nonlinear one to effectively represent the system behavior. In this paper, it is achieved by applying an efficient iterative approach, where the terms in the regression model are selected and refined using a forward and backward subset selection algorithm. The method is applied to model identification for the MAPK signal transduction pathway and the Brusselator using noisy data of different sizes. Simulation results confirm the efficacy of the black-box modelling method which offers an alternative to the computationally expensive conventional approach

Effect of commercial breakfast fibre cereals compared with corn flakes on postprandial blood glucose, gastric emptying and satiety in healthy subjects: a randomized blinded crossover trial

<p>Abstract</p> <p>Background</p> <p>Dietary fibre food intake is related to a reduced risk of developing diabetes mellitus. However, the mechanism of this effect is still not clear. The aim of this study was to evaluate the effect of commercial fibre cereals on the rate of gastric emptying, postprandial glucose response and satiety in healthy subjects.</p> <p>Methods</p> <p>Gastric emptying rate (GER) was measured by standardized real time ultrasonography. Twelve healthy subjects were assessed using a randomized crossover blinded trial. The subjects were examined after an 8 hour fast and after assessment of normal fasting blood glucose level. Satiety scores were estimated and blood glucose measurements were taken before and at 0, 20, 30, 40, 60, 80, 100 and 120 min after the end of the meal. GER was calculated as the percentage change in the antral cross-sectional area 15 and 90 min after ingestion of sour milk with corn flakes (GER1), cereal bran flakes (GER2) or wholemeal oat flakes (GER3).</p> <p>Results</p> <p>The median value was, respectively, 42% for GER1, 33 % for GER2 and 51% for GER3. The difference between the GER after ingestion of bran flakes compared to wholemeal oat flakes was statistically significant (p = 0.023). The postprandial delta blood glucose level was statistically significantly lower at 40 min (p = 0.045) and 120 min (p = 0.023) after the cereal bran flakes meal. There was no statistical significance between the areas under the curve (AUCs) of the cereals as far as blood glucose and satiety were concerned.</p> <p>Conclusion</p> <p>The result of this study demonstrates that the intake of either bran flakes or wholemeal oat flakes has no effect on the total postprandial blood glucose response or satiety when compared to corn flakes. However, the study does show that the intake of cereal bran flakes slows the GER when compared to oat flakes and corn flakes, probably due to a higher fibre content. Since these products do not differ in terms of glucose response and satiety on healthy subjects, they should be considered equivalent in this respect.</p> <p>Trial registration</p> <p>ISRCTN90535566</p

Forward-Backward Asymmetry in Top Quark Production in ppbar Collisions at sqrt{s}=1.96 TeV

Reconstructable final state kinematics and charge assignment in the reaction ppbar->ttbar allows tests of discrete strong interaction symmetries at high energy. We define frame dependent forward-backward asymmetries for the outgoing top quark in both the ppbar and ttbar rest frames, correct for experimental distortions, and derive values at the parton-level. Using 1.9/fb of ppbar collisions at sqrt{s}=1.96 TeV recorded with the CDF II detector at the Fermilab Tevatron, we measure forward-backward top quark production asymmetries in the ppbar and ttbar rest frames of A_{FB,pp} = 0.17 +- 0.08 and A_{FB,tt} = 0.24 +- 0.14.Comment: 7 pages, 2 figures, submitted to Phys.Rev.Lett, corrected references and change of tex

Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron

We study the underlying event in proton-antiproton collisions by examining the behavior of charged particles (transverse momentum pT > 0.5 GeV/c, pseudorapidity |\eta| < 1) produced in association with large transverse momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan production) or the leading jet (in high-pT jet production) in each event to define three regions of \eta-\phi space; toward, away, and transverse, where \phi is the azimuthal scattering angle. For Drell-Yan production (excluding the leptons) both the toward and transverse regions are very sensitive to the underlying event. In high-pT jet production the transverse region is very sensitive to the underlying event and is separated into a MAX and MIN transverse region, which helps separate the hard component (initial and final-state radiation) from the beam-beam remnant and multiple parton interaction components of the scattering. The data are corrected to the particle level to remove detector effects and are then compared with several QCD Monte-Carlo models. The goal of this analysis is to provide data that can be used to test and improve the QCD Monte-Carlo models of the underlying event that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.