Colorectal Cancers from Distinct Ancestral Populations Show Variations in BRAF Mutation Frequency

It has been demonstrated for some cancers that the frequency of somatic oncogenic mutations may vary in ancestral populations. To determine whether key driver alterations might occur at different frequencies in colorectal cancer, we applied a high-throughput genotyping platform (OncoMap) to query 385 mutations across 33 known cancer genes in colorectal cancer DNA from 83 Asian, 149 Black and 195 White patients. We found that Asian patients had fewer canonical oncogenic mutations in the genes tested (60% vs Black 79% (P = 0.011) and White 77% (P = 0.015)), and that BRAF mutations occurred at a higher frequency in White patients (17% vs Asian 4% (P = 0.004) and Black 7% (P = 0.014)). These results suggest that the use of genomic approaches to elucidate the different ancestral determinants harbored by patient populations may help to more precisely and effectively treat colorectal cancer

Focus on the research utility of intravascular ultrasound - comparison with other invasive modalities

Intravascular ultrasound (IVUS) is an invasive modality which provides cross-sectional images of a coronary artery. In these images both the lumen and outer vessel wall can be identified and accurate estimations of their dimensions and of the plaque burden can be obtained. In addition, further processing of the IVUS backscatter signal helps in the characterization of the type of the plaque and thus it has been used to study the natural history of the atherosclerotic evolution. On the other hand its indigenous limitations do not allow IVUS to assess accurately stent struts coverage, existence of thrombus or exact site of plaque rupture and to identify some of the features associated with increased plaque vulnerability. In order this information to be obtained, other modalities such as optical coherence tomography, angioscopy, near infrared spectroscopy and intravascular magnetic resonance imaging have either been utilized or are under evaluation. The aim of this review article is to present the current utilities of IVUS in research and to discuss its advantages and disadvantages over the other imaging techniques

Skeletal Muscle Apoptotic Signaling Predicts Thigh Muscle Volume and Gait Speed in Community-Dwelling Older Persons: An Exploratory Study

Preclinical studies strongly suggest that accelerated apoptosis in skeletal myocytes may be involved in the pathogenesis of sarcopenia. However, evidence in humans is sparse. In the present study, we investigated whether apoptotic signaling in the skeletal muscle was associated with indices of muscle mass and function in older persons.Community-dwelling older adults were categorized into high-functioning (HF) or low-functioning (LF) groups according to their short physical performance battery (SPPB) summary score. Participants underwent an isokinetic knee extensor strength test and 3-dimensional magnetic resonance imaging of the thigh. Vastus lateralis muscle samples were obtained by percutaneous needle biopsy and assayed for the expression of a set of apoptotic signaling proteins. Age, sex, number of comorbid conditions and medications as well as knee extensor strength were not different between groups. HF participants displayed greater thigh muscle volume compared with LF persons. Multivariate partial least squares (PLS) regressions showed significant correlations between caspase-dependent apoptotic signaling proteins and the muscular percentage of thigh volume (R(2) = 0.78; Q(2) = 0.61) as well as gait speed (R(2) = 0.81; Q(2) = 0.56). Significant variables in the PLS model of percent muscle volume were active caspase-8, cleaved caspase-3, cytosolic cytochrome c and mitochondrial Bak. The regression model of gait speed was mainly described by cleaved caspase-3 and mitochondrial Bax and Bak. PLS predictive apoptotic variables did not differ between functional groups. No correlation was determined between apoptotic signaling proteins and muscle strength or quality (strength per unit volume).Data from this exploratory study show for the first time that apoptotic signaling is correlated with indices of muscle mass and function in a cohort of community-dwelling older persons. Future larger-scale studies are needed to corroborate these preliminary findings and determine if down-regulation of apoptotic signaling in skeletal myocytes will provide improvements in the muscle mass and functional status of older persons

SEDLIN Forms Homodimers: Characterisation of SEDLIN Mutations and Their Interactions with Transcription Factors MBP1, PITX1 and SF1

BACKGROUND: SEDLIN, a 140 amino acid subunit of the Transport Protein Particle (TRAPP) complex, is ubiquitously expressed and interacts with the transcription factors c-myc promoter-binding protein 1 (MBP1), pituitary homeobox 1 (PITX1) and steroidogenic factor 1 (SF1). SEDLIN mutations cause X-linked spondyloepiphyseal dysplasia tarda (SEDT). METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effects of 4 missense (Asp47Tyr, Ser73Leu, Phe83Ser and Val130Asp) and the most C-terminal nonsense (Gln131Stop) SEDT-associated mutations on interactions with MBP1, PITX1 and SF1 by expression in COS7 cells. Wild-type SEDLIN was present in the cytoplasm and nucleus and interacted with MBP1, PITX1 and SF1; the SEDLIN mutations did not alter these subcellular localizations or the interactions. However, SEDLIN was found to homodimerize, and the formation of dimers between wild-type and mutant SEDLIN would mask a loss in these interactions. A mammalian SEDLIN null cell-line is not available, and the interactions between SEDLIN and the transcription factors were therefore investigated in yeast, which does not endogenously express SEDLIN. This revealed that all the SEDT mutations, except Asp47Tyr, lead to a loss of interaction with MBP1, PITX1 and SF1. Three-dimensional modelling studies of SEDLIN revealed that Asp47 resides on the surface whereas all the other mutant residues lie within the hydrophobic core of the protein, and hence are likely to affect the correct folding of SEDLIN and thereby disrupt protein-protein interactions. CONCLUSIONS/SIGNIFICANCE: Our studies demonstrate that SEDLIN is present in the nucleus, forms homodimers and that SEDT-associated mutations cause a loss of interaction with the transcription factors MBP1, PITX1 and SF1

A functional AT/G polymorphism in the 5'-untranslated region (UTR) of SETDB2 in the IgE locus on human chromosome 13q14

The immunoglobulin E (IgE)-associated locus on human chromosome 13q14 influencing asthma-related traits contains the genes PHF11 and SETDB2. SETDB2 is located in the same linkage disequilibrium region as PHF11 and polymorphisms within SETDB2 have been shown to associate with total serum IgE levels. In this report, we sequenced the 15 exons of SETDB2 and identified a single previously ungenotyped mutation (AT/G, rs386770867) in the 5′-untranslated region of the gene. The polymorphism was found to be significantly associated with serum IgE levels in our asthma cohort (P=0.0012). Electrophoretic mobility shift assays revealed that the transcription factor Ying Yang 1 binds to the AT allele, whereas SRY (Sex determining Region Y) binds to the G allele. Allele-specific transcription analysis (allelotyping) was performed in 35 individuals heterozygous for rs386770867 from a panel of 200 British families ascertained through probands with severe stage 3 asthma. The AT allele was found to be significantly overexpressed in these individuals (P=1.26 × 10(−21)). A dual-luciferase assay with the pGL3 luciferase reporter gene showed that the AT allele significantly affects transcriptional activities. Our results indicate that the IgE-associated AT/G polymorphism (rs386770867) regulates transcription of SETDB2

The Increase in Balloon Size to Over 15 mm Does Not Affect the Development of Pancreatitis After Endoscopic Papillary Large Balloon Dilatation for Bile Duct Stone Removal

BACKGROUND: Endoscopic papillary large balloon dilatation (EPLBD) after endoscopic sphincterotomy (EST) has recently become widely used for common bile duct (CBD) stone removal, but many clinicians remain concerned about post-procedural pancreatitis with increasing the balloon size to over 15 mm. AIMS: We aimed to evaluate the safety and efficacy of EPLBD with a relatively large balloon (15-20 mm) after EST and to evaluate the factors related to post-EPLBD pancreatitis. METHODS: A retrospective review was undertaken of the endoscopic database of 101 patients with CBD stones who underwent EPLBD using a larger balloon size of over 15 mm (15-20 mm). Clinical parameters, endoscopic data, and outcomes were analyzed. RESULTS: The mean age of the subjects was 69 years. All patients had a dilated CBD of over 11 mm (mean = 22.6 mm). The mean size of balloon used in EPLBD was 17.1 ± 1.9 mm (range 15-20 mm). Mechanical lithotripsy was required in seven patients (6.9%). The rate of complete stone removal in the first session was 92.1%. Post-procedural pancreatitis developed in five cases (5.4%), but none were graded as severe. The smaller dilatation of the CBD, longer cannulation time, and longer time for stone removal were associated with post-procedural pancreatitis, but larger size of balloon did not affect the development of post-EPLBD pancreatitis. CONCLUSIONS: EPLBD with a large balloon of over 15 mm with EST is an effective and safe procedure with a very low probability of severe post-procedural pancreatitis. Post-EPLBD pancreatitis was not associated with larger balloon size, but was associated with longer procedure time and smaller dilatation of the CBD.ope

Measurement of the Dipion Mass Spectrum in X(3872) -> J/Psi Pi+ Pi- Decays

We measure the dipion mass spectrum in X(3872)--> J/Psi Pi+ Pi- decays using 360 pb-1 of pbar-p collisions at 1.96 TeV collected with the CDF II detector. The spectrum is fit with predictions for odd C-parity (3S1, 1P1, and 3DJ) charmonia decaying to J/Psi Pi+ Pi-, as well as even C-parity states in which the pions are from Rho0 decay. The latter case also encompasses exotic interpretations, such as a D0-D*0Bar molecule. Only the 3S1 and J/Psi Rho hypotheses are compatible with our data. Since 3S1 is untenable on other grounds, decay via J/Psi Rho is favored, which implies C=+1 for the X(3872). Models for different J/Psi-Rho angular momenta L are considered. Flexibility in the models, especially the introduction of Rho-Omega interference, enable good descriptions of our data for both L=0 and 1.Comment: 7 pages, 4 figures -- Submitted to Phys. Rev. Let

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.

Search for New Physics in Lepton + Photon + X Events with L=305 pb-1 of ppbar Collisions at roots=1.96 TeV

We present results of a search for anomalous production of events containing a charged lepton (either electron or muon) and a photon, both with high transverse momentum, accompanied by additional signatures, X, including missing transverse energy (MET) and additional leptons and photons. We use the same kinematic selection criteria as in a previous CDF search, but with a substantially larger data set, 305 pb-1, a ppbar collision energy of 1.96 TeV, and the upgraded CDF II detector. We find 42 Lepton+Photon+MET events versus a standard model expectation of 37.3 +- 5.4 events. The level of excess observed in Run I, 16 events with an expectation of 7.6 +- 0.7 events (corresponding to a 2.7 sigma effect), is not supported by the new data. In the signature of Multi-Lepton+Photon+X we observe 31 events versus an expectation of 23.0 +- 2.7 events. In this sample we find no events with an extra photon or MET and so find no events like the one ee+gg+MET event observed in Run I.Comment: 7 pages, 3 figures, 1 table. Accepted to PR

Top Quark Mass Measurement from Dilepton Events at CDF II with the Matrix-Element Method

We describe a measurement of the top quark mass using events with two charged leptons collected by the CDF II detector from $p\bar{p}$ collisions with $\sqrt s = 1.96$ TeV at the Fermilab Tevatron. The likelihood in top mass is calculated for each event by convoluting the leading order matrix element describing $q\bar{q} \to t\bar{t} \to b\ell\nu_{\ell}\bar{b}\ell'\nu_{\ell'}$ with detector resolution functions. The presence of background events in the data sample is modeled using similar calculations involving the matrix elements for major background processes. In a data sample with integrated luminosity of 340 pb$^{-1}$, we observe 33 candidate events and measure $M_{top} = 165.2 \pm 6.1(\textrm{stat.}) \pm 3.4(\textrm{syst.}) \mathrm{~GeV}/c^2.$ This measurement represents the first application of this method to events with two charged leptons and is the most precise single measurement of the top quark mass in this channel.Comment: 21 pages, 14 figure