Biomarker analyses of clinical outcomes in patients with advanced hepatocellular carcinoma treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Purpose: Sorafenib is the current standard therapy for advanced HCC, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in HCC patients from the phase 3 SEARCH trial. Experimental Design: 720 patients were randomized to receive oral sorafenib 400 mg BID plus erlotinib 150 mg QD or placebo. Fifteen growth factors relevant to the treatment regimen and/or to HCC were measured in baseline plasma samples. Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n=243; sorafenib plus placebo, n=251). Treatment arm–independent analyses showed that elevated HGF (HR, 1.687 [high vs low expression]; endpoint multiplicity adjusted [e-adj] P=0.0001) and elevated plasma VEGF-A (HR, 1.386; e-adj P=0..0377) were significantly associated with poor OS in multivariate analyses, and low plasma KIT (HR, 0.75 [high vs low]; P=0.0233; e-adj P=0.2793) tended to correlate with poorer OS. High plasma VEGF-C independently correlated with longer TTP (HR, 0.633; e-adj P=0.0010) and trended toward associating with improved disease control rate (univariate:OR, 2.047; P=0.030; e-adj P=0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGF-A, KIT, epigen, and VEGF-C correlated with improved median OS in multivariate analysis (HR, 0.150; P<0.00001). No biomarker predicted efficacy from erlotinib. Conclusions: Baseline plasma HGF, VEGF-A, KIT, and VEGF-C correlated with clinical outcomes in HCC patients treated with sorafenib with or without erlotinib. These biomarkers plus epigen constituted a multimarker signature for improved OS

The quark part of the non-forward BFKL kernel and the ``bootstrap'' for the gluon Reggeization

We calculate the quark part of the kernel of the generalized non-forward BFKL equation at non-zero momentum transfer $t$ in the next-to-leading logarithmic approximation. Along with the quark contribution to the gluon Regge trajectory, this part includes pieces coming from the quark-antiquark production and from the quark contribution to the radiative corrections in one-gluon production in the Reggeon-Reggeon collisions. The results obtained can be used for an arbitrary representation of the colour group in the $t-$channel. Using the results for the adjoint representation, we demonstrate explicitly the fulfillment of the ``bootstrap'' condition for the gluon Reggeization in the next-to-leading logarithmic approximation in the part concerning the quark contribution.Comment: 26 pages, LaTeX, uses axodraw.sty; revised final comment; to appear on Phys. Rev.

Low PCA3 expression is a marker of poor differentiation in localized prostate tumors: exploratory analysis from 12,076 patients

Contains fulltext : 177804.pdf (publisher's version ) (Open Access)BACKGROUND: Prostate cancer antigen 3 (PCA3) is a prostate cancer diagnostic biomarker that has been clinically validated. The limitations of the diagnostic role of PCA3 in initial biopsy and the prognostic role are not well established. Here, we elucidate the limitations of tissue PCA3 to predict high grade tumors in initial biopsy. RESULTS: PCA3 has a bimodal distribution in both biopsy and radical prostatectomy (RP) tissues, where low PCA3 expression was significantly associated with high grade disease (p/=8) with 55% sensitivity and high false negative rates; 42% of high Gleason (>/=8) samples had low PCA3. In RP, low PCA3 is associated with adverse pathological features, clinical recurrence outcome and greater probability of metastatic progression (p<0.001). MATERIALS AND METHODS: A total of 1,694 expression profiles from biopsy and 10,382 from RP patients with high risk tumors were obtained from the Decipher Genomic Resource Information Database (GRIDTM)prostate cancer database. The primary clinical endpoint was distant metastasis-free survival for RP and high Gleason grade for biopsy. Logistic regression analyses and Cox proportional hazards models were used to evaluate the association of PCA3 with clinical variables and risk of metastasis. CONCLUSIONS: There is high prevalence of high grade tumors with low PCA3 expression in the biopsy setting. Therefore, urologists should be warned that using PCA3 as stand-alone test may lead to high rate of under-diagnosis of high grade disease in initial biopsy setting

The Quark Impact Factors

We calculate in the next-to-leading approximation the non-forward quark impact factors for both singlet and octet color representation in the $t$-channel. The integral representation of the octet impact factor in the general case of arbitrary space-time dimension and massive quark flavors is used to check the so-called "second bootstrap condition" for the gluon Reggeization at the next-to-leading logarithmic approximation in perturbative QCD. We find that it is satisfied for both helicity conserving and non-conserving parts. The integrations are then performed for the explicit calculation of the impact factors in the massless quark case.Comment: 23 pages, LaTeX, 1 EPS figure, uses epsf.sty and axodraw.st

Continuity theorems for the M/M/1/nM/M/1/n queueing system

In this paper continuity theorems are established for the number of losses during a busy period of the $M/M/1/n$ queue. We consider an $M/GI/1/n$ queueing system where the service time probability distribution, slightly different in a certain sense from the exponential distribution, is approximated by that exponential distribution. Continuity theorems are obtained in the form of one or two-sided stochastic inequalities. The paper shows how the bounds of these inequalities are changed if further assumptions, associated with specific properties of the service time distribution (precisely described in the paper), are made. Specifically, some parametric families of service time distributions are discussed, and the paper establishes uniform estimates (given for all possible values of the parameter) and local estimates (where the parameter is fixed and takes only the given value). The analysis of the paper is based on the level crossing approach and some characterization properties of the exponential distribution.Comment: Final revision; will be published as i

Scherk-Schwarz Supersymmetry Breaking for Quasi-localized Matter Fields and Supersymmetry Flavor Violation

We examine the soft supersymmetry breaking parameters induced by the Scherk-Schwarz (SS) boundary condition in 5-dimensional orbifold field theory in which the quark and lepton zero modes are quasi-localized at the orbifold fixed points to generate the hierarchical Yukawa couplings. In such theories, the radion corresponds to a flavon to generate the flavor hierarchy and at the same time plays the role of the messenger of supersymmetry breaking. As a consequence, the resulting soft scalar masses and trilinear $A$-parameters of matter zero modes at the compactification scale are highly flavor-dependent, thereby can lead to dangerous flavor violations at low energy scales. We analyze in detail the low energy flavor violations in SS-dominated supersymmetry breaking scenario under the assumption that the compactification scale is close to the grand unification scale and the 4-dimensional effective theory below the compactification scale is given by the minimal supersymmetric standard model. Our analysis can be applied to any supersymmetry breaking mechanism giving a sizable $F$-component of the radion superfield, e.g. the hidden gaugino condensation model.Comment: revtex4, 22 pages, some numerical errors are corrected in phenomenological analysis, main conclusion does not chang

Bottom-Tau Unification in SUSY SU(5) GUT and Constraints from b to s gamma and Muon g-2

An analysis is made on bottom-tau Yukawa unification in supersymmetric (SUSY) SU(5) grand unified theory (GUT) in the framework of minimal supergravity, in which the parameter space is restricted by some experimental constraints including Br(b to s gamma) and muon g-2. The bottom-tau unification can be accommodated to the measured branching ratio Br(b to s gamma) if superparticle masses are relatively heavy and higgsino mass parameter \mu is negative. On the other hand, if we take the latest muon g-2 data to require positive SUSY contributions, then wrong-sign threshold corrections at SUSY scale upset the Yukawa unification with more than 20 percent discrepancy. It has to be compensated by superheavy threshold corrections around the GUT scale, which constrains models of flavor in SUSY GUT. A pattern of the superparticle masses preferred by the three requirements is also commented.Comment: 21pages, 6figure

Quantum Kinetic Theory III: Quantum kinetic master equation for strongly condensed trapped systems

We extend quantum kinetic theory to deal with a strongly Bose-condensed atomic vapor in a trap. The method assumes that the majority of the vapor is not condensed, and acts as a bath of heat and atoms for the condensate. The condensate is described by the particle number conserving Bogoliubov method developed by one of the authors. We derive equations which describe the fluctuations of particle number and phase, and the growth of the Bose-Einstein condensate. The equilibrium state of the condensate is a mixture of states with different numbers of particles and quasiparticles. It is not a quantum superposition of states with different numbers of particles---nevertheless, the stationary state exhibits the property of off-diagonal long range order, to the extent that this concept makes sense in a tightly trapped condensate.Comment: 3 figures submitted to Physical Review

Defining the genomic signature of the parous breast.

ABSTRACT: BACKGROUND: It is accepted that a woman's lifetime risk of developing breast cancer after menopause is reduced by early full term pregnancy and multiparity. This phenomenon is thought to be associated with the development and differentiation of the breast during pregnancy. METHODS: In order to understand the underlying molecular mechanisms of pregnancy induced breast cancer protection, we profiled and compared the transcriptomes of normal breast tissue biopsies from 71 parous (P) and 42 nulliparous (NP) healthy postmenopausal women using Affymetrix Human Genome U133 Plus 2.0 arrays. To validate the results, we performed real time PCR and immunohistochemistry. RESULTS: We identified 305 differentially expressed probesets (208 distinct genes). Of these, 267 probesets were up- and 38 down-regulated in parous breast samples; bioinformatics analysis using gene ontology enrichment revealed that up-regulated genes in the parous breast represented biological processes involving differentiation and development, anchoring of epithelial cells to the basement membrane, hemidesmosome and cell-substrate junction assembly, mRNA and RNA metabolic processes and RNA splicing machinery. The down-regulated genes represented biological processes that comprised cell proliferation, regulation of IGF-like growth factor receptor signaling, somatic stem cell maintenance, muscle cell differentiation and apoptosis. CONCLUSIONS: This study suggests that the differentiation of the breast imprints a genomic signature that is centered in the mRNA processing reactome. These findings indicate that pregnancy may induce a safeguard mechanism at post-transcriptional level that maintains the fidelity of the transcriptional process