Gene-based outcome prediction in multiple cohorts of pediatric T-cell acute lymphoblastic leukemia: a Children's Oncology Group study

<p>Abstract</p> <p>Background</p> <p>Continuous complete clinical remission in T-cell acute lymphoblastic leukemia (T-ALL) is now approaching 80% due to the implementation of aggressive chemotherapy protocols but patients that relapse continue to have a poor prognosis. Such patients could benefit from augmented therapy if their clinical outcome could be more accurately predicted at the time of diagnosis. Gene expression profiling offers the potential to identify additional prognostic markers but has had limited success in generating robust signatures that predict outcome across multiple patient cohorts. This study aimed to identify robust gene classifiers that could be used for the accurate prediction of relapse in independent cohorts and across different experimental platforms.</p> <p>Results</p> <p>Using HG-U133Plus2 microarrays we modeled a five-gene classifier (5-GC) that accurately predicted clinical outcome in a cohort of 50 T-ALL patients. The 5-GC was further tested against three independent cohorts of T-ALL patients, using either qRT-PCR or microarray gene expression, and could predict patients with significantly adverse clinical outcome in each. The 5-GC featured the interleukin-7 receptor (<it>IL-7R</it>), low-expression of which was independently predictive of relapse in T-ALL patients. In T-ALL cell lines, low <it>IL-7R </it>expression was correlated with diminished growth response to IL-7 and enhanced glucocorticoid resistance. Analysis of biological pathways identified the NF-κB and Wnt pathways, and the cell adhesion receptor family (particularly integrins) as being predictive of relapse. Outcome modeling using genes from these pathways identified patients with significantly worse relapse-free survival in each T-ALL cohort.</p> <p>Conclusions</p> <p>We have used two different approaches to identify, for the first time, robust gene signatures that can successfully discriminate relapse and CCR patients at the time of diagnosis across multiple patient cohorts and platforms. Such genes and pathways represent markers for improved patient risk stratification and potential targets for novel T-ALL therapies.</p

Finding Z' bosons coupled preferentially to the third family at CERN LEP and the Fermilab Tevatron

Z' bosons that couple preferentially to the third generation fermions can arise in models with extended weak (SU(2)xSU(2)) or hypercharge (U(1)xU(1)) gauge groups. We show that existing limits on quark-lepton compositeness set by the LEP and Tevatron experiments translate into lower bounds of order a few hundred GeV on the masses of these Z' bosons. Resonances of this mass can be directly produced at the Tevatron. Accordingly, we explore in detail the limits that can be set at Run II using the process p pbar -> Z' -> tau tau -> e mu. We also comment on the possibility of using hadronically-decaying taus to improve the limits.Comment: LaTeX2e, 24 pages (including title page), 13 figures; version 2: corrected typographical errors and bad figure placement; version 3: added references and updated introduction; version 4: changes to compensate for old latex version on arXiv server; version 5: additional references, and embedded fonts in eps files for PRD; version 6: corrected some minor typos to address PRD referee's comment

Theory-Motivated Benchmark Models and Superpartners at the Tevatron

Recently published benchmark models have contained rather heavy superpartners. To test the robustness of this result, several benchmark models have been constructed based on theoretically well-motivated approaches, particularly string-based ones. These include variations on anomaly and gauge-mediated models, as well as gravity mediation. The resulting spectra often have light gauginos that are produced in significant quantities at the Tevatron collider, or will be at a 500 GeV linear collider. The signatures also provide interesting challenges for the LHC. In addition, these models usually account for electroweak symmetry breaking with relatively less fine-tuning than previous benchmark models.Comment: 44 pages, 4 figures; some typos corrected. Revisions reflect published versio

Dimensionless supersymmetry breaking couplings, flat directions, and the origin of intermediate mass scales

The effects of supersymmetry breaking are usually parameterized by soft couplings of positive mass dimensions. However, realistic models also predict the existence of suppressed, but non-vanishing, dimensionless supersymmetry-breaking couplings. These couplings are technically hard, but do not lead to disastrous quadratic divergences in scalar masses, and may be crucial for understanding low-energy physics. In particular, analytic scalar quartic couplings that break supersymmetry can lead to intermediate scale vacuum expectation values along nearly-flat directions. I study the one-loop effective potential for flat directions in the presence of dimensionless supersymmetry-breaking terms, and discuss the corresponding renormalization group equations. I discuss two applications: a minimal model of automatic R-parity conservation, and an extension of this minimal model which provides a solution to the \mu problem and an invisible axion.Comment: 28 pages, LaTeX with epsf and axodraw.st

Collider signals from slow decays in supersymmetric models with an intermediate-scale solution to the mu problem

The problem of the origin of the mu parameter in the Minimal Supersymmetric Standard Model can be solved by introducing singlet supermultiplets with non-renormalizable couplings to the ordinary Higgs supermultiplets. The Peccei-Quinn symmetry is broken at a scale which is the geometric mean between the weak scale and the Planck scale, yielding a mu term of the right order of magnitude and an invisible axion. These models also predict one or more singlet fermions which have electroweak-scale masses and suppressed couplings to MSSM states. I consider the case that such a singlet fermion, containing the axino as an admixture, is the lightest supersymmetric particle. I work out the relevant couplings in several of the simplest models of this type, and compute the partial decay widths of the next-to-lightest supersymmetric particle involving leptons or jets. Although these decays will have an average proper decay length which is most likely much larger than a typical collider detector, they can occasionally occur within the detector, providing a striking signal. With a large sample of supersymmetric events, there will be an opportunity to observe these decays, and so gain direct information about physics at very high energy scales.Comment: 24 pages, LaTeX, 4 figure

1-Mb Resolution Array-Based Comparative Genomic Hybridization Using a BAC Clone Set Optimized for Cancer Gene Analysis

Array-based comparative genomic hybridization (aCGH) is a recently developed tool for genome-wide determination of DNA copy number alterations. This technology has tremendous potential for disease-gene discovery in cancer and developmental disorders as well as numerous other applications. However, widespread utilization of a CGH has been limited by the lack of well characterized, high-resolution clone sets optimized for consistent performance in aCGH assays and specifically designed analytic software. We have assembled a set of ∼4100 publicly available human bacterial artificial chromosome (BAC) clones evenly spaced at ∼1-Mb resolution across the genome, which includes direct coverage of ∼400 known cancer genes. This aCGH-optimized clone set was compiled from five existing sets, experimentally refined, and supplemented for higher resolution and enhancing mapping capabilities. This clone set is associated with a public online resource containing detailed clone mapping data, protocols for the construction and use of arrays, and a suite of analytical software tools designed specifically for aCGH analysis. These resources should greatly facilitate the use of aCGH in gene discovery