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

Wnt4 is essential to normal mammalian lung development

AbstractWnt signaling is essential to many events during organogenesis, including the development of the mammalian lung. The Wnt family member Wnt4 has been shown to be required for the development of kidney, gonads, thymus, mammary and pituitary glands. Here, we show that Wnt4 is critical for proper morphogenesis and growth of the respiratory system. Using in situ hybridization in mouse embryos, we identify a previously uncharacterized site of Wnt4 expression in the anterior trunk mesoderm. This expression domain initiates as early as E8.25 in the mesoderm abutting the tracheoesophageal endoderm, between the fusing dorsal aortae and the heart. Analysis of Wnt4−/− embryos reveals severe lung hypoplasia and tracheal abnormalities; however, aortic fusion and esophageal development are unaffected. We find decreased cell proliferation in Wnt4−/− lung buds, particularly in tip domains. In addition, we observe reduction of the important lung growth factors Fgf9, Fgf10, Sox9 and Wnt2 in the lung bud during early stages of organogenesis, as well as decreased tracheal expression of the progenitor factor Sox9. Together, these data reveal a previously unknown role for the secreted protein Wnt4 in respiratory system development

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

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

Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1

Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell-intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis. This is achieved through the activation of a transcriptional program affecting metabolic gene targets of hypoxia-inducible factor (HIF1α) and sterol regulatory element-binding protein (SREBP1 and SREBP2). We find that SREBP1 and 2 promote proliferation downstream of mTORC1, and the activation of these transcription factors is mediated by S6K1. Therefore, in addition to promoting protein synthesis, mTORC1 activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease

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

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

‘It Takes Two Hands to Clap’: How Gaddi Shepherds in the Indian Himalayas Negotiate Access to Grazing

This article examines the effects of state intervention on the workings of informal institutions that coordinate the communal use and management of natural resources. Specifically it focuses on the case of the nomadic Gaddi shepherds and official attempts to regulate their access to grazing pastures in the Indian Himalayas. It is often predicted that the increased presence of the modern state critically undermines locally appropriate and community-based resource management arrangements. Drawing on the work of Pauline Peters and Francis Cleaver, I identify key instances of socially embedded ‘common’ management institutions and explain the evolution of these arrangements through dynamic interactions between individuals, communities and the agents of the state. Through describing the ‘living space’ of Gaddi shepherds across the annual cycle of nomadic migration with their flocks I explore the ways in which they have been able to creatively reinterpret external interventions, and suggest how contemporary arrangements for accessing pasture at different moments of the annual cycle involve complex combinations of the formal and the informal, the ‘traditional’ and the ‘modern’

The Influence of Disorder on Thermotropic Nematic Liquid Crystals Phase Behavior

We review the theoretical research on the influence of disorder on structure and phase behavior of condensed matter system exhibiting continuous symmetry breaking focusing on liquid crystal phase transitions. We discuss the main properties of liquid crystals as adequate systems in which several open questions with respect to the impact of disorder on universal phase and structural behavior could be explored. Main advantages of liquid crystalline materials and different experimental realizations of random field-type disorder imposed on liquid crystal phases are described