IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

Background: Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment. Methods and Findings: We performed whole genome sequencing on paired pre-treatment (diagnostic) and post-treatment (remission) samples from 13 patients, and targeted exome sequencing of pre-treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R) signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146) of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX). Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome. To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we expressed wild-type and mutant IL7R signaling molecules in two steroid-sensitive T-ALL cell lines (SUPT1 and P12 Ichikawa cells) using inducible lentiviral expression constructs. We found that expressing mutant IL7R, JAK1, or NRAS, or wild-type NRAS or AKT, specifically induced steroid resistance without affecting sensitivity to vincristine or L-asparaginase. In contrast, wild-type IL7R, JAK1, and JAK3, as well as mutant JAK3 and mutant AKT, had no effect. We then performed a functional study to examine the mechanisms underlying steroid resistance and found that, rather than changing the steroid receptor’s ability to activate downstream targets, steroid resistance was associated with strong activation of MEK-ERK and AKT, downstream components of the IL7R signaling pathway, thereby inducing a robust antiapoptotic response by upregulating MCL1 and BCLXL expression. Both the MEK-ERK and AKT pathways also inactivate BIM, an essential molecule for steroid-induced cell death, and inhibit GSK3B, an important regulator of proapoptotic BIM. Importantly, treating our cell lines with IL7R signaling inhibitors restored steroid sensitivity. To address clinical relevance, we treated primary T-ALL cells obtained from 11 patients with steroids either alone or in combination with IL7R signaling inhibitors; we found that including a MEK, AKT, mTOR, or dual PI3K/mTOR inhibitor strongly increased steroid-induced cell death. Therefore, combining these inhibitors with steroid treatment may enhance steroid sensitivity in pat

A Millennium Learning Goal for education post‐2015: a question of outcomes or processes

As the target year for the current Millennium Development Goal of universal completion of primary education approaches, three World Bank economists have proposed its replacement with a Millennium Learning Goal. This is part of a trend of increased privileging of learning outcomes. The proposal is assessed from the perspective of human rights-based and social justice conceptualisations of education quality. A Millennium Learning Goal may enhance information on inclusion, conceived as equal opportunity to achieve learning outcomes. However, there is a danger that it would be misused to generate high stakes tests that can be detrimental to the achievement of goals that are not readily measurable and hence to the relevance of education. It is argued that a process goal with qualitative targets for the assessment of learning, for the monitoring of educational processes and for the processes by which learning goals are determined would be more appropriate for the international level.As the target year for the current Millennium Development Goal of universal completion of primary education approaches, three World Bank economists have proposed its replacement with a Millennium Learning Goal. This is part of a trend of increased privileging of learning outcomes. The proposal is assessed from the perspective of human rights-based and social justice conceptualisations of education quality. A Millennium Learning Goal may enhance information on inclusion, conceived as equal opportunity to achieve learning outcomes. However, there is a danger that it would be misused to generate high stakes tests that can be detrimental to the achievement of goals that are not readily measurable and hence to the relevance of education. It is argued that a process goal with qualitative targets for the assessment of learning, for the monitoring of educational processes and for the processes by which learning goals are determined would be more appropriate for the international level

Moral courage in the workplace: moving to and from the desire and decision to act

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72135/1/j.1467-8608.2007.00484.x.pd

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters

Measurement of isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV

Isolated photon production is measured in proton-proton and lead-lead collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80 GeV with the CMS detector at the LHC. The measured ET spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon ET-differential yields, scaled by the number of incoherent nucleon-nucleon collisions, is consistent with unity for all PbPb reaction centralities.Comment: Submitted to Physics Letters

Governing Boards and Profound Organizational Change in Hospitals

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69047/2/10.1177_107755878904600204.pd

Psychosocial Treatment of Children in Foster Care: A Review

A substantial number of children in foster care exhibit psychiatric difficulties. Recent epidemiologi-cal and historical trends in foster care, clinical findings about the adjustment of children in foster care, and adult outcomes are reviewed, followed by a description of current approaches to treatment and extant empirical support. Available interventions for these children can be categorized as either symptom-focused or systemic, with empirical support for specific methods ranging from scant to substantial. Even with treatment, behavioral and emotional problems often persist into adulthood, resulting in poor functional outcomes. We suggest that self-regulation may be an important mediat-ing factor in the appearance of emotional and behavioral disturbance in these children

Dissipative transport in quantum Hall ferromagnets by spin-wave scattering

We report on a study of the effect upon electrical transport of spin-wave scattering from charged quasiparticles in nu = 1 quantum Hall ferromagnets, including both Heisenberg (single layer) and easy-plane (bilayer) cases. We derive a quantum Langevin equation to describe the resulting diffusive motion of the charged particle and use this to calculate the contribution to low-temperature conductivity from a density of charged particles. This conductivity has a power-law dependence upon temperature. The contribution is small at low temperatures increasing to a large value at relatively modest temperatures. We comment upon high-temperature transport and upon the contribution of scattering to the width of the zero bias peak in tunneling conductivity

The parent?infant dyad and the construction of the subjective self

Developmental psychology and psychopathology has in the past been more concerned with the quality of self-representation than with the development of the subjective agency which underpins our experience of feeling, thought and action, a key function of mentalisation. This review begins by contrasting a Cartesian view of pre-wired introspective subjectivity with a constructionist model based on the assumption of an innate contingency detector which orients the infant towards aspects of the social world that react congruently and in a specifically cued informative manner that expresses and facilitates the assimilation of cultural knowledge. Research on the neural mechanisms associated with mentalisation and social influences on its development are reviewed. It is suggested that the infant focuses on the attachment figure as a source of reliable information about the world. The construction of the sense of a subjective self is then an aspect of acquiring knowledge about the world through the caregiver's pedagogical communicative displays which in this context focuses on the child's thoughts and feelings. We argue that a number of possible mechanisms, including complementary activation of attachment and mentalisation, the disruptive effect of maltreatment on parent-child communication, the biobehavioural overlap of cues for learning and cues for attachment, may have a role in ensuring that the quality of relationship with the caregiver influences the development of the child's experience of thoughts and feelings