1,106 research outputs found
CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition.
Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy
Undergraduate Financial Stress, Financial Self-Efficacy, and Major Choice: A Multi-Institutional Study
Over time, undergraduates students been increasingly forced to assume a greater portion of college costs. For most students, this means borrowing larger sums and cutting back on expenses to fulfill their college dreams, which often leads to financial stress. Using financial self-efficacy theory, we sought to better understand how a lack of financial confidence and a diminished sense of financial well-being may serve to undermine students’ intended short and long-term goals. To this end, we examined the predictors of financial stress based upon a multi-institutional sample of senior undergraduates and focus on the role of the earnings potential of different majors
Examining Walkability and Social Capital as Indicators of Quality of Life at the Municipal and Neighborhood Scales
Walkability has been linked to quality of life in many ways. Health related benefits of physical exercise, the accessibility and access benefits of being able to walk to obtain some of your daily needs, or the mental health and social benefits of reduced isolation are a few of the many positive impacts on quality of life that can result from a walkable neighborhood. In the age of increasing energy costs and climate considerations, the ability to walk to important locations is a key component of sustainable communities. While the health and environmental implications of walkable communities are being extensively studied, the social benefits have not been investigated as broadly. Social capital is a measure of an individual’s or group’s networks, personal connections, and involvement. Like economic and human capital, social capital is considered to have important values to both individuals and communities. Through a case study approach this article argues that the generation and maintenance of social capital is another important component of quality of life that may be facilitated by living in a walkable community. Residents living in neighborhoods of varying built form and thus varying levels of walkability in three communities in New Hampshire were surveyed about their levels of social capital and travel behaviors. Comparisons between the more walkable and less walkable neighborhoods show that levels of social capital are higher in more walkable neighborhoods
Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K Îł-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3KÎł-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner
Monomorphic Ventricular Arrhythmias in Athletes.
Ventricular arrhythmias are challenging to manage in athletes with concern for an elevated risk of sudden cardiac death (SCD) during sports competition. Monomorphic ventricular arrhythmias (MMVA), while often benign in athletes with a structurally normal heart, are also associated with a unique subset of idiopathic and malignant substrates that must be clearly defined. A comprehensive evaluation for structural and/or electrical heart disease is required in order to exclude cardiac conditions that increase risk of SCD with exercise, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Unique issues for physicians who manage this population include navigating athletes through the decision of whether they can safely continue their chosen sport. In the absence of structural heart disease, therapies such as radiofrequency catheter ablation are very effective for certain arrhythmias and may allow for return to competitive sports participation. In this comprehensive review, we summarise the recommendations for evaluating and managing athletes with MMVA
Evidence of Titan's Climate History from Evaporite Distribution
Water-ice-poor, 5-m-bright material on Saturn's moon Titan has
previously been geomorphologically identified as evaporitic. Here we present a
global distribution of the occurrences of the 5-m-bright spectral unit,
identified with Cassini's Visual Infrared Mapping Spectrometer (VIMS) and
examined with RADAR when possible. We explore the possibility that each of
these occurrences are evaporite deposits. The 5-m-bright material covers
1\% of Titan's surface and is not limited to the poles (the only regions with
extensive, long-lived surface liquid). We find the greatest areal concentration
to be in the equatorial basins Tui Regio and Hotei Regio. Our interpretations,
based on the correlation between 5-m-bright material and lakebeds, imply
that there was enough liquid present at some time to create the observed
5-m-bright material. We address the climate implications surrounding a
lack of evaporitic material at the south polar basins: if the south pole basins
were filled at some point in the past, then where is the evaporite
Doppler tissue imaging to localize accessory pathways in pediatric patients with Wolff-Parkinson-White syndrome
The proteome of extracellular vesicles released by clastic cells differs based on their substrate
Extracellular vesicles (EVs) from osteoclasts are important regulators in intercellular communication. Here, we investigated the proteome of EVs from clastic cells plated on plastic
(clasts), bone (osteoclasts) and dentin (odontoclasts) by two-dimensional high performance
liquid chromatography mass spectrometry seeking differences attributable to distinct mineralized matrices. A total of 1,952 proteins were identified. Of the 500 most abundant proteins
in EVs, osteoclast and odontoclast EVs were 83.3% identical, while clasts shared 70.7% of
the proteins with osteoclasts and 74.2% of proteins with odontoclasts. For each protein, the
differences between the total ion count values were mapped to an expression ratio histogram (Z-score) in order to detect proteins differentially expressed. Stabilin-1 and macrophage mannose receptor-1 were significantly-enriched in EVs from odontoclasts compared
with osteoclasts (Z = 2.45, Z = 3.34) and clasts (Z = 13.86, Z = 1.81) and were abundant in
odontoclast EVs. Numerous less abundant proteins were differentially-enriched. Subunits of
known protein complexes were abundant in clastic EVs, and were present at levels consistent with them being in assembled protein complexes. These included the proteasome,
COP1, COP9, the T complex and a novel sub-complex of vacuolar H+
-ATPase (V-ATPase),
which included the (pro) renin receptor. The (pro) renin receptor was immunoprecipitated
using an anti-E-subunit antibody from detergent-solubilized EVs, supporting the idea that
the V-ATPase subunits present were in the same protein complex. We conclude that the
protein composition of EVs released by clastic cells changes based on the substrate. Clastic
EVs are enriched in various protein complexes including a previously undescribed VATPase sub-complex
Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation
Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic Nras[superscript G12D] in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased Nras[superscript G12D] gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of Nras[superscript G12D over G12D] hematopoietic cells. Modulating Nras[superscript G12D] dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MAP-ERK kinase (MEK) inhibition. Furthermore, enforced WT N-Ras expression neither suppressed the growth of Nras-mutant cells nor inhibited myeloid transformation by exogenous Nras[superscript G12D]. Importantly, NRAS expression increased in human cancer cell lines with NRAS mutations. These data have therapeutic implications and support reconsidering the proposed tumor suppressor activity of WT Ras in other cancers.Pfizer Inc. (PD0325901)National Institutes of Health (U.S.) (Grant R37CA72614)National Institutes of Health (U.S.) (Grant P01CA40046)National Institutes of Health (U.S.) (Grant K08CA134649)Leukemia & Lymphoma Society of America (Specialized Center of Research Award LLS 7019-04))American Lebanese Syrian Associated Charitie
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