21 research outputs found
Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets.
BackgroundLiposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management.MethodsLarge RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial.ResultsScreening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model.ConclusionsTwo large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor
The Two Faces of Anomaly Mediation
Anomaly mediation is a ubiquitous source of supersymmetry (SUSY) breaking
which appears in almost every theory of supergravity. In this paper, we show
that anomaly mediation really consists of two physically distinct phenomena,
which we dub "gravitino mediation" and "Kahler mediation". Gravitino mediation
arises from minimally uplifting SUSY anti-de Sitter (AdS) space to Minkowski
space, generating soft masses proportional to the gravitino mass. Kahler
mediation arises when visible sector fields have linear couplings to SUSY
breaking in the Kahler potential, generating soft masses proportional to beta
function coefficients. In the literature, these two phenomena are lumped
together under the name "anomaly mediation", but here we demonstrate that they
can be physically disentangled by measuring associated couplings to the
goldstino. In particular, we use the example of gaugino soft masses to show
that gravitino mediation generates soft masses without corresponding goldstino
couplings. This result naively violates the goldstino equivalence theorem but
is in fact necessary for supercurrent conservation in AdS space. Since
gravitino mediation persists even when the visible sector is sequestered from
SUSY breaking, we can use the absence of goldstino couplings as an unambiguous
definition of sequestering.Comment: 21 pages, 1 table; v2, references added, extended discussion in
introduction and appendix; v3, JHEP versio
Minimal Conformal Technicolor and Precision Electroweak Tests
We study the minimal model of conformal technicolor, an SU(2) gauge theory
near a strongly coupled conformal fixed point, with conformal symmetry softly
broken by technifermion mass terms. Conformal symmetry breaking triggers chiral
symmetry breaking in the pattern SU(4) -> Sp(4), which gives rise to a
pseudo-Nambu-Goldstone boson that can act as a composite Higgs boson. The top
quark is elementary, and the top and electroweak gauge loop contributions to
the Higgs mass are cut off entirely by Higgs compositeness. In particular, the
model requires no top partners and no "little Higgs" mechanism. A nontrivial
vacuum alignment results from the interplay of the top loop and technifermion
mass terms. The composite Higgs mass is completely determined by the top loop,
in the sense that m_h/m_t is independent of the vacuum alignment and is
computable by a strong-coupling calculation. There is an additional composite
pseudoscalar A with mass larger than m_h and suppressed direct production at
LHC. We discuss the electroweak fit in this model in detail. Corrections to Z
-> bb and the T parameter from the top sector are suppressed by the enhanced
Sp(4) custodial symmetry. Even assuming that the strong contribution to the S
parameter is positive and usuppressed, a good electroweak fit can be obtained
for v/f ~ 0.25, where v and f are the electroweak and chiral symmetry breaking
scales respectively. This requires fine tuning at the 10% level.Comment: 34 pages, 4 figures; v2: updated precision electroweak fi
Flavor in Minimal Conformal Technicolor
We construct a complete, realistic, and natural UV completion of minimal
conformal technicolor that explains the origin of quark and lepton masses and
mixing angles. As in "bosonic technicolor", we embed conformal technicolor in a
supersymmetric theory, with supersymmetry broken at a high scale. The exchange
of heavy scalar doublets generates higher-dimension interactions between
technifermions and quarks and leptons that give rise to quark and lepton masses
at the TeV scale. Obtaining a sufficiently large top quark mass requires strong
dynamics at the supersymmetry breaking scale in both the top and technicolor
sectors. This is natural if the theory above the supersymmetry breaking also
has strong conformal dynamics. We present two models in which the strong top
dynamics is realized in different ways. In both models, constraints from
flavor-changing effects can be easily satisfied. The effective theory below the
supersymmetry breaking scale is minimal conformal technicolor with an
additional light technicolor gaugino. We argue that this light gaugino is a
general consequence of conformal technicolor embedded into a supersymmetric
theory. If the gaugino has mass below the TeV scale it will give rise to an
additional pseudo Nambu-Goldstone boson that is observable at the LHC.Comment: 37 pages; references adde
Radius Stabilization and Anomaly-Mediated Supersymmetry Breaking
We analyze in detail a specific 5-dimensional realization of a
"brane-universe" scenario where the visible and hidden sectors are localized on
spatially separated 3-branes coupled only by supergravity, with supersymmetry
breaking originating in the hidden sector. Although general power counting
allows order 1/M_{Planck}^2 contact terms between the two sectors in the
4-dimensional theory from exchange of supergravity Kaluza-Klein modes, we show
that they are not present by carefully matching to the 5-dimensional theory. We
also find that the radius modulus corresponding to the size of the compactified
dimension must be stabilized by additional dynamics in order to avoid run-away
behavior after supersymmetry breaking and to understand the communication of
supersymmetry breaking. We stabilize the radius by adding two pure Yang--Mills
sectors, one in the bulk and the other localized on a brane. Gaugino
condensation in the 4-dimensional effective theory generates a superpotential
that can naturally fix the radius at a sufficiently large value that
supersymmetry breaking is communicated dominantly by the recently-discovered
mechanism of anomaly mediation. The mass of the radius modulus is large
compared to m_{3/2}. The stabilization mechanism requires only parameters of
order one at the fundamental scale, with no fine-tuning except for the
cosmological constant.Comment: 20 pages, LaTeX2
Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets
Abstract Background Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management. Methods Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial. Results Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model. Conclusions Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor
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Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets.
BackgroundLiposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management.MethodsLarge RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial.ResultsScreening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model.ConclusionsTwo large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor
JAK2V617I results in cytokine hypersensitivity without causing an overt myeloproliferative disorder in a mouse transduction–transplantation model
A germline JAK2(V617I) point mutation results in hereditary thrombocytosis and shares some phenotypic features with myeloproliferative neoplasm, a hematologic malignancy associated with a somatically acquired JAK2(V617F) mutation. We established a mouse transduction-transplantation model of JAK2(V617I) that recapitulated the phenotype of humans with germline JAK2(V617I). We directly compared the phenotypes of JAK2(V617I) and JAK2(V617F) mice. The JAK2(V617I) mice had increased marrow cellularity with expanded myeloid progenitor and megakaryocyte populations, but this phenotype was less severe than that of JAK2(V617F) mice. JAK2(V617I) resulted in cytokine hyperresponsiveness without constitutive activation in the absence of ligand, whereas JAK2(V617F) resulted in constitutive activation. This may explain why JAK2(V617I) produces a mild myeloproliferative phenotype in the mouse model, as well as in humans with germline JAK2(V617I) mutations