11 research outputs found
Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer
RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1–6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective. Lei et al. show that transcriptionally active estrogen receptor gene (ESR1) fusions identified from late-stage, treatment-refractory estrogen receptor-positive (ER+) breast cancer drive pan-endocrine therapy resistance and metastatic progression. Growth of breast tumors driven by ESR1 fusions at primary and metastatic sties can be suppressed with a CDK4/6 inhibitor
Transcriptional activation of tyrosinase gene by human placental sphingolipid
The sphingolipids, a class of complex bioactive
lipids, are involved in diverse cellular functions such
as proliferation, differentiation, and apoptosis as well as
growth inhibition. Recently sphingosylphosphorylcholine
(SPC), sphingosine-1-phosphate (S1P), and C2-ceramide
(C2-Cer), sphingolipid containing acetic acid are emerging
as melanogenic regulators. A bioactive sphingolipid (PSL)
was isolated from hydroalcoholic extract of fresh term human
placenta and it induced melanogenesis in an in vitro
culture of mouse melanoma B16F10 cells. Tyrosinase, the
rate-limiting enzyme for melanogenesis, is required to be
upregulated for the increased melanin production. The expression
of tyrosinase, both at protein as well as mRNA
level, was higher in the PSL treated B16F10 cells as evidenced
by Western blot and RT-PCR analysis. Actinomycin
D and cycloheximide, inhibitors of transcription and translation,
respectively, inhibited PSL-induced tyrosinase activity
and its protein expression showing decrease in melanogenesis,
correspondingly. The activity of GFP coupled tyrosinase
promoter was upregulated in transfected B16F10 cells after
treating with PSL as determined by fluorescence microscopy,
fluorometric analysis, and Western blot. These results, thus,
suggested that PSL upregulated tyrosinase gene expression
at transcription level through promoter activation to show
increased melanogenesis. Therefore, PSL as an inducer of
melanogenesis might account for the recovery of pigment in depigmentation disorder
Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study
10.1016/S1470-2045(10)70203-5The Lancet Oncology1110962-972LOAN
A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer
10.1210/jc.2012-1520Journal of Clinical Endocrinology and Metabolism9793179-3184JCEM
A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H
10.1210/jc.2013-3713Journal of Clinical Endocrinology and Metabolism9951687-1693JCEM
Direct observation of the dead-cone effect in quantum chromodynamics
At particle collider experiments, elementary particle interactions with large momentum transfer produce quarks and gluons (known as partons) whose evolution is governed by the strong force, as described by the theory of quantum chromodynamics (QCD) [1]. The vacuum is not transparent to the partons and induces gluon radiation and quark pair production in a process that can be described as a parton shower [2]. Studying the pattern of the parton shower is one of the key experimental tools in understanding the properties of QCD. This pattern is expected to depend on the mass of the initiating parton, through a phenomenon known as the dead-cone effect, which predicts a suppression of the gluon spectrum emitted by a heavy quark of mass m and energy E, within a cone of angular size m/E around the emitter [3]. A direct observation of the dead-cone effect in QCD has not been possible until now, due to the challenge of reconstructing the cascading quarks and gluons from the experimentally accessible bound hadronic states. Here we show the first direct observation of the QCD dead-cone by using new iterative declustering techniques [4, 5] to reconstruct the parton shower of charm quarks. This result confirms a fundamental feature of QCD, which is derived more generally from its origin as a gauge quantum field theory. Furthermore, the measurement of a dead-cone angle constitutes the first direct experimental observation of the non-zero mass of the charm quark, which is a fundamental constant in the standard model of particle physics.The direct measurement of the QCD dead cone in charm quark fragmentation is reported, using iterative declustering of jets tagged with a fully reconstructed charmed hadron.In particle collider experiments, elementary particle interactions with large momentum transfer produce quarks and gluons (known as partons) whose evolution is governed by the strong force, as described by the theory of quantum chromodynamics (QCD). These partons subsequently emit further partons in a process that can be described as a parton shower which culminates in the formation of detectable hadrons. Studying the pattern of the parton shower is one of the key experimental tools for testing QCD. This pattern is expected to depend on the mass of the initiating parton, through a phenomenon known as the dead-cone effect, which predicts a suppression of the gluon spectrum emitted by a heavy quark of mass and energy , within a cone of angular size / around the emitter. Previously, a direct observation of the dead-cone effect in QCD had not been possible, owing to the challenge of reconstructing the cascading quarks and gluons from the experimentally accessible hadrons. We report the direct observation of the QCD dead cone by using new iterative declustering techniques to reconstruct the parton shower of charm quarks. This result confirms a fundamental feature of QCD. Furthermore, the measurement of a dead-cone angle constitutes a direct experimental observation of the non-zero mass of the charm quark, which is a fundamental constant in the standard model of particle physics