1,479 research outputs found
Adrenal-permissive HSD3B1 genetic inheritance and risk of estrogen-driven postmenopausal breast cancer.
BACKGROUNDGenetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor-positive (ER-positive) breast cancer.METHODSA prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer.RESULTSProspective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03).CONCLUSIONAdrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer.FUNDINGNational Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award
Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.
Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies
Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production
Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of enveloped DNA viruses. It was previously shown that HBV can induce endoplasmic reticulum (ER) stress and activate the IRE1-XBP1 pathway of the unfolded protein response (UPR), through the expression of the viral regulatory protein X (HBx). However, it remained obscure whether or not this activation had any functional consequences on the target genes of the UPR pathway. Of these targets, the ER degradation-enhancing, mannosidase-like proteins (EDEMs) are thought to play an important role in relieving the ER stress during UPR, by recognizing terminally misfolded glycoproteins and delivering them to the ER-associated degradation (ERAD). In this study, we investigated the role of EDEMs in the HBV life-cycle. We found that synthesis of EDEMs (EDEM1 and its homologues, EDEM2 and EDEM3) is significantly up-regulated in cells with persistent or transient HBV replication. Co-expression of the wild-type HBV envelope proteins with EDEM1 resulted in their massive degradation, a process reversed by EDEM1 silencing. Surprisingly, the autophagy/lysosomes, rather than the proteasome were involved in disposal of the HBV envelope proteins. Importantly, inhibition of the endogenous EDEM1 expression in HBV replicating cells significantly increased secretion of both, enveloped virus and subviral particles. This is the first report showing that HBV activates the ERAD pathway, which, in turn, reduces the amount of envelope proteins, possibly as a mechanism to control the level of virus particles in infected cells and facilitate the establishment of chronic infections
Double Diffraction Dissociation at the Fermilab Tevatron Collider
We present results from a measurement of double diffraction dissociation in
collisions at the Fermilab Tevatron collider. The production cross
section for events with a central pseudorapidity gap of width
(overlapping ) is found to be [] at [630]
GeV. Our results are compared with previous measurements and with predictions
based on Regge theory and factorization.Comment: 10 pages, 4 figures, using RevTeX. Submitted to Physical Review
Letter
Search for Kaluza-Klein Graviton Emission in Collisions at TeV using the Missing Energy Signature
We report on a search for direct Kaluza-Klein graviton production in a data
sample of 84 of \ppb collisions at = 1.8 TeV, recorded
by the Collider Detector at Fermilab. We investigate the final state of large
missing transverse energy and one or two high energy jets. We compare the data
with the predictions from a -dimensional Kaluza-Klein scenario in which
gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for
=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71
TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure
Search for Gluinos and Scalar Quarks in Collisions at TeV using the Missing Energy plus Multijets Signature
We have performed a search for gluinos (\gls) and squarks (\sq) in a data
sample of 84 pb of \ppb collisions at = 1.8 TeV, recorded by
the Collider Detector at Fermilab, by investigating the final state of large
missing transverse energy and 3 or more jets, a characteristic signature in
R-parity-conserving supersymmetric models. The analysis has been performed
`blind', in that the inspection of the signal region is made only after the
predictions from Standard Model backgrounds have been calculated. Comparing the
data with predictions of constrained supersymmetric models, we exclude gluino
masses below 195 \gev (95% C.L.), independent of the squark mass. For the case
\msq \approx \mgls, gluino masses below 300 \gev are excluded.Comment: 7 pages, 3 figure
Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron
We study the underlying event in proton-antiproton collisions by examining
the behavior of charged particles (transverse momentum pT > 0.5 GeV/c,
pseudorapidity |\eta| < 1) produced in association with large transverse
momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the
Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV
center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan
production) or the leading jet (in high-pT jet production) in each event to
define three regions of \eta-\phi space; toward, away, and transverse, where
\phi is the azimuthal scattering angle. For Drell-Yan production (excluding the
leptons) both the toward and transverse regions are very sensitive to the
underlying event. In high-pT jet production the transverse region is very
sensitive to the underlying event and is separated into a MAX and MIN
transverse region, which helps separate the hard component (initial and
final-state radiation) from the beam-beam remnant and multiple parton
interaction components of the scattering. The data are corrected to the
particle level to remove detector effects and are then compared with several
QCD Monte-Carlo models. The goal of this analysis is to provide data that can
be used to test and improve the QCD Monte-Carlo models of the underlying event
that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.
Measurement of the average time-integrated mixing probability of b-flavored hadrons produced at the Tevatron
We have measured the number of like-sign (LS) and opposite-sign (OS) lepton
pairs arising from double semileptonic decays of and -hadrons,
pair-produced at the Fermilab Tevatron collider. The data samples were
collected with the Collider Detector at Fermilab (CDF) during the 1992-1995
collider run by triggering on the existence of and candidates
in an event. The observed ratio of LS to OS dileptons leads to a measurement of
the average time-integrated mixing probability of all produced -flavored
hadrons which decay weakly, (stat.)
(syst.), that is significantly larger than the world average .Comment: 47 pages, 10 figures, 15 tables Submitted to Phys. Rev.
Search for lepton flavor violating decays of a heavy neutral particle in p-pbar collisions at root(s)=1.8 TeV
We report on a search for a high mass, narrow width particle that decays
directly to e+mu, e+tau, or mu+tau. We use approximately 110 pb^-1 of data
collected with the Collider Detector at Fermilab from 1992 to 1995. No evidence
of lepton flavor violating decays is found. Limits are set on the production
and decay of sneutrinos with R-parity violating interactions.Comment: Figure 2 fixed. Reference 4 fixed. Minor changes to tex
Diffractive Dijet Production at sqrt(s)=630 and 1800 GeV at the Fermilab Tevatron
We report a measurement of the diffractive structure function of
the antiproton obtained from a study of dijet events produced in association
with a leading antiproton in collisions at GeV at the
Fermilab Tevatron. The ratio of at GeV to
obtained from a similar measurement at GeV is compared with
expectations from QCD factorization and with theoretical predictions. We also
report a measurement of the (-Pomeron) and ( of parton in
Pomeron) dependence of at GeV. In the region
, GeV and , is
found to be of the form , which obeys
- factorization.Comment: LaTeX, 9 pages, Submitted to Phys. Rev. Letter
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