405 research outputs found
A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer
Background: In the USA, the breast cancer mortality rate is 41% higher for African-American women than non-Hispanic White women. While numerous gene expression studies have classified biological features that vary by race and may contribute to poorer outcomes, few studies have experimentally tested these associations. CRYβB2 gene expression has drawn particular interest because of its association with overall survival and African-American ethnicity in multiple cancers. Several reports indicate that overexpression of the CRYβB2 pseudogene, CRYβB2P1, and not CRYβB2 is linked with race and poor outcome. It remains unclear whether either or both genes are linked to breast cancer outcomes. This study investigates CRYβB2 and CRYβB2P1 expression in human breast cancers and breast cancer cell line models, with the goal of elucidating the mechanistic contribution of CRYβB2 and CRYβB2P1 to racial disparities. Methods: Custom scripts for CRYβB2 or CRYβB2P1 were generated and used to identify reads that uniquely aligned to either gene. Gene expression according to race and tumor subtype were assessed using all available TCGA breast cancer RNA sequencing alignment samples (n = 1221). In addition, triple-negative breast cancer models engineered to have each gene overexpressed or knocked out were developed and evaluated by in vitro, biochemical, and in vivo assays to identify biological functions. Results: We provide evidence that CRYβB2P1 is expressed at higher levels in breast tumors compared to CRYβB2, but only CRYβB2P1 is significantly increased in African-American tumors relative to White American tumors. We show that independent of CRYβB2, CRYβB2P1 enhances tumorigenesis in vivo via promoting cell proliferation. Our data also reveal that CRYβB2P1 may function as a non-coding RNA to regulate CRYβB2 expression. A key observation is that the combined overexpression of both genes was found to suppress cell growth. CRYβB2 overexpression in triple-negative breast cancers increases invasive cellular behaviors, tumor growth, IL6 production, immune cell chemoattraction, and the expression of metastasis-associated genes. These data underscore that both CRYβB2 and CRYβB2P1 promote tumor growth, but their mechanisms for tumor promotion are likely distinct. Conclusions: Our findings provide novel data emphasizing the need to distinguish and study the biological effects of both CRYβB2 and CRYβB2P1 as both genes independently promote tumor progression. Our data demonstrate novel molecular mechanisms of two understudied, disparity-linked molecules
Turbulent diffusion and drift in galactic magnetic fields and the explanation of the knee in the cosmic ray spectrum
We reconsider the scenario in which the knee in the cosmic ray spectrum is
explained as due to a change in the escape mechanism of cosmic rays from the
Galaxy from one dominated by transverse diffusion to one dominated by drifts.
We solve the diffusion equations adopting realistic galactic field models and
using diffusion coefficients appropriate for strong turbulence (with a
Kolmogorov spectrum of fluctuations) and consistent with the assumed magnetic
fields. We show that properly taking into account these effects leads to a
natural explanation of the knee in the spectrum, and a transition towards a
heavier composition above the knee is predicted.Comment: 17 pp., 6 figures; revised version with minor changes. To appear in
JHE
Histone deacetylase 11 inhibition promotes breast cancer metastasis from lymph nodes
Lymph node (LN) metastases correspond with a worse prognosis in nearly all cancers, yet the occurrence of cancer spreading from LNs remains controversial. Additionally, the mechanisms explaining how cancers survive and exit LNs are largely unknown. Here, we show that breast cancer patients frequently have LN metastases that closely resemble distant metastases. In addition, using a microsurgical model, we show how LN metastasis development and dissemination is regulated by the expression of a chromatin modifier, histone deacetylase 11 (HDAC11). Genetic and pharmacologic blockade of HDAC11 decreases LN tumor growth, yet substantially increases migration and distant metastasis formation. Collectively, we reveal a mechanism explaining how HDAC11 plasticity promotes breast cancer growth as well as dissemination from LNs and suggest caution with the use of HDAC inhibitors
A functional riboSNitch in the 3' untranslated region of FKBP5 alters MicroRNA-320a binding efficiency and mediates vulnerability to chronic post-traumatic pain
Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (FKBP5), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico, in vivo, and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor (NR3C1) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress-and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene–miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies
Asteroid Confusions with Extremely Large Telescopes
Asteroids can be considered as sources of contamination of point sources and
also sources of confusion noise, depending whether their presence is detected
in the image or their flux is under the detection limit. We estimate that at
low ecliptic latitudes, ~10,000--20,000 asteroids/sq. degree will be detected
with an E-ELT like telescope, while by the end of Spitzer and Herschel
missions, infrared space observatories will provide ~100,000 serendipitous
asteroid detections. The detection and identification of asteroids is therefore
an important step in survey astronomy.Comment: 8 pages, 4 figures, accepted by Earth, Moon and Planets, ELT
Conference (Elba, 2009 Sept.) S
First observation of the KS->pi0 gamma gamma decay
Using the NA48 detector at the CERN SPS, 31 KS->pi0 gamma gamma candidates
with an estimated background of 13.7 +- 3.2 events have been observed. This
first observation leads to a branching ratio of BR(KS->pi0 gamma gamma) = (4.9
+- 1.6(stat) +- 0.9(syst)) x 10^-8 in agreement with Chiral Perturbation theory
predictions.Comment: 10 pages, 4 figures submitted to Phys. Lett.
Search for CP violation in K0 -> 3 pi0 decays
Using data taken during the year 2000 with the NA48 detector at the CERN SPS,
a search for the CP violating decay K_S -> 3 pi0 has been performed. From a fit
to the lifetime distribution of about 4.9 million reconstructed K0/K0bar -> 3
pi0 decays, the CP violating amplitude eta_000 = A(K_S -> 3 pi0)/A(K_L -> 3
pi0) has been found to be Re(eta_000) = -0.002 +- 0.011 +- 0.015 and
Im(eta_000) = -0.003 +- 0.013 +- 0.017. This corresponds to an upper limit on
the branching fraction of Br(K_S -> 3 pi0) < 7.4 x 10^-7 at 90% confidence
level. The result is used to improve knowledge of Re(epsilon) and the CPT
violating quantity Im(delta) via the Bell-Steinberger relation.Comment: 18 pages, 7 figures, submitted to Phys. Lett.
A precision measurement of direct CP violation in the decay of neutral kaons into two pions
The direct CP violation parameter Re(epsilon'/epsilon) has been measured from
the decay rates of neutral kaons into two pions using the NA48 detector at the
CERN SPS. The 2001 running period was devoted to collecting additional data
under varied conditions compared to earlier years (1997-99). The new data yield
the result: Re(epsilon'/epsilon) = (13.7 +/- 3.1) times 10^{-4}. Combining this
result with that published from the 1997, 98 and 99 data, an overall value of
Re(epsilon'/epsilon) = (14.7 +/- 2.2) times 10^{-4} is obtained from the NA48
experiment.Comment: 19 pages, 5 figures, to be published in Physics Letters
Measurement of the Ratio Gamma(KL -> pi+ pi-)/Gamma(KL -> pi e nu) and Extraction of the CP Violation Parameter |eta+-|
We present a measurement of the ratio of the decay rates Gamma(KL -> pi+
pi-)/Gamma(KL -> pi e nu), denoted as Gamma(K2pi)/Gamma(Ke3). The analysis is
based on data taken during a dedicated run in 1999 by the NA48 experiment at
the CERN SPS. Using a sample of 47000 K2pi and five million Ke3 decays, we find
Gamma(K2pi)/Gamma(Ke3) = (4.835 +- 0.022(stat) +- 0.016(syst)) x 10^-3. From
this we derive the branching ratio of the CP violating decay KL -> pi+ pi- and
the CP violation parameter |eta+-|. Excluding the CP conserving direct photon
emission component KL -> pi+ pi- gamma, we obtain the results BR(KL -> pi+ pi-)
= (1.941 +- 0.019) x 10^-3 and |eta+-| = (2.223 +- 0.012) x 10^-3.Comment: 20 pages, 7 figures, accepted by Phys. Lett.
Measurement of K^0_e3 form factors
The semileptonic decay of the neutral K meson, KL -> pi e nu (Ke3), was used
to study the strangeness-changing weak interaction of hadrons. A sample of 5.6
million reconstructed events recorded by the NA48 experiment was used to
measure the Dalitz plot density. Admitting all possible Lorentz-covariant
couplings, the form factors for vector (f_+(q^2)), scalar (f_S) and tensor
(f_T) interactions were measured. The linear slope of the vector form factor
lambda_+ = 0.0284+-0.0007+-0.0013 and values for the ratios |f_S/f_+(0)| =
0.015^{+0.007}_{-0.010}+-0.012 and |f_T/f_+(0)| = 0.05^{+0.03}_{-0.04}+-0.03
were obtained. The values for f_S and f_T are consistent with zero. Assuming
only Vector-Axial vector couplings, lambda_+ = 0.0288+-0.0004+-0.0011 and a
good fit consistent with pure V-A couplings were obtained. Alternatively, a fit
to a dipole form factor yields a pole mass of M = 859+-18 MeV, consistent with
the K^*(892) mass.Comment: 16 pages, 7 figures. submitted to Phys. Lett.
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