Up-regulation of 14-3-3sigma (Stratifin) is associated with high-grade CIN and high-risk human papillomavirus (HPV) at baseline but does not predict outcomes of HR-HPV infections or incident CIN in the LAMS study

To assess whether the potentially high-risk (HR) human papillomavirus (HPV)-related up-regulation of 14-3-3sigma (stratifin) has implications in the outcome of HPV infections or cervical intraepithelial neoplasia (CIN) lesions, cervical biopsy specimens from 225 women in the Latin American Screening Study were analyzed for 14-3-3sigma expression using immunohistochemical analysis. We assessed its associations with CIN grade and HR HPV at baseline and value in predicting outcomes of HR-HPV infections and the development of incident CIN 1+ and CIN 2+. Expression of 14-3-3sigma increased in parallel with the lesion grade. Up-regulation was also significantly related to HR-HPV detection (P = .004; odds ratio, 2.71; 95% confidence interval, 1.37-5.35) and showed a linear relationship to HR-HPV loads (P = .003). 14-3-3sigma expression was of no value in predicting the outcomes (incident, persistent, clearance) of HR-HPV infections or incident CIN 1+ and CIN 2+. 14-3-3sigma is not inactivated in cervical carcinoma and CIN but is up-regulated on transition from CIN 2 to CIN 3. Its normal functions in controlling G(1)/S and G(2)/M checkpoints are being bypassed by HR HPV.LAMS, Latin American Screening Study, funded by European Commission, INCO-DEV contract ICA4-CT-2001-10013

Effects of partner proteins on BCA2 RING ligase activity

Abstract Background BCA2 is an E3 ligase linked with hormone responsive breast cancers. We have demonstrated previously that the RING E3 ligase BCA2 has autoubiquitination activity and is a very unstable protein. Previously, only Rab7, tetherin, ubiquitin and UBC9 were known to directly interact with BCA2. Methods Here, additional BCA2 binding proteins were found using yeast two-hybrid and bacterial-II-hybrid screening techniques with Human breast and HeLa cDNA libraries. Co-expression of these proteins was analyzed through IHC of TMAs. Investigation of the molecular interactions and effects were examined through a series of in vivo and in vitro assays. Results Ten unique BCA2 interacting proteins were identified, two of which were hHR23a and 14-3-3sigma. Both hHR23a and 14-3-3sigma are co-expressed with BCA2 in breast cancer cell lines and patient breast tumors (n = 105). hHR23a and BCA2 expression was significantly correlated (P = \u3c 0.0001 and P = 0.0113) in both nucleus and cytoplasm. BCA2 expression showed a statistically significant correlation with tumor grade. High cytoplasmic hHR23a trended towards negative nodal status. Binding to BCA2 by hHR23a and 14-3-3sigma was confirmed in vitro using tagged partner proteins and BCA2. hHR23a and 14-3-3sigma effect the autoubiquitination and auto-degradation activity of BCA2. Ubiquitination of hHR23a-bound BCA2 was found to be dramatically lower than that of free BCA2, suggesting that hHR23a promotes the stabilization of BCA2 by inactivating its autoubiquitination activity, without degradation of hHR23a. On the other hand, phosphorylated BCA2 protein is stabilized by interaction with 14-3-3sigma both with and without proteasome inhibitor MG-132 suggesting that BCA2 is regulated by multiple degradation pathways. Conclusions The interaction between BCA2 and hHR23a in breast cancer cells stabilizes BCA2. High expression of BCA2 is correlated with grade in breast cancer, suggesting regulation of this E3 ligase is important to cancer progression

Chandra and ASCA X-ray Observations of the Radio Supernova SN1979C IN NGC 4321

We report on the X-ray observation of the radio selected supernova SN1979C carried out with ASCA in 1997 December and serendipitously available from a Chandra Guaranteed Time Observation in 1999 November. The supernova, of type SN II-Linear (SN IIL), was first observed in the optical and occurred in the weakly barred, almost face on spiral galaxy NGC 4321 (M100). The galaxy, a member of the Virgo S cluster, is at a distance of 17.1 Mpc, and contains at least three other supernovae discovered in this century. The useful exposure time was ~25 ks for the Solid-State Imaging Spectrometer (SIS), ~28 ks for the Gas Scintillation Imaging Spectrometer (GIS), and ~2.5 ks for Chandra's Advanced CCD Imaging Spectrometer (ACIS). No point source was detected at the radio position of SN1979C in a 3' diameter half power response circle in the ASCA data. The background and galaxy subtracted SN signal had a 3sigma upper limit to the flux of 6.3x10^-14 ergs/s/cm^-2 in the full ASCA SIS band (0.4-10.0 keV) and a 3sigma upper limit of <3-4x10^-14 erg/s/cm^2 in the 2-10 keV band. In the Chandra data, a source at the position of SN1979C is marginally detected at energies below 2 keV at a flux consistent with the ROSAT HRI detection in 1995. At energies above 2 keV, no source is detected with an upper limit of ~3x10^-14 erg/s/cm^-2. These measurements give the first ever x-ray flux limit of a Type IIL SN above 2 keV which is an important diagnostic of the outgoing shock wave ploughing through the circumstellar medium.Comment: 8 pages, 2 figures, accepted A

A view of PKS 2155-304 with XMM-Newton Reflection Grating Spectrometers

We present the high resolution X-ray spectrum of the BL Lac object PKS 2155-304 taken with the RGS units onboard XMM-Newton in November 2000. We detect a OVII Kalpha resonant absorption line from warm/hot local gas at 21.59A (~4.5 sigma detection). The line profile is possibly double peaked. We do not confirm the strong 20.02 A absorption line seen with Chandra and interpreted as z~0.05 OVIII Kalpha. A 3sigma upper limit of 14 mA on the equivalent width is set. We also detect the ~23.5 A interstellar OI 1s-->2p line and derive a factor <=1.5 subsolar O/H ratio in the ISM along PKS 2155-304 line of sight.Comment: 13 pages, 5 figures, 3 tables, emulateapj style. Accepted by Ap

The controllability of the aeroassist flight experiment atmospheric skip trajectory

The Aeroassist Flight Experiment (AFE) will be the first vehicle to simulate a return from geosynchronous orbit, deplete energy during an aerobraking maneuver, and navigate back out of the atmosphere to a low earth orbit It will gather scientific data necessary for future Aeroasisted Orbitl Transfer Vehicles (AOTV's). Critical to mission success is the ability of the atmospheric guidance to accurately attain a targeted post-aeropass orbital apogee while nulling inclination errors and compensating for dispersions in state, aerodynamic, and atmospheric parameters. In typing to satisfy mission constraints, atmospheric entry-interface (EI) conditions, guidance gains, and trajectory. The results of the investigation are presented; emphasizing the adverse effects of dispersed atmospheres on trajectory controllability

A Search for 6.7 GHz Methanol Masers in M33

We report the negative results from a search for 6.7 GHz methanol masers in the nearby spiral galaxy M33. We observed 14 GMCs in the central 4 kpc of the Galaxy, and found 3 sigma upper limits to the flux density of ~9 mJy in spectral channels having a velocity width of 0.069 km/s. By velocity shifting and combining the spectra from the positions observed, we obtain an effective 3sigma upper limit on the average emission of ~1mJy in a 0.25 km/s channel. These limits lie significantly below what we would expect based on our estimates of the methanol maser luminosity function in the Milky Way. The most likely explanation for the absence of detectable methanol masers appears to be the metallicity of M33, which is modestly less than that of the Milky Way

Detection of H2 pure rotational line emission from the GG~Tau binary system

We present the first detection of the low-lying pure rotational emission lines of H2 from circumstellar disks around T~Tauri stars, using the Short Wavelength Spectrometer on the Infrared Space Observatory. These lines provide a direct measure of the total amount of warm molecular gas in disks. The J=2->0 S(0) line at 28.218 mum and the J=3->1 S(1) line at 17.035 mum have been observed toward the double binary system GG Tau. Together with limits on the J=5->3 S(3) and J=7->5 S(5) lines, the data suggest the presence of gas at T_kin=110+-10 K with a mass of (3.6+-2.0)x10^-3 M_sol (3sigma). This amounts to ~3% of the total gas + dust mass of the circumbinary disk as imaged by millimeter interferometry, but is larger than the estimated mass of the circumstellar disk(s). Possible origins for the warm gas seen in H2 are discussed in terms of photon and wind-shock heating mechanisms of the circumbinary material, and comparisons with model calculations are made.Comment: 14 pages including 1 figure. To appear in Astrophysical Journal Letter

A STUDY ON THE FUNCTION OF 14-3-3SIGMA IN REGULATING CANCER ENERGY METABOLISM

Metabolic reprogramming has been shown to be a major cancer hallmark providing tumor cells with significant advantages for survival, proliferation, growth, metastasis and resistance against anti-cancer therapies. Glycolysis, glutaminolysis and mitochondrial biogenesis are among the most essential cancer metabolic alterations because these pathways provide cancer cells with not only energy but also crucial metabolites to support large-scale biosynthesis, rapid proliferation and tumorigenesis. In this study, we find that 14-3-3σ suppresses all these three metabolic processes by promoting the degradation of their main driver, c-Myc. In fact, 14-3-3s significantly enhances c-Myc poly-ubiquitination and subsequent degradation, reduces c-Myc transcriptional activity, and down-regulates c-Myc-induced metabolic target genes expression. Therefore, 14-3-3σ remarkably blocks glycolysis, decreases glutaminolysis and diminishes mitochondrial mass of cancer cells both in vitro and in vivo, thereby severely suppressing cancer bioenergetics and metabolism. As a result, a high level of 14-3-3σ in tumors is strongly associated with increased breast cancer patients’ overall and metastasis-free survival as well as better clinical outcomes. Thus, this study reveals a new role for 14-3-3s as a significant regulator of cancer bioenergetics and a promising target for the development of anti-cancer metabolism therapies