On the feedback from super stellar clusters. I. The structure of giant HII regions and HII galaxies

We review the structural properties of giant extragalactic HII regions and HII galaxies based on 2D hydrodynamic calculations, and propose an evolutionary sequence that accounts for their observed detailed structure. The model assumes a massive and young stellar cluster surrounded by a large collection of clouds. These are thus exposed to the most important star-formation feedback mechanisms: photoionization and the cluster wind. The models show how the two feedback mechanisms compete in the disruption of clouds and lead to two different hydrodynamic solutions: The storage of clouds into a long lasting ragged shell that inhibits the expansion of the thermalized wind, and the steady filtering of the shocked wind gas through channels carved within the cloud stratum. Both solutions are claimed to be concurrently at work in giant HII regions and HII galaxies, causing their detailed inner structure. This includes multiple large-scale shells, filled with an X-ray emitting gas, that evolve to finally merge with each other, giving the appearance of shells within shells. The models also show how the inner filamentary structure of the giant superbubbles is largely enhanced with matter ablated from clouds and how cloud ablation proceeds within the original cloud stratum. The calculations point at the initial contrast density between the cloud and the intercloud media as the factor that defines which of the two feedback mechanisms becomes dominant throughout the evolution. Animated version of the models can be found at http://www.iaa.csic.es/\~{}eperez/ssc/ssc.html.Comment: 28 pages, 10 figures, accepted for publication in the ApJ. Animated version of the models can be found at http://www.iaa.csic.es/\~{}eperez/ssc/ssc.htm

On the ongoing multiple blowout in NGC 604

Several facts regarding the structure of NGC 604 are examined here. The three main cavities, produced by the mechanical energy from massive stars which in NGC 604 are spread over a volume of 10$^6$ pc$^3$, are shown here to be undergoing blowout into the halo of M33. High resolution long slit spectroscopy is used to track the impact from massive stars while HST archive data is used to display the asymmetry of the nebula. NGC 604 is found to be a collection of photoionized filaments and sections of shells in direct contact with the thermalized matter ejected by massive stars. The multiple blowout events presently drain the energy injected by massive stars and thus the densest photoionized gas is found almost at rest and is expected to suffer a slow evolution.Comment: 15 pages (11 text), 4 figures. To be published in Ap

Bright Stars and Recent Star Formation in the Irregular Magellanic Galaxy NGC2366

The stellar content of the Im galaxy NGC 2366 is discussed on the basis of CCD BVR photometry. The three brightest blue and red stars have been used to estimate its distance, obtaining a balue of 2.9 Mpc. The spatial distribution of the young stellar population is discussed in the light of the integrated color indices and the color-magnitude diagrams of different zones of the galaxy. A generalized star formation burst seems to have taken place about 50 Myr ago. The youngest stars are preferentially formed in the South-West part of the bar, where the giant HII complex NGC 2363 is located, being younger and bluer. The bar seems to play a role favouring star formation in one of its extremes. Self-propagation however, does not seem to be triggering star formation at large scale. A small region, populated by very young stars has also been found at the East of the galaxy.Comment: Astronomical Journal, accepted. This is a uuencoded, compressed, tar file (102 Kbytes) of 1 text, 1 table postscript files. Figures are retrieved as a separate file. One single file with all figures and tables (552Kb) also available from http://www.ast.cam.ac.uk/~etelles/astronomy.htm

Treating breast cancer through novel inhibitors of the phosphatidylinositol 3'-kinase pathway

Recent studies indicate that constitutive signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is a cause of treatment resistance in breast cancer patients. This implies that patients with tumors that exhibit aberrant PI3K signaling may benefit from targeted pathway inhibitors. The first agents to make it to the clinic are the rapamycin analogs. These compounds inhibit the downstream PI3K effector mTOR (mammalian target of rapamycin). A study presented in this issue of Breast Cancer Research suggests that recently developed inhibitors of phosphoinositide-dependent protein kinase 1, a more proximal target of the PI3K pathway, may provide an alternative route to effective PI3K pathway inhibition for breast cancer treatment

Ten Million Degree Gas in M 17 and the Rosette Nebula: X-ray Flows in Galactic H II Regions

We present the first high-spatial-resolution X-ray images of two high-mass star forming regions, the Omega Nebula (M 17) and the Rosette Nebula (NGC 2237--2246), obtained with the Chandra X-ray Observatory Advanced CCD Imaging Spectrometer (ACIS) instrument. The massive clusters powering these H II regions are resolved at the arcsecond level into >900 (M 17) and >300 (Rosette) stellar sources similar to those seen in closer young stellar clusters. However, we also detect soft diffuse X-ray emission on parsec scales that is spatially and spectrally distinct from the point source population. The diffuse emission has luminosity L_x ~ 3.4e33 ergs/s in M~17 with plasma energy components at kT ~0.13 and ~0.6 keV (1.5 and 7 MK), while in Rosette it has L_x \~6e32 ergs/s with plasma energy components at kT ~0.06 and ~0.8 keV (0.7 and 9 MK). This extended emission most likely arises from the fast O-star winds thermalized either by wind-wind collisions or by a termination shock against the surrounding media. We establish that only a small portion of the wind energy and mass appears in the observed diffuse X-ray plasma; in these blister H II regions, we suspect that most of it flows without cooling into the low-density interstellar medium. These data provide compelling observational evidence that strong wind shocks are present in H II regions.Comment: 35 pages, including 11 figures; to appear in ApJ, August 20, 2003. A version with high-resolution figures is available at ftp://ftp.astro.psu.edu/pub/townsley/diffuse.ps.g

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P=0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P=0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor

Expression and localisation of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients

We investigated the correlation between the expression and localisation of Akt-1, Akt-2, Akt-3, phospho-Akt proteins and the clinicopathological parameters in 63 prostate cancer specimens. More than 60% of cancerous tissues overexpressed Akt-1, Akt-2 or Akt-3. Cytoplasmic Akt-1 expression was correlated with a higher risk of postoperative prostate-specific antigen (PSA) recurrence and shorter PSA recurrence interval. Cytoplasmic Akt-2 did not show any significant correlation with clinicopathological parameters predicting outcomes. Cytoplasmic Akt-3 was associated with hormone-refractory disease progression and extracapsular invasion. Nuclear Akt-1 and Akt-2 expression were correlated with favourable outcome parameters such as absence of lymph node and perineural invasion. Kaplan–Meier analysis and Cox regression model also showed that Akt-1 and Akt-2, but not Akt-3 or phospho-Akt was associated with a significantly higher risk of PSA recurrence. In contrast, nuclear Akt-1 was significantly associated with a lower risk of PSA recurrence. Multivariate analysis revealed that clinical stage, Gleason score and the combined cytoplasmic nuclear Akt-1 marker in cancerous tissues were significant independent prognostic factors of PSA recurrence. This is the first report demonstrating in patients with prostate cancer and the particular role of Akt-1 isoform expression as a prognostic marker depending of its localisation

Neuregulin-1 Regulates Cell Adhesion via an ErbB2/Phosphoinositide-3 Kinase/Akt-Dependent Pathway: Potential Implications for Schizophrenia and Cancer

Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer.Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1alpha induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1alpha-induced migration (r(2) = 0.61). NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1alpha-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063).Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion

TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation

<p>Abstract</p> <p>Introduction</p> <p>Signaling downstream of Ras is mediated by three major pathways, Raf/ERK, phosphatidylinositol 3 kinase (PI3K), and Ral guanine nucleotide exchange factor (RalGEF). Ras signal transduction pathways play an important role in breast cancer progression, as evidenced by the frequent over-expression of the Ras-activating epidermal growth factor receptors EGFR and ErbB2. Here we investigated which signal transduction pathways downstream of Ras contribute to EGFR-dependent transformation of telomerase-immortalized mammary epithelial cells HME16C. Furthermore, we examined whether a highly transcriptionally regulated ERK pathway target, PHLDA1 (TDAG51), suggested to be a tumor suppressor in breast cancer and melanoma, might modulate the transformation process.</p> <p>Methods</p> <p>Cellular transformation of human mammary epithelial cells by downstream Ras signal transduction pathways was examined using anchorage-independent growth assays in the presence and absence of EGFR inhibition. TDAG51 protein expression was down-regulated by interfering small hairpin RNA (shRNA), and the effects on cell proliferation and death were examined in Ras pathway-transformed breast epithelial cells.</p> <p>Results</p> <p>Activation of both the ERK and PI3K signaling pathways was sufficient to induce cellular transformation, which was accompanied by up-regulation of EGFR ligands, suggesting autocrine EGFR stimulation during the transformation process. Only activation of the ERK pathway was sufficient to transform cells in the presence of EGFR inhibition and was sufficient for tumorigenesis in xenografts. Up-regulation of the PHLDA1 gene product, TDAG51, was found to correlate with persistent ERK activation and anchorage-independent growth in the absence or presence of EGFR inhibition. Knockdown of this putative breast cancer tumor-suppressor gene resulted in increased ERK pathway activation and enhanced matrix-detached cellular proliferation of Ras/Raf transformed cells.</p> <p>Conclusion</p> <p>Our results suggest that multiple Ras signal transduction pathways contribute to mammary epithelial cell transformation, but that the ERK signaling pathway may be a crucial component downstream of EGFR activation during tumorigenesis. Furthermore, persistent activation of ERK signaling up-regulates TDAG51. This event serves as a negative regulator of both Erk activation as well as matrix-detached cellular proliferation and suggests that TDAG51 opposes ERK-mediated transformation in breast epithelial cells.</p