Low CO Luminosities in Dwarf Galaxies

[Abridged] We present maps of CO 2-1 emission covering the entire star-forming disks of 16 nearby dwarf galaxies observed by the IRAM HERACLES survey. The data have 13 arcsec angular resolution, ~250 pc at our average distance of 4 Mpc, and sample the galaxies by 10-1000 resolution elements. We apply stacking techniques to perform the first sensitive search for CO emission in dwarfs outside the Local Group ranging from single lines-of-sight, stacked over IR-bright regions of embedded star formation, and stacked over the entire galaxy. We detect 5 dwarfs in CO with total luminosities of L_CO = 3-28 1e6 Kkmspc2. The other 11 dwarfs remain undetected in CO even in the stacked data and have L_CO < 0.4-8 1e6 Kkmspc2. We combine our sample of dwarfs with a large literature sample of spirals to study scaling relations of L_CO with M_B and metallicity. We find that dwarfs with metallicities of Z ~ 1/2-1/10 Z_sun have L_CO about 1e2-1e4x smaller than spirals and that their L_CO per unit L_B is 10-100x smaller. A comparison with tracers of star formation (FUV and 24 micron) shows that L_CO per unit SFR is 10-100x smaller in dwarfs. One possible interpretation is that dwarfs form stars much more efficiently, however we argue that the low L_CO/SFR ratio is due to significant changes of the CO-to-H2 conversion factor, alpha_CO, in low metallicity environments. Assuming a constant H2 depletion time of 1.8 Gyr (as found for nearby spirals) implies alpha_CO values for dwarfs with Z ~ 1/2-1/10 Z_sun that are more than 10x higher than those found in solar metallicity spirals. This significant increase of alpha_CO at low metallicity is consistent with previous studies, in particular those which model dust emission to constrain H2 masses. Even though it is difficult to parameterize the metallicity dependence of alpha_CO, our results suggest that CO is increasingly difficult to detect at lower metallicities.Comment: Accepted for publication in the Astronomical Journal, 19 pages, 7 figure

Molecular Gas and Star Formation in Nearby Disk Galaxies

We compare molecular gas traced by ^(12)CO (2-1) maps from the HERACLES survey, with tracers of the recent star formation rate (SFR) across 30 nearby disk galaxies. We demonstrate a first-order linear correspondence between Σ_(mol) and Σ_(SFR) but also find important second-order systematic variations in the apparent molecular gas depletion time, τ_(dep)^(mol) = ∑_(mol)/∑_(SFR). At the 1 kpc common resolution of HERACLES, CO emission correlates closely with many tracers of the recent SFR. Weighting each line of sight equally, using a fixed α_(CO) equivalent to the Milky Way value, our data yield a molecular gas depletion time, τ_(dep)^(mol)= ∑_(mol)∑_(SFR) ≈ 2.2 Gyr with 0.3 dex 1σ scatter, in very good agreement with recent literature data. We apply a forward-modeling approach to constrain the power-law index, N, that relates the SFR surface density and the molecular gas surface density, ∑_(SFR) ∝ ∑_(mol)^N. We find N = 1 ± 0.15 for our full data set with some scatter from galaxy to galaxy. This also agrees with recent work, but we caution that a power-law treatment oversimplifies the topic given that we observe correlations between τ_(dep)^(mol) and other local and global quantities. The strongest of these are a decreased τ_(dep)^(mol) in low-mass, low-metallicity galaxies and a correlation of the kpc-scale τ_(dep)^(mol) with dust-to-gas ratio, D/G. These correlations can be explained by a CO-to-H_2 conversion factor (α_(CO)) that depends on dust shielding, and thus D/G, in the theoretically expected way. This is not a unique interpretation, but external evidence of conversion factor variations makes this the most conservative explanation of the strongest observed τ_(dep)^(mol) trends. After applying a D/G-dependent α_(CO), some weak correlations between τ_(dep)^(mol) and local conditions persist. In particular, we observe lower τ_(dep)^(mol) and enhanced CO excitation associated with nuclear gas concentrations in a subset of our targets. These appear to reflect real enhancements in the rate of star formation per unit gas, and although the distribution of τ_(dep) does not appear bimodal in galaxy centers, τ_(dep) does appear multivalued at fixed Σ_(H2), supporting the idea of "disk" and "starburst" modes driven by other environmental parameters

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Plasma Proteome Profiles Associated with Inflammation, Angiogenesis, and Cancer

Tumor development is accompanied by a complex host systemic response, which includes inflammatory and angiogenic reactions. Both tumor-derived and systemic response proteins are detected in plasma from cancer patients. However, given their non-specific nature, systemic response proteins can confound the detection or diagnosis of neoplasia. Here, we have applied an in-depth quantitative proteomic approach to analyze plasma protein changes in mouse models of subacute irritant-driven inflammation, autoreactive inflammation, and matrix associated angiogenesis and compared results to previously described findings from mouse models of polyoma middle T-driven breast cancer and Pdx1-Cre KrasG12D Ink4a/Arf lox/lox -induced pancreatic cancer. Among the confounding models, approximately 1/3 of all quantified plasma proteins exhibited a significant change in abundance compared to control mice. Of the proteins that changed in abundance, the majority were unique to each model. Altered proteins included those involved in acute phase response, inflammation, extracellular matrix remodeling, angiogenesis, and TGFβ signaling. Comparison of changes in plasma proteins between the confounder models and the two cancer models revealed proteins that were restricted to the cancer-bearing mice, reflecting the known biology of these tumors. This approach provides a basis for distinguishing between protein changes in plasma that are cancer-related and those that are part of a non-specific host response