Metabolic Profiles Associated With Metformin Efficacy in Cancer

Metformin is one of the most commonly prescribed medications for the treatment of type 2 diabetes. Numerous reports have suggested potential anti-cancerous and cancer preventive properties of metformin, although these findings vary depending on the intrinsic properties of the tumor, as well as the systemic physiology of patients. These intriguing studies have led to a renewed interest in metformin use in the oncology setting, and fueled research to unveil its elusive mode of action. It is now appreciated that metformin inhibits complex I of the electron transport chain in mitochondria, causing bioenergetic stress in cancer cells, and rendering them dependent on glycolysis for ATP production. Understanding the mode of action of metformin and the consequences of its use on cancer cell bioenergetics permits the identification of cancer types most susceptible to metformin action. Such knowledge may also shed light on the varying results to metformin usage that have been observed in clinical trials. In this review, we discuss metabolic profiles of cancer cells that are associated with metformin sensitivity, and rationalize combinatorial treatment options. We use the concept of bioenergetic flexibility, which has recently emerged in the field of cancer cell metabolism, to further understand metabolic rearrangements that occur upon metformin treatment. Finally, we advance the notion that metabolic fitness of cancer cells increases during progression to metastatic disease and the emergence of therapeutic resistance. As a result, sophisticated combinatorial approaches that prevent metabolic compensatory mechanisms will be required to effectively manage metastatic disease

Nitric oxide regulates skeletal muscle fatigue, fiber type, microtubule organization, and mitochondrial ATP synthesis efficiency through cGMP-dependent mechanisms

Aim: Skeletal muscle nitric oxide–cyclic guanosine monophosphate (NO-cGMP) pathways are impaired in Duchenne and Becker muscular dystrophy partly because of reduced nNOSμ and soluble guanylate cyclase (GC) activity. However, GC function and the consequences of reduced GC activity in skeletal muscle are unknown. In this study, we explore the functions of GC and NO-cGMP signaling in skeletal muscle. Results: GC1, but not GC2, expression was higher in oxidative than glycolytic muscles. GC1 was found in a complex with nNOSμ and targeted to nNOS compartments at the Golgi complex and neuromuscular junction. Baseline GC activity and GC agonist responsiveness was reduced in the absence of nNOS. Structural analyses revealed aberrant microtubule directionality in GC1−/− muscle. Functional analyses of GC1−/− muscles revealed reduced fatigue resistance and postexercise force recovery that were not due to shifts in type IIA–IIX fiber balance. Force deficits in GC1−/− muscles were also not driven by defects in resting mitochondrial adenosine triphosphate (ATP) synthesis. However, increasing muscle cGMP with sildenafil decreased ATP synthesis efficiency and capacity, without impacting mitochondrial content or ultrastructure. Innovation: GC may represent a new target for alleviating muscle fatigue and that NO-cGMP signaling may play important roles in muscle structure, contractility, and bioenergetics. Conclusions: These findings suggest that GC activity is nNOS dependent and that muscle-specific control of GC expression and differential GC targeting may facilitate NO-cGMP signaling diversity. They suggest that nNOS regulates muscle fiber type, microtubule organization, fatigability, and postexercise force recovery partly through GC1 and suggest that NO-cGMP pathways may modulate mitochondrial ATP synthesis efficiency

Compact non-invasive millimeter-wave glucose sensor

The authors describe a compact non-invasive CMOS-circuit-based glucose monitor using millimeter-wave transmission for use on animal and human subjects. Using an earlier device, in vivo measurements were performed through the ear in anesthetized animals and correlated with blood glucose concentration from test strips. In addition, millimeter wave absorption through glucose-containing solutions was measured in specialized liquid transmission cells and is shown to correlate with the animal and separate in vitro data. Design and performance information on the CMOS transceiver are given

Faint NUV/FUV Standards from Swift/UVOT, GALEX and SDSS Photometry

At present, the precision of deep ultraviolet photometry is somewhat limited by the dearth of faint ultraviolet standard stars. In an effort to improve this situation, we present a uniform catalog of eleven new faint (u sim17) ultraviolet standard stars. High-precision photometry of these stars has been taken from the Sloan Digital Sky Survey and Galaxy Evolution Explorer and combined with new data from the Swift Ultraviolet Optical Telescope to provide precise photometric measures extending from the Near Infrared to the Far Ultraviolet. These stars were chosen because they are known to be hot (20,000 < T_eff < 50,000 K) DA white dwarfs with published Sloan spectra that should be photometrically stable. This careful selection allows us to compare the combined photometry and Sloan spectroscopy to models of pure hydrogen atmospheres to both constrain the underlying properties of the white dwarfs and test the ability of white dwarf models to predict the photometric measures. We find that the photometry provides good constraint on white dwarf temperatures, which demonstrates the ability of Swift/UVOT to investigate the properties of hot luminous stars. We further find that the models reproduce the photometric measures in all eleven passbands to within their systematic uncertainties. Within the limits of our photometry, we find the standard stars to be photometrically stable. This success indicates that the models can be used to calibrate additional filters to our standard system, permitting easier comparison of photometry from heterogeneous sources. The largest source of uncertainty in the model fitting is the uncertainty in the foreground reddening curve, a problem that is especially acute in the UV.Comment: Accepted for publication in Astrophysical Journal. 31 pages, 13 figures, electronic tables available from ApJ or on reques

Initial State Interactions for K−K^--Proton Radiative Capture

The effects of the initial state interactions on the $K^--p$ radiative capture branching ratios are examined and found to be quite sizable. A general coupled-channel formalism for both strong and electromagnetic channels using a particle basis is presented, and applied to all the low energy $K^--p$ data with the exception of the {\it 1s} atomic level shift. Satisfactory fits are obtained using vertex coupling constants for the electromagnetic channels that are close to their expected SU(3) values.Comment: 16 pages, uses revte

Composition and distribution of the peracarid crustacean fauna along a latitudinal transect off Victoria Land (Ross Sea, Antarctica) with special emphasis on the Cumacea

The following study was the first to describe composition and structure of the peracarid fauna systematically along a latitudinal transect off Victoria Land (Ross Sea, Antarctica). During the 19th Antarctic expedition of the Italian research vessel “Italica” in February 2004, macrobenthic samples were collected by means of a Rauschert dredge with a mesh size of 500 m at depths between 85 and 515 m. The composition of peracarid crustaceans, especially Cumacea was investigated. Peracarida contributed 63% to the total abundance of the fauna. The peracarid samples were dominated by amphipods (66%), whereas cumaceans were represented with 7%. Previously, only 13 cumacean species were known, now the number of species recorded from the Ross Sea increased to 34. Thus, the cumacean fauna of the Ross Sea, which was regarded as the poorest in terms of species richness, has to be considered as equivalent to that of other high Antarctic areas. Most important cumacean families concerning abundance and species richness were Leuconidae, Nannastacidae, and Diastylidae. Cumacean diversity was lowest at the northernmost area (Cape Adare). At the area off Coulman Island, which is characterized by muddy sediment, diversity was highest. Diversity and species number were higher at the deeper stations and abundance increased with latitude. A review of the bathymetric distribution of the Cumacea from the Ross Sea reveals that most species distribute across the Antarctic continental shelf and slope. So far, only few deep-sea records justify the assumption of a shallow-water–deep-sea relationship in some species of Ross Sea Cumacea, which is discussed from an evolutionary point of view

A Large Catalog of Homogeneous Ultra-Violet/Optical GRB Afterglows: Temporal and Spectral Evolution

We present the second Swift Ultra-Violet/Optical Telescope (UVOT) gamma-ray burst (GRB) afterglow catalog, greatly expanding on the first Swift UVOT GRB afterglow catalog. The second catalog is constructed from a database containing over 120,000 independent UVOT observations of 538 GRBs first detected by Swift, the High Energy Transient Explorer 2 (HETE2), the INTErnational Gamma-Ray Astrophysics Laboratory (INTEGRAL), the Interplanetary Network (IPN), Fermi, and Astro-rivelatore Gamma a Immagini Leggero (AGILE). The catalog covers GRBs discovered from 2005 Jan 17 to 2010 Dec 25. Using photometric information in three UV bands, three optical bands, and a `white' or open filter, the data are optimally co-added to maximize the number of detections and normalized to one band to provide a detailed light curve. The catalog provides positional, temporal, and photometric information for each burst, as well as Swift Burst Alert Telescope (BAT) and X-Ray Telescope (XRT) GRB parameters. Temporal slopes are provided for each UVOT filter. The temporal slope per filter of almost half the GRBs are fit with a single power-law, but one to three breaks are required in the remaining bursts. Morphological comparisons with the X-ray reveal that approximately 75% of the UVOT light curves are similar to one of the four morphologies identified by Evans et al. (2009). The remaining approximately 25% have a newly identified morphology. For many bursts, redshift and extinction corrected UV/optical spectral slopes are also provided at 2000, 20,000, and 200,000 seconds.Comment: 44 pages, 14 figures, to be published in Astrophysical Journal Supplementa

The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L

Epithelial cells that lose attachment to the extracellular matrix undergo a specialized form of apoptosis called anoikis. Here, using large-scale RNA interference (RNAi) screening, we find that KDM3A, a histone H3 lysine 9 (H3K9) mono- and di-demethylase, plays a pivotal role in anoikis induction. In attached breast epithelial cells, KDM3A expression is maintained at low levels by integrin signaling. Following detachment, integrin signaling is decreased resulting in increased KDM3A expression. RNAi-mediated knockdown of KDM3A substantially reduces apoptosis following detachment and, conversely, ectopic expression of KDM3A induces cell death in attached cells. We find that KDM3A promotes anoikis through transcriptional activation of BNIP3 and BNIP3L, which encode pro-apoptotic proteins. Using mouse models of breast cancer metastasis we show that knockdown of Kdm3a enhances metastatic potential. Finally, we find defective KDM3A expression in human breast cancer cell lines and tumors. Collectively, our results reveal a novel transcriptional regulatory program that mediates anoikis

Exploring Halo Substructure with Giant Stars. VI. Extended Distributions of Giant Stars Around the Carina Dwarf Spheroidal Galaxy -- How Reliable Are They?

The question of the existence of active tidal disruption around various dSph galaxies remains controversial. That debate often centers on the nature (bound vs. unbound) of extended populations of stars. However, the more fundamental issue of the very existence of the extended populations is still contentious. We present an evaluation of the debate centering on one particular dSph, Carina, for which claims both for and against the existence of stars beyond the King radius have been made. Our review includes an examination of all previous studies bearing on the Carina radial profile and shows that the survey method which achieves the highest detected dSph signal-to-background in the outer parts of the galaxy is the Washington M, T2 + DDO51 (MTD) filter approach from Paper II in this series. We then address statistical methods used to evaluate the reliability of MTD surveys in the presence of photometric errors and for which a new, a posteriori statistical analysis methodology is provided. Finally, these statistical methods are tested by new spectroscopy of stars in the MTD-selected Carina candidate sample. Of 74 candidate giants with follow-up spectroscopy, the MTD technique identified 61 new Carina members, including 8 stars outside the King radius. From a sample of 29 stars not initially identified as candidate Carina giants but that lie just outside of our selection criteria, 12 have radial velocities consistent with membership, including 5 extratidal stars. Carina is shown to have an extended population of giant stars extending to a major axis radius of 40' (1.44x the nominal King radius).Comment: 56 pages, 10 figures. Submitted to the Astronomical Journal, 2004 Sep 2