Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells

Energy metabolism is key to the promotion of tumor growth, development, and metastasis. At the same time, cellular metabolism also mediates immune cell survival, proliferation and cytotoxic responses within the tumor microenvironment. The ability of natural killer cells to eradicate tumors relies on their ability to functionally persist for the duration of their anti-tumor effector activity. However, a tumor's altered metabolic requirements lead to compromised functional responses of cytokine-activated natural killer cells, which result in decreased effectiveness of adoptive cell-based immunotherapies. Tumors exert these immunosuppressive effects through a number of mechanisms, a key driver of which is hypoxia. Hypoxia also fuels the generation of adenosine from the cancer-associated ectoenzymes CD39 and CD73. Adenosine's immunosuppression manifests in decreased proliferation and impaired anti-tumor function, with adenosinergic signaling emerging as an immunometabolic checkpoint blockade target. Understanding such immunometabolic suppression is critical in directing the engineering of a new generation of natural killer cell-based immunotherapies that have the ability to more effectively target difficult-to-treat solid tumors

Chemistry in Infrared Dark Cloud Clumps: a Molecular Line Survey at 3 mm

We have observed 37 Infrared Dark Clouds (IRDCs), containing a total of 159 clumps, in high-density molecular tracers at 3 mm using the 22-meter ATNF Mopra Telescope located in Australia. After determining kinematic distances, we eliminated clumps that are not located in IRDCs and clumps with a separation between them of less than one Mopra beam. Our final sample consists of 92 IRDC clumps. The most commonly detected molecular lines are (detection rates higher than 8%): N2H+, HNC, HN13C, HCO+, H13CO+, HCN, C2H, HC3N, HNCO, and SiO. We investigate the behavior of the different molecular tracers and look for chemical variations as a function of an evolutionary sequence based on Spitzer IRAC and MIPS emission. We find that the molecular tracers behave differently through the evolutionary sequence and some of them can be used to yield useful relative age information. The presence of HNC and N2H+ lines do not depend on the star formation activity. On the other hand, HC3N, HNCO, and SiO are predominantly detected in later stages of evolution. Optical depth calculations show that in IRDC clumps the N2H+ line is optically thin, the C2H line is moderately optically thick, and HNC and HCO+ are optically thick. The HCN hyperfine transitions are blended, and, in addition, show self-absorbed line profiles and extended wing emission. These factors combined prevent the use of HCN hyperfine transitions for the calculation of physical parameters. Total column densities of the different molecules, except C2H, increase with the evolutionary stage of the clumps. Molecular abundances increase with the evolutionary stage for N2H+ and HCO+. The N2H+/HCO+ and N2H+/HNC abudance ratios act as chemical clocks, increasing with the evolution of the clumps.Comment: Accepted to ApJ. 29 page

Adenosinergic Signaling Alters Natural Killer Cell Functional Responses

Adenosine is a potent immunosuppressive purine metabolite contributing to the pathogenesis of solid tumors. Extracellular adenosine signals on tumor-infiltrating NK cells to inhibit their proliferation, maturation, and cytotoxic function. Cytokine priming imparts upon NK cells distinct activation statuses, which modulate NK anti-tumor immunity and responses to purinergic metabolism. Here, for the first time, we investigated human NK cell responses to adenosinergic signaling in the context of distinct cytokine priming programs. NK cells were shown to be hyper-responsive to adenosine when primed with IL-12 and IL-15 compared to IL-2, exhibiting enhanced IFN-γ expression from CD56bright and CD56dim subsets while modulating the expression of activation marker NKG2D. These responses resulted in signaling that was dependent on mTOR. Adenosine induced upregulation of transcriptional signatures for genes involved in immune responses while downregulating cellular metabolism and other protein synthesis functions that correlate to inhibited oxidative phosphorylation and glycolysis. Overall, our findings show that adenosine acts on specific cellular pathways rather than inducing a broad inhibition of NK cell functions. These responses are dependent on cytokine priming signatures and are important in designing therapeutic interventions that can reprogram NK cell immunometabolism for improved immunotherapies of solid tumors

Sprouty2 mediated tuning of signalling is essential for somite myogenesis

Background: Negative regulators of signal transduction cascades play critical roles in controlling different aspects of normal embryonic development. Sprouty2 (Spry2) negatively regulates receptor tyrosine kinases (RTK) and FGF signalling and is important in differentiation, cell migration and proliferation. In vertebrate embryos, Spry2 is expressed in paraxial mesoderm and in forming somites. Expression is maintained in the myotome until late stages of somite differentiation. However, its role and mode of action during somite myogenesis is still unclear. Results: Here, we analysed chick Spry2 expression and showed that it overlaps with that of myogenic regulatory factors MyoD and Mgn. Targeted mis-expression of Spry2 led to inhibition of myogenesis, whilst its C-terminal domain led to an increased number of myogenic cells by stimulating cell proliferation. Conclusions: Spry2 is expressed in somite myotomes and its expression overlaps with myogenic regulatory factors. Overexpression and dominant-negative interference showed that Spry2 plays a crucial role in regulating chick myogenesis by fine tuning of FGF signaling through a negative feedback loop. We also propose that mir-23, mir-27 and mir-128 could be part of the negative feedback loop mechanism. Our analysis is the first to shed some light on in vivo Spry2 function during chick somite myogenesis

Observational and Dynamical Characterization of Main-Belt Comet P/2010 R2 (La Sagra)

We present observations of comet-like main-belt object P/2010 R2 (La Sagra) obtained by Pan-STARRS 1 and the Faulkes Telescope-North on Haleakala in Hawaii, the University of Hawaii 2.2 m, Gemini-North, and Keck I telescopes on Mauna Kea, the Danish 1.54 m telescope at La Silla, and the Isaac Newton Telescope on La Palma. An antisolar dust tail is observed from August 2010 through February 2011, while a dust trail aligned with the object's orbit plane is also observed from December 2010 through August 2011. Assuming typical phase darkening behavior, P/La Sagra is seen to increase in brightness by >1 mag between August 2010 and December 2010, suggesting that dust production is ongoing over this period. These results strongly suggest that the observed activity is cometary in nature (i.e., driven by the sublimation of volatile material), and that P/La Sagra is therefore the most recent main-belt comet to be discovered. We find an approximate absolute magnitude for the nucleus of H_R=17.9+/-0.2 mag, corresponding to a nucleus radius of ~0.7 km, assuming an albedo of p=0.05. Using optical spectroscopy, we find no evidence of sublimation products (i.e., gas emission), finding an upper limit CN production rate of Q_CN<6x10^23 mol/s, from which we infer an H2O production rate of Q_H2O<10^26 mol/s. Numerical simulations indicate that P/La Sagra is dynamically stable for >100 Myr, suggesting that it is likely native to its current location and that its composition is likely representative of other objects in the same region of the main belt, though the relatively close proximity of the 13:6 mean-motion resonance with Jupiter and the (3,-2,-1) three-body mean-motion resonance with Jupiter and Saturn mean that dynamical instability on larger timescales cannot be ruled out.Comment: 23 pages, 13 figures, accepted for publication in A

Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on childre

An Overview of Research and Evaluation Designs for Dissemination and Implementation

The wide variety of dissemination and implementation designs now being used to evaluate and improve health systems and outcomes warrants review of the scope, features, and limitations of these designs

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st