A Search for Dark Matter Annihilation in Galaxy Groups

We use 413 weeks of publicly-available $\textit{Fermi}$ Pass 8 gamma-ray data, combined with recently-developed galaxy group catalogs, to search for evidence of dark matter annihilation in extragalactic halos. In our study, we use luminosity-based mass estimates and mass-to-concentration relations to infer the $J$-factors and associated uncertainties for hundreds of galaxy groups within a redshift range $z \lesssim 0.03$. We employ a conservative substructure boost-factor model, which only enhances the sensitivity by an $\mathcal{O}(1)$ factor. No significant evidence for dark matter annihilation is found and we exclude thermal relic cross sections for dark matter masses below $\sim$30 GeV to 95% confidence in the $b\bar{b}$ annihilation channel. These bounds are comparable to those from Milky Way dwarf spheroidal satellite galaxies. The results of our analysis increase the tension, but do not rule out, the dark matter interpretation of the Galactic Center excess. We provide a catalog of the galaxy groups used in this study and their inferred properties, which can be broadly applied to searches for extragalactic dark matter.Comment: 5+18 pages, 1+14 figures, catalog available at: https://github.com/bsafdi/DMCat; v2 updated to journal version with several updates, results and conclusions unchange

Mapping Extragalactic Dark Matter Annihilation with Galaxy Surveys: A Systematic Study of Stacked Group Searches

Dark matter in the halos surrounding galaxy groups and clusters can annihilate to high-energy photons. Recent advancements in the construction of galaxy group catalogs provide many thousands of potential extragalactic targets for dark matter. In this paper, we outline a procedure to infer the dark matter signal associated with a given galaxy group. Applying this procedure to a catalog of sources, one can create a full-sky map of the brightest extragalactic dark matter targets in the nearby Universe ($z\lesssim 0.03$), supplementing sources of dark matter annihilation from within the Local Group. As with searches for dark matter in dwarf galaxies, these extragalactic targets can be stacked together to enhance the signals associated with dark matter. We validate this procedure on mock $\textit{Fermi}$ gamma-ray data sets using a galaxy catalog constructed from the $\texttt{DarkSky}$ $N$-body cosmological simulation and demonstrate that the limits are robust, at $\mathcal{O}(1)$ levels, to systematic uncertainties on halo mass and concentration. We also quantify other sources of systematic uncertainty arising from the analysis and modeling assumptions. Our results suggest that a stacking analysis using galaxy group catalogs provides a powerful opportunity to discover extragalactic dark matter and complements existing studies of Milky Way dwarf galaxies.Comment: 17+7 pages, 9+4 figures; v2, updated to PRD version with several updates, results and conclusions unchange

Cholesterol and mevalonate : two metabolites involved in breast cancer progression and drug resistance through the ERRα pathway

Breast cancer is the second greatest cause of cancer-related death in women. Resistance to endocrine treatments or chemotherapy is a limiting drawback. In this context, this work aims to evaluate the effects of cholesterol and mevalonate during tumor progression and their contribution in the onset of resistance to clinical treatments in use today. In this study, we demonstrated that cholesterol and mevalonate treatments were able to activate the estrogen-related receptor alpha (ERRα) pathway, increasing the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ERbB2/human epithelial receptor (HER2), tumor protein D52 (TPD52), and NOTCH2 proteins in breast cancer cells. The activation of this pathway is shown to be responsible for intense metabolic switching, higher proliferation rates, sustained motility, the propagation of cancer stem-like cells (CSCs), and lipid droplet formation. All of these events are related to greater tumor propagation, aggressiveness, and drug resistance. Furthermore, the activation and expression of proteins induced by the treatment with cholesterol or mevalonate are consistent with those obtained from the MCF-7/TAMr cell line, which is largely used as a breast cancer model of acquired endocrine therapy resistance. Altogether, our data indicate that cholesterol and mevalonate are two metabolites implicated in breast cancer progression, aggressiveness, and drug resistance, through the activation of the ERRα pathway. Our findings enable us to identify the ERRα receptor as a poor prognostic marker in patients with breast carcinoma, suggesting the correlation between cholesterol/mevalonate and ERRα as a new possible target in breast cancer treatment

Anti-CTLA-4 therapy for malignant mesothelioma

Immunotherapy is an emerging therapeutic strategy with a promising clinical outcome in some solid tumors, particularly metastatic melanoma. One approach to immunotherapy is immune checkpoint inhibitors, such as blockage of CTLA-4 and PD-1/PD-L1. This special report aims to describe the state of clinical trials of tremelimumab in patients with unresectable malignant mesothelioma (MM) in particular with regard to the clinical efficacy, safety and tolerability. Criticism and perspective of this treatment are also discussed. Biological and clinical considerations rule out the use of tremelimumab as single agent for MM and, more generally, the use of immune checkpoint inhibitors for MM is still largely questionable and not supported by evidences

Essential role of STAT5a in DCIS formation and invasion following estrogen treatment

Ductal carcinoma in situ (DCIS) is one of the earliest stages of breast cancer (BCa). The mechanisms by which DCIS lesions progress to an invasive state while others remain indolent are yet to be fully characterized and both diagnosis and treatment of this pre-invasive disease could benefit from better understanding the pathways involved. While a decreased expression of Caveolin-1 (Cav-1) in the tumor microenvironment of patients with DCIS breast cancer was linked to progression to invasive breast cancer (IBC), the downstream effector(s) contributing to this process remain elusive. The current report shows elevated expression of Signal Transducer and Activator of Transcription 5a (STAT5a) within the DCIS-like lesions in Cav-1 KO mice following estrogen treatment and inhibition of STAT5a expression prevented the formation of these mammary lesions. In addition, STAT5a overexpression in a human DCIS cell line (MCF10DCIS.com) promoted their invasion, a process accelerated by estrogen treatment and associated with increased levels of the matrix metalloproteinase-9 (MMP-9) precursor. In sum, our results demonstrate a novel regulatory axis (Cav-1♦STAT5a♦MMP-9) in DCIS that is fully activated by the presence of estrogen. Our studies suggest to further study phosphorylated STAT5a (Y694) as a potential biomarker to guide and predict outcome of DCIS patient population

Influence of berry ripening stages over phenolics and volatile compounds in aged aglianicowine

The harvest time of grapes is a major determinant of berry composition and of the wine quality, and it is usually established through empirical testing of main biochemical parameters of the berry. In this work, we studied how the ripening stage of Aglianico grapes modulates key secondary metabolites of wines, phenolics and volatile compounds. Specifically, we analyzed and compared four berry ripening stages corresponding to total soluble solids of 18, 20, 22, and 25 Brix and related aged wines. Wine color intensity, anthocyanins level and total trans-resveratrol (free + glycosidic form) increased with grape maturity degree. Wines obtained from late-harvested grapes significantly differed from the others for a higher content of aliphatic alcohols, esters, acetates, a-terpineol and benzyl alcohol. The content of glycosidic terpene compounds, such as nerol, geraniol and a-terpineol, was higher in wines obtained with grapes harvested at 25 Brix compared to the earlier harvests. Our work indicated that the maturity of the grape is a determining factor in phenolic and volatile compounds of red Aglianico wines. Moreover, extending grape ripening to a sugar concentration higher than 22 Brix improves the biochemical profile of aged wine in terms of aroma compounds and of phytochemicals with known health-related benefits

Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism

Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed “BMF”, has a statin-like properties, which blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl- CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/ beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration (OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion diagnostic for BMF-directed personalized therapy