921 research outputs found

    The Poker Face of Inelastic Dark Matter: Prospects at Upcoming Direct Detection Experiments

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    The XENON100 and CRESST experiments will directly test the inelastic dark matter explanation for DAMA's 8.9? sigma anomaly. This article discusses how predictions for direct detection experiments depend on uncertainties in quenching factor measurements, the dark matter interaction with the Standard Model and the halo velocity distribution. When these uncertainties are accounted for, an order of magnitude variation is found in the number of expected events at CRESST and XENON100.Comment: 5 pages, 3 figure

    Electromagnetic Models of Extragalactic Jets

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    Direct Detection of Dark Matter Debris Flows

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    Tidal stripping of dark matter from subhalos falling into the Milky Way produces narrow, cold tidal streams as well as more spatially extended "debris flows" in the form of shells, sheets, and plumes. Here we focus on the debris flow in the Via Lactea II simulation, and show that this incompletely phase-mixed material exhibits distinctive high velocity behavior. Unlike tidal streams, which may not necessarily intersect the Earth's location, debris flow is spatially uniform at 8 kpc and thus guaranteed to be present in the dark matter flux incident on direct detection experiments. At Earth-frame speeds greater than 450 km/s, debris flow comprises more than half of the dark matter at the Sun's location, and up to 80% at even higher speeds. Therefore, debris flow is most important for experiments that are particularly sensitive to the high speed tail of the dark matter distribution, such as searches for light or inelastic dark matter or experiments with directional sensitivity. We show that debris flow yields a distinctive recoil energy spectrum and a broadening of the distribution of incidence direction.Comment: 22 pages, 7 figures; accepted for publication in PR

    Wedding Organizer Order Management

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    This information system is used as a solution that can help to meet the requirements of the couples. The research methods are data collection, analysis and design. Data collection method implemented by surveys including interviews with 58 clients, 15 vendors, and 12 WO (Wedding Organizer) and by literature study that includes books and journal related. Object oriented is used as the method for system analysis and design. The result is a web based information system that connects vendors and clients in one online place. The web based application can be used to book the reception hall, catering food for guests, entertainments, bridal, car loan, prewed and receptions photos. The benefits of the web based applications are user can costumize or choose the packages, check the price information and get reports related to Wedding Organizer Order Management business process. The results of the qualitative interviews to 58 clients who already used the applications is the client get shorter time compare to clients who manage their own wedding reception

    Mitochondrial and ribosomal biogenesis are new hallmarks of stemness, oncometabolism and biomass accumulation in cancer : mito-stemness and ribo-stemness features

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    Using proteomics analysis, we previously compared MCF7 breast cancer cells grown as 3D tumor spheres, with the same cell line grown as monolayers. Our results indicated that during 3D anchorage‐independent growth, the cellular machinery associated with i) mitochondrial biogenesis and ii) ribosomal biogenesis, were both significantly increased. Here, for simplicity, we refer to these two new oncogenic hallmarks as “mito‐stemness” and “ribo‐stemness” features. We have now applied this same type of strategy to begin to understand how fibroblasts and MCF7 breast cancer cells change their molecular phenotype, when they are co‐cultured together. We have previously shown that MCF7‐fibroblast co‐cultures are a valuable model of resistance to apoptosis induced by hormonal therapies, such as Tamoxifen and Fulvestrant. Here, we directly show that these mixed co‐cultures demonstrate the induction of mito‐stemness and ribo‐stemness features, likely reflecting a mechanism for cancer cells to increase their capacity for accumulating biomass. In accordance with the onset of a stem‐like phenotype, KRT19 (keratin 19) was induced by ~6‐fold during co‐culture. KRT19 is a well‐established epithelial CSC marker that is used clinically to identify metastatic breast cancer cells in sentinel lymph node biopsies. The potential molecular therapeutic targets that we identified by label‐free proteomics of MCF7‐fibroblast co‐cultures were then independently validated using a bioinformatics approach. More specifically, we employed publically‐available transcriptional profiling data derived from primary tumor samples from breast cancer patients, which were previously subjected to laser‐capture micro‐dissection, to physically separate breast cancer cells from adjacent tumor stroma. This allowed us to directly validate that the proteins up‐regulated in this co‐culture model were also transcriptionally elevated in patient‐derived breast cancer cells in vivo. This powerful approach for target identification and translational validation, including the use of patient outcome data, can now be applied to other tumor types as well, to validate new therapeutic targets that are more clinically relevant, for patient benefit. Moreover, we discuss the therapeutic implications of these findings for new drug development, drug repurposing and Tamoxifen‐resistance, to effectively target mito‐stemness and ribo‐stemness features in breast cancer patients. We also discuss the broad implications of this “organelle biogenesis” approach to cancer therapy

    Deferiprone (DFP) targets cancer stem cell (CSC) propagation by inhibiting mitochondrial metabolism and inducing ROS production

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    Deferiprone (DFP), also known as Ferriprox, is an FDA-approved, orally active, iron chelator that is currently used clinically for the treatment of iron-overload, especially in thalassaemia major. As iron is a critical factor in Fe-S cluster assembly that is absolutely required for the metabolic function of mitochondria, we hypothesized that DFP treatment could be used to selectively target mitochondria in cancer stem cells (CSCs). For this purpose, we used two ER(+) human breast cancer cell lines, namely MCF7 and T47D cells, as model systems. More specifically, a 3D tumorsphere assay was employed as a functional readout of CSC activity which measures anchorage-independent growth under low attachment conditions. Here, we show that DFP dose dependently inhibited the propagation of CSCs, with an IC-50 of ~100 nM for MCF7 and an IC-50 of ~0.5 to 1 ÎŒM for T47D cells, making DFP one the most potent FDA-approved drugs that we and others have thus far identified for targeting CSCs. Mechanistically, we show that high concentrations of DFP metabolically targeted both mitochondrial oxygen consumption (OCR) and glycolysis (extracellular acidification rates (ECAR)) in MCF7 and T47D cell monolayers. Most importantly, we demonstrate that DFP also induced a generalized increase in reactive oxygen species (ROS) and mitochondrial superoxide production, and its effects reverted in the presence of N-acetyl-cysteine (NAC). Therefore, we propose that DFP is a new candidate therapeutic for drug repurposing and for Phase II clinical trials aimed at eradicating CSCs

    Mitochondrial fission as a driver of stemness in tumor cells : mDIVI1 inhibits mitochondrial function, cell migration and cancer stem cell (CSC) signalling

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    Mitochondria are dynamic organelles frequently undergoing fission and fusion events to maintain their integrity, bioenergetics and spatial distribution, which is fundamental to the processes of cell survival. Disruption in mitochondrial dynamics plays a role in cancer. Therefore, proteins involved in regulating mitochondrial dynamics are potential targets for treatment. mDIVI1 is an inhibitor of the mitochondrial fission protein DRP1, which induces i) mitochondrial oxidative stress and ii) effectively reduces mitochondrial metabolism. We show here that mDIVI1 is able to inhibit 3D tumorsphere forming capacity, cell migration and stemness-related signalling in breast cancer cells, indicating that mDIVI1 can potentially be used for the therapeutic elimination of cancer stem cells (CSCs)

    Unusual Medial-End Clavicle Fracture Combined with Double Disruption of the Superior Shoulder Suspensory Complex (SSSC) : A Case Report in Triathlon Athlete

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    Most published floating clavicle report a dislocation or fracture of one or both ends of the clavicle

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

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    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

    Proteomic identification of prognostic tumour biomarkers, using chemotherapy-induced cancer-associated fibroblasts

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    Cancer cells grow in highly complex stromal microenvironments, which through metabolic remodelling, catabolism, autophagy and inflammation nurture them and are able to facilitate metastasis and resistance to therapy. However, these changes in the metabolic profile of stromal cancer-associated fibroblasts and their impact on cancer initiation, progression and metastasis are not well-known. This is the first study to provide a comprehensive proteomic portrait of the azathioprine and taxol-induced catabolic state on human stromal fibroblasts, which comprises changes in the expression of metabolic enzymes, myofibroblastic differentiation markers, antioxidants, proteins involved in autophagy, senescence, vesicle trafficking and protein degradation, and inducers of inflammation. Interestingly, many of these features are major contributors to the aging process. A catabolic stroma signature, generated with proteins found differentially up-regulated in taxol-treated fibroblasts, strikingly correlates with recurrence, metastasis and poor patient survival in several solid malignancies. We therefore suggest the inhibition of the catabolic state in healthy cells as a novel approach to improve current chemotherapy efficacies and possibly avoid future carcinogenic processes
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