Histological evaluation of AMPK signalling in primary breast cancer

International Nuclear Information System (INIS)

Hadad, Sirwan M; Hardie, David G; Fleming, Stewart; Thompson, Alastair M; Baker, Lee; Quinlan, Philip R; Robertson, Katherine E; Bray, Susan E; Thomson, George; Kellock, David; Jordan, Lee B; Purdie, Colin A

2009-01-01

AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge that responds to energy stress by suppressing cell growth and biosynthetic processes, thus ensuring that energy-consuming processes proceed only if there are sufficient metabolic resources. Malfunction of the AMPK pathway may allow cancer cells to undergo uncontrolled proliferation irrespective of their molecular energy levels. The aim of this study was to examine the state of AMPK phosphorylation histologically in primary breast cancer in relation to clinical and pathological parameters. Immunohistochemistry was performed using antibodies to phospho-AMPK (pAMPK), phospho-Acetyl Co-A Carboxylase (pACC) an established target for AMPK, HER2, ERα, and Ki67 on Tissue Micro-Array (TMA) slides of two cohorts of 117 and 237 primary breast cancers. The quick score method was used for scoring and patterns of protein expression were compared with clinical and pathological data, including a minimum 5 years follow up. Reduced signal, compared with the strong expression in normal breast epithelium, using a pAMPK antibody was demonstrated in 101/113 (89.4%) and 217/236 (91.9%) of two cohorts of patients. pACC was significantly associated with pAMPK expression (p = 0.007 & p = 0.014 respectively). For both cohorts, reduced pAMPK signal was significantly associated with higher histological grade (p = 0.010 & p = 0.021 respectively) and axillary node metastasis (p = 0.061 & p = 0.039 respectively). No significant association was found between pAMPK and any of HER2, ERα, or Ki67 expression, disease-free survival or overall survival. This study extends in vitro evidence through immunohistochemistry to confirm that AMPK is dysfunctional in primary breast cancer. Reduced signalling via the AMPK pathway, and the inverse relationship with histological grade and axillary node metastasis, suggests that AMPK re-activation could have therapeutic potential in breast cancer

Activation of the Cph1-dependent MAP kinase signaling pathway induces white-opaque switching in Candida albicans.

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Bernardo Ramírez-Zavala

Full Text Available Depending on the environmental conditions, the pathogenic yeast Candida albicans can undergo different developmental programs, which are controlled by dedicated transcription factors and upstream signaling pathways. C. albicans strains that are homozygous at the mating type locus can switch from the normal yeast form (white to an elongated cell type (opaque, which is the mating-competent form of this fungus. Both white and opaque cells use the Ste11-Hst7-Cek1/Cek2 MAP kinase signaling pathway to react to the presence of mating pheromone. However, while opaque cells employ the transcription factor Cph1 to induce the mating response, white cells recruit a different downstream transcription factor, Tec1, to promote the formation of a biofilm that facilitates mating of opaque cells in the population. The switch from the white to the opaque cell form is itself induced by environmental signals that result in the upregulation of the transcription factor Wor1, the master regulator of white-opaque switching. To get insight into the upstream signaling pathways controlling the switch, we expressed all C. albicans protein kinases from a tetracycline-inducible promoter in a switching-competent strain. Screening of this library of strains showed that a hyperactive form of Ste11 lacking its N-terminal domain (Ste11(ΔN467 efficiently stimulated white cells to switch to the opaque phase, a behavior that did not occur in response to pheromone. Ste11(ΔN467-induced switching specifically required the downstream MAP kinase Cek1 and its target transcription factor Cph1, but not Cek2 and Tec1, and forced expression of Cph1 also promoted white-opaque switching in a Wor1-dependent manner. Therefore, depending on the activation mechanism, components of the pheromone-responsive MAP kinase pathway can be reconnected to stimulate an alternative developmental program, switching of white cells to the mating-competent opaque phase.

CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling.

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Lin, C; Liao, W; Jian, Y; Peng, Y; Zhang, X; Ye, L; Cui, Y; Wang, B; Wu, X; Xiong, Z; Wu, S; Li, J; Wang, X; Song, L

2017-06-29

Metastatic relapse remains largely incurable and a major challenge of clinical management in breast cancer, but the underlying mechanisms are poorly understood. Herein, we report that CGI-99 is overexpressed in breast cancer tissues from patients with metastatic recurrence within 5 years. High CGI-99 significantly predicts poorer 5-year metastasis-free patient survival. We find that CGI-99 increases breast cancer stem cell properties, and potentiates efficient tumor lung colonization and outgrowth in vivo. Furthermore, we demonstrate that CGI-99 activates the autocrine interleukin-6 (IL-6)/STAT3 signaling by increasing the accumulation and activity of RNA polymerase II and p300 cofactor at the proximal promoter of IL-6. Importantly, delivery of the IL-6-receptor humanized monoclonal antibody tocilizumab robustly abrogates CGI-99-induced metastasis in vivo. Finally, we find that high levels of CGI-99 are significantly correlated with STAT3 hyperactivation in breast cancer patients. These findings reveal a potential mechanism for constitutive activation of autocrine IL-6/STAT3 signaling and may suggest a novel target for clinical intervention in breast cancer.

Integrated analysis of breast cancer cell lines reveals unique signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Heiser, Laura M.; Wang, Nicholas J.; Talcott, Carolyn L.; Laderoute, Keith R.; Knapp, Merrill; Guan, Yinghui; Hu, Zhi; Ziyad, Safiyyah; Weber, Barbara L.; Laquerre, Sylvie; Jackson, Jeffrey R.; Wooster, Richard F.; Kuo, Wen-Lin; Gray, Joe W.; Spellman, Paul T.

2009-03-31

Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EGFR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes. We were interested in identifying subnetworks within the EGFR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EGFR-MEK signaling. This model was comprised of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype specific subnetworks, including one that suggested PAK1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that PAK1 overexpressing cell lines would have increased sensitivity to MEK inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three MEK inhibitors. We found that PAK1 over-expressing luminal breast cancer cell lines are significantly more sensitive to MEK inhibition as compared to those that express PAK1 at low levels. This indicates that PAK1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to MEK inhibitors. All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.

Integrated analysis of breast cancer cell lines reveals unique signaling pathways.

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Heiser, Laura M; Wang, Nicholas J; Talcott, Carolyn L; Laderoute, Keith R; Knapp, Merrill; Guan, Yinghui; Hu, Zhi; Ziyad, Safiyyah; Weber, Barbara L; Laquerre, Sylvie; Jackson, Jeffrey R; Wooster, Richard F; Kuo, Wen Lin; Gray, Joe W; Spellman, Paul T

2009-01-01

Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EgfR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes. We were interested in identifying subnetworks within the EgfR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EgfR-MAPK signaling. This model was composed of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype-specific subnetworks, including one that suggested Pak1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that Pak1 over-expressing cell lines would have increased sensitivity to Mek inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three Mek inhibitors. We found that Pak1 over-expressing luminal breast cancer cell lines are significantly more sensitive to Mek inhibition compared to those that express Pak1 at low levels. This indicates that Pak1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to Mek inhibitors. All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.

Estrogen signalling and the DNA damage response in hormone dependent breast cancers

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C Elizabeth Caldon

2014-05-01

Full Text Available Estrogen is necessary for the normal growth and development of breast tissue, but high levels of estrogen are a major risk factor for breast cancer. One mechanism by which estrogen could contribute to breast cancer is via the induction of DNA damage. This perspective discusses the mechanisms by which estrogen alters the DNA damage response (DDR and DNA repair through the regulation of key effector proteins including ATM, ATR, CHK1, BRCA1 and p53 and the feedback on estrogen receptor signalling from these proteins. We put forward the hypothesis that estrogen receptor signalling converges to suppress effective DNA repair and apoptosis in favour of proliferation. This is important in hormone-dependent breast cancer as it will affect processing of estrogen-induced DNA damage, as well as other genotoxic insults. DDR and DNA repair proteins are frequently mutated or altered in estrogen responsive breast cancer which will further change the processing of DNA damage. Finally the action of estrogen signalling on DNA damage is also relevant to the therapeutic setting as the suppression of a DNA damage response by estrogen has the potential to alter the response of cancers to anti-hormone treatment or chemotherapy that induces DNA damage.

cGMP signaling as a target for the prevention and treatment of breast cancer.

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Windham, Perrin F; Tinsley, Heather N

2015-04-01

One in eight women in the United States will be diagnosed with invasive breast cancer in her lifetime. Advances in therapeutic strategies, diagnosis, and improved awareness have resulted in a significant reduction in breast cancer related mortality. However, there is a continued need for more effective and less toxic drugs for both the prevention and the treatment of breast cancer in order to see a continued decline in the morbidity and mortality associated with this disease. Recent studies suggest that the cGMP signaling pathway may be aberrantly regulated in breast cancer. As such, this pathway may serve as a source of novel targets for future breast cancer drug discovery efforts. This review provides an overview of cGMP signaling in normal physiology and in breast cancer as well as current strategies being investigated for targeting this pathway in breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Switch I-dependent allosteric signaling in a G-protein chaperone-B12 enzyme complex.

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Campanello, Gregory C; Lofgren, Michael; Yokom, Adam L; Southworth, Daniel R; Banerjee, Ruma

2017-10-27

G-proteins regulate various processes ranging from DNA replication and protein synthesis to cytoskeletal dynamics and cofactor assimilation and serve as models for uncovering strategies deployed for allosteric signal transduction. MeaB is a multifunctional G-protein chaperone, which gates loading of the active 5'-deoxyadenosylcobalamin cofactor onto methylmalonyl-CoA mutase (MCM) and precludes loading of inactive cofactor forms. MeaB also safeguards MCM, which uses radical chemistry, against inactivation and rescues MCM inactivated during catalytic turnover by using the GTP-binding energy to offload inactive cofactor. The conserved switch I and II signaling motifs used by G-proteins are predicted to mediate allosteric regulation in response to nucleotide binding and hydrolysis in MeaB. Herein, we targeted conserved residues in the MeaB switch I motif to interrogate the function of this loop. Unexpectedly, the switch I mutations had only modest effects on GTP binding and on GTPase activity and did not perturb stability of the MCM-MeaB complex. However, these mutations disrupted multiple MeaB chaperone functions, including cofactor editing, loading, and offloading. Hence, although residues in the switch I motif are not essential for catalysis, they are important for allosteric regulation. Furthermore, single-particle EM analysis revealed, for the first time, the overall architecture of the MCM-MeaB complex, which exhibits a 2:1 stoichiometry. These EM studies also demonstrate that the complex exhibits considerable conformational flexibility. In conclusion, the switch I element does not significantly stabilize the MCM-MeaB complex or influence the affinity of MeaB for GTP but is required for transducing signals between MeaB and MCM. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

A density-dependent switch drives stochastic clustering and polarization of signaling molecules.

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Alexandra Jilkine

2011-11-01

Full Text Available Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered "off" state is desired? And, what limits the spread of clusters when an "on" state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the "neutral drift polarity model." Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization.

PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling.

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Shrestha, Y; Schafer, E J; Boehm, J S; Thomas, S R; He, F; Du, J; Wang, S; Barretina, J; Weir, B A; Zhao, J J; Polyak, K; Golub, T R; Beroukhim, R; Hahn, W C

2012-07-19

Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK MAPK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified p21-activated kinase 1 (PAK1) as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 30--33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation.

Seismic switch for strong motion measurement

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Harben, P.E.; Rodgers, P.W.; Ewert, D.W.

1995-05-30

A seismic switching device is described that has an input signal from an existing microseismic station seismometer and a signal from a strong motion measuring instrument. The seismic switch monitors the signal level of the strong motion instrument and passes the seismometer signal to the station data telemetry and recording systems. When the strong motion instrument signal level exceeds a user set threshold level, the seismometer signal is switched out and the strong motion signal is passed to the telemetry system. The amount of time the strong motion signal is passed before switching back to the seismometer signal is user controlled between 1 and 15 seconds. If the threshold level is exceeded during a switch time period, the length of time is extended from that instant by one user set time period. 11 figs.

Budget Impact Analysis of Switching to Digital Mammography in a Population-Based Breast Cancer Screening Program: A Discrete Event Simulation Model

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Comas, Mercè; Arrospide, Arantzazu; Mar, Javier; Sala, Maria; Vilaprinyó, Ester; Hernández, Cristina; Cots, Francesc; Martínez, Juan; Castells, Xavier

2014-01-01

Objective To assess the budgetary impact of switching from screen-film mammography to full-field digital mammography in a population-based breast cancer screening program. Methods A discrete-event simulation model was built to reproduce the breast cancer screening process (biennial mammographic screening of women aged 50 to 69 years) combined with the natural history of breast cancer. The simulation started with 100,000 women and, during a 20-year simulation horizon, new women were dynamically entered according to the aging of the Spanish population. Data on screening were obtained from Spanish breast cancer screening programs. Data on the natural history of breast cancer were based on US data adapted to our population. A budget impact analysis comparing digital with screen-film screening mammography was performed in a sample of 2,000 simulation runs. A sensitivity analysis was performed for crucial screening-related parameters. Distinct scenarios for recall and detection rates were compared. Results Statistically significant savings were found for overall costs, treatment costs and the costs of additional tests in the long term. The overall cost saving was 1,115,857€ (95%CI from 932,147 to 1,299,567) in the 10th year and 2,866,124€ (95%CI from 2,492,610 to 3,239,638) in the 20th year, representing 4.5% and 8.1% of the overall cost associated with screen-film mammography. The sensitivity analysis showed net savings in the long term. Conclusions Switching to digital mammography in a population-based breast cancer screening program saves long-term budget expense, in addition to providing technical advantages. Our results were consistent across distinct scenarios representing the different results obtained in European breast cancer screening programs. PMID:24832200

RGS16 inhibits breast cancer cell growth by mitigating phosphatidylinositol 3-kinase signaling.

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Liang, Genqing; Bansal, Geetanjali; Xie, Zhihui; Druey, Kirk M

2009-08-07

Aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway supports growth of many tumors including those of breast, lung, and prostate. Resistance of breast cancer cells to targeted chemotherapies including tyrosine kinase inhibitors (TKI) has been linked to persistent PI3K activity, which may in part be due to increased membrane expression of epidermal growth factor (EGF) receptors (HER2 and HER3). Recently we found that proteins of the RGS (regulator of G protein signaling) family suppress PI3K activity downstream of the receptor by sequestering its p85alpha subunit from signaling complexes. Because a substantial percentage of breast tumors have RGS16 mutations and reduced RGS16 protein expression, we investigated the link between regulation of PI3K activity by RGS16 and breast cancer cell growth. RGS16 overexpression in MCF7 breast cancer cells inhibited EGF-induced proliferation and Akt phosphorylation, whereas shRNA-mediated extinction of RGS16 augmented cell growth and resistance to TKI treatment. Exposure to TKI also reduced RGS16 expression in MCF7 and BT474 cell lines. RGS16 bound the amino-terminal SH2 and inter-SH2 domains of p85alpha and inhibited its interaction with the EGF receptor-associated adapter protein Gab1. These results suggest that the loss of RGS16 in some breast tumors enhances PI3K signaling elicited by growth factors and thereby promotes proliferation and TKI evasion downstream of HER activation.

Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.

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Aurélien Naldi

2017-03-01

Full Text Available The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the generation of an interaction-based network of signaling pathways controlled by Syk in breast cancer cells. Pathway enrichment of the Syk targets previously identified by quantitative phospho-proteomics indicated that Syk is engaged in cell adhesion, motility, growth and death. Using the components and interactions of these pathways, we bootstrapped the reconstruction of a comprehensive network covering Syk signaling in breast cancer cells. To generate in silico hypotheses on Syk signaling propagation, we developed a method allowing to rank paths between Syk and its targets. We first annotated the network according to experimental datasets. We then combined shortest path computation with random walk processes to estimate the importance of individual interactions and selected biologically relevant pathways in the network. Molecular and cell biology experiments allowed to distinguish candidate mechanisms that underlie the impact of Syk on the regulation of cortactin and ezrin, both involved in actin-mediated cell adhesion and motility. The Syk network was further completed with the results of our biological validation experiments. The resulting Syk signaling sub-networks can be explored via an online visualization platform.

Tyrosine kinase signalling in breast cancer

International Nuclear Information System (INIS)

Hynes, Nancy E

2000-01-01

Cells are continuously exposed to diverse stimuli ranging from soluble endocrine and paracrine factors to signalling molecules on neighbouring cells. Receptors of the tyrosine kinase family play an important role in the integration and interpretation of these external stimuli, allowing a cell to respond appropriately to its environment. The activation of receptor tyrosine kinases (RTKs) is tightly controlled, allowing a normal cell to correctly integrate its external environment with internal signal transduction pathways. In contrast, due to numerous molecular alterations arising during the course of malignancy, a tumour is characterized by an abnormal response to its environment, which allows cancer cells to evade the normal mechanisms controlling cellular proliferation. Alterations in the expression of various RTKs, in their activation, and in the signalling molecules lying downstream of the receptors play important roles in the development of cancer. This topic is the major focus of the thematic review section of this issue of Breast Cancer Research

STAT3 can be activated through paracrine signaling in breast epithelial cells

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Lieblein, Jacqueline C; Ball, Sarah; Hutzen, Brian; Sasser, A Kate; Lin, Huey-Jen; Huang, Tim HM; Hall, Brett M; Lin, Jiayuh

2008-01-01

Many cancers, including breast cancer, have been identified with increased levels of phosphorylated or the active form of Signal Transducers and Activators of Transcription 3 (STAT3) protein. However, whether the tumor microenvironment plays a role in this activation is still poorly understood. Conditioned media, which contains soluble factors from MDA-MB-231 and MDA-MB-468 breast cancer cells and breast cancer associated fibroblasts, was added to MCF-10A breast epithelial and MDA-MB-453 breast cancer cells. The stimulation of phosphorylated STAT3 (p-STAT3) levels by conditioned media was assayed by Western blot in the presence or absence of neutralized IL-6 antibody, or a JAK/STAT3 inhibitor, JSI-124. The stimulation of cell proliferation in MCF-10A cells by conditioned media in the presence or absence of JSI-124 was subjected to MTT analysis. IL-6, IL-10, and VEGF levels were determined by ELISA analysis. Our results demonstrated that conditioned media from cell lines with constitutively active STAT3 are sufficient to induce p-STAT3 levels in various recipients that do not possess elevated p-STAT3 levels. This signaling occurs through the JAK/STAT3 pathway, leading to STAT3 phosphorylation as early as 30 minutes and is persistent for at least 24 hours. ELISA analysis confirmed a correlation between elevated levels of IL-6 production and p-STAT3. Neutralization of the IL-6 ligand or gp130 was sufficient to block increased levels of p-STAT3 (Y705) in treated cells. Furthermore, soluble factors within the MDA-MB-231 conditioned media were also sufficient to stimulate an increase in IL-6 production from MCF-10A cells. These results demonstrate STAT3 phosphorylation in breast epithelial cells can be stimulated by paracrine signaling through soluble factors from both breast cancer cells and breast cancer associated fibroblasts with elevated STAT3 phosphorylation. The induction of STAT3 phosphorylation is through the IL-6/JAK pathway and appears to be associated with

The Wnt Signaling Landscape of Mammary Stem Cells and Breast Tumors.

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Alexander, Caroline M

2018-01-01

Attention has been focused on Wnt signaling in the mouse mammary gland for several decades, firstly by the discovery of several Wnt loci among the oncogenes revealed by MMTV-based insertional mutagenesis screening of mouse mammary gland, and then by the remarkable visualization of Wnt-dependent specification of mammary placodes in embryonic skin. This review aims to summarize the impact of recent data for our understanding of the roles of Wnt signaling in these roles. The amount and identity of both familiar and novel Wnt signaling components is examined for mouse mammary epithelial cells. The hierarchical arrangement of mammary epithelial cell progenitors and stem cells inferred from the study of isolated cells is reinterpreted in an era that has demonstrated almost limitless cellular plasticity. Functional definitions of stem and progenitor activities are reevaluated with the discovery of novel stem cell activities and regulators, and we draw parallels with the arrangement of replication-competent cells in other tissues. Although Wnt signaling is highly oncogenic for mouse mammary epithelia, the data supporting Wnt signaling as a tumor driver for human breast cancer are still flimsy, and there is little support for the recruitment of normal Wnt-dependent breast stem cells as tumor precursor cells for either mouse or human. We discuss possible explanations for this paradox and questions still unanswered, including the potential impact of recent discoveries of Wnt-secreting microenvironments, oncogenic changes in the Rspo/Lgr/Ubiquitin ligase amplifier complex, as they could apply to breast tissues, and the feedback suppression of Wnt signaling that characterizes its developmental activity and may hide Wnt signatures in tumors. Copyright © 2018 Elsevier Inc. All rights reserved.

Microwave Imaging Using CMOS Integrated Circuits with Rotating 4 × 4 Antenna Array on a Breast Phantom

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Hang Song

2017-01-01

Full Text Available A digital breast cancer detection system using 65 nm technology complementary metal oxide semiconductor (CMOS integrated circuits with rotating 4 × 4 antenna array is presented. Gaussian monocycle pulses are generated by CMOS logic circuits and transmitted by a 4 × 4 matrix antenna array via two CMOS single-pole-eight-throw (SP8T switching matrices. Radar signals are received and converted to digital signals by CMOS equivalent time sampling circuits. By rotating the 4 × 4 antenna array, the reference signal is obtained by averaging the waveforms from various positions to extract the breast phantom target response. A signal alignment algorithm is proposed to compensate the phase shift of the signals caused by the system jitter. After extracting the scattered signal from the target, a bandpass filter is applied to reduce the noise caused by imperfect subtraction between original and the reference signals. The confocal imaging algorithm for rotating antennas is utilized to reconstruct the breast image. A 1 cm3 bacon block as a cancer phantom target in a rubber substrate as a breast fat phantom can be detected with reduced artifacts.

Telocinobufagin inhibits the epithelial-mesenchymal transition of breast cancer cells through the phosphoinositide 3-kinase/protein kinase B/extracellular signal-regulated kinase/Snail signaling pathway.

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Gao, Yuxue; Shi, Lihong; Cao, Zhen; Zhu, Xuetao; Li, Feng; Wang, Ruyan; Xu, Jinyuan; Zhong, Jinyi; Zhang, Baogang; Lu, Shijun

2018-05-01

Telocinobufagin (TBG), an active ingredient of Venenumbufonis , exhibits an immunomodulatory activity. However, its antimetastatic activity in breast cancer remains unknown. The present study investigated whether TBG prevents breast cancer metastasis and evaluated its regulatory mechanism. TBG inhibited the migration and invasion of 4T1 breast cancer cells. Furthermore, TBG triggered the collapse of F-actin filaments in breast cancer. The epithelial-mesenchymal transition (EMT) markers, vimentin and fibronectin, were downregulated following TBG treatment. However, E-cadherin was upregulated following TBG treatment. Snail, a crucial transcriptional factor of EMT, was downregulated following TBG treatment. Signaling pathway markers, including phosphorylated protein kinase B (P-Akt), p-mechanistic target of rapamycin (mTOR) and p-extracellular signal-regulated kinase (ERK), were decreased following TBG treatment. The same results were obtained from in vivo experiments. In conclusion, in vitro and in vivo experiments reveal that TBG inhibited migration, invasion and EMT via the phosphoinositide 3-kinase (PI3K)/Akt/ERK/Snail signaling pathway in breast cancer.

Canonical and Non-Canonical NF-κB Signaling Promotes Breast Cancer Tumor-Initiating Cells

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Kendellen, Megan F.; Bradford, Jennifer W.; Lawrence, Cortney L.; Clark, Kelly S.; Baldwin, Albert S.

2014-01-01

Tumor-initiating cells (TICs) are a sub-population of cells that exhibit a robust ability to self-renew and contribute to the formation of primary tumors, the relapse of previously treated tumors, and the development of metastases. TICs have been identified in various tumors, including those of the breast, and are particularly enriched in the basal-like and claudin-low subtypes of breast cancer. The signaling pathways that contribute to the function and maintenance of TICs are under intense study. We explored the potential involvement of the NF-κB family of transcription factors in TICs in cell lines that are representative of basal-like and claudin-low breast cancer. NF-κB was found to be activated in breast cancer cells that form tumorspheres efficiently. Moreover, both canonical and non-canonical NF-κB signaling is required for these cells to self-renew in vitro and to form xenograft tumors efficiently in vivo using limiting dilutions of cells. Consistent with this, canonical and non-canonical NF-κB signaling is activated in TICs isolated from breast cancer cell lines. Experimental results indicate that NF-κB promotes the function of TICs by stimulating epithelial-to-mesenchymal transition (EMT) and by upregulating the expression of the inflammatory cytokines IL-1β and IL-6. The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers. PMID:23474754

CIRCADIAN REGULATION METABOLIC SIGNALING MECHANISMS OF HUMAN BREAST CANCER GROWTH BY THE NOCTURNAL MELATONIN SIGNAL AND THE CONSEQUENCES OF ITS DISRUPTION BY LIGHT AT NIGHT

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Blask, David E.; Hill, Steven M.; Dauchy, Robert T.; Xiang, Shulin; Yuan, Lin; Duplessis, Tamika; Mao, Lulu; Dauchy, Erin; Sauer, Leonard A.

2011-01-01

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light-at-night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT1-induced activation of Gαi2 signaling and reduction of cAMP levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT1-mediated suppression of cAMP leading to blockade of linoleic acid (LA) uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN. PMID:21605163

Wnt signalling via the epidermal growth factor receptor: a role in breast cancer?

International Nuclear Information System (INIS)

Musgrove, Elizabeth A

2004-01-01

Recent data have suggested the epidermal-growth-factor receptor (EGFR) as a point of convergence for several different classes of receptor. Civenni and colleagues have now demonstrated crosstalk between Wnt signalling and the EGFR, showing that in breast epithelial cells Wnts activate downstream targets of the EGFR, including cyclin D1. Given the role of members of these pathways in the aetiology of breast cancer and as markers of outcome and potential therapeutic targets in breast cancer, this observation has a number of potential implications important for both the basic biology of breast cancer and the clinical management of the disease

Biexponential signal attenuation analysis of diffusion-weighted imaging of breast

International Nuclear Information System (INIS)

Tamura, Takayuki; Naito, Kumiko; Usui, Shuji; Akiyama, Mitoshi; Murakami, Shigeru; Arihiro, Koji; Akiyama, Yuji

2010-01-01

In vivo, the attenuation of diffusion-weighted imaging (DWI) signal at high b-values is sometimes nonlinear when plotted with semilogarithmic function and is fit well by a biexponential function. Previous reports have indicated that the fast and slow component fractions of the apparent diffusion coefficient (ADC) can be derived by biexponential fitting and that these fractions correspond to the actual diffusion components in the extra- and intracellular space. In this study, we investigated the clinical utility of DWI for the breast by performing DWI using multiple b-factors on healthy volunteers and clinical subjects, analyzing the signal by fitting it with a biexponential equation, and comparing the fitting parameters of breast lesions. We investigated 8 healthy women as normal cases and 80 female patients with a total of 100 breast tumors (42 benign, 58 malignant tumors) as clinical cases. We performed DWI using 12 b-values for the healthy cases and 6 b-values for the clinical cases, up to a maximum b-value of 3500 s/mm 2 . Decay of DWI signal of normal mammary glands, most cysts, and some fibroadenomas showed a monoexponential relationship, and conversely, that of intraductal papilloma (IDP) and malignant tumors was well fitted by a biexponential function. Comparison of parameters derived from biexponential fitting demonstrated no significant difference between benign and malignant lesions. For malignant tumor subtype, the fast component fraction of noninvasive ductal carcinoma was statistically greater than that of invasive ductal carcinoma. Although the parameters from biexponential fitting may reflect the character of tumor cellularity, because pathological diagnosis was performed with an emphasis on cell configuration or shape rather than cellularity, it was difficult to distinguish malignant from benign tumors, including many IDPs, or to distinguish tissue types using DWI signal attenuation alone. (author)

Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival.

Science.gov (United States)

Maiti, Aparna; Takabe, Kazuaki; Hait, Nitai C

2017-04-01

About 40,000 American women die from metastatic breast cancer each year despite advancements in treatment. Approximately, 15% of breast cancers are triple-negative for estrogen receptor, progesterone receptor, and HER2. Triple-negative cancer is characterized by more aggressive, harder to treat with conventional approaches and having a greater possibility of recurrence. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid signaling mediator has emerged as a key regulatory molecule in breast cancer progression. Therefore, we investigated whether cytosolic sphingosine kinase type 1 (SphK1) and nuclear sphingosine kinase type 2 (SphK2), the enzymes that make S1P are critical for growth and PI3K/AKT, ERK-MAP kinase mediated survival signaling of lung metastatic variant LM2-4 breast cancer cells, generated from the parental triple-negative MDA-MB-231 human breast cancer cell line. Similar with previous report, SphKs/S1P signaling is critical for the growth and survival of estrogen receptor positive MCF-7 human breast cancer cells, was used as our study control. MDA-MB-231 did not show a significant effect of SphKs/S1P signaling on AKT, ERK, and p38 pathways. In contrast, LM2-4 cells that gained lung metastatic phenotype from primary MDA-MB-231 cells show a significant effect of SphKs/S1P signaling requirement on cell growth, survival, and cell motility. PF-543, a selective potent inhibitor of SphK1, attenuated epidermal growth factor (EGF)-mediated cell growth and survival signaling through inhibition of AKT, ERK, and p38 MAP kinase pathways mainly in LM2-4 cells but not in parental MDA-MB-231 human breast cancer cells. Moreover, K-145, a selective inhibitor of SphK2, markedly attenuated EGF-mediated cell growth and survival of LM2-4 cells. We believe this study highlights the importance of SphKs/S1P signaling in metastatic triple-negative breast cancers and targeted therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Traffic analysis and signal processing in optical packet switched networks

DEFF Research Database (Denmark)

Fjelde, Tina

2002-01-01

/s optical packet switched network exploiting the best of optics and electronics, is used as a thread throughout the thesis. An overview of the DAVID network architecture is given, focussing on the MAN and WAN architecture as well as the MPLS-based network hierarchy. Subsequently, the traffic performance...... of the DAVID core optical packet router, which exploits wavelength conversion and fibre delay-line buffers for contention resolution, is analysed using a numerical model developed for that purpose. The robustness of the shared recirculating loop buffer with respect to´bursty traffic is demonstrated...... the injection of an additional clock signal into the IWC is presented. Results show very good transmission capabilities combined with a high-speed response. It is argued that signal regeneration is an inherent attribute of the IWC employed as a wavelength converter due to the sinusoidal transfer function...

Exciter switch

Science.gov (United States)

Mcpeak, W. L.

1975-01-01

A new exciter switch assembly has been installed at the three DSN 64-m deep space stations. This assembly provides for switching Block III and Block IV exciters to either the high-power or 20-kW transmitters in either dual-carrier or single-carrier mode. In the dual-carrier mode, it provides for balancing the two drive signals from a single control panel located in the transmitter local control and remote control consoles. In addition to the improved switching capabilities, extensive monitoring of both the exciter switch assembly and Transmitter Subsystem is provided by the exciter switch monitor and display assemblies.

PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling

OpenAIRE

Shrestha, Yashaswi; Schafer, Eric J.; Boehm, Jesse S.; Thomas, Sapana R.; He, Frank; Du, Jinyan; Wang, Shumei; Barretina, Jordi; Weir, Barbara A.; Zhao, Jean J.; Polyak, Kornelia; Golub, Todd R.; Beroukhim, Rameen; Hahn, William C.

2011-01-01

Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK Mitogen-Activated Protein Kinase (MAPK) pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce ...

Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling

Science.gov (United States)

XIE, GUI'E; YU, XINPEI; LIANG, HUICHAO; CHEN, JINGSONG; TANG, XUEWEI; WU, SHAOQING; LIAO, CAN

2016-01-01

Breast cancer remains a major public health problem worldwide. Chemotherapy serves an important role in the treatment of breast cancer. However, resistance to chemotherapeutic agents, in particular, multi-drug resistance (MDR), is a major cause of treatment failure in cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. Pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, has been shown to possess antitumor, anti-inflammatory, antioxidant and insecticidal properties. The aim of the present study was to investigate whether pristimerin can override chemoresistance in MCF-7/adriamycin (ADR)-resistant human breast cancer cells. The results demonstrated that pristimerin indeed displayed potent cytocidal effect on multidrug-resistant MCF-7/ADR breast cancer cells, and that these effects occurred through the suppression of Akt signaling, which in turn led to the downregulation of antiapoptotic effectors and increased apoptosis. These findings indicate that use of pristimerin may represent a potentially promising approach for the treatment of ADR-resistant breast cancer. PMID:27123073

Synchronization Between Two Different Switched Chaotic Systems By Switching Control

Directory of Open Access Journals (Sweden)

Du Li Ming

2016-01-01

Full Text Available This paper is concerned with the synchronization problem of two different switched chaotic systems, considering the general case that the master-slave switched chaotic systems have uncertainties. Two basic problems are considered: one is projective synchronization of switched chaotic systems under arbitrary switching; the other is projective synchronization of switched chaotic systems by design of switching when synchronization cannot achieved by using any subsystems alone. For the two problems, common Lyapunov function method and multiple Lyapunov function method are used respectively, an adaptive control scheme has been presented, some sufficient synchronization conditions are attainted, and the switching signal is designed. Finally, the numerical simulation is provide to show the effectiveness of our method.

Optimal algorithm switching for the estimation of systole period from cardiac microacceleration signals (SonR).

Science.gov (United States)

Giorgis, L; Frogerais, P; Amblard, A; Donal, E; Mabo, P; Senhadji, L; Hernández, A I

2012-11-01

Previous studies have shown that cardiac microacceleration signals, recorded either cutaneously, or embedded into the tip of an endocardial pacing lead, provide meaningful information to characterize the cardiac mechanical function. This information may be useful to personalize and optimize the cardiac resynchronization therapy, delivered by a biventricular pacemaker, for patients suffering from chronic heart failure (HF). This paper focuses on the improvement of a previously proposed method for the estimation of the systole period from a signal acquired with a cardiac microaccelerometer (SonR sensor, Sorin CRM SAS, France). We propose an optimal algorithm switching approach, to dynamically select the best configuration of the estimation method, as a function of different control variables, such as the signal-to-noise ratio or heart rate. This method was evaluated on a database containing recordings from 31 patients suffering from chronic HF and implanted with a biventricular pacemaker, for which various cardiac pacing configurations were tested. Ultrasound measurements of the systole period were used as a reference and the improved method was compared with the original estimator. A reduction of 11% on the absolute estimation error was obtained for the systole period with the proposed algorithm switching approach.

Autoinhibition and signaling by the switch II motif in the G-protein chaperone of a radical B12 enzyme.

Science.gov (United States)

Lofgren, Michael; Koutmos, Markos; Banerjee, Ruma

2013-10-25

MeaB is an accessory GTPase protein involved in the assembly, protection, and reactivation of 5'-deoxyadenosyl cobalamin-dependent methylmalonyl-CoA mutase (MCM). Mutations in the human ortholog of MeaB result in methylmalonic aciduria, an inborn error of metabolism. G-proteins typically utilize conserved switch I and II motifs for signaling to effector proteins via conformational changes elicited by nucleotide binding and hydrolysis. Our recent discovery that MeaB utilizes an unusual switch III region for bidirectional signaling with MCM raised questions about the roles of the switch I and II motifs in MeaB. In this study, we addressed the functions of conserved switch II residues by performing alanine-scanning mutagenesis. Our results demonstrate that the GTPase activity of MeaB is autoinhibited by switch II and that this loop is important for coupling nucleotide-sensitive conformational changes in switch III to elicit the multiple chaperone functions of MeaB. Furthermore, we report the structure of MeaB·GDP crystallized in the presence of AlFx(-) to form the putative transition state analog, GDP·AlF4(-). The resulting crystal structure and its comparison with related G-proteins support the conclusion that the catalytic site of MeaB is incomplete in the absence of the GTPase-activating protein MCM and therefore unable to stabilize the transition state analog. Favoring an inactive conformation in the absence of the client MCM protein might represent a strategy for suppressing the intrinsic GTPase activity of MeaB in which the switch II loop plays an important role.

Identification and analysis of signaling networks potentially involved in breast carcinoma metastasis to the brain.

Directory of Open Access Journals (Sweden)

Feng Li

Full Text Available Brain is a common site of breast cancer metastasis associated with significant neurologic morbidity, decreased quality of life, and greatly shortened survival. However, the molecular and cellular mechanisms underpinning brain colonization by breast carcinoma cells are poorly understood. Here, we used 2D-DIGE (Difference in Gel Electrophoresis proteomic analysis followed by LC-tandem mass spectrometry to identify the proteins differentially expressed in brain-targeting breast carcinoma cells (MB231-Br compared with parental MDA-MB-231 cell line. Between the two cell lines, we identified 12 proteins consistently exhibiting greater than 2-fold (p<0.05 difference in expression, which were associated by the Ingenuity Pathway Analysis (IPA with two major signaling networks involving TNFα/TGFβ-, NFκB-, HSP-70-, TP53-, and IFNγ-associated pathways. Remarkably, highly related networks were revealed by the IPA analysis of a list of 19 brain-metastasis-associated proteins identified recently by the group of Dr. A. Sierra using MDA-MB-435-based experimental system (Martin et al., J Proteome Res 2008 7:908-20, or a 17-gene classifier associated with breast cancer brain relapse reported by the group of Dr. J. Massague based on a microarray analysis of clinically annotated breast tumors from 368 patients (Bos et al., Nature 2009 459: 1005-9. These findings, showing that different experimental systems and approaches (2D-DIGE proteomics used on brain targeting cell lines or gene expression analysis of patient samples with documented brain relapse yield highly related signaling networks, suggest strongly that these signaling networks could be essential for a successful colonization of the brain by metastatic breast carcinoma cells.

Analysis of the Degradation of MOSFETs in Switching Mode Power Supply by Characterizing Source Oscillator Signals

Directory of Open Access Journals (Sweden)

Xueyan Zheng

2013-01-01

Full Text Available Switching Mode Power Supply (SMPS has been widely applied in aeronautics, nuclear power, high-speed railways, and other areas related to national strategy and security. The degradation of MOSFET occupies a dominant position in the key factors affecting the reliability of SMPS. MOSFETs are used as low-voltage switches to regulate the DC voltage in SMPS. The studies have shown that die-attach degradation leads to an increase in on-state resistance due to its dependence on junction temperature. On-state resistance is the key indicator of the health of MOSFETs. In this paper, an online real-time method is presented for predicting the degradation of MOSFETs. First, the relationship between an oscillator signal of source and on-state resistance is introduced. Because oscillator signals change when they age, a feature is proposed to capture these changes and use them as indicators of the state of health of MOSFETs. A platform for testing characterizations is then established to monitor oscillator signals of source. Changes in oscillator signal measurement were observed with aged on-state resistance as a result of die-attach degradation. The experimental results demonstrate that the method is efficient. This study will enable a method to predict the failure of MOSFETs to be developed.

Global identification of genes regulated by estrogen signaling and demethylation in MCF-7 breast cancer cells

Energy Technology Data Exchange (ETDEWEB)

Putnik, Milica, E-mail: milica.putnik@ki.se [Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge S-14183 (Sweden); Zhao, Chunyan, E-mail: chunyan.zhao@ki.se [Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge S-14183 (Sweden); Gustafsson, Jan-Ake, E-mail: jan-ake.gustafsson@ki.se [Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge S-14183 (Sweden); Department of Biology and Biochemistry, Science and Engineering Research Center Bldg, University of Houston, Houston, TX 77204-5056 (United States); Dahlman-Wright, Karin, E-mail: karin.dahlman-wright@ki.se [Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge S-14183 (Sweden)

2012-09-14

Highlights: Black-Right-Pointing-Pointer Estrogen signaling and demethylation can both control gene expression in breast cancers. Black-Right-Pointing-Pointer Cross-talk between these mechanisms is investigated in human MCF-7 breast cancer cells. Black-Right-Pointing-Pointer 137 genes are influenced by both 17{beta}-estradiol and demethylating agent 5-aza-2 Prime -deoxycytidine. Black-Right-Pointing-Pointer A set of genes is identified as targets of both estrogen signaling and demethylation. Black-Right-Pointing-Pointer There is no direct molecular interplay of mediators of estrogen and epigenetic signaling. -- Abstract: Estrogen signaling and epigenetic modifications, in particular DNA methylation, are involved in regulation of gene expression in breast cancers. Here we investigated a potential regulatory cross-talk between these two pathways by identifying their common target genes and exploring underlying molecular mechanisms in human MCF-7 breast cancer cells. Gene expression profiling revealed that the expression of approximately 140 genes was influenced by both 17{beta}-estradiol (E2) and a demethylating agent 5-aza-2 Prime -deoxycytidine (DAC). Gene ontology (GO) analysis suggests that these genes are involved in intracellular signaling cascades, regulation of cell proliferation and apoptosis. Based on previously reported association with breast cancer, estrogen signaling and/or DNA methylation, CpG island prediction and GO analysis, we selected six genes (BTG3, FHL2, PMAIP1, BTG2, CDKN1A and TGFB2) for further analysis. Tamoxifen reverses the effect of E2 on the expression of all selected genes, suggesting that they are direct targets of estrogen receptor. Furthermore, DAC treatment reactivates the expression of all selected genes in a dose-dependent manner. Promoter CpG island methylation status analysis revealed that only the promoters of BTG3 and FHL2 genes are methylated, with DAC inducing demethylation, suggesting DNA methylation directs repression of

Global identification of genes regulated by estrogen signaling and demethylation in MCF-7 breast cancer cells

International Nuclear Information System (INIS)

Putnik, Milica; Zhao, Chunyan; Gustafsson, Jan-Åke; Dahlman-Wright, Karin

2012-01-01

Highlights: ► Estrogen signaling and demethylation can both control gene expression in breast cancers. ► Cross-talk between these mechanisms is investigated in human MCF-7 breast cancer cells. ► 137 genes are influenced by both 17β-estradiol and demethylating agent 5-aza-2′-deoxycytidine. ► A set of genes is identified as targets of both estrogen signaling and demethylation. ► There is no direct molecular interplay of mediators of estrogen and epigenetic signaling. -- Abstract: Estrogen signaling and epigenetic modifications, in particular DNA methylation, are involved in regulation of gene expression in breast cancers. Here we investigated a potential regulatory cross-talk between these two pathways by identifying their common target genes and exploring underlying molecular mechanisms in human MCF-7 breast cancer cells. Gene expression profiling revealed that the expression of approximately 140 genes was influenced by both 17β-estradiol (E2) and a demethylating agent 5-aza-2′-deoxycytidine (DAC). Gene ontology (GO) analysis suggests that these genes are involved in intracellular signaling cascades, regulation of cell proliferation and apoptosis. Based on previously reported association with breast cancer, estrogen signaling and/or DNA methylation, CpG island prediction and GO analysis, we selected six genes (BTG3, FHL2, PMAIP1, BTG2, CDKN1A and TGFB2) for further analysis. Tamoxifen reverses the effect of E2 on the expression of all selected genes, suggesting that they are direct targets of estrogen receptor. Furthermore, DAC treatment reactivates the expression of all selected genes in a dose-dependent manner. Promoter CpG island methylation status analysis revealed that only the promoters of BTG3 and FHL2 genes are methylated, with DAC inducing demethylation, suggesting DNA methylation directs repression of these genes in MCF-7 cells. In a further analysis of the potential interplay between estrogen signaling and DNA methylation, E2 treatment

Global characterization of signalling networks associated with tamoxifen resistance in breast cancer

DEFF Research Database (Denmark)

Browne, Brigid C.; Hochgräfe, Falko; Wu, Jianmin

2013-01-01

R cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin‐binding protein myristoylated alanine‐rich C‐kinase substrate (MARCKS) were increased two‐ and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in Tam......Acquired resistance to the anti‐estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen‐resistant MCF7 breast cancer cells (Tam...... was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell–cell and cell matrix‐initiated signalling. Consistent with known roles for Ras/MAPK and PI3‐kinase signalling in tamoxifen resistance, tyrosine‐phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in Tam...

3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response.

Science.gov (United States)

Gangadhara, Sharath; Smith, Chris; Barrett-Lee, Peter; Hiscox, Stephen

2016-06-01

The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. A 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting. Breast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response. These data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.

Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer

Science.gov (United States)

Banerji, Christopher R. S.; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E.

2015-01-01

The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample’s genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID:25793737

Intra-tumour signalling entropy determines clinical outcome in breast and lung cancer.

Directory of Open Access Journals (Sweden)

Christopher R S Banerji

2015-03-01

Full Text Available The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample's genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers.

SOX1 links the function of neural patterning and Notch signalling in the ventral spinal cord during the neuron-glial fate switch

Energy Technology Data Exchange (ETDEWEB)

Genethliou, Nicholas; Panayiotou, Elena [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Department of Biological Sciences, University of Cyprus, P.O. Box 20537, 1678 Nicosia (Cyprus); Panayi, Helen; Orford, Michael; Mean, Richard; Lapathitis, George; Gill, Herman; Raoof, Sahir [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Gasperi, Rita De; Elder, Gregory [James J. Peters VA Medical Center, Research and Development (3F22), 130 West Kingsbridge Road, Bronx, NY 10468 (United States); Kessaris, Nicoletta; Richardson, William D. [Wolfson Institute for Biomedical Research and Research Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT (United Kingdom); Malas, Stavros, E-mail: smalas@cing.ac.cy [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Department of Biological Sciences, University of Cyprus, P.O. Box 20537, 1678 Nicosia (Cyprus)

2009-12-25

During neural development the transition from neurogenesis to gliogenesis, known as the neuron-glial ({Nu}/G) fate switch, requires the coordinated function of patterning factors, pro-glial factors and Notch signalling. How this process is coordinated in the embryonic spinal cord is poorly understood. Here, we demonstrate that during the N/G fate switch in the ventral spinal cord (vSC) SOX1 links the function of neural patterning and Notch signalling. We show that, SOX1 expression in the vSC is regulated by PAX6, NKX2.2 and Notch signalling in a domain-specific manner. We further show that SOX1 regulates the expression of Hes1 and that loss of Sox1 leads to enhanced production of oligodendrocyte precursors from the pMN. Finally, we show that Notch signalling functions upstream of SOX1 during this fate switch and is independently required for the acquisition of the glial fate perse by regulating Nuclear Factor I A expression in a PAX6/SOX1/HES1/HES5-independent manner. These data integrate functional roles of neural patterning factors, Notch signalling and SOX1 during gliogenesis.

MR diffusion weighted imaging with background signal suppression in breast cancer

International Nuclear Information System (INIS)

Li Ming; Zhang Bing; Zhou Zhengyang; Yu Haiping; Yuan Lei; Zhu Bin

2009-01-01

Objective: To explore the feasibility of echo planar imaging with short time inversion recovery (STIR-EPI) diffusion weighted imaging with background signal (DWIBS) suppression in breast cancer. Methods: The diffusion weighted imaging (DWI)with background suppression (b=800 mm 2 /s) was performed in 26 patients with breast cancer. Apparent diffusion coefficient(ADC) of all lesions were measured and compared. 3D maximum intensity projection (3D-MIP)and reverse black and white technique were used to show the lesions. DWI and DWIBS were performed and compared for the detection of breast cancer. Randomized blocks analysis of variance was used for the ADC values in different breast tissues, the ADC values in breast cancer and benign lesion were compared using t test. The paired chi square test was used for the detection rate of breast cancer in two different imaging methods. Results: Most of the breast cancers were hyperintense on DWI (b=800 mm 2 /s). The ADC value of cancer tissue was (0.93±0.25) x 10 -3 mm 2 /s, tumor necrosis was (2.06±0.17) x 10 -3 mm 2 /s, normal breast tissue was (1.92±0.23) x 10 -3 mm 2 /s and metastatic lymph node was (1.10±0.14) x 10 -3 mm 2 /s and the differences were statistically significant between two structures (P 2 =8.307, P 2 = 12.235, P -3 mm 2 /s and benign lesion (2.15±0.53) x 10 -3 mm 2 /s had significant statistical differences (t=8.626,P<0.05). Conclusion: Diffusion weighted MRI with background suppression can detect more lesions than DWI and can be potentially applied for the detection of the breast cancer combining the ADC value. (authors)

Snail/beta-catenin signaling protects breast cancer cells from hypoxia attack

Energy Technology Data Exchange (ETDEWEB)

Scherbakov, Alexander M., E-mail: alex.scherbakov@gmail.com [Laboratory of Clinical Biochemistry, Institute of Clinical Oncology, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478 (Russian Federation); Stefanova, Lidia B.; Sorokin, Danila V.; Semina, Svetlana E. [Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478 (Russian Federation); Berstein, Lev M. [Laboratory of Oncoendocrinology, N.N. Petrov Research Institute of Oncology, St. Petersburg 197758 (Russian Federation); Krasil’nikov, Mikhail A. [Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478 (Russian Federation)

2013-12-10

The tolerance of cancer cells to hypoxia depends on the combination of different factors – from increase of glycolysis (Warburg Effect) to activation of intracellular growth/apoptotic pathways. Less is known about the influence of epithelial–mesenchymal transition (EMT) and EMT-associated pathways on the cell sensitivity to hypoxia. The aim of this study was to explore the role of Snail signaling, one of the key EMT pathways, in the mediating of hypoxia response and regulation of cell sensitivity to hypoxia, using as a model in vitro cultured breast cancer cells. Earlier we have shown that estrogen-independent HBL-100 breast cancer cells differ from estrogen-dependent MCF-7 cells with increased expression of Snail1, and demonstrated Snail1 involvement into formation of hormone-resistant phenotype. Because Snail1 belongs to hypoxia-activated proteins, here we studied the influence of Snail1 signaling on the cell tolerance to hypoxia. We found that Snail1-enriched HBL-100 cells were less sensitive to hypoxia-induced growth suppression if compared with MCF-7 line (31% MCF-7 vs. 71% HBL-100 cell viability after 1% O{sub 2} atmosphere for 3 days). Snail1 knock-down enhanced the hypoxia-induced inhibition of cell proliferation giving the direct evidence of Snail1 involvement into cell protection from hypoxia attack. The protective effect of Snail1 was shown to be mediated, at least in a part, via beta-catenin which positively regulated expression of HIF-1-dependent genes. Finally, we found that cell tolerance to hypoxia was accompanied with the failure in the phosphorylation of AMPK – the key energy sensor, and demonstrated an inverse relationship between AMPK and Snail/beta-catenin signaling. Totally, our data show that Snail1 and beta-catenin, besides association with loss of hormone dependence, protect cancer cells from hypoxia and may serve as an important target in the treatment of breast cancer. Moreover, we suggest that the level of these proteins as well

Progesterone receptors (PR) mediate STAT actions: PR and prolactin receptor signaling crosstalk in breast cancer models.

Science.gov (United States)

Leehy, Katherine A; Truong, Thu H; Mauro, Laura J; Lange, Carol A

2018-02-01

Estrogen is the major mitogenic stimulus of mammary gland development during puberty wherein ER signaling acts to induce abundant PR expression. PR signaling, in contrast, is the primary driver of mammary epithelial cell proliferation in adulthood. The high circulating levels of progesterone during pregnancy signal through PR, inducing expression of the prolactin receptor (PRLR). Cooperation between PR and prolactin (PRL) signaling, via regulation of downstream components in the PRL signaling pathway including JAKs and STATs, facilitates the alveolar morphogenesis observed during pregnancy. Indeed, these pathways are fully integrated via activation of shared signaling pathways (i.e. JAKs, MAPKs) as well as by the convergence of PRs and STATs at target genes relevant to both mammary gland biology and breast cancer progression (i.e. proliferation, stem cell outgrowth, tissue cell type heterogeneity). Thus, rather than a single mediator such as ER, transcription factor cascades (ER>PR>STATs) are responsible for rapid proliferative and developmental programming in the normal mammary gland. It is not surprising that these same mediators typify uncontrolled proliferation in a majority of breast cancers, where ER and PR are most often co-expressed and may cooperate to drive malignant tumor progression. This review will primarily focus on the integration of PR and PRL signaling in breast cancer models and the importance of this cross-talk in cancer progression in the context of mammographic density. Components of these PR/PRL signaling pathways could offer alternative drug targets and logical complements to anti-ER or anti-estrogen-based endocrine therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Wireless Nanoionic-Based Radio Frequency Switch

Science.gov (United States)

Nessel, James A. (Inventor); Miranda, Felix A (Inventor)

2017-01-01

A nanoionic switch connected to one or more rectenna modules is disclosed. The rectenna module is configured to receive a wireless signal and apply a first bias to change a state of the nanoionic switch from a first state to a second state. The rectenna module can receive a second wireless signal and apply a second bias to change the nanoionic switch from the second state back to the first state. The first bias is generally opposite of the first bias. The rectenna module accordingly permits operation of the nanoionic switch without onboard power.

160-Gb/s Silicon All-Optical Packet Switch for Buffer-less Optical Burst Switching

DEFF Research Database (Denmark)

Hu, Hao; Ji, Hua; Pu, Minhao

2015-01-01

We experimentally demonstrate a 160-Gb/s Ethernet packet switch using an 8.6-mm-long silicon nanowire for optical burst switching, based on cross phase modulation in silicon. One of the four packets at the bit rate of 160 Gb/s is switched by an optical control signal using a silicon based 1 × 1 all......-optical packet switch. Error free performance (BER silicon packet switch based optical burst switching, which might be desirable for high-speed interconnects within a short...

Methods of Cell Propulsion through the Local Stroma in Breast Cancer

Directory of Open Access Journals (Sweden)

Kerry J. Davies

2014-01-01

Full Text Available In the normal breast, cellular structures change cyclically in response to ovarian hormones. Cell proliferation, apoptosis, invasion, and differentiation are integral processes that are precisely regulated. Normal epithelial cells depend on the formation of intercellular adhesion contacts to form a continuous sheet of stratifying cell layers that are attached to one and other horizontally and vertically. Cells migrate by extending membrane protrusions to explore the extracellular space locating their targets in a chemotactic manner. The formation of cell protrusions is driven by the assembly of actin filaments at the leading edge. Reorganisation is regulated by a highly integrated signalling cascade that transduces extracellular stimuli to the actin filaments. This signalling cascade is governed by GTPases which act as molecular switches leading to actin polymerisation and the formation of filopodia and lamellipodia. This process is linked to downstream molecules known collectively as WASP proteins, which, in the presence of cortactin, form a complex leading to nucleation and formation of branched filaments. In breast cancer, the cortactin is over expressed leading to increased cellular motility and invasiveness. This hugely complex and integrated signalling cascade transduces extracellular stimuli. There are multiple genes related to cell motility which are dysregulated in human breast cancers.

WW domain-binding protein 2: an adaptor protein closely linked to the development of breast cancer.

Science.gov (United States)

Chen, Shuai; Wang, Han; Huang, Yu-Fan; Li, Ming-Li; Cheng, Jiang-Hong; Hu, Peng; Lu, Chuan-Hui; Zhang, Ya; Liu, Na; Tzeng, Chi-Meng; Zhang, Zhi-Ming

2017-07-19

The WW domain is composed of 38 to 40 semi-conserved amino acids shared with structural, regulatory, and signaling proteins. WW domain-binding protein 2 (WBP2), as a binding partner of WW domain protein, interacts with several WW-domain-containing proteins, such as Yes kinase-associated protein (Yap), paired box gene 8 (Pax8), WW-domain-containing transcription regulator protein 1 (TAZ), and WW-domain-containing oxidoreductase (WWOX) through its PPxY motifs within C-terminal region, and further triggers the downstream signaling pathway in vitro and in vivo. Studies have confirmed that phosphorylated form of WBP2 can move into nuclei and activate the transcription of estrogen receptor (ER) and progesterone receptor (PR), whose expression were the indicators of breast cancer development, indicating that WBP2 may participate in the progression of breast cancer. Both overexpression of WBP2 and activation of tyrosine phosphorylation upregulate the signal cascades in the cross-regulation of the Wnt and ER signaling pathways in breast cancer. Following the binding of WBP2 to the WW domain region of TAZ which can accelerate migration, invasion and is required for the transformed phenotypes of breast cancer cells, the transformation of epithelial to mesenchymal of MCF10A is activated, suggesting that WBP2 is a key player in regulating cell migration. When WBP2 binds with WWOX, a tumor suppressor, ER transactivation and tumor growth can be suppressed. Thus, WBP2 may serve as a molecular on/off switch that controls the crosstalk between E2, WWOX, Wnt, TAZ, and other oncogenic signaling pathways. This review interprets the relationship between WBP2 and breast cancer, and provides comprehensive views about the function of WBP2 in the regulation of the pathogenesis of breast cancer and endocrine therapy in breast cancer treatment.

Multi-Channel Data Recording of Marx switch closures

International Nuclear Information System (INIS)

Lockwood, G.J.; Ruggles, L.E.; Ziska, G.R.

1984-01-01

The authors have measured the optical signals associated with switch closure on the Demon marx at Sandia National Laboratories. Using the High Speed Multi-Channel Data Recorder(HSMCDR), they have recorded the time histories of the optical signals from the thirty switches in the marx generator. All thirty switches were fiber connected to the HSMCDR. The HSMCDR consists of a high speed streak camera, and a microcomputer-based video digitizing system. Since the thirty signals are recorded on a single streak, the time sequence can be determined with great accuracy. The appearance of a given signal can be determined to within two samples of the 256 samples that make up the time streak. The authors have found that the light intensity and time history of any given switch varied over a large range from shot to shot. Thus, the ability to record the entire optical signal as a function of time for each switch on every shot is necessary if accurate timing results are required

Bootstrapped Low-Voltage Analog Switches

DEFF Research Database (Denmark)

Steensgaard-Madsen, Jesper

1999-01-01

Novel low-voltage constant-impedance analog switch circuits are proposed. The switch element is a single MOSFET, and constant-impedance operation is obtained using simple circuits to adjust the gate and bulk voltages relative to the switched signal. Low-voltage (1-volt) operation is made feasible...

Oridonin inhibits breast cancer growth and metastasis through blocking the Notch signaling

Directory of Open Access Journals (Sweden)

Shixin Xia

2017-05-01

Full Text Available Background: Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to inhibit growth and metastasis of human breast cancer cells. Methods: The effect of oridonin on proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in human breast cancer cells. The inhibitive effect of oridonin in vivo was determined by using xenografted nude mice. In addition, the expression of Notch receptors (Notch 1–4 was detected by western blot. Results: Oridonin inhibited human breast cancer cells in vitro and in vivo. In addition, oridonin significantly induced human breast cancer cells apoptosis. Furthermore, the oridonin treatment not only inhibited cancer cell migration and invasion, but more significantly, decreased the expression of Notch 1-4 protein. Conclusion: Our results suggest that the inhibitive effect of oridonin is likely to be driven by the inhibition of Notch signaling pathway and the resulting increased apoptosis.

4-tert-Octylphenol stimulates the expression of cathepsins in human breast cancer cells and xenografted breast tumors of a mouse model via an estrogen receptor-mediated signaling pathway

International Nuclear Information System (INIS)

Lee, Hye-Rim; Choi, Kyung-Chul

2013-01-01

Highlights: ► Cathepsins B and D were markedly enhanced by octylphenol (OP) in MCF-7 cells. ► OP may accelerate breast cancer cell growth and cathepsins via ER-mediated signaling. ► Breast cancer cells exposed with OP to mouse model were more aggressive. ► OP can promote metastasis through the amplification of cathepsins B and D via ER-mediated signaling pathway. -- Abstract: Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48 h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERα. In conclusion, our findings suggest that OP at 10 −6 M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of

GPER1-mediated IGFBP-1 induction modulates IGF-1-dependent signaling in tamoxifen-treated breast cancer cells.

Science.gov (United States)

Vaziri-Gohar, Ali; Houston, Kevin D

2016-02-15

Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant therapy for estrogen receptor-α (ERα)-positive breast cancer patients. To determine if extracellular factors contribute to the modulation of IGF-1 signaling after tamoxifen treatment, MCF-7 cells were treated with IGF-1 in conditioned medium (CM) obtained from 4-OHT-treated MCF-7 cells and the accumulation of phospho-Akt (S473) was measured. CM inhibited IGF-1-dependent cell signaling and suggesting the involvement of extracellular factors (ie. IGFBPs). A significant increase in IGFBP-1 mRNA and extracellular IGFBP-1 protein was observed in 4-OHT-treated MCF-7 cells. Knockdown experiments demonstrated that both GPER1 and CREB mediate IGFBP-1 induction. Furthermore, experiments showed that 4-OHT-dependent IGFBP-1 transcription is downstream of GPER1-activation in breast cancer cells. Additionally, neutralization and knockdown experiments demonstrated a role for IGFBP-1 in the observed inhibition of IGF-1 signaling. These results suggested that 4-OHT inhibits IGF-1 signaling via GPER1 and CREB mediated extracellular IGFBP-1 accumulation in breast cancer cells. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

UCH-L1-containing exosomes mediate chemotherapeutic resistance transfer in breast cancer.

Science.gov (United States)

Ning, Kuan; Wang, Teng; Sun, Xu; Zhang, Pengfei; Chen, Yun; Jin, Jian; Hua, Dong

2017-06-01

Chemotherapy resistance has become a serious challenge in the treatment of breast cancer. Previous studies showed cells can transfer proteins, including those responsible for drug resistance to adjacent cells via exosomes. The switches of drug resistance via exosomes transfer were assessed by CellTiter-Blue Viability assay, flow cytometry, and immunostaining analysis. Relative protein levels of Ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1), P-glycoprotein (P-gp), extracellular-signal regulated protein kinase1/2 (ERK1/2), and phospho-extracellular-signal regulated protein kinase1/2 (p-ERK1/2) were measured by Western blot. Immunohistochemistry was performed on 93 breast cancer samples to assess the associations of UCH-L1 levels with immunofluorescence value of UCH-L1 in circulating exosomes. The Adriamycin-resistant human breast cancer cells (MCF7/ADM) secreted exosomes carrying UCH-L1 and P-gp proteins into the extracellular microenvironment then integrated into Adriamycin-sensitive human breast cancer cells (MCF7/WT) in a time-dependent manner, transferring the chemoresistance phenotype. Notably, in blood samples from patients with breast cancer, the level of exosomes carrying UCH-L1 before chemotherapy was significantly negatively correlated with prognosis. Our study demonstrated that UCH-L1-containing exosomes can transfer chemoresistance to recipient cells and these exosomes may be useful as non-invasive diagnostic biomarkers for detection of chemoresitance in breast cancer patients, achieving more effective and individualized chemotherapy. © 2017 Wiley Periodicals, Inc.

Targeting the NFκB signaling pathways for breast cancer prevention and therapy.

Science.gov (United States)

Wang, Wei; Nag, Subhasree A; Zhang, Ruiwen

2015-01-01

The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium

International Nuclear Information System (INIS)

Gajalakshmi, Palanivel; Priya, Mani Krishna; Pradeep, Thangaraj; Behera, Jyotirmaya; Muthumani, Kandasamy; Madhuwanti, Srinivasan; Saran, Uttara; Chatterjee, Suvro

2013-01-01

Widely used chemotherapeutic breast cancer drugs such as Tamoxifen citrate (TC), Capecitabine (CP) and Epirubicin (EP) are known to cause various cardiovascular side-effects among long term cancer survivors. Vascular modulation warrants nitric oxide (NO) signal transduction, which targets the vascular endothelium. We hypothesize that TC, CP and EP interference with the nitric oxide downstream signaling specifically, could lead to cardiovascular dysfunctions. The results demonstrate that while all three drugs attenuate NO and cyclic guanosine mono-phosphate (cGMP) production in endothelial cells, they caused elevated levels of NO in the plasma and RBC. However, PBMC and platelets did not show any significant changes under treatment. This implies that the drug effects are specific to the endothelium. Altered eNOS and phosphorylated eNOS (Ser-1177) localization patterns in endothelial cells were observed following drug treatments. Similarly, the expression of phosphorylated eNOS (Ser-1177) protein was decreased under the treatment of drugs. Altered actin polymerization was also observed following drug treatment, while addition of SpNO and 8Br-cGMP reversed this effect. Incubation with the drugs decreased endothelial cell migration whereas addition of YC-1, SC and 8Br-cGMP recovered the effect. Additionally molecular docking studies showed that all three drugs exhibited a strong binding affinity with the catalytic domain of human sGC. In conclusion, results indicate that TC, CP and EP cause endothelial dysfunctions via the NO–sGC–cGMP pathway and these effects could be recovered using pharmaceutical agonists of NO signaling pathway. Further, the study proposes a combination therapy of chemotherapeutic drugs and cGMP analogs, which would confer protection against chemotherapy mediated vascular dysfunctions in cancer patients. - Highlights: • NO production is reduced in endothelial cells under breast cancer drug treatment. • Cellular cGMP level is decreased under

Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium

Energy Technology Data Exchange (ETDEWEB)

Gajalakshmi, Palanivel; Priya, Mani Krishna; Pradeep, Thangaraj; Behera, Jyotirmaya; Muthumani, Kandasamy; Madhuwanti, Srinivasan; Saran, Uttara; Chatterjee, Suvro, E-mail: soovro@yahoo.ca

2013-06-01

Widely used chemotherapeutic breast cancer drugs such as Tamoxifen citrate (TC), Capecitabine (CP) and Epirubicin (EP) are known to cause various cardiovascular side-effects among long term cancer survivors. Vascular modulation warrants nitric oxide (NO) signal transduction, which targets the vascular endothelium. We hypothesize that TC, CP and EP interference with the nitric oxide downstream signaling specifically, could lead to cardiovascular dysfunctions. The results demonstrate that while all three drugs attenuate NO and cyclic guanosine mono-phosphate (cGMP) production in endothelial cells, they caused elevated levels of NO in the plasma and RBC. However, PBMC and platelets did not show any significant changes under treatment. This implies that the drug effects are specific to the endothelium. Altered eNOS and phosphorylated eNOS (Ser-1177) localization patterns in endothelial cells were observed following drug treatments. Similarly, the expression of phosphorylated eNOS (Ser-1177) protein was decreased under the treatment of drugs. Altered actin polymerization was also observed following drug treatment, while addition of SpNO and 8Br-cGMP reversed this effect. Incubation with the drugs decreased endothelial cell migration whereas addition of YC-1, SC and 8Br-cGMP recovered the effect. Additionally molecular docking studies showed that all three drugs exhibited a strong binding affinity with the catalytic domain of human sGC. In conclusion, results indicate that TC, CP and EP cause endothelial dysfunctions via the NO–sGC–cGMP pathway and these effects could be recovered using pharmaceutical agonists of NO signaling pathway. Further, the study proposes a combination therapy of chemotherapeutic drugs and cGMP analogs, which would confer protection against chemotherapy mediated vascular dysfunctions in cancer patients. - Highlights: • NO production is reduced in endothelial cells under breast cancer drug treatment. • Cellular cGMP level is decreased under

Activation of ERα signaling differentially modulates IFN-γ induced HLA-class II expression in breast cancer cells.

Directory of Open Access Journals (Sweden)

Ahmed A Mostafa

Full Text Available The coordinate regulation of HLA class II (HLA-II is controlled by the class II transactivator, CIITA, and is crucial for the development of anti-tumor immunity. HLA-II in breast carcinoma is associated with increased IFN-γ levels, reduced expression of the estrogen receptor (ER and reduced age at diagnosis. Here, we tested the hypothesis that estradiol (E₂ and ERα signaling contribute to the regulation of IFN-γ inducible HLA-II in breast cancer cells. Using a panel of established ER⁻ and ER⁺ breast cancer cell lines, we showed that E₂ attenuated HLA-DR in two ER⁺ lines (MCF-7 and BT-474, but not in T47D, while it augmented expression in ER⁻ lines, SK-BR-3 and MDA-MB-231. To further study the mechanism(s, we used paired transfectants: ERα⁺ MC2 (MDA-MB-231 c10A transfected with the wild type ERα gene and ERα⁻ VC5 (MDA-MB-231 c10A transfected with the empty vector, treated or not with E₂ and IFN-γ. HLA-II and CIITA were severely reduced in MC2 compared to VC5 and were further exacerbated by E₂ treatment. Reduced expression occurred at the level of the IFN-γ inducible CIITA promoter IV. The anti-estrogen ICI 182,780 and gene silencing with ESR1 siRNA reversed the E2 inhibitory effects, signifying an antagonistic role for activated ERα on CIITA pIV activity. Moreover, STAT1 signaling, necessary for CIITA pIV activation, and selected STAT1 regulated genes were variably downregulated by E₂ in transfected and endogenous ERα positive breast cancer cells, whereas STAT1 signaling was noticeably augmented in ERα⁻ breast cancer cells. Collectively, these results imply immune escape mechanisms in ERα⁺ breast cancer may be facilitated through an ERα suppressive mechanism on IFN-γ signaling.

Endothelial induced EMT in breast epithelial cells with stem cell properties

DEFF Research Database (Denmark)

Sigurdsson, Valgardur; Hilmarsdottir, Bylgja; Sigmundsdottir, Hekla

2011-01-01

endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression...... of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44(high)/CD24(low) ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D......492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close...

Dynamic Testing of Signal Transduction Deregulation During Breast Cancer Initiation

Science.gov (United States)

2012-07-01

Std. Z39.18 Victoria Seewaldt, M.D. Dynamic Testing of Signal Transduction Deregulation During Breast Cancer Initiation Duke University Durham...attomole- zeptomole range. Internal dilution curves insure a high-dynamic calibration range. DU -26 8L DU -26 6L DU -29 5R DU -22 9.2 L DU...3: Nanobiosensor technology is translated to test for pathway deregulation in RPFNA cytology obtained from 10 high-risk women with cytological

Increased STAT1 signaling in endocrine-resistant breast cancer.

Directory of Open Access Journals (Sweden)

Rui Huang

that STAT signaling is important in endocrine resistance, and that STAT inhibitors may represent potential therapies in breast cancer, even in the resistant setting.

Preoperative diagnosis of breast diseases by dynamic MR mammography. Cut off point establishment for signal intensity ratio

International Nuclear Information System (INIS)

Tsuchiya, Juji; Nagata, Takayasu; Kawagoe, Hajime; Tachibana, Susumu; Kajima, Toshihiko; Hoshino, Mutsuo; Uno, Takashi; Shimokawa, Kuniyasu.

1997-01-01

We have revealed that a dynamic study of the breast using MR imaging technique can estimate objectively benign-malignant differentiative diagnosis. Subjects were 41 cases of breast lesion, including 13 cases of breast cancer, 21 cases of mastopathy, six cases of fibroadenoma and one case of intraductal papillomatosis and the results of them were investigated in comparison with histopathological diagnosis. As so the method, we drew up time-signal intensity ratio curve plotting signal intensity ratio at each 30 second of dynamic MR mammography after Gd-DTPA administration. We found a especially high significant difference between cancer and mastopathy, within 90 second after Gd-DTPA administration (p=0.0000). Still more, we established cut off point concerning with establishment of 95% confidence interval, that is, at 30 second after Gd-DTPA administration of point equivalent 1.53 at 60 second equivalent 2.00, at 90 second equivalent 2.47, and about this estimating maneuver using the cut off point we named Dynamic ratio method. We can estimate preoperatively not only benign-malignant differentiative diagnosis with breast tumor, but also neighboring infiltration and lymph node metastasis of breast cancer using this Dynamic ratio method. Over again, Dynamic ratio method provides fine information to preoperative decision of resecting region for breast conserving surgery. The efficiency of this method is sensitivity=92.3%, specificity=89.3% and positive predictive value=80.0%. (author)

Preoperative diagnosis of breast diseases by dynamic MR mammography. Cut off point establishment for signal intensity ratio

Energy Technology Data Exchange (ETDEWEB)

Tsuchiya, Juji; Nagata, Takayasu; Kawagoe, Hajime; Tachibana, Susumu; Kajima, Toshihiko; Hoshino, Mutsuo [Ibi General Hospital, Gifu (Japan); Uno, Takashi; Shimokawa, Kuniyasu

1997-12-01

We have revealed that a dynamic study of the breast using MR imaging technique can estimate objectively benign-malignant differentiative diagnosis. Subjects were 41 cases of breast lesion, including 13 cases of breast cancer, 21 cases of mastopathy, six cases of fibroadenoma and one case of intraductal papillomatosis and the results of them were investigated in comparison with histopathological diagnosis. As so the method, we drew up time-signal intensity ratio curve plotting signal intensity ratio at each 30 second of dynamic MR mammography after Gd-DTPA administration. We found a especially high significant difference between cancer and mastopathy, within 90 second after Gd-DTPA administration (p=0.0000). Still more, we established cut off point concerning with establishment of 95% confidence interval, that is, at 30 second after Gd-DTPA administration of point equivalent 1.53 at 60 second equivalent 2.00, at 90 second equivalent 2.47, and about this estimating maneuver using the cut off point we named Dynamic ratio method. We can estimate preoperatively not only benign-malignant differentiative diagnosis with breast tumor, but also neighboring infiltration and lymph node metastasis of breast cancer using this Dynamic ratio method. Over again, Dynamic ratio method provides fine information to preoperative decision of resecting region for breast conserving surgery. The efficiency of this method is sensitivity=92.3%, specificity=89.3% and positive predictive value=80.0%. (author)

Separation of random telegraph sSignals from 1/f noise in MOSFETs under constant and switched bias conditions

NARCIS (Netherlands)

Kolhatkar, J.S.; Vandamme, L.K.J.; Salm, Cora; Wallinga, Hans

2004-01-01

The low-frequency noise power spectrum of small dimension MOSFETs is dominated by Lorentzians arising from random telegraph signals (RTS). The low-frequency noise is observed to decrease when the devices are periodically switched 'off'. The technique of determining the statistical lifetimes and

Optically triggered high voltage switch network and method for switching a high voltage

Science.gov (United States)

El-Sharkawi, Mohamed A.; Andexler, George; Silberkleit, Lee I.

1993-01-19

An optically triggered solid state switch and method for switching a high voltage electrical current. A plurality of solid state switches (350) are connected in series for controlling electrical current flow between a compensation capacitor (112) and ground in a reactive power compensator (50, 50') that monitors the voltage and current flowing through each of three distribution lines (52a, 52b and 52c), which are supplying three-phase power to one or more inductive loads. An optical transmitter (100) controlled by the reactive power compensation system produces light pulses that are conveyed over optical fibers (102) to a switch driver (110') that includes a plurality of series connected optical triger circuits (288). Each of the optical trigger circuits controls a pair of the solid state switches and includes a plurality of series connected resistors (294, 326, 330, and 334) that equalize or balance the potential across the plurality of trigger circuits. The trigger circuits are connected to one of the distribution lines through a trigger capacitor (340). In each switch driver, the light signals activate a phototransistor (300) so that an electrical current flows from one of the energy reservoir capacitors through a pulse transformer (306) in the trigger circuit, producing gate signals that turn on the pair of serially connected solid state switches (350).

Optically triggered high voltage switch network and method for switching a high voltage

Energy Technology Data Exchange (ETDEWEB)

El-Sharkawi, Mohamed A. (Renton, WA); Andexler, George (Everett, WA); Silberkleit, Lee I. (Mountlake Terrace, WA)

1993-01-19

An optically triggered solid state switch and method for switching a high voltage electrical current. A plurality of solid state switches (350) are connected in series for controlling electrical current flow between a compensation capacitor (112) and ground in a reactive power compensator (50, 50') that monitors the voltage and current flowing through each of three distribution lines (52a, 52b and 52c), which are supplying three-phase power to one or more inductive loads. An optical transmitter (100) controlled by the reactive power compensation system produces light pulses that are conveyed over optical fibers (102) to a switch driver (110') that includes a plurality of series connected optical triger circuits (288). Each of the optical trigger circuits controls a pair of the solid state switches and includes a plurality of series connected resistors (294, 326, 330, and 334) that equalize or balance the potential across the plurality of trigger circuits. The trigger circuits are connected to one of the distribution lines through a trigger capacitor (340). In each switch driver, the light signals activate a phototransistor (300) so that an electrical current flows from one of the energy reservoir capacitors through a pulse transformer (306) in the trigger circuit, producing gate signals that turn on the pair of serially connected solid state switches (350).

Differences in time-domain and spectral indexes of skin-surface laser-Doppler signals between controls and breast-cancer subjects.

Science.gov (United States)

Hsiu, Hsin; Chen, Chao-Tsung; Hung, Shuo-Hui; Chen, Guan-Zhang; Huang, Yu-Ling

2018-04-13

There is an urgent need to improve the early diagnosis of breast cancer. The present study applied spectral and beat-to-beat analyses to laser-Doppler (LDF) data sequences measured on the skin surface on the back of the right hands, with the aim of comparing the different peripheral microcirculatory-blood-flow (MBF) perfusion condition between breast-cancer and control subjects. ECG and LDF signals were obtained simultaneously and noninvasively from 23 breast-cancer patients and 23 age-matched control subjects. Time-domain beat-to-beat indexes and their variability parameters were calculated. Spectral indexes were calculated using the Morlet wavelet transform. The beat-to-beat LDF pulse width and its variability were significantly smaller in cancer patients than in the controls. The energy contributions of endothelial-, neural-, and myogenic-related frequency bands were also significantly smaller in cancer patients. The present study has revealed significant differences in the beat-to-beat and spectral indexes of skin-surface-acquired LDF signals between control subjects and breast-cancer patients. This illustrates that LDF indexes may be useful for monitoring the changes in the MBF perfusion condition induced by breast cancer. Since the breast-cancer patients were at TNM stages 0- 2, the present findings may aid the development of indexes for detecting breast cancer.

Signal Detection Theory-Based Information Processing for the Detection of Breast Cancer at Microwave Frequencies

National Research Council Canada - National Science Library

Nolte, Loren

2002-01-01

The hypothesis is that one can use signal detection theory to improve the performance in detecting tumors in the breast by using this theory to develop task-oriented information processing techniques...

Epigenetic silencing of ADAMTS18 promotes cell migration and invasion of breast cancer through AKT and NF-κB signaling.

Science.gov (United States)

Xu, Hongying; Xiao, Qian; Fan, Yu; Xiang, Tingxiu; Li, Chen; Li, Chunhong; Li, Shuman; Hui, Tianli; Zhang, Lu; Li, Hongzhong; Li, Lili; Ren, Guosheng

2017-06-01

ADAMTS18 dysregulation plays an important role in many disease processes including cancer. We previously found ADAMTS18 as frequently methylated tumor suppressor gene (TSG) for multiple carcinomas, however, its biological functions and underlying molecular mechanisms in breast carcinogenesis remain unknown. Here, we found that ADAMTS18 was silenced or downregulated in breast cancer cell lines. ADAMTS18 was reduced in primary breast tumor tissues as compared with their adjacent noncancer tissues. ADAMTS18 promoter methylation was detected in 70.8% of tumor tissues by methylation-specific PCR, but none of the normal tissues. Demethylation treatment restored ADAMTS18 expression in silenced breast cell lines. Ectopic expression of ADAMTS18 in breast tumor cells resulted in inhibition of cell migration and invasion. Nude mouse model further confirmed that ADAMTS18 suppressed breast cancer metastasis in vivo. Further mechanistic studies showed that ADAMTS18 suppressed epithelial-mesenchymal transition (EMT), further inhibited migration and invasion of breast cancer cells. ADAMT18 deregulated AKT and NF-κB signaling, through inhibiting phosphorylation levels of AKT and p65. Thus, ADAMTS18 as an antimetastatic tumor suppressor antagonizes AKT and NF-κB signaling in breast tumorigenesis. Its methylation could be a potential tumor biomarker for breast cancer. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Reduction of pattern effects in SOA-based all-optical switches by using cross-gain modulated holding signal

DEFF Research Database (Denmark)

Bischoff, Svend; Mørk, Jesper

2002-01-01

The effective carrier lifetime of SOAs is typically shortened by an intense Continuous Wave (CW) holding signal. However, the SOA gain is reduced by the holding signal resulting in smaller gain and refractive index changes induced by the data signal. Accordingly, an optimum exists for the CW...... and data signal power. Here, we demonstrate that the modulation bandwidth (amplitude jitter) is significantly improved (reduced) by replacing the CW holding beam with a signal, which is low-pass filtered and inverted with respect to the data signal. Such a holding beam can be generated by XGM WC in an SOA......, and reduces the fluctuations of the total energy injected into the interferometer within a bit-slot. Thus, we demonstrate a technique for reducing pattern effects in SOAs by employing a partially inverted holding beam. The method should be useful for increasing the data rates of all-optical switches....

Integration of Nuclear- and Extranuclear-Initiated Estrogen Receptor Signaling in Breast Cancer Cells

Science.gov (United States)

Madak Erdogan, Zeynep

2009-01-01

Estrogenic hormones exert their effects through binding to Estrogen Receptors (ERs), which work in concert with coregulators and extranuclear signaling pathways to control gene expression in normal as well as cancerous states, including breast tumors. In this thesis, we have used multiple genome-wide analysis tools to elucidate various ways that…

Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Ahn, Hee-Jin [Department of Biomedical Science, College of Life Science, CHA University, Seoul (Korea, Republic of); Kim, Gwangil [Department of Pathology, CHA Bundang Medical Center, CHA University, Seoul (Korea, Republic of); Park, Kyung-Soon, E-mail: kspark@cha.ac.kr [Department of Biomedical Science, College of Life Science, CHA University, Seoul (Korea, Republic of)

2013-08-09

Highlights: •Ell3 enhances proliferation and drug resistance of breast cancer cell lines. •Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. •Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven−nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK−extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway.

Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

International Nuclear Information System (INIS)

Ahn, Hee-Jin; Kim, Gwangil; Park, Kyung-Soon

2013-01-01

Highlights: •Ell3 enhances proliferation and drug resistance of breast cancer cell lines. •Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. •Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven−nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK−extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway

Switched periodic systems in discrete time: stability and input-output norms

Science.gov (United States)

Bolzern, Paolo; Colaneri, Patrizio

2013-07-01

This paper deals with the analysis of stability and the characterisation of input-output norms for discrete-time periodic switched linear systems. Such systems consist of a network of time-periodic linear subsystems sharing the same state vector and an exogenous switching signal that triggers the jumps between the subsystems. The overall system exhibits a complex dynamic behaviour due to the interplay between the time periodicity of the subsystem parameters and the switching signal. Both arbitrary switching signals and signals satisfying a dwell-time constraint are considered. Linear matrix inequality conditions for stability and guaranteed H2 and H∞ performances are provided. The results heavily rely on the merge of the theory of linear periodic systems and recent developments on switched linear time-invariant systems.

The unique transcriptional response produced by concurrent estrogen and progesterone treatment in breast cancer cells results in upregulation of growth factor pathways and switching from a Luminal A to a Basal-like subtype

International Nuclear Information System (INIS)

Need, Eleanor F.; Selth, Luke A.; Trotta, Andrew P.; Leach, Damien A.; Giorgio, Lauren; O’Loughlin, Melissa A.; Smith, Eric; Gill, Peter G.; Ingman, Wendy V.; Graham, J. Dinny; Buchanan, Grant

2015-01-01

In breast cancer, progesterone receptor (PR) positivity or abundance is positively associated with survival and treatment response. It was initially believed that PR was a useful diagnostic marker of estrogen receptor activity, but increasingly PR has been recognised to play an important biological role in breast homeostasis, carcinogenesis and metastasis. Although PR expression is almost exclusively observed in estrogen receptor positive tumors, few studies have investigated the cellular mechanisms of PR action in the context of ongoing estrogen signalling. In this study, we contrast PR function in estrogen pretreated ZR-75-1 breast cancer cells with vehicle treated ZR-75-1 and T-47D breast cancer cells using expression microarrays and chromatin immunoprecipitation-sequencing. Estrogen cotreatment caused a dramatic increase in the number of genes regulated by progesterone in ZR-75-1 cells. In T-47D cells that have naturally high levels of PR, estrogen and progesterone cotreatment resulted in a reduction in the number of regulated genes in comparison to treatment with either hormone alone. At a genome level, estrogen pretreatment of ZR-75-1 cells led to a 10-fold increase in the number of PR DNA binding sites detected using ChIP-sequencing. Time course assessment of progesterone regulated genes in the context of estrogen pretreatment highlighted a series of important regulatory pathways, including those driven by epithelial growth factor receptor (EGFR). Importantly, progesterone applied to cells pretreated with estradiol resulted in switching of the PAM50-determined intrinsic breast cancer subtype from Luminal A to Basal-like, and increased the Oncotype DX® Unscaled Recurrence Score. Estrogen pretreatment of breast cancer cells increases PR steady state levels, resulting in an unequivocal progesterone response that upregulates key members of growth factor pathways. The transformative changes progesterone exerts on the breast cancer subtype suggest that these

IGF-IR Signaling in Breast Cancer

National Research Council Canada - National Science Library

Surmacz, Ewa

1997-01-01

Experimental and clinical evidence suggests that the insulin-like growth factor (IGF) system is involved in the growth of breast cancer cells in vitro and may be important in breast cancer etiology and progression...

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

Science.gov (United States)

Tang, X; Ding, C-K; Wu, J; Sjol, J; Wardell, S; Spasojevic, I; George, D; McDonnell, D P; Hsu, D S; Chang, J T; Chi, J-T

2017-07-27

Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable. To identify such a nutrient, we performed a nutrigenetic screen by removing individual amino acids to identify possible addictions across a panel of breast cancer cells. This screen revealed that cystine deprivation triggered rapid programmed necrosis, but not apoptosis, in the basal-type breast cancer cells mostly seen in TNBC tumors. In contrast, luminal-type breast cancer cells are cystine-independent and exhibit little death during cystine deprivation. The cystine addiction phenotype is associated with a higher level of cystine-deprivation signatures noted in the basal type breast cancer cells and tumors. We found that the cystine-addicted breast cancer cells and tumors have strong activation of TNFα and MEKK4-p38-Noxa pathways that render them susceptible to cystine deprivation-induced necrosis. Consistent with this model, silencing of TNFα and MEKK4 dramatically reduces cystine-deprived death. In addition, the cystine addiction phenotype can be abrogated in the cystine-addictive cells by miR-200c, which converts the mesenchymal-like cells to adopt epithelial features. Conversely, the introduction of inducers of epithelial-mesenchymal transition (EMT) in cystine-independent breast cancer cells conferred the cystine-addiction phenotype by modulating the signaling components of cystine addiction. Together, our data reveal that cystine-addiction is associated with EMT in breast cancer during tumor progression. These findings provide the genetic and

Low doses of Paclitaxel repress breast cancer invasion through DJ-1/KLF17 signalling pathway.

Science.gov (United States)

Ismail, Ismail Ahmed; El-Sokkary, Gamal H; Saber, Saber H

2018-04-27

Paclitaxel (taxol) is an important agent against many tumours, including breast cancer. Ample data documents that paclitaxel inhibits breast cancer metastasis while others prove that paclitaxel enhances breast cancer metastasis. The mechanisms by which paclitaxel exerts its action are not well established. This study focuses on the effect of paclitaxel, particularly the low doses on breast cancer metastasis and the mechanisms that regulate it. Current results show that, paclitaxel exerts significant cytotoxicity even at low doses in both MCF-7 and MDA-MB-231 cells. Interestingly, paclitaxel significantly inhibits cell invasion and migration, decreases Snail and increases E-cadherin mRNA expression levels at the indicated low doses. Furthermore, paclitaxel-inhibiting breast cancer metastasis is associated with down-regulation of DJ-1 and ID-1 mRNA expression level with a concurrent increase in KLF17 expression. Under the same experimental conditions, paclitaxel induces KLF17 and concurrently represses ID-1 protein levels. Our results show for the first time that paclitaxel inhibits breast cancer metastasis through regulating DJ-1/KLF17/ID-1 signalling pathway; repressed DJ-1 and ID-1 and enhanced KLF17 expression. © 2018 John Wiley & Sons Australia, Ltd.

Behavioral plasticity through the modulation of switch neurons.

Science.gov (United States)

Vassiliades, Vassilis; Christodoulou, Chris

2016-02-01

A central question in artificial intelligence is how to design agents capable of switching between different behaviors in response to environmental changes. Taking inspiration from neuroscience, we address this problem by utilizing artificial neural networks (NNs) as agent controllers, and mechanisms such as neuromodulation and synaptic gating. The novel aspect of this work is the introduction of a type of artificial neuron we call "switch neuron". A switch neuron regulates the flow of information in NNs by selectively gating all but one of its incoming synaptic connections, effectively allowing only one signal to propagate forward. The allowed connection is determined by the switch neuron's level of modulatory activation which is affected by modulatory signals, such as signals that encode some information about the reward received by the agent. An important aspect of the switch neuron is that it can be used in appropriate "switch modules" in order to modulate other switch neurons. As we show, the introduction of the switch modules enables the creation of sequences of gating events. This is achieved through the design of a modulatory pathway capable of exploring in a principled manner all permutations of the connections arriving on the switch neurons. We test the model by presenting appropriate architectures in nonstationary binary association problems and T-maze tasks. The results show that for all tasks, the switch neuron architectures generate optimal adaptive behaviors, providing evidence that the switch neuron model could be a valuable tool in simulations where behavioral plasticity is required. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-kappaB signaling.

Science.gov (United States)

Jiang, Jiahua; Slivova, Veronika; Harvey, Kevin; Valachovicova, Tatiana; Sliva, Daniel

2004-01-01

Ganoderma lucidum (Reishi, Lingzhi) is a popular Asian mushroom that has been used for more than 2 millennia for the general promotion of health and was therefore called the "Mushroom of Immortality." Ganoderma lucidum was also used in traditional Chinese medicine to prevent or treat a variety of diseases, including cancer. We previously demonstrated that Ganoderma lucidum suppresses the invasive behavior of breast cancer cells by inhibiting the transcription factor NF-kappaB. However, the molecular mechanisms responsible for the inhibitory effects of Ganoderma lucidum on the growth of highly invasive and metastatic breast cancer cells has not been fully elucidated. Here, we show that Ganoderma lucidum inhibits proliferation of breast cancer MDA-MB-231 cells by downregulating Akt/NF-kappaB signaling. Ganoderma lucidum suppresses phosphorylation of Akt on Ser473 and downregulates the expression of Akt, which results in the inhibition of NF-kappaB activity in MDA-MB-231 cells. The biological effect of Ganoderma lucidum was demonstrated by cell cycle arrest at G0/G1, which was the result of the downregulation of expression of NF-kappaB-regulated cyclin D1, followed by the inhibition of cdk4. Our results suggest that Ganoderma lucidum inhibits the growth of MDA-MB-231 breast cancer cells by modulating Akt/NF-kappaB signaling and could have potential therapeutic use for the treatment of breast cancer.

WISP3 (CCN6 Is a Secreted Tumor-Suppressor Protein that Modulates IGF Signaling in Inflammatory Breast Cancer

Directory of Open Access Journals (Sweden)

Celina G. Kleer

2004-03-01

Full Text Available Inflammatory breast cancer (IBC is the most lethal form of locally advanced breast cancer. We have found that WISP3 is lost in 80% of human IBC tumors and that it has growth- and angiogenesis-inhibitory functions in breast cancer in vitro and in vivo. WISP3 is a cysteine-rich, putatively secreted protein that belongs to the CCN family. It contains a signal peptide at the N-terminus and four highly conserved motifs. Here, for the first time, we investigate the function of WISP3 protein in relationship to its structural features. We found that WISP3 is secreted into the conditioned media and into the lumens of normal breast ducts. Once secreted, WISP3 was able to decrease, directly or through induction of other molecule(s, the IGF-1-induced activation of the IGF-IR, and two of its main downstream signaling molecules, IRS1 and ERK-1/2, in SUM149 IBC cells. Furthermore, WISP3 containing conditioned media decreased the growth rate of SUM149 cells. This work sheds light into the mechanism of WISP3 function by demonstrating that it is secreted and that, once in the extracellular media, it induces a series of molecular events that leads to modulation of IGF-IR signaling pathways and cellular growth in IBC cells.

Control synthesis of switched systems

CERN Document Server

Zhao, Xudong; Niu, Ben; Wu, Tingting

2017-01-01

This book offers its readers a detailed overview of the synthesis of switched systems, with a focus on switching stabilization and intelligent control. The problems investigated are not only previously unsolved theoretically but also of practical importance in many applications: voltage conversion, naval piloting and navigation and robotics, for example. The book considers general switched-system models and provides more efficient design methods to bring together theory and application more closely than was possible using classical methods. It also discusses several different classes of switched systems. For general switched linear systems and switched nonlinear systems comprising unstable subsystems, it introduces novel ideas such as invariant subspace theory and the time-scheduled Lyapunov function method of designing switching signals to stabilize the underlying systems. For some typical switched nonlinear systems affected by various complex dynamics, the book proposes novel design approaches based on inte...

Enhanced resting-state dynamics of the hemoglobin signal as a novel biomarker for detection of breast cancer

Energy Technology Data Exchange (ETDEWEB)

Graber, Harry L., E-mail: harry.graber@downstate.edu; Xu, Yong; Barbour, Randall L. [SUNY Downstate Medical Center, Brooklyn, New York 11203 (United States); NIRx Medical Technologies, LLC, Glen Head, New York 11545 (United States); Al abdi, Rabah [Department of Biomedical Engineering, Jordan University of Science and Technology, Irbid 22110 (Jordan); Asarian, Armand P.; Pappas, Peter J. [The Brooklyn Hospital Center, Brooklyn, New York 11201 (United States); Dresner, Lisa [SUNY Downstate Medical Center, Brooklyn, New York 11203 (United States); Patel, Naresh [Kaiser Permanente-Modesto Medical Center, Modesto, California 95356 (United States); Jagarlamundi, Kuppuswamy [Sarah Bush Lincoln Regional Cancer Center, 1000 Health Center Drive, Mattoon, Illinois 61938 (United States); Solomon, William B. [Maimonides Medical Center, Brooklyn, New York 11219 (United States)

2015-11-15

Purpose: The work presented here demonstrates an application of diffuse optical tomography (DOT) to the problem of breast-cancer diagnosis. The potential for using spatial and temporal variability measures of the hemoglobin signal to identify useful biomarkers was studied. Methods: DOT imaging data were collected using two instrumentation platforms the authors developed, which were suitable for exploring tissue dynamics while performing a simultaneous bilateral exam. For each component of the hemoglobin signal (e.g., total, oxygenated), the image time series was reduced to eight scalar metrics that were affected by one or more dynamic properties of the breast microvasculature (e.g., average amplitude, amplitude heterogeneity, strength of spatial coordination). Receiver-operator characteristic (ROC) analyses, comparing groups of subjects with breast cancer to various control groups (i.e., all noncancer subjects, only those with diagnosed benign breast pathology, and only those with no known breast pathology), were performed to evaluate the effect of cancer on the magnitudes of the metrics and of their interbreast differences and ratios. Results: For women with known breast cancer, simultaneous bilateral DOT breast measures reveal a marked increase in the resting-state amplitude of the vasomotor response in the hemoglobin signal for the affected breast, compared to the contralateral, noncancer breast. Reconstructed 3D spatial maps of observed dynamics also show that this behavior extends well beyond the tumor border. In an effort to identify biomarkers that have the potential to support clinical aims, a group of scalar quantities extracted from the time series measures was systematically examined. This analysis showed that many of the quantities obtained by computing paired responses from the bilateral scans (e.g., interbreast differences, ratios) reveal statistically significant differences between the cancer-positive and -negative subject groups, while the

Enhanced resting-state dynamics of the hemoglobin signal as a novel biomarker for detection of breast cancer

International Nuclear Information System (INIS)

Graber, Harry L.; Xu, Yong; Barbour, Randall L.; Al abdi, Rabah; Asarian, Armand P.; Pappas, Peter J.; Dresner, Lisa; Patel, Naresh; Jagarlamundi, Kuppuswamy; Solomon, William B.

2015-01-01

Purpose: The work presented here demonstrates an application of diffuse optical tomography (DOT) to the problem of breast-cancer diagnosis. The potential for using spatial and temporal variability measures of the hemoglobin signal to identify useful biomarkers was studied. Methods: DOT imaging data were collected using two instrumentation platforms the authors developed, which were suitable for exploring tissue dynamics while performing a simultaneous bilateral exam. For each component of the hemoglobin signal (e.g., total, oxygenated), the image time series was reduced to eight scalar metrics that were affected by one or more dynamic properties of the breast microvasculature (e.g., average amplitude, amplitude heterogeneity, strength of spatial coordination). Receiver-operator characteristic (ROC) analyses, comparing groups of subjects with breast cancer to various control groups (i.e., all noncancer subjects, only those with diagnosed benign breast pathology, and only those with no known breast pathology), were performed to evaluate the effect of cancer on the magnitudes of the metrics and of their interbreast differences and ratios. Results: For women with known breast cancer, simultaneous bilateral DOT breast measures reveal a marked increase in the resting-state amplitude of the vasomotor response in the hemoglobin signal for the affected breast, compared to the contralateral, noncancer breast. Reconstructed 3D spatial maps of observed dynamics also show that this behavior extends well beyond the tumor border. In an effort to identify biomarkers that have the potential to support clinical aims, a group of scalar quantities extracted from the time series measures was systematically examined. This analysis showed that many of the quantities obtained by computing paired responses from the bilateral scans (e.g., interbreast differences, ratios) reveal statistically significant differences between the cancer-positive and -negative subject groups, while the

Estrogen switches pure mucinous breast cancer to invasive lobular carcinoma with mucinous features.

Science.gov (United States)

Jambal, Purevsuren; Badtke, Melanie M; Harrell, J Chuck; Borges, Virginia F; Post, Miriam D; Sollender, Grace E; Spillman, Monique A; Horwitz, Kathryn B; Jacobsen, Britta M

2013-01-01

Mucinous breast cancer (MBC) is mainly a disease of postmenopausal women. Pure MBC is rare and augurs a good prognosis. In contrast, MBC mixed with other histological subtypes of invasive disease loses the more favorable prognosis. Because of the relative rarity of pure MBC, little is known about its cell and tumor biology and relationship to invasive disease of other subtypes. We have now developed a human breast cancer cell line called BCK4, in which we can control the behavior of MBC. BCK4 cells were derived from a patient whose poorly differentiated primary tumor was treated with chemotherapy, radiation and tamoxifen. Malignant cells from a recurrent pleural effusion were xenografted in mammary glands of a nude mouse. Cells from the solid tumor xenograft were propagated in culture to generate the BCK4 cell line. Multiple marker and chromosome analyses demonstrate that BCK4 cells are human, near diploid and luminal, expressing functional estrogen, androgen, and progesterone receptors. When xenografted back into immunocompromised cycling mice, BCK4 cells grow into small pure MBC. However, if mice are supplemented with continuous estradiol, tumors switch to invasive lobular carcinoma (ILC) with mucinous features (mixed MBC), and growth is markedly accelerated. Tamoxifen prevents the expansion of this more invasive component. The unexpected ability of estrogens to convert pure MBC into mixed MBC with ILC may explain the rarity of the pure disease in premenopausal women. These studies show that MBC can be derived from lobular precursors and that BCK4 cells are new, unique models to study the phenotypic plasticity, hormonal regulation, optimal therapeutic interventions, and metastatic patterns of MBC.

MFAP5 promotes tumor progression and bone metastasis by regulating ERK/MMP signaling pathways in breast cancer.

Science.gov (United States)

Wu, Zhiqiang; Wang, Ting; Fang, Meng; Huang, Wending; Sun, Zhengwang; Xiao, Jianru; Yan, Wangjun

2018-04-06

Breast cancer accounts for about 30% of all cancers in women, while approximately 70% breast cancer patients developed bone metastases throughout the course of their disease, highlighting the importance of exploring new therapeutic targets. Microfibrillar-associated protein 5 (MFAP5) is a component of extracellular elastic microfibril which has been confirmed to function in tissue development and cancer progression. But the role of MFAP5 in breast cancer remains unclear. The present study demonstrated that MFAP5 was up-regulated in breast cancers compared with that in normal breast tissues, and further increased in breast cancer bone metastasis. Functionally, MFAP5 overexpression accelerated breast cancer cell proliferation and migration, while an opposite effect was observed when MFAP5 was knocked down. In addition, up-regulation of MFAP5 increased the expression of MMP2 and MMP9 and activated the ERK signaling pathway. Conversely, inhibition of MFAP5 suppressed the expression of MMP2, MMP9, p-FAK, p-Erk1/2 and p-cJun. These findings may provide a better understanding about the mechanism of breast cancer and suggest that MFAP5 may be a potential prognostic biomarker and therapeutic target for breast cancer, especially for bone metastasis of breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Biosensors for breast cancer diagnosis: A review of bioreceptors, biotransducers and signal amplification strategies.

Science.gov (United States)

Mittal, Sunil; Kaur, Hardeep; Gautam, Nandini; Mantha, Anil K

2017-02-15

Breast cancer is highly prevalent in females and accounts for second highest number of deaths, worldwide. Cumbersome, expensive and time consuming detection techniques presently available for detection of breast cancer potentiates the need for development of novel, specific and ultrasensitive devices. Biosensors are the promising and selective detection devices which hold immense potential as point of care (POC) tools. Present review comprehensively scrutinizes various breast cancer biosensors developed so far and their technical evaluation with respect to efficiency and potency of selected bioreceptors and biotransducers. Use of glycoproteins, DNA biomarkers, micro-RNA, circulatory tumor cells (CTC) and some potential biomarkers are introduced briefly. The review also discusses various strategies used in signal amplification such as nanomaterials, redox mediators, p19 protein, duplex specific nucleases (DSN) and redox cycling. Copyright © 2016 Elsevier B.V. All rights reserved.

Optical Switching for Dynamic Distribution of Wireless-over-Fiber Signals

DEFF Research Database (Denmark)

Rodes Lopez, Guillermo Arturo; Vegas Olmos, Juan José; Karinou, Fotini

2012-01-01

In this paper, we report on an experimental validation of dynamic distribution of wireless-over-fiber by employing optical switching using semiconductor optical amplifiers; the rest of the network was designed according to the channel distribution over the optical spectra required by the optical...... switch. An experimental validation was also conducted. The experiment consists of a four wavelength division multiplexed (WDM) channel system operating on a WiMax frequency band, and employing an orthogonal frequency-division multiplexing (OFDM) modulation at 625 Mbit/s per channel, transmission...... of the data over 20 km of optical fiber, and active switching in a one-by-sixteen active optical switch. The results show a negligible power penalty on each channel, for both the best and the worst case in terms of inter-channel crosstalk....

HIF-inducible miR-191 promotes migration in breast cancer through complex regulation of TGFβ-signaling in hypoxic microenvironment.

Science.gov (United States)

Nagpal, Neha; Ahmad, Hafiz M.; Chameettachal, Shibu; Sundar, Durai; Ghosh, Sourabh; Kulshreshtha, Ritu

2015-01-01

The molecular mechanisms of hypoxia induced breast cell migration remain incompletely understood. Our results show that hypoxia through hypoxia-inducible factor (HIF) brings about a time-dependent increase in the level of an oncogenic microRNA, miR-191 in various breast cancer cell lines. miR-191 enhances breast cancer aggressiveness by promoting cell proliferation, migration and survival under hypoxia. We further established that miR-191 is a critical regulator of transforming growth factor beta (TGFβ)-signaling and promotes cell migration by inducing TGFβ2 expression under hypoxia through direct binding and indirectly by regulating levels of a RNA binding protein, human antigen R (HuR). The levels of several TGFβ pathway genes (like VEGFA, SMAD3, CTGF and BMP4) were found to be higher in miR-191 overexpressing cells. Lastly, anti-miR-191 treatment given to breast tumor spheroids led to drastic reduction in spheroid tumor volume. This stands as a first report of identification of a microRNA mediator that links hypoxia and the TGFβ signaling pathways, both of which are involved in regulation of breast cancer metastasis. Together, our results show a critical role of miR-191 in hypoxia-induced cancer progression and suggest that miR-191 inhibition may offer a novel therapy for hypoxic breast tumors. PMID:25867965

Coupling switches and oscillators as a means to shape cellular signals in biomolecular systems

International Nuclear Information System (INIS)

Zhou, Peipei; Cai, Shuiming; Liu, Zengrong; Chen, Luonan; Wang, Ruiqi

2013-01-01

To understand how a complex biomolecular network functions, a decomposition or a reconstruction process of the network is often needed so as to provide new insights into the regulatory mechanisms underlying various dynamical behaviors and also to gain qualitative knowledge of the network. Unfortunately, it seems that there are still no general rules on how to decompose a complex network into simple modules. An alternative resolution is to decompose a complex network into small modules or subsystems with specified functions such as switches and oscillators and then integrate them by analyzing the interactions between them. The main idea of this approach can be illustrated by considering a bidirectionally coupled network in this paper, i.e., coupled Toggle switch and Repressilator, and analyzing the occurrence of various dynamics, although the theoretical principle may hold for a general class of networks. We show that various biomolecular signals can be shaped by regulating the coupling between the subsystems. The approach presented here can be expected to simplify and analyze even more complex biological networks

Coupling switches and oscillators as a means to shape cellular signals in biomolecular systems

Energy Technology Data Exchange (ETDEWEB)

Zhou, Peipei [Institute of Systems Biology, Shanghai University, Shanghai 200444 (China); Faculty of Science, Jiangsu University, Zhenjiang, Jiangsu 212013 (China); Cai, Shuiming [Faculty of Science, Jiangsu University, Zhenjiang, Jiangsu 212013 (China); Liu, Zengrong [Institute of Systems Biology, Shanghai University, Shanghai 200444 (China); Chen, Luonan [Key Laboratory of Systems Biology, SIBS-Novo Nordisk Translational Research Center for PreDiabetes, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Collaborative Research Center for Innovative Mathematical Modeling, Institute of Industrial Science, University of Tokyo, Tokyo 153-8505 (Japan); Wang, Ruiqi [Institute of Systems Biology, Shanghai University, Shanghai 200444 (China)

2013-05-15

To understand how a complex biomolecular network functions, a decomposition or a reconstruction process of the network is often needed so as to provide new insights into the regulatory mechanisms underlying various dynamical behaviors and also to gain qualitative knowledge of the network. Unfortunately, it seems that there are still no general rules on how to decompose a complex network into simple modules. An alternative resolution is to decompose a complex network into small modules or subsystems with specified functions such as switches and oscillators and then integrate them by analyzing the interactions between them. The main idea of this approach can be illustrated by considering a bidirectionally coupled network in this paper, i.e., coupled Toggle switch and Repressilator, and analyzing the occurrence of various dynamics, although the theoretical principle may hold for a general class of networks. We show that various biomolecular signals can be shaped by regulating the coupling between the subsystems. The approach presented here can be expected to simplify and analyze even more complex biological networks.

Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.

Directory of Open Access Journals (Sweden)

Megan Leander

Full Text Available Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS, a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 interactions would reflect our structure-activity relationship (SAR data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus, the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3-6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue-specific signaling existed, which was in line with our SAR data. We identified R. prolixus (RhpMS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3-6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3-6 lock

Noise-constrained switching times for heteroclinic computing

Science.gov (United States)

Neves, Fabio Schittler; Voit, Maximilian; Timme, Marc

2017-03-01

Heteroclinic computing offers a novel paradigm for universal computation by collective system dynamics. In such a paradigm, input signals are encoded as complex periodic orbits approaching specific sequences of saddle states. Without inputs, the relevant states together with the heteroclinic connections between them form a network of states—the heteroclinic network. Systems of pulse-coupled oscillators or spiking neurons naturally exhibit such heteroclinic networks of saddles, thereby providing a substrate for general analog computations. Several challenges need to be resolved before it becomes possible to effectively realize heteroclinic computing in hardware. The time scales on which computations are performed crucially depend on the switching times between saddles, which in turn are jointly controlled by the system's intrinsic dynamics and the level of external and measurement noise. The nonlinear dynamics of pulse-coupled systems often strongly deviate from that of time-continuously coupled (e.g., phase-coupled) systems. The factors impacting switching times in pulse-coupled systems are still not well understood. Here we systematically investigate switching times in dependence of the levels of noise and intrinsic dissipation in the system. We specifically reveal how local responses to pulses coact with external noise. Our findings confirm that, like in time-continuous phase-coupled systems, piecewise-continuous pulse-coupled systems exhibit switching times that transiently increase exponentially with the number of switches up to some order of magnitude set by the noise level. Complementarily, we show that switching times may constitute a good predictor for the computation reliability, indicating how often an input signal must be reiterated. By characterizing switching times between two saddles in conjunction with the reliability of a computation, our results provide a first step beyond the coding of input signal identities toward a complementary coding for

Compound semiconductor optical waveguide switch

Science.gov (United States)

Spahn, Olga B.; Sullivan, Charles T.; Garcia, Ernest J.

2003-06-10

An optical waveguide switch is disclosed which is formed from III-V compound semiconductors and which has a moveable optical waveguide with a cantilevered portion that can be bent laterally by an integral electrostatic actuator to route an optical signal (i.e. light) between the moveable optical waveguide and one of a plurality of fixed optical waveguides. A plurality of optical waveguide switches can be formed on a common substrate and interconnected to form an optical switching network.

ERK/CANP rapid signaling mediates 17β-estradiol-induced proliferation of human breast cancer cell line MCF-7 cells.

Science.gov (United States)

Wang, Guo-Sheng; Huang, Yan-Gang; Li, Huan; Bi, Shi-Jie; Zhao, Jin-Long

2014-01-01

17β-estradiol (E2) exerts its functions through both genomic and non-genomic signaling pathways. Because E2 is important in breast cancer development, we investigated whether its actions in promoting breast cancer cell proliferation occur through the non-genomic signaling pathway via extracellular signal-regulated kinase 1/2 (ERK1/2)/calcium-activated neutral protease (CANP). MCF-7 breast cancer cells were treated with ERKl/2 inhibitor (PD98059) or CANP inhibitor (calpeptin) before exposure to 1×10(-8) M E2. MTT colorimetry and flow cytometry were used to analyze effects on cell proliferation and cell cycle progression, respectively. Expression of phosphorylated-ERK (p-ERK), total ERK, and Capn4 proteins were assessed by Western blotting. Cell proliferation increased in cells treated with E2 for 24 h (P<0.05), and the proportion of cells in G0/G1 was decreased, accompanied by accelerated G1/S. Calpeptin pre-treatment significantly inhibited the E2-induced proliferation of MCF-7 cells (P<0.05), while also ameliorating the effects of E2 on cell cycle progression. Further, expression of p-ERK was rapidly up-regulated (after 10 min) by E2 (P<0.05), an effect that persisted 16 h after E2 exposure but which was significantly inhibited by PD98059 (P<0.05). Finally, expression of Capn4 protein was rapidly up-regulated in E2-exposed cells (P<0.05), but this change was significantly inhibited by PD98059 or calpeptin (P<0.05) pre-treatment. Thus, the rapid, non-genomic ERK/CANP signaling pathway mediates E2-induced proliferation of human breast cancer cells.

The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

International Nuclear Information System (INIS)

Loh, Yan Ni; Hedditch, Ellen L; Baker, Laura A; Jary, Eve; Ward, Robyn L; Ford, Caroline E

2013-01-01

Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically. An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays. TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT. These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt

Signal transducers and activators of transcription as regulators of growth, apoptosis and breast development

International Nuclear Information System (INIS)

Bromberg, Jacqueline

2000-01-01

STAT transcription factors were discovered 10 years ago as mediators of interferon-induced gene expression. They now form an important group, comprising seven members, that are activated by virtually every cytokine and growth factor. Their critical role in development and normal cell signaling has been largely determined through the analysis of transgenic mice lacking individual STAT genes. In addition, cell culture work has further delineated their importance in cellular transformation, apoptosis, differentiation and growth control. This review discusses the specific phenotypes of STAT-deficient animals with a focus on STAT5 and STAT3, as these two STAT molecules are required for normal breast development and involution, respectively, and may play an important role in breast carcinogenesis

Gate Driver Circuit of Power Electronic Switches with Reduced Number of Isolated DC/DC Converter for a Switched Reluctance Motor

International Nuclear Information System (INIS)

Memon, A.A.

2013-01-01

This paper presents a gate driver circuit for the switching devices used in the asymmetrical converter for a switched reluctance machine with reduced number of isolated dc/dc converters. Isolation required in the gate driver circuit of switching devices is indispensable. For the purpose of isolation different arrangements may be used such as pulse transformers. The dc/dc converter for isolation and powering the gate drive circuits is suitable, cheaper in cost and simple to implement. It is also significant that required number of isolation converters is much less than the switches used in converter. In addition, a simple logic circuit has been presented for producing the gate signals at correct phase sequence which is compared with the gated signals directly obtained from the encoder of an existing machine. (author)

N-3 poly-unsaturated fatty acids shift estrogen signaling to inhibit human breast cancer cell growth.

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Wenqing Cao

Full Text Available Although evidence has shown the regulating effect of n-3 poly-unsaturated fatty acid (n-3 PUFA on cell signaling transduction, it remains unknown whether n-3 PUFA treatment modulates estrogen signaling. The current study showed that docosahexaenoic acid (DHA, C22:6, eicosapentaenoic acid (EPA, C20:5 shifted the pro-survival and proliferative effect of estrogen to a pro-apoptotic effect in human breast cancer (BCa MCF-7 and T47D cells. 17 β-estradiol (E2 enhanced the inhibitory effect of n-3 PUFAs on BCa cell growth. The IC50 of DHA or EPA in MCF-7 cells decreased when combined with E2 (10 nM treatment (from 173 µM for DHA only to 113 µM for DHA+E2, and from 187 µm for EPA only to 130 µm for EPA+E2. E2 also augmented apoptosis in n-3 PUFA-treated BCa cells. In contrast, in cells treated with stearic acid (SA, C18:0 as well as cells not treated with fatty acid, E2 promoted breast cancer cell growth. Classical (nuclear estrogen receptors may not be involved in the pro-apoptotic effects of E2 on the n-3 PUFA-treated BCa cells because ERα agonist failed to elicit, and ERα knockdown failed to block E2 pro-apoptotic effects. Subsequent studies reveal that G protein coupled estrogen receptor 1 (GPER1 may mediate the pro-apoptotic effect of estrogen. N-3 PUFA treatment initiated the pro-apoptotic signaling of estrogen by increasing GPER1-cAMP-PKA signaling response, and blunting EGFR, Erk 1/2, and AKT activity. These findings may not only provide the evidence to link n-3 PUFAs biologic effects and the pro-apoptotic signaling of estrogen in breast cancer cells, but also shed new insight into the potential application of n-3 PUFAs in BCa treatment.

Determination of the mechanical thermostat electrical contacts switching quality with sound and vibration analysis

Energy Technology Data Exchange (ETDEWEB)

Rejc, Jure; Munih, Marko [University of Ljubljana, Ljubljana (Slovenia)

2017-05-15

A mechanical thermostat is a device that switches heating or cooling appliances on or off based on temperature. For this kind of use, electronic or mechanical switching concepts are applied. During the production of electrical contacts, several irregularities can occur leading to improper switching events of the thermostat electrical contacts. This paper presents a non-obstructive method based on the fact that when the switching event occurs it can be heard and felt by human senses. We performed several laboratory tests with two different methods. The first method includes thermostat switch sound signal analysis during the switching event. The second method is based on sampling of the accelerometer signal during the switching event. The results show that the sound analysis approach has great potential. The approach enables an accurate determination of the switching event even if the sampled signal carries also the switching event of the neighbour thermostat.

Optimization of multi-branch switched diversity systems

KAUST Repository

Nam, Haewoon

2009-10-01

A performance optimization based on the optimal switching threshold(s) for a multi-branch switched diversity system is discussed in this paper. For the conventional multi-branch switched diversity system with a single switching threshold, the optimal switching threshold is a function of both the average channel SNR and the number of diversity branches, where computing the optimal switching threshold is not a simple task when the number of diversity branches is high. The newly proposed multi-branch switched diversity system is based on a sequence of switching thresholds, instead of a single switching threshold, where a different diversity branch uses a different switching threshold for signal comparison. Thanks to the fact that each switching threshold in the sequence can be optimized only based on the number of the remaining diversity branches, the proposed system makes it easy to find these switching thresholds. Furthermore, some selected numerical and simulation results show that the proposed switched diversity system with the sequence of optimal switching thresholds outperforms the conventional system with the single optimal switching threshold. © 2009 IEEE.

Exemestane in early breast cancer: a review

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Michael Untch

2008-12-01

Full Text Available Michael Untch1, Christian Jackisch21Interdisciplinary Breast Centre, Helios Klinikum Berlin-Buch, University Charité, Berlin, Germany; 2Department of Gynecology/Obstetrics, Klinikum Offenbach GmbH, Offenbach, GermanyAbstract: The adjuvant treatment of women with endocrine-sensitive early breast cancer has been dominated for the last 40 years by tamoxifen. However, the side-effects associated with this therapy have prompted a search for safer and biochemically more selective endocrine agents and led to the development of the third-generation aromatase inhibitors (AIs anastrozole, letrozole and exemestane. Promising results in advanced disease have paved the way for treating early breast cancer, and AIs are increasingly replacing tamoxifen in the adjuvant setting. Several large, randomized trials with AIs have been completed or are ongoing in women with early-stage breast cancer, documenting the significant impact that these drugs are making on the risk for recurrence of breast cancer. As a result, there is increasing and widespread use of AI therapy for the treatment of early-stage endocrine-responsive breast cancer. This review summarizes the data for exemestane in the adjuvant setting, showing that a switch to exemestane after 2 to 3 years of tamoxifen therapy is associated with a statistically significant survival benefit and is regarded as being sensitive by international and national experts.Keywords: early breast cancer, adjuvant setting, endocrine-sensitive, tamoxifen, aromatase inhibitor, exemestane, switch, IES 31, NSABP B-33, TEAM

Secure videoconferencing equipment switching system and method

Science.gov (United States)

Hansen, Michael E [Livermore, CA

2009-01-13

A switching system and method are provided to facilitate use of videoconference facilities over a plurality of security levels. The system includes a switch coupled to a plurality of codecs and communication networks. Audio/Visual peripheral components are connected to the switch. The switch couples control and data signals between the Audio/Visual peripheral components and one but nor both of the plurality of codecs. The switch additionally couples communication networks of the appropriate security level to each of the codecs. In this manner, a videoconferencing facility is provided for use on both secure and non-secure networks.

The Wnt Transcriptional Switch: TLE Removal or Inactivation?

Science.gov (United States)

Ramakrishnan, Aravinda-Bharathi; Sinha, Abhishek; Fan, Vinson B; Cadigan, Ken M

2018-02-01

Many targets of the Wnt/β-catenin signaling pathway are regulated by TCF transcription factors, which play important roles in animal development, stem cell biology, and oncogenesis. TCFs can regulate Wnt targets through a "transcriptional switch," repressing gene expression in unstimulated cells and promoting transcription upon Wnt signaling. However, it is not clear whether this switch mechanism is a general feature of Wnt gene regulation or limited to a subset of Wnt targets. Co-repressors of the TLE family are known to contribute to the repression of Wnt targets in the absence of signaling, but how they are inactivated or displaced by Wnt signaling is poorly understood. In this mini-review, we discuss several recent reports that address the prevalence and molecular mechanisms of the Wnt transcription switch, including the finding of Wnt-dependent ubiquitination/inactivation of TLEs. Together, these findings highlight the growing complexity of the regulation of gene expression by the Wnt pathway. © 2017 WILEY Periodicals, Inc.

All-optical switching using a new photonic crystal directional coupler

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B. Vakili

2015-07-01

Full Text Available In this paper all-optical switching in a new photonic crystal directional coupler is performed.  The structure of the switch consists of a directional coupler and a separate path for a control signal called “control waveguide”. In contrast to the former reported structures in which the directional couplers are made by removing a row of rods entirely, the directional coupler in our optical switch is constructed by two reduced-radius line-defect waveguides separated by the control waveguide. Furthermore, in our case the background material has the nonlinear Kerr property. Therefore, in the structure of this work, no frequency overlap occurs between the control waveguide mode and the directional coupler modes. It is shown that such a condition provides a very good isolation between the control and the probe signals at the output ports. In the control waveguide, nonlinear Kerr effect causes the required refractive index change by the presence of a high power control (pump signal. Even and odd modes of the coupler are investigated by applying the distribution of the refractive index change in the nonlinear region of a super-cell so that a switching length of about 94 µm is obtained at the wavelength of 1.55 µm. Finally, all-optical switching of the 1.55 µm probe signal using a control signal at the wavelength of 1.3 µm, is simulated through the finite-difference time-domain method, where both signals are desirable in optical communication systems. A very high extinction ratio of 67 dB is achieved and the temporal characteristics of the switch are demonstrated.

Nonlinear switching dynamics in a photonic-crystal nanocavity

International Nuclear Information System (INIS)

Yu, Yi; Palushani, Evarist; Heuck, Mikkel; Vukovic, Dragana; Peucheret, Christophe; Yvind, Kresten; Mork, Jesper

2014-01-01

We report the experimental observation of nonlinear switching dynamics in an InP photonic crystal nanocavity. Usually, the regime of relatively small cavity perturbations is explored, where the signal transmitted through the cavity follows the temporal variation of the cavity resonance. When the cavity is perturbed by strong pulses, we observe several nonlinear effects, i.e., saturation of the switching contrast, broadening of the switching window, and even initial reduction of the transmission. The effects are analyzed by comparison with nonlinear coupled mode theory and explained in terms of large dynamical variations of the cavity resonance in combination with nonlinear losses. The results provide insight into the nonlinear optical processes that govern the dynamics of nanocavities and are important for applications in optical signal processing, where one wants to optimize the switching contrast.

Nonlinear switching dynamics in a photonic-crystal nanocavity

DEFF Research Database (Denmark)

Yu, Yi; Palushani, Evarist; Heuck, Mikkel

2014-01-01

We report the experimental observation of nonlinear switching dynamics in an InP photonic crystal nanocavity. Usually, the regime of relatively small cavity perturbations is explored, where the signal transmitted through the cavity follows the temporal variation of the cavity resonance. When...... of large dynamical variations of the cavity resonance in combination with nonlinear losses. The results provide insight into the nonlinear optical processes that govern the dynamics of nanocavities and are important for applications in optical signal processing, where one wants to optimize the switching...... the cavity is perturbed by strong pulses, we observe several nonlinear effects, i.e., saturation of the switching contrast, broadening of the switching window, and even initial reduction of the transmission. The effects are analyzed by comparison with nonlinear coupled mode theory and explained in terms...

Quality assurance in MRI breast screening: comparing signal-to-noise ratio in dynamic contrast-enhanced imaging protocols

Science.gov (United States)

Kousi, Evanthia; Borri, Marco; Dean, Jamie; Panek, Rafal; Scurr, Erica; Leach, Martin O.; Schmidt, Maria A.

2016-01-01

MRI has been extensively used in breast cancer staging, management and high risk screening. Detection sensitivity is paramount in breast screening, but variations of signal-to-noise ratio (SNR) as a function of position are often overlooked. We propose and demonstrate practical methods to assess spatial SNR variations in dynamic contrast-enhanced (DCE) breast examinations and apply those methods to different protocols and systems. Four different protocols in three different MRI systems (1.5 and 3.0 T) with receiver coils of different design were employed on oil-filled test objects with and without uniformity filters. Twenty 3D datasets were acquired with each protocol; each dataset was acquired in under 60 s, thus complying with current breast DCE guidelines. In addition to the standard SNR calculated on a pixel-by-pixel basis, we propose other regional indices considering the mean and standard deviation of the signal over a small sub-region centred on each pixel. These regional indices include effects of the spatial variation of coil sensitivity and other structured artefacts. The proposed regional SNR indices demonstrate spatial variations in SNR as well as the presence of artefacts and sensitivity variations, which are otherwise difficult to quantify and might be overlooked in a clinical setting. Spatial variations in SNR depend on protocol choice and hardware characteristics. The use of uniformity filters was shown to lead to a rise of SNR values, altering the noise distribution. Correlation between noise in adjacent pixels was associated with data truncation along the phase encoding direction. Methods to characterise spatial SNR variations using regional information were demonstrated, with implications for quality assurance in breast screening and multi-centre trials.

GnRH receptor activation competes at a low level with growth signaling in stably transfected human breast cell lines

International Nuclear Information System (INIS)

Morgan, Kevin; Meyer, Colette; Miller, Nicola; Sims, Andrew H; Cagnan, Ilgin; Faratian, Dana; Harrison, David J; Millar, Robert P; Langdon, Simon P

2011-01-01

Gonadotrophin releasing hormone (GnRH) analogs lower estrogen levels in pre-menopausal breast cancer patients. GnRH receptor (GnRH-R) activation also directly inhibits the growth of certain cells. The applicability of GnRH anti-proliferation to breast cancer was therefore analyzed. GnRH-R expression in 298 primary breast cancer samples was measured by quantitative immunofluorescence. Levels of functional GnRH-R in breast-derived cell lines were assessed using 125 I-ligand binding and stimulation of 3 H-inositol phosphate production. Elevated levels of GnRH-R were stably expressed in cells by transfection. Effects of receptor activation on in vitro cell growth were investigated in comparison with IGF-I and EGF receptor inhibition, and correlated with intracellular signaling using western blotting. GnRH-R immunoscoring was highest in hormone receptor (triple) negative and grade 3 breast tumors. However prior to transfection, functional endogenous GnRH-R were undetectable in four commonly studied breast cancer cell lines (MCF-7, ZR-75-1, T47D and MDA-MB-231). After transfection with GnRH-R, high levels of cell surface GnRH-R were detected in SVCT and MDA-MB-231 clones while low-moderate levels of GnRH-R occurred in MCF-7 clones and ZR-75-1 clones. MCF-7 sub-clones with high levels of GnRH-R were isolated following hygromycin phosphotransferase transfection. High level cell surface GnRH-R enabled induction of high levels of 3 H-inositol phosphate and modest growth-inhibition in SVCT cells. In contrast, growth of MCF-7, ZR-75-1 or MDA-MB-231 clones was unaffected by GnRH-R activation. Cell growth was inhibited by IGF-I or EGF receptor inhibitors. IGF-I receptor inhibitor lowered levels of p-ERK1/2 in MCF-7 clones. Washout of IGF-I receptor inhibitor resulted in transient hyper-elevation of p-ERK1/2, but co-addition of GnRH-R agonist did not alter the dynamics of ERK1/2 re-phosphorylation. Breast cancers exhibit a range of GnRH-R immunostaining, with higher levels of

Switched-Observer-Based Adaptive Neural Control of MIMO Switched Nonlinear Systems With Unknown Control Gains.

Science.gov (United States)

Long, Lijun; Zhao, Jun

2017-07-01

In this paper, the problem of adaptive neural output-feedback control is addressed for a class of multi-input multioutput (MIMO) switched uncertain nonlinear systems with unknown control gains. Neural networks (NNs) are used to approximate unknown nonlinear functions. In order to avoid the conservativeness caused by adoption of a common observer for all subsystems, an MIMO NN switched observer is designed to estimate unmeasurable states. A new switched observer-based adaptive neural control technique for the problem studied is then provided by exploiting the classical average dwell time (ADT) method and the backstepping method and the Nussbaum gain technique. It effectively handles the obstacle about the coexistence of multiple Nussbaum-type function terms, and improves the classical ADT method, since the exponential decline property of Lyapunov functions for individual subsystems is no longer satisfied. It is shown that the technique proposed is able to guarantee semiglobal uniformly ultimately boundedness of all the signals in the closed-loop system under a class of switching signals with ADT, and the tracking errors converge to a small neighborhood of the origin. The effectiveness of the approach proposed is illustrated by its application to a two inverted pendulum system.

Estrogen and Resveratrol Regulate Rac and Cdc42 Signaling to the Actin Cytoskeleton of Metastatic Breast Cancer Cells

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Nicolas G. Azios

2007-02-01

Full Text Available Estrogen and structurally related molecules play critical roles in breast cancer. We reported that resveratrol (50 µM, an estrogen-like phytosterol from grapes, acts in an antiestrogenic manner in breast cancer cells to reduce cell migration and to induce a global and sustained extension of actin structures called filopodia. Herein, we report that resveratrol-induced filopodia formation is time-dependent and concentration-dependent. In contrast to resveratrol at 50 µM, resveratrol at 5 µM acts in a manner similar to estrogen by increasing lamellipodia, as well as cell migration and invasion. Because Rho GTPases regulate the extension of actin structures, we investigated a role for Rac and Cdc42 in estrogen and resveratrol signaling. Our results demonstrate that 50 µM resveratrol decreases Rac and Cdc42 activity, whereas estrogen and 5 µM resveratrol increase Rac activity in breast cancer cells. MDA-MB-231 cells expressing dominant-negative Cdc42 or dominantnegative Rac retain filopodia response to 50 µM resveratrol. Lamellipodia response to 5 µM resveratrol, estrogen, or epidermal growth factor is inhibited in cells expressing dominant-negative Rac, indicating that Rac regulates estrogen and resveratrol (5 µM signaling to the actin cytoskeleton. These results indicate that signaling to the actin cytoskeleton by low and high concentrations of resveratrol may be differentially regulated by Rac and Cdc42.

Linear population allocation by bistable switches in response to transient stimulation.

Science.gov (United States)

Srimani, Jaydeep K; Yao, Guang; Neu, John; Tanouchi, Yu; Lee, Tae Jun; You, Lingchong

2014-01-01

Many cellular decision processes, including proliferation, differentiation, and phenotypic switching, are controlled by bistable signaling networks. In response to transient or intermediate input signals, these networks allocate a population fraction to each of two distinct states (e.g. OFF and ON). While extensive studies have been carried out to analyze various bistable networks, they are primarily focused on responses of bistable networks to sustained input signals. In this work, we investigate the response characteristics of bistable networks to transient signals, using both theoretical analysis and numerical simulation. We find that bistable systems exhibit a common property: for input signals with short durations, the fraction of switching cells increases linearly with the signal duration, allowing the population to integrate transient signals to tune its response. We propose that this allocation algorithm can be an optimal response strategy for certain cellular decisions in which excessive switching results in lower population fitness.

Multilevel inverter switching controller using a field programmable ...

African Journals Online (AJOL)

Conducted simulation and measurement results verified and validated the switching controller design functionality and requirement. Keywords: multilevel inverter, switching controller; FPGA, general purpose processor (GPP);digital signal processing (DSP); IGBT; Verilog, power consumption; harmonic elimination (SHE).

Identification of H-Ras-Specific Motif for the Activation of Invasive Signaling Program in Human Breast Epithelial Cells

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Hae-Young Yong

2011-02-01

Full Text Available Increased expression and/or activation of H-Ras are often associated with tumor aggressiveness in breast cancer. Previously, we showed that H-Ras, but not N-Ras, induces MCF10A human breast epithelial cell invasion and migration, whereas both H-Ras and N-Ras induce cell proliferation and phenotypic transformation. In an attempt to determine the sequence requirement directing the divergent phenotype induced by H-Ras and N-Ras with a focus on the induction of human breast cell invasion, we investigated the structural and functional relationships between H-Ras and N-Ras using domain-swap and site-directed mutagenesis approaches. Here, we report that the hypervariable region (HVR, consisting of amino acids 166 to 189 in H-Ras, determines the invasive/migratory signaling program as shown by the exchange of invasive phenotype by swapping HVR sequences between H-Ras and N-Ras. We also demonstrate that the H-Ras-specific additional palmitoylation site at Cys184 is not responsible for the signaling events that distinguish between H-Ras and N-Ras. Importantly, this work identifies the C-terminal HVR, especially the flexible linker domain with two consecutive proline residues Pro173 and Pro174, as a critical domain that contributes to activation of H-Ras and its invasive potential in human breast epithelial cells. The present study sheds light on the structural basis for the Ras isoform-specific invasive program of breast epithelial cells, providing information for the development of agents that specifically target invasion-related H-Ras pathways in human cancer.

Signaling Network Assessment of Mutations and Copy Number Variations Predict Breast Cancer Subtype-Specific Drug Targets

Directory of Open Access Journals (Sweden)

Naif Zaman

2013-10-01

Full Text Available Individual cancer cells carry a bewildering number of distinct genomic alterations (e.g., copy number variations and mutations, making it a challenge to uncover genomic-driven mechanisms governing tumorigenesis. Here, we performed exome sequencing on several breast cancer cell lines that represent two subtypes, luminal and basal. We integrated these sequencing data and functional RNAi screening data (for the identification of genes that are essential for cell proliferation and survival onto a human signaling network. Two subtype-specific networks that potentially represent core-signaling mechanisms underlying tumorigenesis were identified. Within both networks, we found that genes were differentially affected in different cell lines; i.e., in some cell lines a gene was identified through RNAi screening, whereas in others it was genomically altered. Interestingly, we found that highly connected network genes could be used to correctly classify breast tumors into subtypes on the basis of genomic alterations. Further, the networks effectively predicted subtype-specific drug targets, which were experimentally validated.

Breast cancer oestrogen independence mediated by BCAR1 or BCAR3 genes is transmitted through mechanisms distinct from the oestrogen receptor signalling pathway or the epidermal growth factor receptor signalling pathway

International Nuclear Information System (INIS)

Dorssers, Lambert CJ; Agthoven, Ton van; Brinkman, Arend; Veldscholte, Jos; Smid, Marcel; Dechering, Koen J

2005-01-01

Tamoxifen is effective for endocrine treatment of oestrogen receptor-positive breast cancers but ultimately fails due to the development of resistance. A functional screen in human breast cancer cells identified two BCAR genes causing oestrogen-independent proliferation. The BCAR1 and BCAR3 genes both encode components of intracellular signal transduction, but their direct effect on breast cancer cell proliferation is not known. The aim of this study was to investigate the growth control mediated by these BCAR genes by gene expression profiling. We have measured the expression changes induced by overexpression of the BCAR1 or BCAR3 gene in ZR-75-1 cells and have made direct comparisons with the expression changes after cell stimulation with oestrogen or epidermal growth factor (EGF). A comparison with published gene expression data of cell models and breast tumours is made. Relatively few changes in gene expression were detected in the BCAR-transfected cells, in comparison with the extensive and distinct differences in gene expression induced by oestrogen or EGF. Both BCAR1 and BCAR3 regulate discrete sets of genes in these ZR-75-1-derived cells, indicating that the proliferation signalling proceeds along distinct pathways. Oestrogen-regulated genes in our cell model showed general concordance with reported data of cell models and gene expression association with oestrogen receptor status of breast tumours. The direct comparison of the expression profiles of BCAR transfectants and oestrogen or EGF-stimulated cells strongly suggests that anti-oestrogen-resistant cell proliferation is not caused by alternative activation of the oestrogen receptor or by the epidermal growth factor receptor signalling pathway

n-3 Polyunsaturated Fatty Acids and Mechanisms to Mitigate Inflammatory Paracrine Signaling in Obesity-Associated Breast Cancer

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Jennifer M. Monk

2014-10-01

Full Text Available Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.

A support vector machine designed to identify breasts at high risk using multi-probe generated REIS signals: a preliminary assessment

Science.gov (United States)

Gur, David; Zheng, Bin; Lederman, Dror; Dhurjaty, Sreeram; Sumkin, Jules; Zuley, Margarita

2010-02-01

A new resonance-frequency based electronic impedance spectroscopy (REIS) system with multi-probes, including one central probe and six external probes that are designed to contact the breast skin in a circular form with a radius of 60 millimeters to the central ("nipple") probe, has been assembled and installed in our breast imaging facility. We are conducting a prospective clinical study to test the performance of this REIS system in identifying younger women (detection of a highly suspicious breast lesion and 50 were determined negative during mammography screening. REIS output signal sweeps that we used to compute an initial feature included both amplitude and phase information representing differences between corresponding (matched) EIS signal values acquired from the left and right breasts. A genetic algorithm was applied to reduce the feature set and optimize a support vector machine (SVM) to classify the REIS examinations into "biopsy recommended" and "non-biopsy" recommended groups. Using the leave-one-case-out testing method, the classification performance as measured by the area under the receiver operating characteristic (ROC) curve was 0.816 +/- 0.042. This pilot analysis suggests that the new multi-probe-based REIS system could potentially be used as a risk stratification tool to identify pre-screened young women who are at higher risk of having or developing breast cancer.

CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness.

Science.gov (United States)

Grass, G Daniel; Tolliver, Lauren B; Bratoeva, Momka; Toole, Bryan P

2013-09-06

The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777-788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer.

CD147, CD44, and the Epidermal Growth Factor Receptor (EGFR) Signaling Pathway Cooperate to Regulate Breast Epithelial Cell Invasiveness*

Science.gov (United States)

Grass, G. Daniel; Tolliver, Lauren B.; Bratoeva, Momka; Toole, Bryan P.

2013-01-01

The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777–788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer. PMID:23888049

Identification of a PEAK1/ZEB1 signaling axis during TGFβ/fibronectin-induced EMT in breast cancer

Energy Technology Data Exchange (ETDEWEB)

Agajanian, Megan; Runa, Farhana; Kelber, Jonathan A., E-mail: jonathan.kelber@csun.edu

2015-09-25

Transforming Growth Factor beta (TGFβ) is the archetypal member of the TGFβ superfamily of ligands and has pleiotropic functions during normal development, adult tissue homeostasis and pathophysiological processes such as cancer. In epithelial cancers TGFβ signaling can either suppress tumor growth or promote metastasis via the induction of a well-characterized epithelial–mesenchymal transition (EMT) program. We recently reported that PEAK1 kinase mediates signaling cross talk between TGFβ receptors and integrin/Src/MAPK pathways and functions as a critical molecular regulator of TGFβ-induced breast cancer cell proliferation, migration, EMT and metastasis. Here, we examined the breast cancer cell contexts in which TGFβ induces both EMT and PEAK1, and discovered this event to be unique to oncogene-transformed mammary epithelial cells and triple-negative breast cancer cells. Using the Cancer BioPortal database, we identified PEAK1 co-expressors across multiple malignancies that are also common to the TGFβ response gene signature (TBRS). We then used the ScanSite database to identify predicted protein–protein binding partners of PEAK1 and the PEAK1-TBRS co-expressors. Analysis of the Cytoscape interactome and Babelomics-derived gene ontologies for a novel gene set including PEAK1, CRK, ZEB1, IL11 and COL4A1 enabled us to hypothesize that PEAK1 may be regulating TGFβ-induced EMT via its interaction with or regulation of these other genes. In this regard, we have demonstrated that PEAK1 is necessary for TGFβ to induce ZEB1-mediated EMT in the context of fibronectin/ITGB3 activation. These studies and future mechanistic studies will pave the way toward identifying the context in which TGFβ blockade may significantly improve breast cancer patient outcomes. - Highlights: • PEAK1 is upregulated in mammary epithelial cells during TGFβ-induced EMT. • TGFβ-induced EMT upregulates PEAK1 in triple negative breast cancer. • PEAK1 is necessary for TGF�

Mucuna pruriens (L.) DC chemo sensitize human breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling.

Science.gov (United States)

Sinha, Sonam; Sharma, Sonal; Vora, Jaykant; Shah, Heta; Srivastava, Anshu; Shrivastava, Neeta

2018-05-10

Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer. We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance. Methanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo-resistivity of breast cancer cells. Our results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A

Signal Processing for Wireless Communication MIMO System with Nano- Scaled CSDG MOSFET based DP4T RF Switch.

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Srivastava, Viranjay M

2015-01-01

In the present technological expansion, the radio frequency integrated circuits in the wireless communication technologies became useful because of the replacement of increasing number of functions, traditional hardware components by modern digital signal processing. The carrier frequencies used for communication systems, now a day, shifted toward the microwave regime. The signal processing for the multiple inputs multiple output wireless communication system using the Metal- Oxide-Semiconductor Field-Effect-Transistor (MOSFET) has been done a lot. In this research the signal processing with help of nano-scaled Cylindrical Surrounding Double Gate (CSDG) MOSFET by means of Double- Pole Four-Throw Radio-Frequency (DP4T RF) switch, in terms of Insertion loss, Isolation, Reverse isolation and Inter modulation have been analyzed. In addition to this a channel model has been presented. Here, we also discussed some patents relevant to the topic.

Cell Identity Switching Regulated by Retinoic Acid Signaling Maintains Homogeneous Segments in the Hindbrain.

Science.gov (United States)

Addison, Megan; Xu, Qiling; Cayuso, Jordi; Wilkinson, David G

2018-06-04

The patterning of tissues to form subdivisions with distinct and homogeneous regional identity is potentially disrupted by cell intermingling. Transplantation studies suggest that homogeneous segmental identity in the hindbrain is maintained by identity switching of cells that intermingle into another segment. We show that switching occurs during normal development and is mediated by feedback between segment identity and the retinoic acid degrading enzymes, cyp26b1 and cyp26c1. egr2, which specifies the segmental identity of rhombomeres r3 and r5, underlies the lower expression level of cyp26b1 and cyp26c1 in r3 and r5 compared with r2, r4, and r6. Consequently, r3 or r5 cells that intermingle into adjacent segments encounter cells with higher cyp26b1/c1 expression, which we find is required for downregulation of egr2b expression. Furthermore, egr2b expression is regulated in r2, r4, and r6 by non-autonomous mechanisms that depend upon the number of neighbors that express egr2b. These findings reveal that a community regulation of retinoid signaling maintains homogeneous segmental identity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch

OpenAIRE

Rao, Sujata; Lobov, Ivan B.; Vallance, Jefferson E.; Tsujikawa, Kaoru; Shiojima, Ichiro; Akunuru, Shailaja; Walsh, Kenneth; Benjamin, Laura E.; Lang, Richard A.

2007-01-01

Macrophages have a critical function in the recognition and engulfment of dead cells. In some settings, macrophages also actively signal programmed cell death. Here we show that during developmentally scheduled vascular regression, resident macrophages are an obligatory participant in a signaling switch that favors death over survival. This switch occurs when the signaling ligand angiopoietin 2 has the dual effect of suppressing survival signaling in vascular endothelial cells (VECs) and stim...

The acetate switch of an intestinal pathogen disrupts host insulin signaling and lipid metabolism.

Science.gov (United States)

Hang, Saiyu; Purdy, Alexandra E; Robins, William P; Wang, Zhipeng; Mandal, Manabendra; Chang, Sarah; Mekalanos, John J; Watnick, Paula I

2014-11-12

Vibrio cholerae is lethal to the model host Drosophila melanogaster through mechanisms not solely attributable to cholera toxin. To examine additional virulence determinants, we performed a genetic screen in V. cholerae-infected Drosophila and identified the two-component system CrbRS. CrbRS controls transcriptional activation of acetyl-CoA synthase-1 (ACS-1) and thus regulates the acetate switch, in which bacteria transition from excretion to assimilation of environmental acetate. The resultant loss of intestinal acetate leads to deactivation of host insulin signaling and lipid accumulation in enterocytes, resulting in host lethality. These metabolic effects are not observed upon infection with ΔcrbS or Δacs1 V. cholerae mutants. Additionally, uninfected flies lacking intestinal commensals, which supply short chain fatty acids (SCFAs) such as acetate, also exhibit altered insulin signaling and intestinal steatosis, which is reversed upon acetate supplementation. Thus, acetate consumption by V. cholerae alters host metabolism, and dietary acetate supplementation may ameliorate some sequelae of cholera. Copyright © 2014 Elsevier Inc. All rights reserved.

Time-dependent switched discrete-time linear systems control and filtering

CERN Document Server

Zhang, Lixian; Shi, Peng; Lu, Qiugang

2016-01-01

This book focuses on the basic control and filtering synthesis problems for discrete-time switched linear systems under time-dependent switching signals. Chapter 1, as an introduction of the book, gives the backgrounds and motivations of switched systems, the definitions of the typical time-dependent switching signals, the differences and links to other types of systems with hybrid characteristics and a literature review mainly on the control and filtering for the underlying systems. By summarizing the multiple Lyapunov-like functions (MLFs) approach in which different requirements on comparisons of Lyapunov function values at switching instants, a series of methodologies are developed for the issues on stability and stabilization, and l2-gain performance or tube-based robustness for l∞ disturbance, respectively, in Chapters 2 and 3. Chapters 4 and 5 are devoted to the control and filtering problems for the time-dependent switched linear systems with either polytopic uncertainties or measurable time-varying...

Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

Science.gov (United States)

Sansone, Pasquale; Ceccarelli, Claudio; Berishaj, Marjan; Chang, Qing; Rajasekhar, Vinagolu K; Perna, Fabiana; Bowman, Robert L; Vidone, Michele; Daly, Laura; Nnoli, Jennifer; Santini, Donatella; Taffurelli, Mario; Shih, Natalie N C; Feldman, Michael; Mao, Jun J; Colameco, Christopher; Chen, Jinbo; DeMichele, Angela; Fabbri, Nicola; Healey, John H; Cricca, Monica; Gasparre, Giuseppe; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

2016-02-09

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.

A nonlinear plasmonic waveguide based all-optical bidirectional switching

Science.gov (United States)

Bana, Xiaoqiang; Pang, Xingxing; Li, Xiaohui; Hu, Bin; Guo, Yixuan; Zheng, Hairong

2018-01-01

In this paper, an all-optical switching with a nanometer coupled ring resonator is demonstrated based on the nonlinear material. By adjusting the light intensity, we implement the resonance wavelength from 880 nm to 940 nm in the nonlinear material structure monocyclic. In the bidirectional switch structure, the center wavelength (i.e. 880 nm) is fixed. By changing the light intensity from I = 0 to I = 53 . 1 MW /cm2, the function of optical switching can be obtained. The results demonstrate that both the single-ring cavity and the T-shaped double-ring structure can realize the optical switching effect. This work takes advantage of the simple structure. The single-ring cavity plasmonic switches have many advantages, such as nanoscale size, low pumping light intensity, ultrafast response time (femtosecond level), etc. It is expected that the proposed all-optical integrated devices can be potentially applied in optical communication, signal processing, and signal sensing, etc.

Switching algorithm for maglev train double-modular redundant positioning sensors.

Science.gov (United States)

He, Ning; Long, Zhiqiang; Xue, Song

2012-01-01

High-resolution positioning for maglev trains is implemented by detecting the tooth-slot structure of the long stator installed along the rail, but there are large joint gaps between long stator sections. When a positioning sensor is below a large joint gap, its positioning signal is invalidated, thus double-modular redundant positioning sensors are introduced into the system. This paper studies switching algorithms for these redundant positioning sensors. At first, adaptive prediction is applied to the sensor signals. The prediction errors are used to trigger sensor switching. In order to enhance the reliability of the switching algorithm, wavelet analysis is introduced to suppress measuring disturbances without weakening the signal characteristics reflecting the stator joint gap based on the correlation between the wavelet coefficients of adjacent scales. The time delay characteristics of the method are analyzed to guide the algorithm simplification. Finally, the effectiveness of the simplified switching algorithm is verified through experiments.

Switching Algorithm for Maglev Train Double-Modular Redundant Positioning Sensors

Directory of Open Access Journals (Sweden)

Song Xue

2012-08-01

Full Text Available High-resolution positioning for maglev trains is implemented by detecting the tooth-slot structure of the long stator installed along the rail, but there are large joint gaps between long stator sections. When a positioning sensor is below a large joint gap, its positioning signal is invalidated, thus double-modular redundant positioning sensors are introduced into the system. This paper studies switching algorithms for these redundant positioning sensors. At first, adaptive prediction is applied to the sensor signals. The prediction errors are used to trigger sensor switching. In order to enhance the reliability of the switching algorithm, wavelet analysis is introduced to suppress measuring disturbances without weakening the signal characteristics reflecting the stator joint gap based on the correlation between the wavelet coefficients of adjacent scales. The time delay characteristics of the method are analyzed to guide the algorithm simplification. Finally, the effectiveness of the simplified switching algorithm is verified through experiments.

Activation status of Wnt/ß-catenin signaling in normal and neoplastic breast tissues: relationship to HER2/neu expression in human and mouse.

Directory of Open Access Journals (Sweden)

Sara Khalil

Full Text Available Wnt/ß-catenin signaling is strongly implicated in neoplasia, but the role of this pathway in human breast cancer has been controversial. Here, we examined Wnt/ß-catenin pathway activation as a function of breast cancer progression, and tested for a relationship with HER2/neu expression, using a human tissue microarray comprising benign breast tissues, ductal carcinoma in situ (DCIS, and invasive carcinomas. Cores were scored for membranous ß-catenin, a key functional component of adherens junctions, and for nucleocytoplasmic ß-catenin, a hallmark of Wnt/ß-catenin pathway activation. Only 82% of benign samples exhibited membrane-associated ß-catenin, indicating a finite frequency of false-negative staining. The frequency of membrane positivity was similar in DCIS samples, but was significantly reduced in carcinomas (45%, P<0.001, consistent with loss of adherens junctions during acquisition of invasiveness. Negative membrane status in cancers correlated with higher grade (P = 0.04 and estrogen receptor-negative status (P = 0.03, both indices of poor prognosis. Unexpectedly, a substantial frequency of nucleocytoplasmic ß-catenin was observed in benign breast tissues (36%, similar to that in carcinomas (35%. Positive-staining basal nuclei observed in benign breast may identify putative stem cells. An increased frequency of nucleocytoplasmic ß-catenin was observed in DCIS tumors (56%, suggesting that pathway activation may be an early event in human breast neoplasia. A correlation was observed between HER2/neu expression and nucleocytoplasmic ß-catenin in node-positive carcinomas (P = 0.02. Furthermore, cytoplasmic ß-catenin was detected in HER2/neu-induced mouse mammary tumors. The Axin2(NLSlacZ mouse strain, a previously validated reporter of mammary Wnt/ß-catenin signaling, was utilized to define in vivo transcriptional consequences of HER2/neu-induced ß-catenin accumulation. Discrete hyperplastic foci observed in mammary

Flexible circuits with integrated switches for robotic shape sensing

Science.gov (United States)

Harnett, C. K.

2016-05-01

Digital switches are commonly used for detecting surface contact and limb-position limits in robotics. The typical momentary-contact digital switch is a mechanical device made from metal springs, designed to connect with a rigid printed circuit board (PCB). However, flexible printed circuits are taking over from the rigid PCB in robotics because the circuits can bend while carrying signals and power through moving joints. This project is motivated by a previous work where an array of surface-mount momentary contact switches on a flexible circuit acted as an all-digital shape sensor compatible with the power resources of energy harvesting systems. Without a rigid segment, the smallest commercially-available surface-mount switches would detach from the flexible circuit after several bending cycles, sometimes violently. This report describes a low-cost, conductive fiber based method to integrate electromechanical switches into flexible circuits and other soft, bendable materials. Because the switches are digital (on/off), they differ from commercially-available continuous-valued bend/flex sensors. No amplification or analog-to-digital conversion is needed to read the signal, but the tradeoff is that the digital switches only give a threshold curvature value. Boundary conditions on the edges of the flexible circuit are key to setting the threshold curvature value for switching. This presentation will discuss threshold-setting, size scaling of the design, automation for inserting a digital switch into the flexible circuit fabrication process, and methods for reconstructing a shape from an array of digital switch states.

Automatic limit switch system for scintillation device and method of operation

International Nuclear Information System (INIS)

Brunnett, C.J.; Ioannou, B.N.

1976-01-01

A scintillation scanner is described having an automatic limit switch system for setting the limits of travel of the radiation detection device which is carried by a scanning boom. The automatic limit switch system incorporates position responsive circuitry for developing a signal representative of the position of the boom, reference signal circuitry for developing a signal representative of a selected limit of travel of the boom, and comparator circuitry for comparng these signals in order to control the operation of a boom drive and indexing mechanism. (author)

Cathepsin K induces platelet dysfunction and affects cell signaling in breast cancer - molecularly distinct behavior of cathepsin K in breast cancer

International Nuclear Information System (INIS)

Andrade, Sheila Siqueira; Gouvea, Iuri Estrada; Silva, Mariana Cristina C.; Castro, Eloísa Dognani; Paula, Cláudia A. A. de; Okamoto, Debora; Oliveira, Lilian; Peres, Giovani Bravin; Ottaiano, Tatiana; Facina, Gil; Nazário, Afonso Celso Pinto; Campos, Antonio Hugo J. F. M.; Paredes-Gamero, Edgar Julian; Juliano, Maria; Silva, Ismael D. C. G. da; Oliva, Maria Luiza V.; Girão, Manoel J. B. C.

2016-01-01

Breast cancer comprises clinically and molecularly distinct tumor subgroups that differ in cell histology and biology and show divergent clinical phenotypes that impede phase III trials, such as those utilizing cathepsin K inhibitors. Here we correlate the epithelial-mesenchymal-like transition breast cancer cells and cathepsin K secretion with activation and aggregation of platelets. Cathepsin K is up-regulated in cancer cells that proteolyze extracellular matrix and contributes to invasiveness. Although proteolytically activated receptors (PARs) are activated by proteases, the direct interaction of cysteine cathepsins with PARs is poorly understood. In human platelets, PAR-1 and −4 are highly expressed, but PAR-3 shows low expression and unclear functions. Platelet aggregation was monitored by measuring changes in turbidity. Platelets were immunoblotted with anti-phospho and total p38, Src-Tyr-416, FAK-Tyr-397, and TGFβ monoclonal antibody. Activation was measured in a flow cytometer and calcium mobilization in a confocal microscope. Mammary epithelial cells were prepared from the primary breast cancer samples of 15 women with Luminal-B subtype to produce primary cells. We demonstrate that platelets are aggregated by cathepsin K in a dose-dependent manner, but not by other cysteine cathepsins. PARs-3 and −4 were confirmed as the cathepsin K target by immunodetection and specific antagonists using a fibroblast cell line derived from PARs deficient mice. Moreover, through co-culture experiments, we show that platelets activated by cathepsin K mediated the up-regulation of SHH, PTHrP, OPN, and TGFβ in epithelial-mesenchymal-like cells from patients with Luminal B breast cancer. Cathepsin K induces platelet dysfunction and affects signaling in breast cancer cells. The online version of this article (doi:10.1186/s12885-016-2203-7) contains supplementary material, which is available to authorized users

High frequency modulation circuits based on photoconductive wide bandgap switches

Science.gov (United States)

Sampayan, Stephen

2018-02-13

Methods, systems, and devices for high voltage and/or high frequency modulation. In one aspect, an optoelectronic modulation system includes an array of two or more photoconductive switch units each including a wide bandgap photoconductive material coupled between a first electrode and a second electrode, a light source optically coupled to the WBGP material of each photoconductive switch unit via a light path, in which the light path splits into multiple light paths to optically interface with each WBGP material, such that a time delay of emitted light exists along each subsequent split light path, and in which the WBGP material conducts an electrical signal when a light signal is transmitted to the WBGP material, and an output to transmit the electrical signal conducted by each photoconductive switch unit. The time delay of the photons emitted through the light path is substantially equivalent to the time delay of the electrical signal.

Aschroft Pressure Switch - Monitor for Low SCHe Supply Bottle Pressure

International Nuclear Information System (INIS)

VAN KATWIJK, C.

2000-01-01

These pressure switches are located in the SCHe helium supply lines at the pressure bottles and upstream of the PRV. The switches monitor the SCHe supply bottle pressure and are set to alarm at 2200 psig. There is one switch for each SCHe supply (4). Electronic output signal is NON-SAFETY (GS)

A numerical simulation model of valence-change-based resistive switching

OpenAIRE

Marchewka, Astrid

2017-01-01

Due to their superior scalability and performance, nanoscale resistive switches based on the valence-change mechanism are considered promising candidates for future nonvolatile memory and logic applications. These devices are metal-oxide-metal structures that can be reversibly switched between different resistance states by electrical signals. Typically, they contain one Schottky-like and one ohmic-like metal-oxide contact and exhibit bipolar switching. The switching mechanism and the initial...

Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

Science.gov (United States)

García-Becerra, Rocío; Santos, Nancy; Díaz, Lorenza; Camacho, Javier

2013-01-01

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. PMID:23344024

Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study.

Directory of Open Access Journals (Sweden)

Tess V Clendenen

Full Text Available Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1, and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1. SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OHD concentration in GWAS were also associated with plasma 25(OHD in our study (p-trend <0.005. After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OHD with breast cancer risk, do not support an association between vitamin D and breast cancer risk.

FGFR2-Driven Signaling Counteracts Tamoxifen Effect on ERα-Positive Breast Cancer Cells

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Lukasz Turczyk

2017-10-01

Full Text Available Signaling mediated by growth factors receptors has long been suggested as one of the key factors responsible for failure of endocrine treatment in breast cancer (BCa. Herein we present that in the presence of tamoxifen, FGFs (Fibroblast Growth Factors promote BCa cell growth with the strongest effect being produced by FGF7. FGFR2 was identified as a mediator of FGF7 action and the FGFR2-induced signaling was found to underlie cancer-associated fibroblasts-dependent resistance to tamoxifen. FGF7/FGFR2-triggered pathway was shown to induce ER phosphorylation, ubiquitination and subsequent ER proteasomal degradation which counteracted tamoxifen-promoted ER stabilization. We also identified activation of PI3K/AKT signaling targeting ER-Ser167 and regulation of Bcl-2 expression as a mediator of FGFR2-promoted resistance to tamoxifen. Analysis of tissue samples from patients with invasive ductal carcinoma revealed an inversed correlation between expression of FGFR2 and ER, thus supporting our in vitro data. These results unveil the complexity of ER regulation by FGFR2-mediated signaling likely to be associated with BCa resistance to endocrine therapy.

Selective androgen receptor modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

Science.gov (United States)

Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D; Yepuru, Muralimohan; Miller, Duane D; Steiner, Mitchell S; Dalton, James T

2014-01-01

The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

Selective androgen receptor modulators (SARMs negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

Directory of Open Access Journals (Sweden)

Ramesh Narayanan

Full Text Available The androgen receptor (AR is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer.Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC co-culture signaling studies were performed to understand the mechanisms of action.Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures.1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

Melatonin: an Inhibitor of Breast Cancer

Science.gov (United States)

Hill, Steven M.; Belancio, Victoria P.; Dauchy, Robert T.; Xiang, Shulin; Brimer, Samantha; Mao, Lulu; Hauch, Adam; Lundberg, Peter W.; Summers, Whitney; Yuan, Lin; Frasch, Tripp; Blask, David E.

2015-01-01

This review discusses recent work on melatonin-mediated circadian regulation and metabolic and molecular signaling mechanisms involved in human breast cancer growth and associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin, via the MT1 receptor, suppresses ERα mRNA expression and ERα transcriptional activity. As well, melatonin regulates the transactivation of other members of the nuclear receptor super-family, estrogen metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (Warburg effect), and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways including inhibition of p38 MAPK and repression of epithelial-to-mesenchymal transition. Studies demonstrate that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models indicate that LEN induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer to drive breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms underpinning the epidemiologic demonstration of elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LEN. PMID:25876649

49 CFR 236.207 - Electric lock on hand-operated switch; control.

Science.gov (United States)

2010-10-01

..., AND APPLIANCES Automatic Block Signal Systems Standards § 236.207 Electric lock on hand-operated switch; control. Electric lock on hand-operated switch shall be controlled so that it cannot be unlocked... 49 Transportation 4 2010-10-01 2010-10-01 false Electric lock on hand-operated switch; control...

Ultra High-Speed Radio Frequency Switch Based on Photonics.

Science.gov (United States)

Ge, Jia; Fok, Mable P

2015-11-26

Microwave switches, or Radio Frequency (RF) switches have been intensively used in microwave systems for signal routing. Compared with the fast development of microwave and wireless systems, RF switches have been underdeveloped particularly in terms of switching speed and operating bandwidth. In this paper, we propose a photonics based RF switch that is capable of switching at tens of picoseconds speed, which is hundreds of times faster than any existing RF switch technologies. The high-speed switching property is achieved with the use of a rapidly tunable microwave photonic filter with tens of gigahertz frequency tuning speed, where the tuning mechanism is based on the ultra-fast electro-optics Pockels effect. The RF switch has a wide operation bandwidth of 12 GHz and can go up to 40 GHz, depending on the bandwidth of the modulator used in the scheme. The proposed RF switch can either work as an ON/OFF switch or a two-channel switch, tens of picoseconds switching speed is experimentally observed for both type of switches.

A Novel Silicon-based Wideband RF Nano Switch Matrix Cell and the Fabrication of RF Nano Switch Structures

Directory of Open Access Journals (Sweden)

Yi Xiu YANG

2011-12-01

Full Text Available This paper presents the concept of RF nano switch matrix cell and the fabrication of RF nano switch. The nano switch matrix cell can be implemented into complex switch matrix for signal routing. RF nano switch is the decision unit for the matrix cell; in this research, it is fabricated on a tri-layer high-resistivity-silicon substrate using surface micromachining approach. Electron beam lithography is introduced to define the pattern and IC compatible deposition process is used to construct the metal layers. Silicon-based nano switch fabricated by IC compatible process can lead to a high potential of system integration to perform a cost effective system-on-a-chip solution. In this paper, simulation results of the designed matrix cell are presented; followed by the details of the nano structure fabrication and fabrication challenges optimizations; finally, measurements of the fabricated nano structure along with analytical discussions are also discussed.

Developing Breast Cancer Program at Xavier; Genomic and Proteomic Analysis of Signaling Pathways Involved in Xenohormone and MEK5 Regulation of Breast Cancer

Science.gov (United States)

2010-05-01

Tagatose are rare. In this study we have determined the effect of these rare ketohexoses on breast cancer cell proliferation and estrogen signalling...Cancer Center (TCC) will build a core of human talent that will address scientific problems such as drug resistance and the effect of environmental agents...pathways for ER(+) (MCF-7) and ER(-) (MCF-7-MEK5) as potentially more effective therapeutic targets. 11 Abstract of RCMI proposal submitted to

Magnonic interferometric switch for multi-valued logic circuits

Science.gov (United States)

Balynsky, Michael; Kozhevnikov, Alexander; Khivintsev, Yuri; Bhowmick, Tonmoy; Gutierrez, David; Chiang, Howard; Dudko, Galina; Filimonov, Yuri; Liu, Guanxiong; Jiang, Chenglong; Balandin, Alexander A.; Lake, Roger; Khitun, Alexander

2017-01-01

We investigated a possible use of the magnonic interferometric switches in multi-valued logic circuits. The switch is a three-terminal device consisting of two spin channels where input, control, and output signals are spin waves. Signal modulation is achieved via the interference between the source and gate spin waves. We report experimental data on a micrometer scale prototype based on the Y3Fe2(FeO4)3 structure. The output characteristics are measured at different angles of the bias magnetic field. The On/Off ratio of the prototype exceeds 13 dB at room temperature. Experimental data are complemented by the theoretical analysis and the results of micro magnetic simulations showing spin wave propagation in a micrometer size magnetic junction. We also present the results of numerical modeling illustrating the operation of a nanometer-size switch consisting of just 20 spins in the source-drain channel. The utilization of spin wave interference as a switching mechanism makes it possible to build nanometer-scale logic gates, and minimize energy per operation, which is limited only by the noise margin. The utilization of phase in addition to amplitude for information encoding offers an innovative route towards multi-state logic circuits. We describe possible implementation of the three-value logic circuits based on the magnonic interferometric switches. The advantages and shortcomings inherent in interferometric switches are also discussed.

Endothelial induced EMT in breast epithelial cells with stem cell properties.

Directory of Open Access Journals (Sweden)

Valgardur Sigurdsson

Full Text Available Epithelial to mesenchymal transition (EMT is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad to N-Cadherin (N-Cad and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44(high/CD24(low ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer.

Endothelial induced EMT in breast epithelial cells with stem cell properties.

Science.gov (United States)

Sigurdsson, Valgardur; Hilmarsdottir, Bylgja; Sigmundsdottir, Hekla; Fridriksdottir, Agla J R; Ringnér, Markus; Villadsen, Rene; Borg, Ake; Agnarsson, Bjarni A; Petersen, Ole William; Magnusson, Magnus K; Gudjonsson, Thorarinn

2011-01-01

Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44(high)/CD24(low) ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer.

Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells.

Directory of Open Access Journals (Sweden)

Yu-Jen Chen

Full Text Available Multi-drug resistance (MDR, an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC transporters and activated Sonic hedgehog (Shh signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX, we examined the effect and mechanism of norcantharidin (NCTD, a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S and DOX-resistant (MCF-7R cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells.

Predicting local recurrence following breast-conserving treatment: parenchymal signal enhancement ratio (SER) around the tumor on preoperative MRI

International Nuclear Information System (INIS)

Kim, Mi Young; Cho, Nariya; Koo, Hye Ryoung; Yun, Bo La; Bae, Min Sun; Moon, Woo Kyung; Chie, Eui Kyu

2013-01-01

Background: The level of background parenchymal enhancement around tumor is known to be associated with breast cancer risk. However, there is no study investigating predictive power of parenchymal signal enhancement ratio (SER) around tumor for ipsilateral breast tumor recurrence (IBTR). Purpose: To investigate whether the breast parenchymal SER around the tumor on preoperative dynamic contrast-enhanced magnetic resonance imaging (MRI) is associated with subsequent IBTR in breast cancer patients who had undergone breast-conserving treatment. Material and Methods: Nineteen consecutive women (mean age, 44 years; range, 34-63 years) with breast cancer who developed IBTR following breast-conserving treatment and 114 control women matched for age, as well as T and N stages were included. We compared the clinicopathologic features of the two groups including nuclear grade, histologic grade, hormonal receptor status, human epidermal growth factor receptor-2 (HER-2) status, lymphovascular invasion, negative margin width, use of adjuvant therapy, and parenchymal SER around the tumor on preoperative DCE-MRI. The SER was measured on a slice showing the largest dimension of the tumor. Multivariate conditional logistic regression analysis was used to identify independent factors associated with IBTR. Results: In univariate analysis, ER negativity (odds ratio [OR] = 4.7; P = 0.040), PR negativity (OR = 4.0; P = 0.013), HER-2 positivity (OR = 3.6; P = 0.026), and a parenchymal SER greater than 0.53 (OR = 23.3; P = 0.011) were associated with IBTR. In multivariate analysis, ER negativity (OR = 3.8; P = 0.015) and a parenchymal SER greater than 0.53 (OR = 13.2; P = 0.040) on preoperative MRI were independent factors associated with IBTR. Conclusion: In addition to ER negativity, a higher parenchymal SER on preoperative MRI was an independent factor associated with subsequent IBTR in patients with breast cancer who had undergone breast-conserving treatment

Role of Notch Signaling in Human Breast Cancer Pathogenesis

Science.gov (United States)

2006-11-01

transform HMLE cells. Similarly, overexpression of ErbB2, a receptor tyrosine kinase upstream of Ras normally found overexpressed in many breast cancers ...Assess Notch-Ras cooperation in breast cancers in vivo: Since the major observation in this project has been the cooperation of Notch and Ras in HMLE ...metastasis. The in vitro cooperation between Notch and Ras in HMLE cells is mimicked in naturally arising breast cancers in vivo. Further dissection of the

All-optical membrane inp switch on silicon for access applications

NARCIS (Netherlands)

Raz, O.; Tassaert, M.; Roelkens, G.C.; Dorren, H.J.S.

2012-01-01

Using an integrated membrane switch on SOI, optical clock distribution is achieved while all-optical switching of datapackets is maintained. Transmission through 25km SMF is demonstrated with 1.5dB penalty, limited by signal OSNR and pump extinction.

Reducing radiation dose to the female breast during conventional and dedicated breast computed tomography

Science.gov (United States)

Rupcich, Franco John

The purpose of this study was to quantify the effectiveness of techniques intended to reduce dose to the breast during CT coronary angiography (CTCA) scans with respect to task-based image quality, and to evaluate the effectiveness of optimal energy weighting in improving contrast-to-noise ratio (CNR), and thus the potential for reducing breast dose, during energy-resolved dedicated breast CT. A database quantifying organ dose for several radiosensitive organs irradiated during CTCA, including the breast, was generated using Monte Carlo simulations. This database facilitates estimation of organ-specific dose deposited during CTCA protocols using arbitrary x-ray spectra or tube-current modulation schemes without the need to run Monte Carlo simulations. The database was used to estimate breast dose for simulated CT images acquired for a reference protocol and five protocols intended to reduce breast dose. For each protocol, the performance of two tasks (detection of signals with unknown locations) was compared over a range of breast dose levels using a task-based, signal-detectability metric: the estimator of the area under the exponential free-response relative operating characteristic curve, AFE. For large-diameter/medium-contrast signals, when maintaining equivalent AFE, the 80 kV partial, 80 kV, 120 kV partial, and 120 kV tube-current modulated protocols reduced breast dose by 85%, 81%, 18%, and 6%, respectively, while the shielded protocol increased breast dose by 68%. Results for the small-diameter/high-contrast signal followed similar trends, but with smaller magnitude of the percent changes in dose. The 80 kV protocols demonstrated the greatest reduction to breast dose, however, the subsequent increase in noise may be clinically unacceptable. Tube output for these protocols can be adjusted to achieve more desirable noise levels with lesser dose reduction. The improvement in CNR of optimally projection-based and image-based weighted images relative to photon

Regulatory role of tumor necrosis factor receptor-associated factor 6 in breast cancer by activating the protein kinase B/glycogen synthase kinase 3β signaling pathway.

Science.gov (United States)

Shen, Hongyu; Li, Liangpeng; Yang, Sujin; Wang, Dandan; Zhou, Siying; Chen, Xiu; Tang, Jinhai

2017-08-01

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an endogenous adaptor of innate and adaptive immune responses, and serves a crucial role in tumor necrosis factor receptor and toll‑like/interleukin‑1 receptor signaling. Although studies have demonstrated that TRAF6 has oncogenic activity, its potential contributions to breast cancer in human remains largely uninvestigated. The present study examined the expression levels and function of TRAF6 in breast carcinoma (n=32) and adjacent healthy (n=25) tissue samples. Compared with adjacent healthy tissues, TRAF6 protein expression levels were significantly upregulated in breast cancer tissues. Reverse transcription‑quantitative polymerase chain reaction analysis revealed a significant upregulation of the cellular proliferative marker Ki‑67 and proliferation cell nuclear antigen expression levels in breast carcinoma specimens. Furthermore, protein expression levels of the accessory molecule, transforming growth factor β‑activated kinase 1 (TAK1), were significantly increased in breast cancer patients, as detected by western blot analysis. As determined by MTT assay, TRAF6 exerted profoundly proliferative effects in the MCF‑7 breast cancer cell line; however, these detrimental effects were ameliorated by TAK1 inhibition. Notably, protein kinase B (AKT)/glycogen synthase kinase (GSK)3β phosphorylation levels were markedly upregulated in breast cancer samples, compared with adjacent healthy tissues. In conclusion, an altered TRAF6‑TAK1 axis and its corresponding downstream AKT/GSK3β signaling molecules may contribute to breast cancer progression. Therefore, TRAF6 may represent a potential therapeutic target for the treatment of breast cancer.

Williams syndrome transcription factor (WSTF) acts as an activator of estrogen receptor signaling in breast cancer cells and the effect can be abrogated by 1α,25-dihydroxyvitamin D3

DEFF Research Database (Denmark)

Lundqvist, Johan; Kirkegaard, Tove; Laenkholm, Anne Vibeke

2018-01-01

A majority of estrogen receptor positive (ER+) breast cancers are growth stimulated by estrogens. The ability to inhibit the ER signaling pathway is therefore of critical importance in the current treatment of ER+ breast cancers. It has been reported that 1α,25-dihydroxyvitamin D3 down......-regulates the expression of the CYP19A1 gene, encoding the aromatase enzyme that catalyzes the synthesis of estradiol. Furthermore, 1α,25-dihydroxyvitamin D3 has also been reported to down-regulate the expression of estrogen receptor α (ERα), the main mediator of ER signaling.This study reports a novel transcription...... factor critical to 1α,25-dihydroxyvitamin D3-mediated regulation of estrogenic signaling in MCF-7 breast cancer cells. We have investigated the molecular mechanisms for the 1α,25-dihydroxyvitamin D3-mediated down-regulation of CYP19A1 and ERα gene expression in human MCF-7 breast cancer cells and found...

Reconciling the influence of task-set switching and motor inhibition processes on stop signal after-effects.

Science.gov (United States)

Anguera, Joaquin A; Lyman, Kyle; Zanto, Theodore P; Bollinger, Jacob; Gazzaley, Adam

2013-01-01

Executive response functions can be affected by preceding events, even if they are no longer associated with the current task at hand. For example, studies utilizing the stop signal task have reported slower response times to "GO" stimuli when the preceding trial involved the presentation of a "STOP" signal. However, the neural mechanisms that underlie this behavioral after-effect are unclear. To address this, behavioral and electroencephalography (EEG) measures were examined in 18 young adults (18-30 years) on "GO" trials following a previously "Successful Inhibition" trial (pSI), a previously "Failed Inhibition" trial (pFI), and a previous "GO" trial (pGO). Like previous research, slower response times were observed during both pSI and pFI trials (i.e., "GO" trials that were preceded by a successful and unsuccessful inhibition trial, respectively) compared to pGO trials (i.e., "GO" trials that were preceded by another "GO" trial). Interestingly, response time slowing was greater during pSI trials compared to pFI trials, suggesting executive control is influenced by both task set switching and persisting motor inhibition processes. Follow-up behavioral analyses indicated that these effects resulted from between-trial control adjustments rather than repetition priming effects. Analyses of inter-electrode coherence (IEC) and inter-trial coherence (ITC) indicated that both pSI and pFI trials showed greater phase synchrony during the inter-trial interval compared to pGO trials. Unlike the IEC findings, differential ITC was present within the beta and alpha frequency bands in line with the observed behavior (pSI > pFI > pGO), suggestive of more consistent phase synchrony involving motor inhibition processes during the ITI at a regional level. These findings suggest that between-trial control adjustments involved with task-set switching and motor inhibition processes influence subsequent performance, providing new insights into the dynamic nature of executive control.

Cascaded analysis of signal and noise propagation through a heterogeneous breast model

International Nuclear Information System (INIS)

Mainprize, James G.; Yaffe, Martin J.

2010-01-01

Purpose: The detectability of lesions in radiographic images can be impaired by patterns caused by the surrounding anatomic structures. The presence of such patterns is often referred to as anatomic noise. Others have previously extended signal and noise propagation theory to include variable background structure as an additional noise term and used in simulations for analysis by human and ideal observers. Here, the analytic forms of the signal and noise transfer are derived to obtain an exact expression for any input random distribution and the ''power law'' filter used to generate the texture of the tissue distribution. Methods: A cascaded analysis of propagation through a heterogeneous model is derived for x-ray projection through simulated heterogeneous backgrounds. This is achieved by considering transmission through the breast as a correlated amplification point process. The analytic forms of the cascaded analysis were compared to monoenergetic Monte Carlo simulations of x-ray propagation through power law structured backgrounds. Results: As expected, it was found that although the quantum noise power component scales linearly with the x-ray signal, the anatomic noise will scale with the square of the x-ray signal. There was a good agreement between results obtained using analytic expressions for the noise power and those from Monte Carlo simulations for different background textures, random input functions, and x-ray fluence. Conclusions: Analytic equations for the signal and noise properties of heterogeneous backgrounds were derived. These may be used in direct analysis or as a tool to validate simulations in evaluating detectability.

All-optical signal processing using InP photonic-crystal nanocavity switches

DEFF Research Database (Denmark)

Yu, Yi; Vukovic, Dragana; Heuck, Mikkel

2014-01-01

In this paper, we present recent progress in experimental characterization of InP photonic-crystal nanocavity switches. Pump-probe measurements on an InP PhC H0 cavity show large-contrast ultrafast switching at low pulse energy. At large pulse energies, a large resonance shift passing across...... for the joint effects of fast carrier diffusion, slow surface and bulk recombination. Utilizin g the simple InP PhC nanocavity structure, we successfully dem onstrate 10-Gb/s RZ- OOK all-optical modulation with low energy consumption....

Wireless Chalcogenide Nanoionic-Based Radio-Frequency Switch

Science.gov (United States)

Nessel, James; Miranda, Felix

2013-01-01

A new nonvolatile nanoionic switch is powered and controlled through wireless radio-frequency (RF) transmission. A thin layer of chalcogenide glass doped with a metal ion, such as silver, comprises the operational portion of the switch. For the switch to function, an oxidizable electrode is made positive (anode) with respect to an opposing electrode (cathode) when sufficient bias, typically on the order of a few tenths of a volt or more, is applied. This action causes the metal ions to flow toward the cathode through a coordinated hopping mechanism. At the cathode, a reduction reaction occurs to form a metal deposit. This metal deposit creates a conductive path that bridges the gap between electrodes to turn the switch on. Once this conductive path is formed, no further power is required to maintain it. To reverse this process, the metal deposit is made positive with respect to the original oxidizable electrode, causing the dissolution of the metal bridge thereby turning the switch off. Once the metal deposit has been completely dissolved, the process self-terminates. This switching process features the following attributes. It requires very little to change states (i.e., on and off). Furthermore, no power is required to maintain the states; hence, the state of the switch is nonvolatile. Because of these attributes the integration of a rectenna to provide the necessary power and control is unique to this embodiment. A rectenna, or rectifying antenna, generates DC power from an incident RF signal. The low voltages and power required for the nanoionic switch control are easily generated from this system and provide the switch with a novel capability to be operated and powered from an external wireless device. In one realization, an RF signal of a specific frequency can be used to set the switch into an off state, while another frequency can be used to set the switch to an on state. The wireless, miniaturized, and nomoving- part features of this switch make it

MR images of rupture and leakage of breast implants

International Nuclear Information System (INIS)

Fang Ling; Liu Pengcheng; Huang Rong; Hu Huaxin; Chen Zaizhong; Du Duanming; Liu Hanqiao; Feng Fei

2002-01-01

Objective: To investigate the diagnostic value of magnetic resonance imaging in detecting rupture and leakage of breast implants. Methods: Seventeen cases with breast implants were imaged by MR scanner. 1 normal silicone breast implant outside the body was scanned by MR as an consultative standard. MR images of silicone implants and polypropylene acyl amine implants were classified and analyzed. Results: In 7 cases, 12 single lumen silicone implants were intact, among them 8 were silicone gel-filled implants, 4 were physiological saline-filled implants. 2 physiological saline-filled implants ruptured, among them 1 belonged to intracapsular silicone implant rupture with subsided silicone gel capsule which presented as long T 1 signal and short T 2 signal on MR images; The other belonged to extracapsular silicone implant rapture with physiological saline granule outside breast on MR images. 20 breast implants in 10 cases were injected by polypropylene acyl amine, among them 2 breast implants were intact, 16 breast implants ruptured completely with pieces and nodes of long T 1 signal and long T 2 signal on MR images, 14 of 16 also presented polypropylene acyl amine granule outside breast; 2 breast implants splited inside with linguine sign. Conclusion: The magnetic resonance imaging can make clear the type and the seat of breast implants, the type of rupture of breast implants, and the distribution of leakage material. Therefore magnetic resonance imaging can be an effective guidance for clinical operation and can be an consultative standard for follow-up

Real time pressure signal system for a rotary engine

Science.gov (United States)

Rice, W. J. (Inventor)

1984-01-01

A real-time IMEP signal which is a composite of those produced in any one chamber of a three-lobed rotary engine is developed by processing the signals of four transducers positioned in a Wankel engine housing such that the rotor overlaps two of the transducers for a brief period during each cycle. During the overlap period of any two transducers, their output is compared and sampled for 10 microseconds per 0.18 degree of rotation by a sampling switch and capacitive circuit. When the switch is closed, the instantaneous difference between the value of the transducer signals is provided while with the switch open the average difference is produced. This combined signal, along with the original signal of the second transducer, is fed through a multiplexer to a pressure output terminal. Timing circuits, controlled by a crank angle encoder on the engine, determine which compared transducer signals are applied to the output terminal and when, as well as the open and closed periods of the switches.

Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer.

Science.gov (United States)

Pérez-Gómez, Eduardo; Andradas, Clara; Blasco-Benito, Sandra; Caffarel, María M; García-Taboada, Elena; Villa-Morales, María; Moreno, Estefanía; Hamann, Sigrid; Martín-Villar, Ester; Flores, Juana M; Wenners, Antonia; Alkatout, Ibrahim; Klapper, Wolfram; Röcken, Christoph; Bronsert, Peter; Stickeler, Elmar; Staebler, Annette; Bauer, Maret; Arnold, Norbert; Soriano, Joaquim; Pérez-Martínez, Manuel; Megías, Diego; Moreno-Bueno, Gema; Ortega-Gutiérrez, Silvia; Artola, Marta; Vázquez-Villa, Henar; Quintanilla, Miguel; Fernández-Piqueras, José; Canela, Enric I; McCormick, Peter J; Guzmán, Manuel; Sánchez, Cristina

2015-06-01

Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown. We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided. We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P = .009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P = .003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P = .009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells. Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with

Zener diode controls switching of large direct currents

Science.gov (United States)

1965-01-01

High-current zener diode is connected in series with the positive input terminal of a dc supply to block the flow of direct current until a high-frequency control signal is applied across the zener diode. This circuit controls the switching of large dc signals.

Study of the Switching Errors in an RSFQ Switch by Using a Computerized Test Setup

International Nuclear Information System (INIS)

Kim, Se Hoon; Baek, Seung Hun; Yang, Jung Kuk; Kim, Jun Ho; Kang, Joon Hee

2005-01-01

The problem of fluctuation-induced digital errors in a rapid single flux quantum (RSFQ) circuit has been a very important issue. In this work, we calculated the bit error rate of an RSFQ switch used in superconductive arithmetic logic unit (ALU). RSFQ switch should have a very low error rate in the optimal bias. Theoretical estimates of the RSFQ error rate are on the order of 10 -50 per bit operation. In this experiment, we prepared two identical circuits placed in parallel. Each circuit was composed of 10 Josephson transmission lines (JTLs) connected in series with an RSFQ switch placed in the middle of the 10 JTLs. We used a splitter to feed the same input signal to both circuits. The outputs of the two circuits were compared with an RSFQ exclusive OR (XOR) to measure the bit error rate of the RSFQ switch. By using a computerized bit-error-rate test setup, we measured the bit error rate of 2.18 x 10 -12 when the bias to the RSFQ switch was 0.398 mA that was quite off from the optimum bias of 0.6 mA.

Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction.

Science.gov (United States)

Tan, Cong-Cong; Li, Gui-Xi; Tan, Li-Duan; Du, Xin; Li, Xiao-Qing; He, Rui; Wang, Qing-Shan; Feng, Yu-Mei

2016-11-29

Bone is one of the most common organs of breast cancer metastasis. Cancer cells that mimic osteoblasts by expressing bone matrix proteins and factors have a higher likelihood of metastasizing to bone. However, the molecular mechanisms of osteomimicry formation of cancer cells remain undefined. Herein, we identified a set of bone-related genes (BRGs) that are ectopically co-expressed in primary breast cancer tissues and determined that osteomimetic feature is obtained due to the osteoblast-like transformation of epithelial breast cancer cells that have undergone epithelial-mesenchymal transition (EMT) followed by bone morphogenetic protein-2 (BMP2) stimulation. Furthermore, we demonstrated that breast cancer cells that transformed into osteoblast-like cells with high expression of BRGs showed enhanced chemotaxis, adhesion, proliferation and multidrug resistance in an osteoblast-mimic bone microenvironment in vitro. During these processes, runt-related transcription factor 2 (RUNX2) functioned as a master mediator by suppressing or activating the transcription of BRGs that underlie the dynamic antagonism between the TGF-β/SMAD and BMP/SMAD signaling pathways in breast cancer cells. Our findings suggest a novel mechanism of osteomimicry formation that arises in primary breast tumors, which may explain the propensity of breast cancer to metastasize to the skeleton and contribute to potential strategies for predicting and targeting breast cancer bone metastasis and multidrug resistance.

Switched-capacitor multiply-by-two amplifier with reduced capacitor mismatches sensitivity and full swing sample signal common-mode voltage

International Nuclear Information System (INIS)

Xu Xinnan; Yao Suying; Xu Jiangtao; Nie Kaiming

2012-01-01

A switched-capacitor amplifier with an accurate gain of two that is insensitive to component mismatch is proposed. This structure is based on associating two sets of two capacitors in cross series during the amplification phase. This circuit permits the common-mode voltage of the sample signal to reach full swing. Using the charge-complement technique, the proposed amplifier can reduce the impact of parasitic capacitors on the gain accuracy effectively. Simulation results show that as sample signal common-mode voltage changes, the difference between the minimum and maximum gain error is less than 0.03%. When the capacitor mismatch is increased from 0 to 0.2%, the gain error is deteriorated by 0.00015%. In all simulations, the gain of amplifier is 69 dB. (semiconductor integrated circuits)

PUMA and NF-kB Are Cell Signaling Predictors of Reovirus Oncolysis of Breast Cancer.

Science.gov (United States)

Thirukkumaran, Chandini; Shi, Zhong-Qiao; Thirukkumaran, Ponnampalam; Luider, Joanne; Kopciuk, Karen; Spurrell, Jason; Elzinga, Kate; Morris, Don

2017-01-01

Reovirus is a ubiquitous RNA virus that exploits aberrant signaling pathways for its replication. The oncolytic potential of reovirus against numerous cancers under pre-clinical/clinical conditions has been documented by us and others. Despite its proven clinical activity, the underlying mechanisms of reovirus oncolysis is still not well elucidated. If reovirus therapy is to be optimized for cancer, including breast cancer patients, it is imperative to understand the mechanisms of reovirus oncolysis, especially in treatment of resistant tumour. In the present study global gene expression profiling was utilized as a preliminary roadmap to tease-out pivotal molecules involved in reovirus induced apoptosis in breast cancer. Reovirus treated HTB133 and MCF7 breast cancer cells revealed transcriptional alteration of a defined subset of apoptotic genes and members of the nuclear factor-kappa B (NF-kB) family and p53 upregulated modulator of apoptosis (PUMA) were prominent. Since NF-kB can paradoxically suppress or promote apoptosis in cancer, the significance of NF-kB in reovirus oncolysis of breast cancer was investigated. Real time PCR analysis indicated a 2.9-4.3 fold increase in NF-kB p65 message levels following reovirus infection of MCF7 and HTB133, respectively. Nuclear translocation of NF-kB p65 protein was also dramatically augmented post reovirus treatment and correlated with enhanced DNA binding. Pharmacologic inhibition of NF-kB lead to oncolytic protection and significant down regulation of PUMA message levels. PUMA down regulation using siRNA suppressed reovirus oncolysis via significantly repressed apoptosis in p53 mutant HTB133 cells. This study demonstrates for the first time that a prominent pathway of reovirus oncolysis of breast cancer is mediated through NF-kB and that PUMA upregulation is dependent on NF-kB activation. These findings represent potential therapeutic indicators of reovirus treatment in future clinical trials.

Cotargeting the lncRNA-PIP3 Interaction and AKT/PI3K Signaling Axis: A Novel Paradigm for Treating Triple-Negative Breast Cancer

Science.gov (United States)

2017-10-01

Negative Breast Cancer PRINCIPAL INVESTIGATOR: Dr. Liuqing Yang CONTRACTING ORGANIZATION: University of Texas MD Anderson Cancer Center Houston, TX...Signaling Axis: A Novel Paradigm for Treating Triple-Negative Breast Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Liuqing Yang 5d...ORGANIZATION REPORT NUMBER UNIVERSITY OF TEXAS M D ANDERSON CANCER HOUSTON TX 77030-0417 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES

Basal-subtype and MEK-Pl3K feedback signaling determine susceptibility of breast cancer cells to MEK inhibition

Energy Technology Data Exchange (ETDEWEB)

Mirzoeva, Olga K.; Das, Debopriya; Heiser, Laura M.; Bhattacharya, Sanchita; Siwak, Doris; Gendelman, Rina; Bayani, Nora; Wang, Nicholas J.; Neve, Richard M.; Knight, Zachary; Feiler, Heidi S.; Gascard, Philippe; Parvin, Bahram; Spellman, Paul T.; Shokat, Kevan M.; Wyrobek, Andrew J.; Bissell, Mina J.; McCormick, Frank; Kuo, Wen-Lin; Mills, Gordon B.; Gray, Joe W.; Korn, W. Michael

2009-01-23

Specific inhibitors of MEK have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway. We employed a systems-based approach to identify breast cancer subtypes particularly susceptible to MEK inhibitors and to understand molecular mechanisms conferring resistance to such compounds. Basal-type breast cancer cells were found to be particularly susceptible to growth-inhibition by small-molecule MEK inhibitors. Activation of the PI3 kinase pathway in response to MEK inhibition through a negative MEK-EGFR-PI3 kinase feedback loop was found to limit efficacy. Interruption of this feedback mechanism by targeting MEK and PI3 kinase produced synergistic effects, including induction of apoptosis and, in some cell lines, cell cycle arrest and protection from apoptosis induced by proapoptotic agents. These findings enhance our understanding of the interconnectivity of oncogenic signal transduction circuits and have implications for the design of future clinical trials of MEK inhibitors in breast cancer by guiding patient selection and suggesting rational combination therapies.

Pregnancy and its role in breast cancer

Directory of Open Access Journals (Sweden)

Filipe Correia Martins

2011-12-01

Full Text Available Early full-term pregnancy is the only recognized factor able to prevent breast cancer. There are several hypotheses to explain the mechanisms of this protection, namely an altered hormonal milieu, a differentiation process or a switch in stem cell properties. To explore them, authors have been using animal models, mainly in rodents. Hormonal administration with estrogen and progesterone was the most widely used process to mimic the mammary changes during pregnancy. We have recently proposed that this enigmatic protective role of a full-term birth in breast cancer is carried out by tumor inhibition mediated by differentiated mammary epithelial cells. This explanation may give a new perspective of breast cancer prevention and treatment.

[Diagnostic efficiency of decline rate of signal intensity and apparent diffusion coefficient with different b values for differentiating benign and malignant breast lesions on diffusion-weighted 3.0T magnetic resonance imaging].

Science.gov (United States)

Jiang, Jing; Liu, Wanhua; Ye, Yuanyuan; Wang, Rui; Li, Fengfang; Peng, Chengyu

2014-06-17

To investigate the diagnostic efficiency of decline rate of signal intensity and apparent diffusion coefficient with different b values for differentiating benign and malignant breast lesions on diffusion-weighted 3.0 T magnetic resonance imaging. A total of 152 patients with 162 confirmed histopathologically breast lesions (85 malignant and 77 benign) underwent 3.0 T diffusion-weighted magnetic resonance imaging. Four b values (0, 400, 800 and 1 000 s/mm²) were used. The signal intensity and ADC values of breast lesions were measured respectively. The signal intensity decline rate (SIDR) and apparent diffusion coefficient decline rate (ADCDR) were calculated respectively. SIDR = (signal intensity of lesions with low b value-signal intensity of lesions with high b value)/signal intensity of lesions with low b value, ADCDR = (ADC value of lesions with low b value-ADC value of lesions with high b value) /ADC value of lesions with low b value. The independent sample t-test was employed for statistical analyses and the receiver operating characteristic (ROC) curve for evaluating the diagnosis efficiency of SIDR and ADCDR values. Significant differences were observed in SIDR between benign and malignant breast lesions with b values of 0-400, 400-800 and 800-1 000 s/mm². The sensitivities of SIDR for differentiating benign and malignant breast lesions were 61.2%, 68.2% and 67.1%, the specificities 74.0%, 85.7% and 67.5%, the diagnosis accordance rates 67.3%, 76.5% and 67.3%, the positive predictive values 72.2%, 84.1% and 69.5% and the negative predictive values 63.3%, 71.0% and 65.0% respectively. Significant differences were observed in ADCDR between benign and malignant breast lesions with b values of 400-800 s/mm² and 800-1 000 s/mm². The sensitivities of SDR for differentiating benign and malignant breast lesions were 80.0% and 65.9%, the specificities 72.7% and 65.0%, the diagnostic accordance rates 76.5% and 65.4%, the positive predictive values 76.4% and 67

A versatile cis-acting inverter module for synthetic translational switches.

Science.gov (United States)

Endo, Kei; Hayashi, Karin; Inoue, Tan; Saito, Hirohide

2013-01-01

Artificial genetic switches have been designed and tuned individually in living cells. A method to directly invert an existing OFF switch to an ON switch should be highly convenient to construct complex circuits from well-characterized modules, but developing such a technique has remained a challenge. Here we present a cis-acting RNA module to invert the function of a synthetic translational OFF switch to an ON switch in mammalian cells. This inversion maintains the property of the parental switch in response to a particular input signal. In addition, we demonstrate simultaneous and specific expression control of both the OFF and ON switches. The module fits the criteria of universality and expands the versatility of mRNA-based information processing systems developed for artificially controlling mammalian cellular behaviour.

The Signaling Cascades of Ginkgolide B-Induced Apoptosis in MCF-7 Breast Cancer Cells

Directory of Open Access Journals (Sweden)

Wen-Hsiung Chan

2007-11-01

Full Text Available Ginkgolide B, the major active component of Ginkgo biloba extracts, can bothstimulate and inhibit apoptotic signaling. Here, we demonstrate that ginkgolide B caninduce the production of reactive oxygen species in MCF-7 breast cancer cells, leading toan increase in the intracellular concentrations of cytoplasmic free Ca2+ and nitric oxide(NO, loss of mitochondrial membrane potential (MMP, activation of caspase-9 and -3,and increase the mRNA expression levels of p53 and p21, which are known to be involvedin apoptotic signaling. In addition, prevention of ROS generation by pretreatment withN-acetyl cysteine (NAC could effectively block intracellular Ca2+ concentrationsincreases and apoptosis in ginkgolide B-treated MCF-7 cells. Moreover, pretreatment withnitric oxide (NO scavengers could inhibit ginkgolide B-induced MMP change andsequent apoptotic processes. Overall, our results signify that both ROS and NO playedimportant roles in ginkgolide B-induced apoptosis of MCF-7 cells. Based on these studyresults, we propose a model for ginkgolide B-induced cell apoptosis signaling cascades inMCF-7 cells.

CMOS SPDT switch for WLAN applications

International Nuclear Information System (INIS)

Bhuiyan, M A S; Reaz, M B I; Rahman, L F; Minhad, K N

2015-01-01

WLAN has become an essential part of our today's life. The advancement of CMOS technology let the researchers contribute low power, size and cost effective WLAN devices. This paper proposes a single pole double through transmit/receive (T/R) switch for WLAN applications in 0.13 μm CMOS technology. The proposed switch exhibit 1.36 dB insertion loss, 25.3 dB isolation and 24.3 dBm power handling capacity. Moreover, it only dissipates 786.7 nW power per cycle. The switch utilizes only transistor aspect ratio optimization and resistive body floating technique to achieve such desired performance. In this design the use of bulky inductor and capacitor is avoided to evade imposition of unwanted nonlinearities to the communication signal. (paper)

Cmos spdt switch for wlan applications

Science.gov (United States)

Bhuiyan, M. A. S.; Reaz, M. B. I.; Rahman, L. F.; Minhad, K. N.

2015-04-01

WLAN has become an essential part of our today's life. The advancement of CMOS technology let the researchers contribute low power, size and cost effective WLAN devices. This paper proposes a single pole double through transmit/receive (T/R) switch for WLAN applications in 0.13 μm CMOS technology. The proposed switch exhibit 1.36 dB insertion loss, 25.3 dB isolation and 24.3 dBm power handling capacity. Moreover, it only dissipates 786.7 nW power per cycle. The switch utilizes only transistor aspect ratio optimization and resistive body floating technique to achieve such desired performance. In this design the use of bulky inductor and capacitor is avoided to evade imposition of unwanted nonlinearities to the communication signal.

49 CFR 218.105 - Additional operational requirements for hand-operated main track switches.

Science.gov (United States)

2010-10-01

... was operated, all crewmembers shall have verbal communication to confirm the position of the switch... switch position to the roadway worker in charge. (d) Releasing authority limits. In non-signaled...

Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

Directory of Open Access Journals (Sweden)

Youn Kyung Choi

2014-01-01

Full Text Available Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.

The Economics of Prepectoral Breast Reconstruction.

Science.gov (United States)

Glasberg, Scot Bradley

2017-12-01

The world of breast reconstruction over the last several years has seen a dramatic shift in focus to discussion and the application of placing tissue expanders and implants back into the prepectoral space. Although this technique failed during the early advent of breast reconstruction, newer technologies such as advances in fat grafting, improved acellular dermal matrices, better methods of assessing breast flap viability, and enhanced implants appear to have set the stage for the resurgence and positive early results seen with this technique. The main benefits of a switch to prepectoral breast reconstruction clinically appears to be less associated pain, lower incidence of animation deformities, and its associated symptoms as well as presumably better aesthetics. Early data suggest that the results are extremely promising and early adopters have attempted to define the ideal patients for prepectoral breast reconstruction. As with any new operative procedure, an assessment of finances and costs are crucial to its successful implementation. Although current data are minimal, this article attempts to build the fundamentals of an economic model that exhibits and displays potential savings through the use of prepectoral breast reconstruction.

Early dissemination seeds metastasis in breast cancer

Science.gov (United States)

Hosseini, Hedayatollah; Obradović, Milan M.S.; Hoffmann, Martin; Harper, Kathryn; Sosa, Maria Soledad; Werner-Klein, Melanie; Nanduri, Lahiri Kanth; Werno, Christian; Ehrl, Carolin; Maneck, Matthias; Patwary, Nina; Haunschild, Gundula; Gužvić, Miodrag; Reimelt, Christian; Grauvogl, Michael; Eichner, Norbert; Weber, Florian; Hartkopf, Andreas; Taran, Florin-Andrei; Brucker, Sara Y.; Fehm, Tanja; Rack, Brigitte; Buchholz, Stefan; Spang, Rainer; Meister, Gunter; Aguirre-Ghiso, Julio A.; Klein, Christoph A.

2016-01-01

Accumulating data suggest that metastatic dissemination often occurs early during tumour formation but the mechanisms of early metastatic spread have not yet been addressed. Here, we studied metastasis in a HER2-driven mouse breast cancer model and found that progesterone-induced signalling triggered migration of cancer cells from early lesions shortly after HER2 activation, but promoted proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by elevated HER2 expression and increased tumour cell density involving miRNA-mediated progesterone receptor (PGR) down-regulation and was reversible. Cells from early, low-density lesions displayed more stemness features than cells from dense, advanced tumours, migrated more and founded more metastases. Strikingly, we found that at least 80% of metastases were derived from early disseminated cancer cells (DCC). Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination. PMID:27974799

Label-free detection of breast masses using multiphoton microscopy.

Directory of Open Access Journals (Sweden)

Xiufeng Wu

Full Text Available Histopathology forms the gold standard for the diagnosis of breast cancer. Multiphoton microscopy (MPM has been proposed to be a potentially powerful adjunct to current histopathological techniques. A label-free imaging based on two- photon excited fluorescence and second-harmonic generation is developed for differentiating normal breast tissues, benign, as well as breast cancer tissues. Human breast biopsies (including human normal breast tissues, benign as well as breast cancer tissues that are first imaged (fresh, unfixed, and unstained with MPM and are then processed for routine H-E histopathology. Our results suggest that the MPM images, obtained from these unprocessed biopsies, can readily distinguish between benign lesions and breast cancers. In the tissues of breast cancers, MPM showed that the tumor cells displayed marked cellular and nuclear pleomorphism. The tumor cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, infiltrated into disrupted connective tissue, leading to the loss of second-harmonic generation signals. For breast cancer, MPM diagnosis was 100% correct because the tissues of breast cancers did not have second-harmonic generation signals in MPM imaging. On the contrary, in benign breast masses, second-harmonic generation signals could be seen easily in MPM imaging. These observations indicate that MPM could be an important potential tool to provide label-free noninvasive diagnostic impressions that can guide surgeon in biopsy and patient management.

Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion

Energy Technology Data Exchange (ETDEWEB)

Zheng, Hao; Li, Ying [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Wang, Yuzhong [Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079 (China); Zhao, Haixia [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Yue, Jiang [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Guo, Austin M., E-mail: Austin_Guo@nymc.edu [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Department of Pharmacology, New York Medical College, Valhalla, NY 10595 (United States); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)

2014-10-01

Flavonoids exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr{sup 458}), phospho-PDK (Ser{sup 241}) and phospho-Akt (Thr{sup 308}). Conversely, the exogenous addition of PGE{sub 2}, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted the in vitro anti-migratory and anti-invasive activities, whereas the addition of PGE{sub 2}, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed the in vitro anti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited the in vivo lung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE{sub 2}, 20-HETE and phospho-Akt (Thr{sup 308}). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasion via downregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities. - Highlights: • Isoliquiritigenin induces anoikis and suppresses

Call for Papers: Photonics in Switching

Science.gov (United States)

Wosinska, Lena; Glick, Madeleine

2006-04-01

Call for Papers: Photonics in Switching Guest Editors: Lena Wosinska, Royal Institute of Technology (KTH) / ICT Sweden Madeleine Glick, Intel Research, Cambridge, UK Technologies based on DWDM systems allow data transmission with bit rates of Tbit/s on a single fiber. To facilitate this enormous transmission volume, high-capacity and high-speed network nodes become inevitable in the optical network. Wideband switching, WDM switching, optical burst switching (OBS), and optical packet switching (OPS) are promising technologies for harnessing the bandwidth of WDM optical fiber networks in a highly flexible and efficient manner. As a number of key optical component technologies approach maturity, photonics in switching is becoming an increasingly attractive and practical solution for the next-generation of optical networks. The scope of this special issue is focused on the technology and architecture of optical switching nodes, including the architectural and algorithmic aspects of high-speed optical networks. Scope of Submission The scope of the papers includes, but is not limited to, the following topics: WDM node architectures Novel device technologies enabling photonics in switching, such as optical switch fabrics, optical memory, and wavelength conversion Routing protocols WDM switching and routing Quality of service Performance measurement and evaluation Next-generation optical networks: architecture, signaling, and control Traffic measurement and field trials Optical burst and packet switching OBS/OPS node architectures Burst/Packet scheduling and routing algorithms Contention resolution/avoidance strategies Services and applications for OBS/OPS (e.g., grid networks, storage-area networks, etc.) Burst assembly and ingress traffic shaping Hybrid OBS/TDM or OBS/wavelength routing Manuscript Submission To submit to this special issue, follow the normal procedure for submission to JON and select ``Photonics in Switching' in the features indicator of the online

EDITORIAL: Molecular switches at surfaces Molecular switches at surfaces

Science.gov (United States)

Weinelt, Martin; von Oppen, Felix

2012-10-01

In nature, molecules exploit interaction with their environment to realize complex functionalities on the nanometer length scale. Physical, chemical and/or biological specificity is frequently achieved by the switching of molecules between microscopically different states. Paradigmatic examples are the energy production in proton pumps of bacteria or the signal conversion in human vision, which rely on switching molecules between different configurations or conformations by external stimuli. The remarkable reproducibility and unparalleled fatigue resistance of these natural processes makes it highly desirable to emulate nature and develop artificial systems with molecular functionalities. A promising avenue towards this goal is to anchor the molecular switches at surfaces, offering new pathways to control their functional properties, to apply electrical contacts, or to integrate switches into larger systems. Anchoring at surfaces allows one to access the full range from individual molecular switches to self-assembled monolayers of well-defined geometry and to customize the coupling between molecules and substrate or between adsorbed molecules. Progress in this field requires both synthesis and preparation of appropriate molecular systems and control over suitable external stimuli, such as light, heat, or electrical currents. To optimize switching and generate function, it is essential to unravel the geometric structure, the electronic properties and the dynamic interactions of the molecular switches on surfaces. This special section, Molecular Switches at Surfaces, collects 17 contributions describing different aspects of this research field. They analyze elementary processes, both in single molecules and in ensembles of molecules, which involve molecular switching and concomitant changes of optical, electronic, or magnetic properties. Two topical reviews summarize the current status, including both challenges and achievements in the field of molecular switches on

Signal/time-relation of benign and malignant lesions in dynamic 2D-MR imaging of the breast. Signalverhalten maligner und benigner Laesionen in der dynamischen 2D-MRT der Mamma

Energy Technology Data Exchange (ETDEWEB)

Fischer, U. (Abteilung Roentgendiagnostik 1, Univ. Goettingen (Germany)); Heyden, D. v. (Abteilung Roentgendiagnostik 1, Univ. Goettingen (Germany)); Vosshenrich, R. (Abteilung Roentgendiagnostik 1, Univ. Goettingen (Germany)); Vieweg, I. (Abteilung Roentgendiagnostik 1, Univ. Goettingen (Germany)); Grabbe, E. (Abteilung Roentgendiagnostik 1, Univ. Goettingen (Germany))

1993-04-01

In a retrospective study of 400 dynamic MR examinations of the breast the signal/time ratio of 62 histopathologically correlated lesions (19 benign, 42 malignant) was evaluated. Points of evaluations were initial signal enhancement (1st and 2nd minute), post-initial signal apperance (2nd to 5th minute) and signal distribution (homogeneous, marginal). Based on these criteria, a point system was defined to help in the assessment of lesions in dynamic breast-MR imaging. The overall sensitivity of this method was 95.3%, the specificity to 89.5% and the accuracy to 93.5%. Pitfalls resulted in two cases of non-invasive carcinoma and in two patients with fibroadenoma. (orig.)

Sonic Hedgehog switches on Wnt/planar cell polarity signaling in commissural axon growth cones by reducing levels of Shisa2

Science.gov (United States)

Onishi, Keisuke

2017-01-01

Commissural axons switch on responsiveness to Wnt attraction during midline crossing and turn anteriorly only after exiting the floor plate. We report here that Sonic Hedgehog (Shh)-Smoothened signaling downregulates Shisa2, which inhibits the glycosylation and cell surface presentation of Frizzled3 in rodent commissural axon growth cones. Constitutive Shisa2 expression causes randomized turning of post-crossing commissural axons along the anterior–posterior (A–P) axis. Loss of Shisa2 led to precocious anterior turning of commissural axons before or during midline crossing. Post-crossing commissural axon turning is completely randomized along the A–P axis when Wntless, which is essential for Wnt secretion, is conditionally knocked out in the floor plate. This regulatory link between Shh and planar cell polarity (PCP) signaling may also occur in other developmental processes. PMID:28885142

Distributed Consensus of Stochastic Delayed Multi-agent Systems Under Asynchronous Switching.

Science.gov (United States)

Wu, Xiaotai; Tang, Yang; Cao, Jinde; Zhang, Wenbing

2016-08-01

In this paper, the distributed exponential consensus of stochastic delayed multi-agent systems with nonlinear dynamics is investigated under asynchronous switching. The asynchronous switching considered here is to account for the time of identifying the active modes of multi-agent systems. After receipt of confirmation of mode's switching, the matched controller can be applied, which means that the switching time of the matched controller in each node usually lags behind that of system switching. In order to handle the coexistence of switched signals and stochastic disturbances, a comparison principle of stochastic switched delayed systems is first proved. By means of this extended comparison principle, several easy to verified conditions for the existence of an asynchronously switched distributed controller are derived such that stochastic delayed multi-agent systems with asynchronous switching and nonlinear dynamics can achieve global exponential consensus. Two examples are given to illustrate the effectiveness of the proposed method.

Disturbance Decoupling of Switched Linear Systems

NARCIS (Netherlands)

Yurtseven, E.; Heemels, W.P.M.H.; Camlibel, M.K.

2010-01-01

In this paper we consider disturbance decoupling problems for switched linear systems. We will provide necessary and sufficient conditions for three different versions of disturbance decoupling, which differ based on which signals are considered to be the disturbance. In the first version the

Roles of SGK Isoform Signaling in Breast Cancer Migration and Invasion

Science.gov (United States)

2011-04-01

significant number of overlapping substrates, and deregulation in breast carcinoma (5,6). To date, no studies have investigated any role for SGK in cell...isoforms in breast carcinoma cell lines (months 2-3) To insure specificity of SGK knockdown in breast cancer cell lines I made two different specific

MR evaluation of breast lesions obtained by diffusion-weighted imaging with background body signal suppression (DWIBS) and correlations with histological findings.

Science.gov (United States)

Moschetta, Marco; Telegrafo, Michele; Rella, Leonarda; Capolongo, Arcangela; Stabile Ianora, Amato Antonio; Angelelli, Giuseppe

2014-07-01

Diffusion imaging represents a new imaging tool for the diagnosis of breast cancer. This study aims to investigate the role of diffusion-weighted MRI with background body signal suppression (DWIBS) for evaluating breast lesions. 90 patients were prospectively evaluated by MRI with STIR, TSE-T2, contrast enhanced THRIVE-T1 and DWIBS sequences. DWIBS were analyzed searching for the presence of breast lesions and calculating the ADC value. ADC values of ≤1.44×10(-3)mm(2)/s were considered suspicious for malignancy. This analysis was then compared with the histological findings. Sensitivity, specificity, diagnostic accuracy (DA), positive predictive value (PPV) and negative (NPV) were calculated. In 53/90 (59%) patients, DWIBS indicated the presence of breast lesions, 16 (30%) with ADC values of >1.44 and 37 (70%) with ADC≤1.44. The comparison with histology showed 25 malignant and 28 benign lesions. DWIBS sequences obtained sensitivity, specificity, DA, PPV and NPV values of 100, 82, 87, 68 and 100%, respectively. DWIBS can be proposed in the MRI breast protocol representing an accurate diagnostic complement. Copyright © 2014 Elsevier Inc. All rights reserved.

Interpretation of photocurrent correlation measurements used for ultrafast photoconductive switch characterization

DEFF Research Database (Denmark)

Jacobsen, R. H.; Birkelund, Karen; Holst, T.

1996-01-01

of the switch. By using both photocurrent measurements and terahertz spectroscopy we verify the importance of space-charge effects on the carrier dynamics. Photocurrent nonlinearities and coherent effects are discussed as they appear in the correlation signals. An analysis based on a simple model allows......Photocurrent correlation measurements used for the characterization of ultrafast photoconductive switches based on GaAs and silicon-on-sapphire are demonstrated. The correlation signal arises from the interplay of the photoexcited carriers, the dynamics of the bias field and a subsequent recharging...

VME Switch for CERN's PS Analog Video System

CERN Document Server

Acebes, I; Heinze, W; Lewis, J; Serrano, J

2003-01-01

Analog video signal switching is used in CERN's Proton Synchrotron (PS) complex to route the video signals coming from Beam Diagnostics systems to the Meyrin Control Room (MCR). Traditionally, this has been done with custom electromechanical relay-based cards controlled serially via CAMAC crates. In order to improve the robustness and maintainability of the system, while keeping it analog to preserve the low latency, a VME card based on Analog Devices' AD8116 analog matrix chip has been developed. Video signals go into the front panel and exit the switch through the P2 connector of the VME backplane. The module is a 16 input, 32 output matrix. Larger matrices can be built using more modules and bussing their outputs together, thanks to the high impedance feature of the AD8116. Another VME module takes the selected signals from the P2 connector and performs automatic gain to send them at nominal output level through its front panel. This paper discusses both designs and presents experimental test results.

Reconciling the influence of task-set switching and motor inhibition processes on stop signal after-effects

Directory of Open Access Journals (Sweden)

Joaquin A. Anguera

2013-09-01

Full Text Available Executive response functions can be affected by preceding events, even if they are no longer associated with the current task at hand. For example, studies utilizing the stop signal task have reported slower response times to ‘GO’ stimuli when the preceding trial involved the presentation of a ‘STOP’ signal. However, the neural mechanisms that underlie this behavioral after-effect are unclear. To address this, behavioral and electroencephalography (EEG measures were examined in 18 young adults (18-30yrs on 'GO' trials following a previously ‘Successful Inhibition’ trial (pSI, a previously ‘Failed Inhibition’ trial (pFI, and a previous ‘GO’ trial (pGO. Like previous research, slower response times were observed during both pSI and pFI trials (i.e., ‘GO’ trials that were preceded by a successful and unsuccessful inhibition trial, respectively compared to pGO trials (i.e., ‘GO’ trials that were preceded by another ‘GO’ trial. Interestingly, response time slowing was greater during pSI trials compared to pFI trials, suggesting executive control is influenced by both task set switching and persisting motor inhibition processes. Follow-up behavioral analyses indicated that these effects resulted from between-trial control adjustments rather than repetition priming effects. Analyses of inter-electrode coherence (IEC and inter-trial coherence (ITC indicated that both pSI and pFI trials showed greater phase synchrony during the inter-trial interval compared to pGO trials. Unlike the IEC findings, differential ITC was present within the beta and alpha frequency bands in line with the observed behavior (pSI > pFI > pGO, suggestive of more consistent phase synchrony involving motor inhibition processes during the ITI at a regional level. These findings suggest that between-trial control adjustments involved with task-set switching and motor inhibition processes influence subsequent performance, providing new insights into the

Switched diversity strategies for dual-hop relaying systems

KAUST Repository

Gaaloul, Fakhreddine

2011-04-29

This paper investigates the effect of different switched diversity configurations on the implementation complexity and achieved performance of dual-hop amplify-and-forward (AF) relaying networks. A low-complexity model of the relay station is adopted, wherein single-input single-output antenna configuration is employed. Each of the transmitter and the receiver however employs multiple antennas to improve the overall link performance. Single-phase and two-phase based receive switching strategies are investigated assuming optimum first hop signal-to-noise ratio (SNR). Moreover, the simple scheme in which the switched diversity is applied independently over the two hops is studied using tight upper bounds. Thorough performance comparisons and switching thresholds optimization for the aforementioned strategies are presented. Simulation results are also provided to validate the mathematical development and to verify the numerical computations.

Switching non-local vector median filter

Science.gov (United States)

Matsuoka, Jyohei; Koga, Takanori; Suetake, Noriaki; Uchino, Eiji

2016-04-01

This paper describes a novel image filtering method that removes random-valued impulse noise superimposed on a natural color image. In impulse noise removal, it is essential to employ a switching-type filtering method, as used in the well-known switching median filter, to preserve the detail of an original image with good quality. In color image filtering, it is generally preferable to deal with the red (R), green (G), and blue (B) components of each pixel of a color image as elements of a vectorized signal, as in the well-known vector median filter, rather than as component-wise signals to prevent a color shift after filtering. By taking these fundamentals into consideration, we propose a switching-type vector median filter with non-local processing that mainly consists of a noise detector and a noise removal filter. Concretely, we propose a noise detector that proactively detects noise-corrupted pixels by focusing attention on the isolation tendencies of pixels of interest not in an input image but in difference images between RGB components. Furthermore, as the noise removal filter, we propose an extended version of the non-local median filter, we proposed previously for grayscale image processing, named the non-local vector median filter, which is designed for color image processing. The proposed method realizes a superior balance between the preservation of detail and impulse noise removal by proactive noise detection and non-local switching vector median filtering, respectively. The effectiveness and validity of the proposed method are verified in a series of experiments using natural color images.

Optical Switching for Dynamic Distribution of Wireless-Over-Fiber Signals in Active Optical Networks

DEFF Research Database (Denmark)

Vegas Olmos, Juan José; Rodes, Guillermo; Tafur Monroy, Idelfonso

2012-01-01

In this paper, we report on an experimental validation of dynamic distribution of wireless-over-fiber by employing optical switching using semiconductor optical amplifiers; we also provide a channel distribution scheme and a generic topology for such an optical switch. The experiment consists...... of a four wavelength-division-multiplexed channel system operating on a WiMax frequency band and employing an orthogonal-frequency-division-multiplexing modulation at 625 Mbits/s per channel, transmission of the data over 20 km of optical fiber, and active switching in a 1 × 16 active optical switch....... The results show a negligible power penalty on each channel for both the best and the worst case in terms of inter-channel crosstalk. The presented system is highly scalable both in terms of port count and throughput, a desirable feature in highly branched access networks, and is modulation- and frequency...

High frequency switched-mode stimulation can evoke postsynaptic responses in cerebellar principal neurons

Directory of Open Access Journals (Sweden)

Marijn Van Dongen

2015-03-01

Full Text Available This paper investigates the efficacy of high frequency switched-mode neural stimulation. Instead of using a constant stimulation amplitude, the stimulus is switched on and off repeatedly with a high frequency (up to 100kHz duty cycled signal. By means of tissue modeling that includes the dynamic properties of both the tissue material as well as the axon membrane, it is first shown that switched-mode stimulation depolarizes the cell membrane in a similar way as classical constant amplitude stimulation.These findings are subsequently verified using in vitro experiments in which the response of a Purkinje cell is measured due to a stimulation signal in the molecular layer of the cerebellum of a mouse. For this purpose a stimulator circuit is developed that is able to produce a monophasic high frequency switched-mode stimulation signal. The results confirm the modeling by showing that switched-mode stimulation is able to induce similar responses in the Purkinje cell as classical stimulation using a constant current source. This conclusion opens up possibilities for novel stimulation designs that can improve the performance of the stimulator circuitry. Care has to be taken to avoid losses in the system due to the higher operating frequency.

Adaptive Neural Tracking Control for Discrete-Time Switched Nonlinear Systems with Dead Zone Inputs

Directory of Open Access Journals (Sweden)

Jidong Wang

2017-01-01

Full Text Available In this paper, the adaptive neural controllers of subsystems are proposed for a class of discrete-time switched nonlinear systems with dead zone inputs under arbitrary switching signals. Due to the complicated framework of the discrete-time switched nonlinear systems and the existence of the dead zone, it brings about difficulties for controlling such a class of systems. In addition, the radial basis function neural networks are employed to approximate the unknown terms of each subsystem. Switched update laws are designed while the parameter estimation is invariable until its corresponding subsystem is active. Then, the closed-loop system is stable and all the signals are bounded. Finally, to illustrate the effectiveness of the proposed method, an example is employed.

Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer

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Ying Su

2015-06-01

Full Text Available Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells.

Investigations and Simulations of All optical Switches in linear state Based on Photonic Crystal Directional Coupler

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S. Maktoobi

2014-10-01

Full Text Available Switching is a principle process in digital computers and signal processing systems. The growth of optical signal processing systems, draws particular attention to design of ultra-fast optical switches. In this paper, All Optical Switches in linear state Based On photonic crystal Directional coupler is analyzed and simulated. Among different methods, the finite difference time domain method (FDTD is a preferable method and is used. We have studied the application of photonic crystal lattices, the physics of optical switching and photonic crystal Directional coupler. In this paper, Electric field intensity and the power output that are two factors to improve the switching performance and the device efficiency are investigated and simulated. All simulations are performed by COMSOL software.

Targeting the Ron-Dek Signaling Axis in Breast Cancer

Science.gov (United States)

2015-09-01

Words 5 Accomplishments 5 Impact & Conclusion 8 Changes/Problems 9 Products 9 Participants and Other Collaborating Organizations 11 Special...may represent an important new therapeutic option for the treatment of breast cancer. 2. KEY WORDS Ron receptor, Dek, beta-catenin, breast cancer 3...Finally, our data showed that Dek overexpression promoted tumorigenic properties in immortalized human mammary epithelial MCF10A cells and in the context

Immunoglobulin class-switch recombination deficiencies.

Science.gov (United States)

Durandy, Anne; Kracker, Sven

2012-07-30

Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.

Functional characterization of E- and P-cadherin in invasive breast cancer cells

International Nuclear Information System (INIS)

Sarrió, David; Palacios, José; Hergueta-Redondo, Marta; Gómez-López, Gonzalo; Cano, Amparo; Moreno-Bueno, Gema

2009-01-01

Alterations in the cadherin-catenin adhesion complexes are involved in tumor initiation, progression and metastasis. However, the functional implication of distinct cadherin types in breast cancer biology is still poorly understood. To compare the functional role of E-cadherin and P-cadherin in invasive breast cancer, we stably transfected these molecules into the MDA-MB-231 cell line, and investigated their effects on motility, invasion and gene expression regulation. Expression of either E- and P-cadherin significantly increased cell aggregation and induced a switch from fibroblastic to epithelial morphology. Although expression of these cadherins did not completely reverse the mesenchymal phenotype of MDA-MB-231 cells, both E- and P-cadherin decreased fibroblast-like migration and invasion through extracellular matrix in a similar way. Moreover, microarray gene expression analysis of MDA-MB-231 cells after expression of E- and P-cadherins revealed that these molecules can activate signaling pathways leading to significant changes in gene expression. Although the expression patterns induced by E- and P-cadherin showed more similarities than differences, 40 genes were differentially modified by the expression of either cadherin type. E- and P-cadherin have similar functional consequences on the phenotype and invasive behavior of MDA-MB-231 cells. Moreover, we demonstrate for the first time that these cadherins can induce both common and specific gene expression programs on invasive breast cancer cells. Importantly, these identified genes are potential targets for future studies on the functional consequences of altered cadherin expression in human breast cancer

Functional characterization of E- and P-cadherin in invasive breast cancer cells

Directory of Open Access Journals (Sweden)

Cano Amparo

2009-03-01

Full Text Available Abstract Background Alterations in the cadherin-catenin adhesion complexes are involved in tumor initiation, progression and metastasis. However, the functional implication of distinct cadherin types in breast cancer biology is still poorly understood. Methods To compare the functional role of E-cadherin and P-cadherin in invasive breast cancer, we stably transfected these molecules into the MDA-MB-231 cell line, and investigated their effects on motility, invasion and gene expression regulation. Results Expression of either E- and P-cadherin significantly increased cell aggregation and induced a switch from fibroblastic to epithelial morphology. Although expression of these cadherins did not completely reverse the mesenchymal phenotype of MDA-MB-231 cells, both E- and P-cadherin decreased fibroblast-like migration and invasion through extracellular matrix in a similar way. Moreover, microarray gene expression analysis of MDA-MB-231 cells after expression of E- and P-cadherins revealed that these molecules can activate signaling pathways leading to significant changes in gene expression. Although the expression patterns induced by E- and P-cadherin showed more similarities than differences, 40 genes were differentially modified by the expression of either cadherin type. Conclusion E- and P-cadherin have similar functional consequences on the phenotype and invasive behavior of MDA-MB-231 cells. Moreover, we demonstrate for the first time that these cadherins can induce both common and specific gene expression programs on invasive breast cancer cells. Importantly, these identified genes are potential targets for future studies on the functional consequences of altered cadherin expression in human breast cancer.

Analysing breast tissue composition with MRI using currently available short, simple sequences

International Nuclear Information System (INIS)

Chau, A.C.M.; Hua, J.; Taylor, D.B.

2016-01-01

Aim: To determine the most robust commonly available magnetic resonance imaging (MRI) sequence to quantify breast tissue composition at 1.5 T. Materials and methods: Two-dimensional (2D) T1-weighted, Dixon fat, Dixon water and SPAIR images were obtained from five participants and a breast phantom using a 1.5 T Siemens Aera MRI system. Manual segmentation of the breasts was performed, and an in-house computer program was used to generate signal intensity histograms. Relative trough depth and relative peak separation were used to determine the robustness of the images for quantifying the two breast tissues. Total breast volumes and percentage breast densities calculated using the four sequences were compared. Results: Dixon fat histograms had consistently low relative trough depth and relative peak separation compared to those obtained using other sequences. There was no significant difference in total breast volumes and percentage breast densities of the participants or breast phantom using Dixon fat and 2D T1-weighted histograms. Dixon water and SPAIR histograms were not suitable for quantifying breast tissue composition. Conclusion: Dixon fat images are the most robust for the quantification of breast tissue composition using a signal intensity histogram. - Highlights: • Signal intensity histogram analysis can determine robustness of images for quantification of breast tissue composition. • Dixon fat images are the most robust. • The characteristics of the signal intensity histograms from Dixon water and SPAIR images make quantification unsuitable.

Y-box Binding Protein-1 Enhances Oncogenic Transforming Growth Factor β Signaling in Breast Cancer Cells via Triggering Phospho-Activation of Smad2.

Science.gov (United States)

Stope, Matthias B; Weiss, Martin; Koensgen, Dominique; Popp, Simone L; Joffroy, Christian; Mustea, Alexander; Buck, Miriam B; Knabbe, Cornelius

2017-12-01

Transforming growth factor β (TGFβ) plays a role in diverse oncogenic pathways including cell proliferation and cell motility and is regulated by the pleiotropic factor Y-box binding protein-1 (YB-1). In breast cancer, Sma/Mad related protein 2 (Smad2) represents the most common downstream transducer in TGFβ signaling. Here, YB-1's impact on Smad2 phospho-activation was characterized by incubation of the breast cancer cell line MCF-7 with or without TGFβ1 in the absence or presence of overexpressed YB-1 protein. The phospho-status of Smad2 was assessed via western blotting. Analysis of MCF-7 cells revealed no induction of total Smad2 neither in the presence of TGFβ1, nor during YB-1 overexpression. In contrast, incubation with TGFβ1 led to an increase of phosphorylated Smad2 forms which was significantly amplified by simultaneously overexpressed YB-1 (2.8±0.2-fold). Oncogenic YB-1 indirectly enhances TGFβ signaling cascades via Smad2 phospho-activation and may represent a promising factor for future diagnosis and therapy of breast cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Unity power factor switching regulator

Science.gov (United States)

Rippel, Wally E. (Inventor)

1983-01-01

A single or multiphase boost chopper regulator operating with unity power factor, for use such as to charge a battery is comprised of a power section for converting single or multiphase line energy into recharge energy including a rectifier (10), one inductor (L.sub.1) and one chopper (Q.sub.1) for each chopper phase for presenting a load (battery) with a current output, and duty cycle control means (16) for each chopper to control the average inductor current over each period of the chopper, and a sensing and control section including means (20) for sensing at least one load parameter, means (22) for producing a current command signal as a function of said parameter, means (26) for producing a feedback signal as a function of said current command signal and the average rectifier voltage output over each period of the chopper, means (28) for sensing current through said inductor, means (18) for comparing said feedback signal with said sensed current to produce, in response to a difference, a control signal applied to the duty cycle control means, whereby the average inductor current is proportionate to the average rectifier voltage output over each period of the chopper, and instantaneous line current is thereby maintained proportionate to the instantaneous line voltage, thus achieving a unity power factor. The boost chopper is comprised of a plurality of converters connected in parallel and operated in staggered phase. For optimal harmonic suppression, the duty cycles of the switching converters are evenly spaced, and by negative coupling between pairs 180.degree. out-of-phase, peak currents through the switches can be reduced while reducing the inductor size and mass.

A three-level support method for smooth switching of the micro-grid operation model

Science.gov (United States)

Zong, Yuanyang; Gong, Dongliang; Zhang, Jianzhou; Liu, Bin; Wang, Yun

2018-01-01

Smooth switching of micro-grid between the grid-connected operation mode and off-grid operation mode is one of the key technologies to ensure it runs flexible and efficiently. The basic control strategy and the switching principle of micro-grid are analyzed in this paper. The reasons for the fluctuations of the voltage and the frequency in the switching process are analyzed from views of power balance and control strategy, and the operation mode switching strategy has been improved targeted. From the three aspects of controller’s current inner loop reference signal, voltage outer loop control strategy optimization and micro-grid energy balance management, a three-level security strategy for smooth switching of micro-grid operation mode is proposed. From the three aspects of controller’s current inner loop reference signal tracking, voltage outer loop control strategy optimization and micro-grid energy balance management, a three-level strategy for smooth switching of micro-grid operation mode is proposed. At last, it is proved by simulation that the proposed control strategy can make the switching process smooth and stable, the fluctuation problem of the voltage and frequency has been effectively improved.

Switched Control Strategies of Aggregated Commercial HVAC Systems for Demand Response in Smart Grids

Directory of Open Access Journals (Sweden)

Kai Ma

2017-07-01

Full Text Available This work proposes three switched control strategies for aggregated heating, ventilation, and air conditioning (HVAC systems in commercial buildings to track the automatic generation control (AGC signal in smart grid. The existing control strategies include the direct load control strategy and the setpoint regulation strategy. The direct load control strategy cannot track the AGC signal when the state of charge (SOC of the aggregated thermostatically controlled loads (TCLs exceeds their regulation capacity, while the setpoint regulation strategy provides flexible regulation capacity, but causes larger tracking errors. To improve the tracking performance, we took the advantages of the two control modes and developed three switched control strategies. The control strategies switch between the direct load control mode and the setpoint regulation mode according to different switching indices. Specifically, we design a discrete-time controller and optimize the controller parameter for the setpoint regulation strategy using the Fibonacci optimization algorithm, enabling us to propose two switched control strategies across multiple time steps. Furthermore, we extend the switched control strategies by introducing a two-stage regulation in a single time step. Simulation results demonstrate that the proposed switched control strategies can reduce the tracking errors for frequency regulation.

Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells.

Directory of Open Access Journals (Sweden)

David Bauer

Full Text Available Mortality associated with breast cancer is attributable to aggressive metastasis, to which TNFα plays a central orchestrating role. TNFα acts on breast tumor TNF receptors evoking the release of chemotactic proteins (e.g. MCP-1/CCL2. These proteins direct inward infiltration/migration of tumor-associated macrophages (TAMs, tumor-associated neutrophils (TANs, myeloid-derived suppressor cells (MDSCs, T-regulatory cells (Tregs, T helper IL-17-producing cells (Th17s, metastasis-associated macrophages (MAMs and cancer-associated fibroblasts (CAFs. Tumor embedded infiltrates collectively enable immune evasion, tumor growth, angiogenesis, and metastasis. In the current study, we investigate the potential of apigenin, a known anti-inflammatory constituent of parsley, to downregulate TNFα mediated release of chemokines from human triple-negative cells (MDA-MB-231 cells. The results show that TNFα stimulation leads to large rise of CCL2, granulocyte macrophage colony-stimulating factor (GMCSF, IL-1α and IL-6, all suppressed by apigenin. While many aspects of the transcriptome for NFkB signaling were evaluated, the data show signaling patterns associated with CCL2 were blocked by apigenin and mediated through suppressed mRNA and protein synthesis of IKBKe. Moreover, the data show that the attenuation of CCL2 by apigenin in the presence TNFα paralleled the suppression of phosphorylated extracellular signal-regulated kinase 1 (ERK 1/ 2. In summary, the obtained findings suggest that there exists a TNFα evoked release of CCL2 and other LSP recruiting cytokines from human breast cancer cells, which can be attenuated by apigenin.

Wideband microwave generation with GaAs photoconductive switches

Science.gov (United States)

Druce, R. L.; Pocha, M. D.; Griffin, K. L.; Stein, J. M.; Obannon, B. J. J.

1991-07-01

We are using solid state photoconductive switches to generate wideband microwave pulses with peak powers to 20 MW. A parallel-plate Blumlein transmission line is used to directly feed an exponential taper antenna to produce single pulses with rise times of 200 ps and pulse durations of 340 ps (FWHM). Voltages up to 21 kV have been generated in a 1 cm tall, 12 cm wide parallel-plate line. With the switches operated in linear mode, we have demonstrated phasing of several switches to generate a coherent wave. Generated and radiated signals agree very well with numerical calculations. Radiation efficiencies approach 30 percent. The Blumlein dielectric can be changed to produce a damped waveform, thereby modifying the bandwidth of the signal. We have generated damped waveforms of up to 3 cycles using this method. The parallel-plate geometry lends itself to coupling to an antenna structure to radiate efficiently. The geometry also lends itself to expanding the generator in height and width. We have stacked two generators to nearly double the output power without degrading the pulse characteristics. Applications of ultrashort microwave pulses require a high repetition rate and long life from the generator. Life times of greater than 10(exp 5) shots have been seen occasionally at low to medium power densities. As the power density of a solid state photoconductive switch is increased, device life decreases. We have the capability to test devices at a repetition rate of 30 Hz and voltages to 25 kV. Preliminary data indicates that repeated pulse biasing (without switching) of large LEC grown devices in a slab geometry with fields as low as 30 kV/cm damages the switch and eventually leads to failure.

Wideband microwave generation with GaAs photoconductive switches

Energy Technology Data Exchange (ETDEWEB)

Druce, R.L.; Pocha, M.D.; Griffin, K.L. (Lawrence Livermore National Lab., CA (United States)); Stein, J.M. (Rockwell International Corp., Albuquerque, NM (United States)); O' Bannon, B.J.J. (Rockwell International Corp., Anaheim, CA (United States))

1991-01-01

We are using solid state photoconductive switches to generate wideband microwave pulses with peak powers to 20 MW. A parallel-plate Blumlein transmission line is used to directly feed an exponential taper antenna to produce single pulses with rise times of 200 ps and pulse durations of 340 ps (FWHM). Voltages up to 21 kV have been generated in a 1 cm tall, 12 cm wide parallel-plate line. With the switches operated in linear mode, we have demonstrated phasing of several switches to generate a coherent wave. Generated and radiated signals agree very well with numerical calculations. Radiation efficiencies approach 30%. The Blumlein dielectric can be changed to produce a damped waveform, thereby modifying the bandwidth of the signal. We have generated damped waveforms of up to 3 cycles using this method. The parallel-plate geometry lends itself to coupling to an antenna structure to radiate efficiently. The geometry also lends itself to expanding the generator in height and width. We have stacked two generators to nearly double the output power without degrading the pulse characteristics. Applications of ultrashort microwave pulses (UWB radar, HPM weapons) require a high repetition rate and long life from the generator. Life times of >10{sup 5} shots have been seen occasionally at low to medium power densities. As the power density of a solid state photoconductive switch is increased, device life decreases. We have the capability to test devices at a repetition rate of 30 Hz and voltages to 25 kV. Preliminary data indicates that repeated pulse biasing (without switching) of large LEC grown devices in a slab geometry with fields as low as 30 kV/cm damages the switch and eventually leads to failure. 6 refs., 10 figs.

Evaluation and comparison of contrast to noise ratio and signal to noise ratio according to change of reconstruction on breast PET/CT

Energy Technology Data Exchange (ETDEWEB)

Lee, Young Jae [Dept. of Nuclear Medicine, Seoul National University Hospital, Seoul (Korea, Republic of); Lee, Eul Kyu [Dept. of Radiology, Inje Paik University Hospital Jeo-dong, Seoul (Korea, Republic of); Kim, Ki Won [Dept. of Radiology, Kyung Hee University Hospital at Gang-dong, Seoul (Korea, Republic of); Jeong, Hoi Woun [Dept. of Radiological Technology, The Baekseok Culture University, Cheonan (Korea, Republic of); Lyu, Kwang Yeul; Park, Hoon Hee; Son, Jin Hyun; Min, Jung Whan [Dept. of Radiological Technology, The Shingu University, Sungnam (Korea, Republic of)

2017-03-15

The purpose of this study was to measure contrast to noise ratio (CNR) and signal to noise ratio (SNR) according to change of reconstruction from region of interest (ROI) in breast positron emission tomography- computed tomography (PET-CT), and to analyze the CNR and SNR statically. We examined images of breast PET-CT of 100 patients in a University-affiliated hospital, Seoul, Korea. Each patient's image of breast PET-CT were calculated by using Image J. Differences of CNR and SNR among four reconstruction algorithms were tested by SPSS Statistics21 ANOVA test for there was statistical significance (p<0.05). We have analysis socio-demographical variables, CNR and SNR according to reconstruction images, 95% confidence according to CNR and SNR of reconstruction and difference in a mean of CNR and SNR. SNR results, with the quality of distributions in the order of PSF{sub T}OF, Iterative and Iterative-TOF, FBP-TOF. CNR, with the quality of distributions in the order of PSF{sub T}OF, Iterative and Iterative-TOF, FBP-TOF. CNR and SNR of PET-CT reconstruction methods of the breast would be useful to evaluate breast diseases.

Modeling Random Telegraph Noise Under Switched Bias Conditions Using Cyclostationary RTS Noise

NARCIS (Netherlands)

van der Wel, A.P.; Klumperink, Eric A.M.; Vandamme, L.K.J.; Nauta, Bram

In this paper, we present measurements and simulation of random telegraph signal (RTS) noise in n-channel MOSFETs under periodic large signal gate-source excitation (switched bias conditions). This is particularly relevant to analog CMOS circuit design where large signal swings occur and where LF

Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

International Nuclear Information System (INIS)

Azuma, Koichi; Tsurutani, Junji; Sakai, Kazuko; Kaneda, Hiroyasu; Fujisaka, Yasuhito; Takeda, Masayuki; Watatani, Masahiro; Arao, Tokuzo; Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu; Nishio, Kazuto; Nakagawa, Kazuhiko

2011-01-01

Highlights: → A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. → Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. → Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC 50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

Energy Technology Data Exchange (ETDEWEB)

Azuma, Koichi [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Tsurutani, Junji, E-mail: tsurutani_j@dotd.med.kindai.ac.jp [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Sakai, Kazuko; Kaneda, Hiroyasu [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Fujisaka, Yasuhito; Takeda, Masayuki [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Watatani, Masahiro [Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Arao, Tokuzo [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nishio, Kazuto [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nakagawa, Kazuhiko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan)

2011-04-01

Highlights: {yields} A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. {yields} Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. {yields} Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC{sub 50} of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

35-kV GaAs subnanosecond photoconductive switches

Science.gov (United States)

Pocha, Michael D.; Druce, Robert L.

1990-12-01

High-voltage, fast-pulse generation using GaAs photoconductive switches is investigated. It is possible to to generate 35-kV pulses with risetimes as short as 135 ps using 5-mm gap switches, and electric field hold-off of greater than 100 kV/cm is achieved. An approximately 500-ps FWHM on/off electrical pulse is generated with an amplitude of approximately 3 kV using neutron-irradiated GaAs having short carrier lifetimes. Experimental results are described, and fabrication of switches and the diagnostics used to measure these fast signals are discussed. Experience with the nonlinear lock-on and avalanche modes of operation observed in GaAs is also described.

Hormone resistance in two MCF-7 breast cancer cell lines is associated with reduced mTOR signaling, decreased glycolysis and increased sensitivity to cytotoxic drugs

Directory of Open Access Journals (Sweden)

Euphemia Yee Leung

2014-09-01

Full Text Available The mTOR pathway is a key regulator of multiple cellular signaling pathways and is a potential target for therapy. We have previously developed two hormone-resistant sub-lines of the MCF-7 human breast cancer line, designated TamC3 and TamR3, which were characterized by reduced mTOR signaling, reduced cell volume and resistance to mTOR inhibition. Here we show that these lines exhibit increased sensitivity to carboplatin, oxaliplatin, 5-fluorouracil, camptothecin, doxorubicin, paclitaxel, docetaxel and hydrogen peroxide. The mechanisms underlying these changes have not yet been characterized but may include a shift from glycolysis to mitochondrial respiration. If this phenotype is found in clinical hormone-resistant breast cancers, conventional cytotoxic therapy may be a preferred option for treatment.

Breast Cancer Research Program (BCRP) - Predoctoral Traineeship - Elucidating the Role of the Type III Transforming Growth Factor-beta Receptor in Bone Morphogenetic Signaling in Breast Cancer

Science.gov (United States)

2008-03-01

phosphorylation in the pancreatic cancer cell model, Panc -1 (data not shown). This data emphasize that TβRIII’s role in BMP signaling is likely to be cell... Panc -1 cells were adenovirally infected with TβRIII, followed by BMP-4-induced EMT. The cells were then plated in Matrigel invasion chambers. A...BMP-2, while loss of TβRIII in Panc -1 (pancreatic cancer cells) increased cell sensitivity to BMP-2 and had no effect on MDA-MB-231 (breast cancer

A genetic bistable switch utilizing nonlinear protein degradation.

Science.gov (United States)

Huang, Daniel; Holtz, William J; Maharbiz, Michel M

2012-07-09

Bistability is a fundamental property in engineered and natural systems, conferring the ability to switch and retain states. Synthetic bistable switches in prokaryotes have mainly utilized transcriptional components in their construction. Using both transcriptional and enzymatic components, creating a hybrid system, allows for wider bistable parameter ranges in a circuit. In this paper, we demonstrate a tunable family of hybrid bistable switches in E. coli using both transcriptional components and an enzymatic component. The design contains two linked positive feedback loops. The first loop utilizes the lambda repressor, CI, and the second positive feedback loop incorporates the Lon protease found in Mesoplasma florum (mf-Lon). We experimentally tested for bistable behavior in exponential growth phase, and found that our hybrid bistable switch was able to retain its state in the absence of an input signal throughout 40 cycles of cell division. We also tested the transient behavior of our switch and found that switching speeds can be tuned by changing the expression rate of mf-Lon. To our knowledge, this work demonstrates the first use of dynamic expression of an orthogonal and heterologous protease to tune a nonlinear protein degradation circuit. The hybrid switch is potentially a more robust and tunable topology for use in prokaryotic systems.

The Regulation of the Angiogenic Factor FGF Binding Protein (FGF-BP) by the APC/Beta-Catenin Signaling Pathway in the Progression of Breast Cancer

National Research Council Canada - National Science Library

Stylianou, Dora

2004-01-01

...) to study the expression of FGF-BP in mammary tumorigenesis progression of the APC/+ mouse and 2) to determine the mechanism of regulation of FGF-BP b the APC/beta-catenin signaling pathway in breast cancer...

The Regulation of the Angiogenic Factor FGF Binding Protein (FGF-BP) by the APC/Beta-Catenin Signaling Pathway in the Progression of Breast Cancer

National Research Council Canada - National Science Library

Stylianou, Dora

2003-01-01

...) to study the expression of FGF-BP in mammary tumorigenesis% progression of the APC/+ mouse and 2) to determine the mechanism of regulation of FGF-BP by the APC/beta- catenin signaling pathway in breast cancer...

Iaverage current mode (ACM) control for switching power converters

OpenAIRE

2014-01-01

Providing a fast current sensor direct feedback path to a modulator for controlling switching of a switched power converter in addition to an integrating feedback path which monitors average current for control of a modulator provides fast dynamic response consistent with system stability and average current mode control. Feedback of output voltage for voltage regulation can be combined with current information in the integrating feedback path to limit bandwidth of the voltage feedback signal.

HPW-RX40 restores anoikis sensitivity of human breast cancer cells by inhibiting integrin/FAK signaling

Energy Technology Data Exchange (ETDEWEB)

Chen, I-Hua; Shih, Hsin-Chu [Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Hsieh, Pei-Wen [Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China); Chang, Fang-Rong [Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan (China); Wu, Yang-Chang, E-mail: yachwu@mail.cmu.edu [School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan (China); Wu, Chin-Chung, E-mail: ccwu@kmu.edu.tw [Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80708, Taiwan (China); Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan (China)

2015-12-01

Anoikis is defined as apoptosis, which is induced by inappropriate cell–matrix interactions. Cancer cells with anoikis resistance tend to undergo metastasis, and this phenomenon has been reported to be associated with integrin and FAK activity. HPW-RX40 is a derivative of 3,4-methylenedioxy-β-nitrostyrene, which is known to prevent platelet aggregation by inhibition of integrin. In the present study, we investigated the effect of HPW-RX40 on an anoikis-resistant human breast cancer cell line MDA-MB-231. HPW-RX40 inhibited cell aggregation and induced cell death in suspending MDA-MB-231 cells, but had only little effect on the monolayer growth of adherent cells. Analysis of caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage confirmed anoikis in HPW-RX40-treated suspending cancer cells. HPW-RX40 also affected the Bcl-2 family proteins in detached cancer cells. Furthermore, HPW-RX40 inhibited detachment-induced activation of FAK and the downstream phosphorylation of Src and paxillin, but did not affect this pathway in adherent cancer cells. We also found that the expression and activation of β1 integrin in MDA-MB-231 cells were reduced by HPW-RX40. The combination of HPW-RX40 with an EGFR inhibitor led to enhanced anoikis and inhibition of the FAK pathway in breast cancer cells. Taken together, our results suggest that HPW-RX40 restores the anoikis sensitivity in the metastatic breast cancer cells by inhibiting integrin and subsequent FAK activation, and reveal a potential strategy for prevention of tumor metastasis. - Highlights: • The β-nitrostyrene derivative, HPW-RX40, induces anoikis in human breast cancer cells. • HPW-RX40 inhibits the integrin/FAK signaling pathway. • The combination of HPW-RX40 with an EGFR inhibitor leads to enhanced anoikis. • HPW-RX40 may have a potential to prevent the spread of metastatic breast cancer.

HPW-RX40 restores anoikis sensitivity of human breast cancer cells by inhibiting integrin/FAK signaling

International Nuclear Information System (INIS)

Chen, I-Hua; Shih, Hsin-Chu; Hsieh, Pei-Wen; Chang, Fang-Rong; Wu, Yang-Chang; Wu, Chin-Chung

2015-01-01

Anoikis is defined as apoptosis, which is induced by inappropriate cell–matrix interactions. Cancer cells with anoikis resistance tend to undergo metastasis, and this phenomenon has been reported to be associated with integrin and FAK activity. HPW-RX40 is a derivative of 3,4-methylenedioxy-β-nitrostyrene, which is known to prevent platelet aggregation by inhibition of integrin. In the present study, we investigated the effect of HPW-RX40 on an anoikis-resistant human breast cancer cell line MDA-MB-231. HPW-RX40 inhibited cell aggregation and induced cell death in suspending MDA-MB-231 cells, but had only little effect on the monolayer growth of adherent cells. Analysis of caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage confirmed anoikis in HPW-RX40-treated suspending cancer cells. HPW-RX40 also affected the Bcl-2 family proteins in detached cancer cells. Furthermore, HPW-RX40 inhibited detachment-induced activation of FAK and the downstream phosphorylation of Src and paxillin, but did not affect this pathway in adherent cancer cells. We also found that the expression and activation of β1 integrin in MDA-MB-231 cells were reduced by HPW-RX40. The combination of HPW-RX40 with an EGFR inhibitor led to enhanced anoikis and inhibition of the FAK pathway in breast cancer cells. Taken together, our results suggest that HPW-RX40 restores the anoikis sensitivity in the metastatic breast cancer cells by inhibiting integrin and subsequent FAK activation, and reveal a potential strategy for prevention of tumor metastasis. - Highlights: • The β-nitrostyrene derivative, HPW-RX40, induces anoikis in human breast cancer cells. • HPW-RX40 inhibits the integrin/FAK signaling pathway. • The combination of HPW-RX40 with an EGFR inhibitor leads to enhanced anoikis. • HPW-RX40 may have a potential to prevent the spread of metastatic breast cancer.

35-kV GaAs subnanosecond photoconductive switches

Energy Technology Data Exchange (ETDEWEB)

Pocha, M.D.; Druce, R.L. (Lawrence Livermore National Lab., CA (United States))

1990-12-01

Photoconductive switches are one of the few devices that allow the generation of high-voltage electrical pulses with subnanosecond rise time. The authors are exploring high-voltage, fast-pulse generation using GaAs photoconductive switches. They have been able to generate 35-kV pulses with rise times as short as 135 ps using 5-mm gap switches and have achieved electric field hold-off of greater than 100 kV/cm. They have also been able to generate an approximately 500-ps FWHM on/off electrical pulse with an amplitude of approximately 3 kV using neutron-irradiated GaAs having short carrier life times. This paper describes the experimental results and discusses fabrication of switches and the diagnostics used to measure these fast signals. They also describe the experience with the nonlinear lock-on and avalanche modes of operation observed in GaAs.

Appearance of low signal intensity lines in MRI of silicone breast implants.

Science.gov (United States)

Stroman, P W; Rolland, C; Dufour, M; Grondin, P; Guidoin, R G

1996-05-01

Magnetic resonance (MR) images of five explanted mammary prostheses were obtained with a 1.5 T GE Signa system using a conventional spin-echo pulse sequence, in order to investigate the low-intensity curvilinear lines which may be observed in MR images of silicone gel-filled breast implants under pressure from fibrous capsules. MR images showed ellipsoid prostheses, often containing multiple low-intensity curvilinear lines which in some cases presented an appearance very similar to that of the linguine sign. Upon opening the fibrous capsules, however, all of the prostheses were found to be completely intact demonstrating that the appearance of multiple low signal intensity curvilinear lines in MR images of silicone gel-filled prostheses is not necessarily a sign of prosthesis rupture. The MR image features which are specific to the linguine sign must be more precisely defined.

Intelligent switches of integrated lightwave circuits with core telecommunication functions

Science.gov (United States)

Izhaky, Nahum; Duer, Reuven; Berns, Neil; Tal, Eran; Vinikman, Shirly; Schoenwald, Jeffrey S.; Shani, Yosi

2001-05-01

We present a brief overview of a promising switching technology based on Silica on Silicon thermo-optic integrated circuits. This is basically a 2D solid-state optical device capable of non-blocking switching operation. Except of its excellent performance (insertion lossvariable output power control (attenuation), for instance, to equalize signal levels and compensate for unbalanced different optical input powers, or to equalize unbalanced EDFA gain curve. We examine the market segments appropriate for the switch size and technology, followed by a discussion of the basic features of the technology. The discussion is focused on important requirements from the switch and the technology (e.g., insertion loss, power consumption, channel isolation, extinction ratio, switching time, and heat dissipation). The mechanical design is also considered. It must take into account integration of optical fiber, optical planar wafer, analog electronics and digital microprocessor controls, embedded software, and heating power dissipation. The Lynx Photon.8x8 switch is compared to competing technologies, in terms of typical market performance requirements.

Dynamic MRI of breast fibroadenoma: pathologic correlation

Energy Technology Data Exchange (ETDEWEB)

Oh, Ki Keun; Hahm, Jin kyeung; Yoon, Pyong Ho; Jeong, Eun Kee [Yonsei University, College of Medicine, Seoul (Korea, Republic of)

1995-09-15

To analyze the dynamic MR imaging of breast fibroadenoma according to the histologic type for differentiation from breast carcinoma. Dynamic MR images of 26 lesions from 22 breasts in 19 patients showing atypical clinical features or film mammogram and ultrasound manifestations were performed. We analyzed the speed and the maximal amount of contrast enhancement and the patterns, such as shape, border, and internal signal intensity, among the histologic types during five minutes after contrast injection. The speed and maximal amount of contrast enhancement of fibroadenoma were in descending order of myxoid, sclerotic, glandular, and calcified types. Among these, the value of maximal amount of contrast enhancement of myxoid and sclerotic type were more than 700 NU, but only myxoid type was enhanced more than 700 NU within the first 1 minute after contrast injection, similar to the findings of carcinoma. In general, fibroadenoma showed the tendency of smooth surface(69%), well-defined border(88%) with safety rim, and internal homogeneous signal intensity(65%). However, sclerotic type of fibroadenoma had relatively high incidence of heterogeneous internal signal intensity(78%) after Gd-DTPA injection. Dynamic MR imaging of atypical breast fibroadenoma mimicking breast malignancy was very useful in differentiation it from carcinoma and had the benefit of classifying fibroadenoma according to its histologic types.

Dynamic MRI of breast fibroadenoma: pathologic correlation

International Nuclear Information System (INIS)

Oh, Ki Keun; Hahm, Jin kyeung; Yoon, Pyong Ho; Jeong, Eun Kee

1995-01-01

To analyze the dynamic MR imaging of breast fibroadenoma according to the histologic type for differentiation from breast carcinoma. Dynamic MR images of 26 lesions from 22 breasts in 19 patients showing atypical clinical features or film mammogram and ultrasound manifestations were performed. We analyzed the speed and the maximal amount of contrast enhancement and the patterns, such as shape, border, and internal signal intensity, among the histologic types during five minutes after contrast injection. The speed and maximal amount of contrast enhancement of fibroadenoma were in descending order of myxoid, sclerotic, glandular, and calcified types. Among these, the value of maximal amount of contrast enhancement of myxoid and sclerotic type were more than 700 NU, but only myxoid type was enhanced more than 700 NU within the first 1 minute after contrast injection, similar to the findings of carcinoma. In general, fibroadenoma showed the tendency of smooth surface(69%), well-defined border(88%) with safety rim, and internal homogeneous signal intensity(65%). However, sclerotic type of fibroadenoma had relatively high incidence of heterogeneous internal signal intensity(78%) after Gd-DTPA injection. Dynamic MR imaging of atypical breast fibroadenoma mimicking breast malignancy was very useful in differentiation it from carcinoma and had the benefit of classifying fibroadenoma according to its histologic types

Gated integrator with signal baseline subtraction

Energy Technology Data Exchange (ETDEWEB)

Wang, X.

1996-12-17

An ultrafast, high precision gated integrator includes an opamp having differential inputs. A signal to be integrated is applied to one of the differential inputs through a first input network, and a signal indicative of the DC offset component of the signal to be integrated is applied to the other of the differential inputs through a second input network. A pair of electronic switches in the first and second input networks define an integrating period when they are closed. The first and second input networks are substantially symmetrically constructed of matched components so that error components introduced by the electronic switches appear symmetrically in both input circuits and, hence, are nullified by the common mode rejection of the integrating opamp. The signal indicative of the DC offset component is provided by a sample and hold circuit actuated as the integrating period begins. The symmetrical configuration of the integrating circuit improves accuracy and speed by balancing out common mode errors, by permitting the use of high speed switching elements and high speed opamps and by permitting the use of a small integrating time constant. The sample and hold circuit substantially eliminates the error caused by the input signal baseline offset during a single integrating window. 5 figs.

Gated integrator with signal baseline subtraction

Energy Technology Data Exchange (ETDEWEB)

Wang, Xucheng (Lisle, IL)

1996-01-01

An ultrafast, high precision gated integrator includes an opamp having differential inputs. A signal to be integrated is applied to one of the differential inputs through a first input network, and a signal indicative of the DC offset component of the signal to be integrated is applied to the other of the differential inputs through a second input network. A pair of electronic switches in the first and second input networks define an integrating period when they are closed. The first and second input networks are substantially symmetrically constructed of matched components so that error components introduced by the electronic switches appear symmetrically in both input circuits and, hence, are nullified by the common mode rejection of the integrating opamp. The signal indicative of the DC offset component is provided by a sample and hold circuit actuated as the integrating period begins. The symmetrical configuration of the integrating circuit improves accuracy and speed by balancing out common mode errors, by permitting the use of high speed switching elements and high speed opamps and by permitting the use of a small integrating time constant. The sample and hold circuit substantially eliminates the error caused by the input signal baseline offset during a single integrating window.

Contrast-enhanced color Doppler ultrasound characteristics in hypervascular breast tumors: comparison with MRI

International Nuclear Information System (INIS)

Alamo, L.; Fischer, U.

2001-01-01

The aim of this study was to evaluate the accuracy of contrast-enhanced color Doppler ultrasound (CE-US) in comparison with contrast-enhanced MR imaging (CE-MRI) in the discrimination of hypervascularized breast tumors. An additional CE-US of the breast was preoperatively performed in 40 patients with a hypervascular breast lesion detected on CE-MRI. The presence of blood flow signals and the morphological characteristics of the vessels in the breast lesions were evaluated pre- and post-contrast administration, as well as the dynamic aspects of the Doppler signal, including time interval to maximum signal enhancement and persistence of the signal enhancement. Twenty-three carcinomas and 17 fibroadenomas were explored. Considering initial signal enhancement > 100 % after the administration of contrast material as a criterion suggesting malignancy, CE-MRI showed a sensitivity of 100 % and a specificity of 76.5 % in the detection of malignant breast tumors. Color Doppler signals were consistently demonstrated in all carcinomas and in 68.7 % of fibroadenomas after the administration of Levovist, with CE-US showing a sensitivity of 95.6 % and a specificity of 5.9 %. Neither the mean number of vessels per tumor, nor the location of vessels, the time to maximum increase of the Doppler signal or the persistence of signal enhancement showed significant differences between benign and malignant lesions. Additional CE-US does not increase the low specificity of MRI in patients with hypervascularized breast tumors. (orig.)

Programmable Power Supply for AC Switching Magnet of Proton Accelerator

CERN Document Server

Jeong, Seong-Hun; Kang Heung Sik; Lee, Chi-Hwan; Lee, Hong-Gi; Park, Ki-Hyeon; Ryu, Chun-Kil; Sik Han, Hong; Suck Suh, Hyung

2005-01-01

The 100-MeV PEFP proton linac has two proton beam extraction lines for user' experiment. Each extraction line has 5 beamlines and has 5 Hz operating frequency. An AC switching magnet is used to distribute the proton beam to the 5 beamlines, An AC switching magnet is powered by PWM-controlled bipolar switching-mode converters. This converter is designed to operate at ±350A, 5 Hz programmable step output. The power supply is employed IGBT module and has controlled by a DSP (Digital Signal Process). This paper describes the design and test results of the power supply.

Optically coupled cavities for wavelength switching

Energy Technology Data Exchange (ETDEWEB)

Costazo-Caso, Pablo A; Granieri, Sergio; Siahmakoun, Azad, E-mail: pcostanzo@ing.unlp.edu.ar, E-mail: granieri@rose-hulman.edu, E-mail: siahmako@rose-hulman.edu [Department of Physics and Optical Engineering, Rose-Hulman Institute of Technology, 5500 Wabash Avenue, Terre Haute, IN 47803 (United States)

2011-01-01

An optical bistable device which presents hysteresis behavior is proposed and experimentally demonstrated. The system finds applications in wavelength switching, pulse reshaping and optical bistability. It is based on two optically coupled cavities named master and slave. Each cavity includes a semiconductor optical amplifier (SOA), acting as the gain medium of the laser, and two pair of fiber Bragg gratings (FBG) which define the lasing wavelength (being different in each cavity). Finally, a variable optical coupler (VOC) is employed to couple both cavities. Experimental characterization of the system performance is made analyzing the effects of the coupling coefficient between the two cavities and the driving current in each SOA. The properties of the hysteretic bistable curve and switching can be controlled by adjusting these parameters and the loss in the cavities. By selecting the output wavelength ({lambda}{sub 1} or {lambda}{sub 2}) with an external filter it is possible to choose either the invert or non-invert switched signal. Experiments were developed employing both optical discrete components and a photonic integrated circuit. They show that for 8 m-long cavities the maximum switching frequency is about 500 KHz, and for 4 m-long cavities a minimum rise-time about 21 ns was measured. The switching time can be reduced by shortening the cavity lengths and using photonic integrated circuits.

General Switch-and-Stay Combing for Space Diversity over Rayleigh Fading Channels

Directory of Open Access Journals (Sweden)

Yawgeng A. Chau

2012-01-01

Full Text Available Three multibranch switch-and-stay combining (MSSC schemes are analyzed for Rayleigh fading channels, where different decision statistics for antenna switching (i.e., switch statistic are used. Let a and r denote the fading factor and the received baseband signal of a diversity branch, respectively. In contrast to the traditional MSSC that uses the faded signal-to-noise ratio (SNR of diversity branches as the corresponding switch statistic, to enhance the receiver performance, |r|, |ar|, and a new linear combination of a and |r| are used as switch statistics of the three MSSC schemes, respectively. For performance evaluation, the bit error rate (BER of BPSK is derived for the three MSSC schemes over both independent-and-identical distributed (i.i.d. and independent-and-nonidentical distributed (i.n.d. Rayleigh fading channels. To pursue optimal performance, the locally optimal switch threshold (ST of each MSSC scheme is obtained for general i.n.d. fading channels. In addition, the locally optimal ST becomes the globally optimal ST for i.i.d. channels. Numerical results based on the analysis and simulations are presented. In contrast to the MSSC over i.i.d. fading channels, we will show that the performance of MSSC schemes can be improved by increasing the number of branches, if i.n.d. channels are considered.

Multilayered proteomics reveals molecular switches dictating ligand-dependent EGFR trafficking

DEFF Research Database (Denmark)

Francavilla, Chiara; Papetti, Moreno; Rigbolt, Kristoffer T G

2016-01-01

, we devised an integrated multilayered proteomics approach (IMPA). We analyzed dynamic changes in the receptor interactome, ubiquitinome, phosphoproteome, and late proteome in response to both ligands in human cells by quantitative MS and identified 67 proteins regulated at multiple levels. We...... identified RAB7 phosphorylation and RCP recruitment to EGFR as switches for EGF and TGF-α outputs, controlling receptor trafficking, signaling duration, proliferation, and migration. By manipulating RCP levels or phosphorylation of RAB7 in EGFR-positive cancer cells, we were able to switch a TGF......-α-mediated response to an EGF-like response or vice versa as EGFR trafficking was rerouted. We propose IMPA as an approach to uncover fine-tuned regulatory mechanisms in cell signaling....

Evaluation of Two Statistical Methods Provides Insights into the Complex Patterns of Alternative Polyadenylation Site Switching

Science.gov (United States)

Li, Jie; Li, Rui; You, Leiming; Xu, Anlong; Fu, Yonggui; Huang, Shengfeng

2015-01-01

Switching between different alternative polyadenylation (APA) sites plays an important role in the fine tuning of gene expression. New technologies for the execution of 3’-end enriched RNA-seq allow genome-wide detection of the genes that exhibit significant APA site switching between different samples. Here, we show that the independence test gives better results than the linear trend test in detecting APA site-switching events. Further examination suggests that the discrepancy between these two statistical methods arises from complex APA site-switching events that cannot be represented by a simple change of average 3’-UTR length. In theory, the linear trend test is only effective in detecting these simple changes. We classify the switching events into four switching patterns: two simple patterns (3’-UTR shortening and lengthening) and two complex patterns. By comparing the results of the two statistical methods, we show that complex patterns account for 1/4 of all observed switching events that happen between normal and cancerous human breast cell lines. Because simple and complex switching patterns may convey different biological meanings, they merit separate study. We therefore propose to combine both the independence test and the linear trend test in practice. First, the independence test should be used to detect APA site switching; second, the linear trend test should be invoked to identify simple switching events; and third, those complex switching events that pass independence testing but fail linear trend testing can be identified. PMID:25875641

The Estrogen Receptor and Its Variants as Risk Factors in Breast Cancer

National Research Council Canada - National Science Library

Murph, Leigh

2001-01-01

The overall goal of this research is to understand how the estrogen receptor (ER) signal transduction pathway is altered during breast tumorigenesis and if altered ER signal transduction increases the risk of developing breast cancer...

Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.

Science.gov (United States)

Bernardo, Ana R; Cosgaya, José M; Aranda, Ana; Jiménez-Lara, Ana M

2017-07-01

Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

Rf power amplification by energy storage and switching

International Nuclear Information System (INIS)

Vernon, W.

1989-01-01

This paper reports that during the last decade there have been several suggestions for RF storage and switching schemes. The principle behind these schemes is simply that energy from a source which is on for a long time at moderate power can be stored in a resonant cavity and dumped (switched) in a short time to yield higher power. This is also the basis of SLED which is driving the SLC, but the major difference is in the switching and the proposed power gains. In the case of SLED there is no switch only a phase agile RF source, and the maximum power gain is about a factor of 3. Proposed storage and switching schemes are often based on large ratios of charge to discharge times, say 5 μsec/50 nsec = 100 which could be the power amplification ratio. An early demonstration of the switching of a superconducting cavity was reported. It was observed that a peak power gain of 9 at low power levels with a cold cavity and a room-temperature switch. The switch was a He gas filled tube positioned in the leg of a waveguide T so that a η/2 stub turned into a η/4 stub when the gas broke down and became a good conductor. All switches encountered to date are some variant of this technique; the stubs reflects back an out-of-phase signal which cancels the one from the cavity so that no power escapes while the low-loss dielectric tube is non-conducting

Modular design strategies for protein sensors and switches

NARCIS (Netherlands)

Merkx, M.; Ryadnov, M.; Brunsveld, L.; Suga, H.

2014-01-01

Protein-based sensors and switches provide attractive tools for the real-time monitoring and control of molecular processes in complex biological environments, with applications ranging from intracellular imaging to the rewiring of signal transduction pathways and molecular diagnostics. A

Recent Advancements in Semiconductor-based Optical Signal Processing

DEFF Research Database (Denmark)

Nielsen, M L; Mørk, Jesper

2006-01-01

Significant advancements in technology and basic understanding of device physics are bringing optical signal processing closer to a commercial breakthrough. In this paper we describe the main challenges in high-speed SOA-based switching.......Significant advancements in technology and basic understanding of device physics are bringing optical signal processing closer to a commercial breakthrough. In this paper we describe the main challenges in high-speed SOA-based switching....

Near-infrared laser, time domain, breast tumour detection system

International Nuclear Information System (INIS)

Joblin, A.J.

1996-01-01

Full text: The use of near-infrared laser, time domain techniques have been proposed for some time now as an alternative to X-ray mammography, as a means of mass screening for breast disease. The great driving force behind this research has been that near-infrared photons are a non-ionising radiation, which affords a greater degree of patient safety than when using X-rays. This would mean that women at risk of breast disease could be screened with a near-infrared laser imaging system, much more regularly than with an X-ray mammography system, which should allow for the earlier detection and treatment of breast disease. This paper presents a theoretical investigation of the performance of a near-infrared, time domain breast imaging system. The performance of the imaging system is characterised by the resolution and contrast parameters, which were studied using a numerical finite difference calculation method. The finite difference method is used to solve the diffusion equation for the photon transport through the inhomogeneous breast tissue medium. Optimal performance was found to be obtained with short photon times of flight. However the signal to noise ratio decreases rapidly as the photon time of flight is decreased. The system performance will therefore be limited by the noise equivalent power of the time resolved detection system, which is the signal incident on the time resolved detection system which gives a signal to noise ratio of 1:1. Photon times of flight shorter than 500 ps are not practical with current technology, which places limits on the resolution and contrast. The photon signal throughput can be increased by increasing the size of the laser beam width, by increasing the size of the aperture stop of the detector, by increasing the laser pulse duration or decreasing the detector time resolution. Best system performance is found by optimising these parameters for a given time gating and detector system characteristic (NEP). It was found that the

Design of a bistable switch to control cellular uptake.

Science.gov (United States)

Oyarzún, Diego A; Chaves, Madalena

2015-12-06

Bistable switches are widely used in synthetic biology to trigger cellular functions in response to environmental signals. All bistable switches developed so far, however, control the expression of target genes without access to other layers of the cellular machinery. Here, we propose a bistable switch to control the rate at which cells take up a metabolite from the environment. An uptake switch provides a new interface to command metabolic activity from the extracellular space and has great potential as a building block in more complex circuits that coordinate pathway activity across cell cultures, allocate metabolic tasks among different strains or require cell-to-cell communication with metabolic signals. Inspired by uptake systems found in nature, we propose to couple metabolite import and utilization with a genetic circuit under feedback regulation. Using mathematical models and analysis, we determined the circuit architectures that produce bistability and obtained their design space for bistability in terms of experimentally tuneable parameters. We found an activation-repression architecture to be the most robust switch because it displays bistability for the largest range of design parameters and requires little fine-tuning of the promoters' response curves. Our analytic results are based on on-off approximations of promoter activity and are in excellent qualitative agreement with simulations of more realistic models. With further analysis and simulation, we established conditions to maximize the parameter design space and to produce bimodal phenotypes via hysteresis and cell-to-cell variability. Our results highlight how mathematical analysis can drive the discovery of new circuits for synthetic biology, as the proposed circuit has all the hallmarks of a toggle switch and stands as a promising design to control metabolic phenotypes across cell cultures. © 2015 The Author(s).

49 CFR 236.528 - Restrictive condition resulting from open hand-operated switch; requirement.

Science.gov (United States)

2010-10-01

... SYSTEMS, DEVICES, AND APPLIANCES Automatic Train Stop, Train Control and Cab Signal Systems Rules and...-operated switch three-eighths inch or more, or hand-operated switch is not locked where facing point lock with circuit controller is used, the resultant restrictive condition of an automatic train stop or...

Dual inhibition of Wnt and Yes-associated protein signaling retards the growth of triple-negative breast cancer in both mesenchymal and epithelial states.

Science.gov (United States)

Sulaiman, Andrew; McGarry, Sarah; Li, Li; Jia, Deyong; Ooi, Sarah; Addison, Christina; Dimitroulakos, Jim; Arnaout, Angel; Nessim, Carolyn; Yao, Zemin; Ji, Guang; Song, Haiyan; Gadde, Suresh; Li, Xuguang; Wang, Lisheng

2018-04-01

Triple-negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer-related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesenchymal-like and epithelial-like states have been revealed in breast CSCs. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed. Wnt/β-catenin and Hippo/YAP pathways are crucial in tumorigenesis, but importantly also possess tumor suppressor functions in certain contexts. One possibility is that TNBC cells in epithelial or mesenchymal state may differently affect Wnt/β-catenin and Hippo/YAP signaling and CSC phenotypes. In this report, we found that YAP signaling and CD44 high /CD24 -/low CSCs were upregulated while Wnt/β-catenin signaling and ALDH+ CSCs were downregulated in mesenchymal-like TNBC cells, and vice versa in their epithelial-like counterparts. Dual knockdown of YAP and Wnt/β-catenin, but neither alone, was required for effective suppression of both CD44 high /CD24 -/low and ALDH+ CSC populations in mesenchymal and epithelial TNBC cells. These observations were confirmed with cultured tumor fragments prepared from patients with TNBC after treatment with Wnt inhibitor ICG-001 and YAP inhibitor simvastatin. In addition, a clinical database showed that decreased gene expression of Wnt and YAP was positively correlated with decreased ALDH and CD44 expression in patients' samples while increased patient survival. Furthermore, tumor growth of TNBC cells in either epithelial or mesenchymal state was retarded, and both CD44 high /CD24 -/low and ALDH+ CSC subpopulations were diminished in a human xenograft model after dual administration of ICG-001 and simvastatin. Tumorigenicity was also hampered after secondary transplantation. These data suggest a new

Experimental and theoretical investigation of semiconductor optical amplifier (SOA) based all-optical switches

DEFF Research Database (Denmark)

Nielsen, Mads Lønstrup

2004-01-01

This thesis analyzes semiconductor optical amplifier (SOA) based all-optical switches experimentally and through numerical simulations. These devices are candidates for optical signal processing functionalities such as wavelength conversion, regeneration, and logic processing in future transparent......, consisting of an SOA and an asymmetric MZI filter, is analyzed in the small-signal regime, and the obtainable modulation bandwidth is expressed analytically. A new optical spectrum approach to small signal analysis is introduced, and is used to assess the bandwidth enhancing effect of different optical...... filters, as well the impact of the filter phase response. Experiments at 40 Gb/s verify the predictions of the small-signal analysis. Wavelength conversion is demonstrated experimentally at 40 Gb/s using a simple filtering-assisted scheme with an ultra-low optical switching energy, and up to 80 Gb...

The ShcA SH2 domain engages a 14-3-3/PI3'K signaling complex and promotes breast cancer cell survival.

Science.gov (United States)

Ursini-Siegel, J; Hardy, W R; Zheng, Y; Ling, C; Zuo, D; Zhang, C; Podmore, L; Pawson, T; Muller, W J

2012-11-29

The ShcA adapter protein transmits activating signals downstream of receptor and cytoplasmic tyrosine kinases through the establishment of phosphotyrosine-dependent complexes. In this regard, ShcA possesses both a phosphotyrosine-binding domain (PTB) and Src homology 2 domain (SH2), which bind phosphotyrosine residues in a sequence-specific manner. Although the majority of receptor tyrosine kinases expressed in breast cancer cells bind the PTB domain, very little is known regarding the biological importance of SH2-driven ShcA signaling during mammary tumorigenesis. To address this, we employed transgenic mice expressing a mutant ShcA allele harboring a non-functional SH2 domain (ShcR397K) under the transcriptional control of the endogenous ShcA promoter. Using transplantation approaches, we demonstrate that SH2-dependent ShcA signaling within the mammary epithelial compartment is essential for breast tumor outgrowth, survival and the development of lung metastases. We further show that the ShcA SH2 domain activates the AKT pathway, potentially through a novel SH2-mediated complex between ShcA, 14-3-3ζ and the p85 regulatory subunit of phosphatidylinositol 3 (PI3') kinase. This study is the first to demonstrate that the SH2 domain of ShcA is critical for tumor survival during mammary tumorigenesis.

The choice of radiopharmaceutical to image breast cancer

International Nuclear Information System (INIS)

Capriotti, G.; Scopinaro, F.; Signore, A.; Wiele, C. van de

2004-01-01

Breast function and development are regulated by a network of local and systemic signals which can exert either stimulatory or inhibitory effects. Many of these signals are mediated by topically produced hormones and cytokines, which are both believed to be part of complex feedback loops. These local feedback loops also play an integral part in the vascularization and invasion of malignant breast tumours. More specifically, it has been demonstrated that the disruption of physiological negative feedback loops in breast tissue may result in the loss of cell cycle control and eventually leading to local breakdown of the adjacent stroma implying interactions between breast tumour cells and their stromal environment. Novel anticancer strategies selectively interacting with breast tumour vascularization and metastasis, include blocking monoclonal antibodies, peptide hormone antagonists, peptide/toxin fusion proteins and inhibitors of signal transduction. As most of these novel drugs are cytostatic, objective response as measured by morphological imaging modalities, e.g., Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) cannot be utilized as a surrogate marker for drug development, nor for clinical decision- making. Accordingly, in order to maximize the benefit from these new treatment paradigms, novel objective markers of therapeutic success are mandatory. This editorial focuses on recently developed radioligands for SPECT imaging as potential markers for the in vivo assessment of ongoing angiogenesis and metastasis in patients suffering from breast carcinoma

High-performance broad-band spectroscopy for breast cancer risk assessment

Science.gov (United States)

Pawluczyk, Olga; Blackmore, Kristina; Dick, Samantha; Lilge, Lothar

2005-09-01

Medical diagnostics and screening are becoming increasingly demanding applications for spectroscopy. Although for many years the demand was satisfied with traditional spectrometers, analysis of complex biological samples has created a need for instruments capable of detecting small differences between samples. One such application is the measurement of absorbance of broad spectrum illumination by breast tissue, in order to quantify the breast tissue density. Studies have shown that breast cancer risk is closely associated with the measurement of radiographic breast density measurement. Using signal attenuation in transillumination spectroscopy in the 550-1100nm spectral range to measure breast density, has the potential to reduce the frequency of ionizing radiation, or making the test accessible to younger women; lower the cost and make the procedure more comfortable for the patient. In order to determine breast density, small spectral variances over a total attenuation of up to 8 OD have to be detected with the spectrophotometer. For this, a high performance system has been developed. The system uses Volume Phase Holographic (VPH) transmission grating, a 2D detector array for simultaneous registration of the whole spectrum with high signal to noise ratio, dedicated optical system specifically optimized for spectroscopic applications and many other improvements. The signal to noise ratio exceeding 50,000 for a single data acquisition eliminates the need for nitrogen cooled detectors and provides sufficient information to predict breast tissue density. Current studies employing transillumination breast spectroscopy (TIBS) relating to breast cancer risk assessment and monitoring are described.

Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions Vitamin D pathways unbalanced in breast lesions

International Nuclear Information System (INIS)

Lopes, Nair; Schmitt, Fernando; Sousa, Bárbara; Martins, Diana; Gomes, Madalena; Vieira, Daniella; Veronese, Luiz A; Milanezi, Fernanda; Paredes, Joana; Costa, José L

2010-01-01

Breast cancer is a heterogeneous disease associated with different patient prognosis and responses to therapy. Vitamin D has been emerging as a potential treatment for cancer, as it has been demonstrated that it modulates proliferation, apoptosis, invasion and metastasis, among others. It acts mostly through the Vitamin D receptor (VDR) and the synthesis and degradation of this hormone are regulated by the enzymes CYP27B1 and CYP24A1, respectively. We aimed to study the expression of these three proteins by immunohistochemistry in a series of breast lesions. We have used a cohort comprising normal breast, benign mammary lesions, carcinomas in situ and invasive carcinomas and assessed the expression of the VDR, CYP27B1 and CYP24A1 by immunohistochemistry. The results that we have obtained show that all proteins are expressed in the various breast tissues, although at different amounts. The VDR was frequently expressed in benign lesions (93.5%) and its levels of expression were diminished in invasive tumours (56.2%). Additionally, the VDR was strongly associated with the oestrogen receptor positivity in breast carcinomas. CYP27B1 expression is slightly lower in invasive carcinomas (44.6%) than in benign lesions (55.8%). In contrast, CYP24A1 expression was augmented in carcinomas (56.0% in in situ and 53.7% in invasive carcinomas) when compared with that in benign lesions (19.0%). From this study, we conclude that there is a deregulation of the Vitamin D signalling and metabolic pathways in breast cancer, favouring tumour progression. Thus, during mammary malignant transformation, tumour cells lose their ability to synthesize the active form of Vitamin D and respond to VDR-mediated Vitamin D effects, while increasing their ability to degrade this hormone

LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells.

Science.gov (United States)

Yue, Zhiying; Yuan, Zengjin; Zeng, Li; Wang, Ying; Lai, Li; Li, Jing; Sun, Peng; Xue, Xiwen; Qi, Junyi; Yang, Zhengfeng; Zheng, Yansen; Fang, Yuanzhang; Li, Dali; Siwko, Stefan; Li, Yi; Luo, Jian; Liu, Mingyao

2018-05-01

The fourth member of the leucine-rich repeat-containing GPCR family (LGR4, frequently referred to as GPR48) and its cognate ligands, R-spondins (RSPOs) play crucial roles in the development of multiple organs as well as the survival of adult stem cells by activation of canonical Wnt signaling. Wnt/β-catenin signaling acts to regulate breast cancer; however, the molecular mechanisms determining its spatiotemporal regulation are largely unknown. In this study, we identified LGR4 as a master controller of Wnt/β-catenin signaling-mediated breast cancer tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. LGR4 expression in breast tumors correlated with poor prognosis. Either Lgr4 haploinsufficiency or mammary-specific deletion inhibited mouse mammary tumor virus (MMTV)- PyMT- and MMTV- Wnt1-driven mammary tumorigenesis and metastasis. Moreover, LGR4 down-regulation decreased in vitro migration and in vivo xenograft tumor growth and lung metastasis. Furthermore, Lgr4 deletion in MMTV- Wnt1 tumor cells or knockdown in human breast cancer cells decreased the number of functional CSCs by ∼90%. Canonical Wnt signaling was impaired in LGR4-deficient breast cancer cells, and LGR4 knockdown resulted in increased E-cadherin and decreased expression of N-cadherin and snail transcription factor -2 ( SNAI2) (also called SLUG), implicating LGR4 in regulation of epithelial-mesenchymal transition. Our findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast CSCs.-Yue, Z., Yuan, Z., Zeng, L., Wang, Y., Lai, L., Li, J., Sun, P., Xue, X., Qi, J., Yang, Z., Zheng, Y., Fang, Y., Li, D., Siwko, S., Li, Y., Luo, J., Liu, M. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells.

Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells.

Directory of Open Access Journals (Sweden)

Shan Wan

Full Text Available Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT, a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-naïve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1 or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through

Ultra-Wide Band Non-reciprocity through Sequentially-Switched Delay Lines.

Science.gov (United States)

Biedka, Mathew M; Zhu, Rui; Xu, Qiang Mark; Wang, Yuanxun Ethan

2017-01-06

Achieving non-reciprocity through unconventional methods without the use of magnetic material has recently become a subject of great interest. Towards this goal a time switching strategy known as the Sequentially-Switched Delay Line (SSDL) is proposed. The essential SSDL configuration consists of six transmission lines of equal length, along with five switches. Each switch is turned on and off sequentially to distribute and route the propagating electromagnetic wave, allowing for simultaneous transmission and receiving of signals through the device. Preliminary experimental results with commercial off the shelf parts are presented which demonstrated non-reciprocal behavior with greater than 40 dB isolation from 200 KHz to 200 MHz. The theory and experimental results demonstrated that the SSDL concept may lead to future on-chip circulators over multi-octaves of frequency.

How input fluctuations reshape the dynamics of a biological switching system

Science.gov (United States)

Hu, Bo; Kessler, David A.; Rappel, Wouter-Jan; Levine, Herbert

2012-12-01

An important task in quantitative biology is to understand the role of stochasticity in biochemical regulation. Here, as an extension of our recent work [Phys. Rev. Lett.PRLTAO0031-900710.1103/PhysRevLett.107.148101 107, 148101 (2011)], we study how input fluctuations affect the stochastic dynamics of a simple biological switch. In our model, the on transition rate of the switch is directly regulated by a noisy input signal, which is described as a non-negative mean-reverting diffusion process. This continuous process can be a good approximation of the discrete birth-death process and is much more analytically tractable. Within this setup, we apply the Feynman-Kac theorem to investigate the statistical features of the output switching dynamics. Consistent with our previous findings, the input noise is found to effectively suppress the input-dependent transitions. We show analytically that this effect becomes significant when the input signal fluctuates greatly in amplitude and reverts slowly to its mean.

Hexachlorobenzene modulates the crosstalk between the aryl hydrocarbon receptor and transforming growth factor-β1 signaling, enhancing human breast cancer cell migration and invasion

International Nuclear Information System (INIS)

Miret, Noelia; Pontillo, Carolina; Ventura, Clara; Carozzo, Alejandro; Chiappini, Florencia

2016-01-01

Highlights: • HCB enhances TGF-β1 expression and activation levels in breast cancer cells. • HCB activates TGF-β1 pathways: Smad3, JNK and p38. • The HCB- induced migration and invasion involves TGF-β1 signaling pathways. • HCB modulates AhR levels and activation. • HCB enhances TGF-β1 mRNA expression in an AhR-dependent manner. - Abstract: Given the number of women affected by breast cancer, considerable interest has been raised in understanding the relationships between environmental chemicals and disease onset. Hexachlorobenzene (HCB) is a dioxin-like compound that is widely distributed in the environment and is a weak ligand of the aryl hydrocarbon receptor (AhR). We previously demonstrated that HCB acts as an endocrine disruptor capable of stimulating cell proliferation, migration, invasion, and metastasis in different breast cancer models. In addition, increasing evidence indicates that transforming growth factor-β1 (TGF-β1) can contribute to tumor maintenance and progression. In this context, this work investigated the effect of HCB (0.005, 0.05, 0.5, and 5 μM) on TGF-β1 signaling and AhR/TGF-β1 crosstalk in the human breast cancer cell line MDA-MB-231 and analyzed whether TGF-β1 pathways are involved in HCB-induced cell migration and invasion. RT-qPCR results indicated that HCB reduces AhR mRNA expression through TGF-β1 signaling but enhances TGF-β1 mRNA levels involving AhR signaling. Western blot analysis demonstrated that HCB could increase TGF-β1 protein levels and activation, as well as Smad3, JNK, and p38 phosphorylation. In addition, low and high doses of HCB were determined to exert differential effects on AhR protein levels, localization, and activation, with a high dose (5 μM) inducing AhR nuclear translocation and AhR-dependent CYP1A1 expression. These findings also revealed that c-Src and AhR are involved in HCB-mediated activation of Smad3. HCB enhances cell migration (scratch motility assay) and invasion (Transwell

Epigenetic suppression of neprilysin regulates breast cancer invasion.

Science.gov (United States)

Stephen, H M; Khoury, R J; Majmudar, P R; Blaylock, T; Hawkins, K; Salama, M S; Scott, M D; Cosminsky, B; Utreja, N K; Britt, J; Conway, R E

2016-03-07

In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer

Intermittent metabolic switching, neuroplasticity and brain health

Science.gov (United States)

Mattson, Mark P.; Moehl, Keelin; Ghena, Nathaniel; Schmaedick, Maggie; Cheng, Aiwu

2018-01-01

During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease. PMID:29321682

FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma

Directory of Open Access Journals (Sweden)

Brunello Eleonora

2012-12-01

Full Text Available Abstract Background Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed. Methods Fifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases. FGFR-1 gene (8p12 amplification was evaluated by chromogenic in situ hybridization (CISH analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals versus gains (3–6 signals of the locus specific FGFR-1 gene. Results Three (20% primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification, six cases (40% had a mean of three (range 3–6 chromogenic signals (gains whereas in 6 (40% was not observed any abnormality. Three of 15 metastasis (20% were amplified, 2/15 (13,4% did not. The ten remaining cases (66,6% showed three chromogenic signals. The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6% case. Topoisomerase-IIα was not amplified in all cases. Conclusions 1 a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2 a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3 in the

Sevoflurane suppresses proliferation by upregulating microRNA-203 in breast cancer cells.

Science.gov (United States)

Liu, Jiaying; Yang, Longqiu; Guo, Xia; Jin, Guangli; Wang, Qimin; Lv, Dongdong; Liu, Junli; Chen, Qiu; Song, Qiong; Li, Baolin

2018-05-03

Rapid proliferation is one of the critical characteristics of breast cancer. However, the underlying regulatory mechanism of breast cancer cell proliferation is largely unclear. The present study indicated that sevoflurane, one of inhalational anesthetics, could significantly suppress breast cancer cell proliferation by arresting cell cycle at G1 phase. Notably, the rescue experiment indicated that miR-203 was upregulated by sevoflurane and mediated the function of sevoflurane on suppressing the breast cancer cell proliferation. The present study indicated the function of the sevoflurane/miR-203 signaling pathway on regulating breast cancer cell proliferation. These results provide mechanistic insight into how the sevoflurane/miR-203 signaling pathway supresses proliferation of breast cancer cells, suggesting the sevoflurane/miR-203 pathway may be a potential target in the treatment of breast cancer.

Multistable decision switches for flexible control of epigenetic differentiation.

Directory of Open Access Journals (Sweden)

Raúl Guantes

2008-11-01

Full Text Available It is now recognized that molecular circuits with positive feedback can induce two different gene expression states (bistability under the very same cellular conditions. Whether, and how, cells make use of the coexistence of a larger number of stable states (multistability is however largely unknown. Here, we first examine how autoregulation, a common attribute of genetic master regulators, facilitates multistability in two-component circuits. A systematic exploration of these modules' parameter space reveals two classes of molecular switches, involving transitions in bistable (progression switches or multistable (decision switches regimes. We demonstrate the potential of decision switches for multifaceted stimulus processing, including strength, duration, and flexible discrimination. These tasks enhance response specificity, help to store short-term memories of recent signaling events, stabilize transient gene expression, and enable stochastic fate commitment. The relevance of these circuits is further supported by biological data, because we find them in numerous developmental scenarios. Indeed, many of the presented information-processing features of decision switches could ultimately demonstrate a more flexible control of epigenetic differentiation.

PBX1 Genomic Pioneer Function Drives ERα Signaling Underlying Progression in Breast Cancer

Science.gov (United States)

Magnani, Luca; Ballantyne, Elizabeth B.; Zhang, Xiaoyang; Lupien, Mathieu

2011-01-01

Altered transcriptional programs are a hallmark of diseases, yet how these are established is still ill-defined. PBX1 is a TALE homeodomain protein involved in the development of different types of cancers. The estrogen receptor alpha (ERα) is central to the development of two-thirds of all breast cancers. Here we demonstrate that PBX1 acts as a pioneer factor and is essential for the ERα-mediated transcriptional response driving aggressive tumors in breast cancer. Indeed, PBX1 expression correlates with ERα in primary breast tumors, and breast cancer cells depleted of PBX1 no longer proliferate following estrogen stimulation. Profiling PBX1 recruitment and chromatin accessibility across the genome of breast cancer cells through ChIP-seq and FAIRE-seq reveals that PBX1 is loaded and promotes chromatin openness at specific genomic locations through its capacity to read specific epigenetic signatures. Accordingly, PBX1 guides ERα recruitment to a specific subset of sites. Expression profiling studies demonstrate that PBX1 controls over 70% of the estrogen response. More importantly, the PBX1-dependent transcriptional program is associated with poor-outcome in breast cancer patients. Correspondingly, PBX1 expression alone can discriminate a priori the outcome in ERα-positive breast cancer patients. These features are markedly different from the previously characterized ERα-associated pioneer factor FoxA1. Indeed, PBX1 is the only pioneer factor identified to date that discriminates outcome such as metastasis in ERα-positive breast cancer patients. Together our results reveal that PBX1 is a novel pioneer factor defining aggressive ERα-positive breast tumors, as it guides ERα genomic activity to unique genomic regions promoting a transcriptional program favorable to breast cancer progression. PMID:22125492

Breast Cancer Screening in a Low Income Managed Care Populaton

Science.gov (United States)

1999-10-01

early to know for sure if these things affect breast cancer risk. can help prevent heart disease and osteoporosis after menopause. .,.- Experts generally...firmly in small massaging motions with the pads of your fingers (not the tips). Don’t forget the area in your armpit. Gently squeeze the nipple. Switch

Localized scleroderma of the breast

International Nuclear Information System (INIS)

Opere, Elisa; Oleaga, Laura; Ibanez, Teresa; Grande, Domingo

2002-01-01

We report a 44-year-old patient with right-breast morphea. Mammography, MRI and needle biopsy were used for assessment of the case. Mammography demonstrated thickening of the skin and the subcutaneous tissue. The MRI showed replacement of the subcutaneous and breast fat by a low signal intensity, non-enhancing tissue. Skin biopsy confirmed the histological features of scleroderma. (orig.)

Localized scleroderma of the breast

Energy Technology Data Exchange (ETDEWEB)

Opere, Elisa; Oleaga, Laura; Ibanez, Teresa; Grande, Domingo [Department of Radiology, Hospital de Basurto, Bilbao (Spain)

2002-06-01

We report a 44-year-old patient with right-breast morphea. Mammography, MRI and needle biopsy were used for assessment of the case. Mammography demonstrated thickening of the skin and the subcutaneous tissue. The MRI showed replacement of the subcutaneous and breast fat by a low signal intensity, non-enhancing tissue. Skin biopsy confirmed the histological features of scleroderma. (orig.)

The cascaded amplifier and saturable absorber (CASA) all-optical switch

DEFF Research Database (Denmark)

Hilliger, E.; Berger, J.; Weber, H. G.

2001-01-01

The cascaded amplifier and saturable absorber is presented as a new all-optical switching scheme for optical signal processing applications. First demultiplexing experiments demonstrate the principle of operation of this scheme....

Cluster analysis of signal-intensity time course in dynamic breast MRI: does unsupervised vector quantization help to evaluate small mammographic lesions?

Energy Technology Data Exchange (ETDEWEB)

Leinsinger, Gerda; Schlossbauer, Thomas; Scherr, Michael; Lange, Oliver; Reiser, Maximilian; Wismueller, Axel [Institute for Clinical Radiology University of Munich, Munich (Germany)

2006-05-15

We examined whether neural network clustering could support the characterization of diagnostically challenging breast lesions in dynamic magnetic resonance imaging (MRI). We examined 88 patients with 92 breast lesions (51 malignant, 41 benign). Lesions were detected by mammography and classified Breast Imaging and Reporting Data System (BIRADS) III (median diameter 14 mm). MRI was performed with a dynamic T1-weighted gradient echo sequence (one precontrast and five postcontrast series). Lesions with an initial contrast enhancement {>=}50% were selected with semiautomatic segmentation. For conventional analysis, we calculated the mean initial signal increase and postinitial course of all voxels included in a lesion. Secondly, all voxels within the lesions were divided into four clusters using minimal-free-energy vector quantization (VQ). With conventional analysis, maximum accuracy in detecting breast cancer was 71%. With VQ, a maximum accuracy of 75% was observed. The slight improvement using VQ was mainly achieved by an increase of sensitivity, especially in invasive lobular carcinoma and ductal carcinoma in situ (DCIS). For lesion size, a high correlation between different observers was found (R{sup 2} = 0.98). VQ slightly improved the discrimination between malignant and benign indeterminate lesions (BIRADS III) in comparison with a standard evaluation method. (orig.)

A signal processing analysis of Purkinje cells in vitro

Directory of Open Access Journals (Sweden)

Ze'ev R Abrams

2010-05-01

Full Text Available Cerebellar Purkinje cells in vitro fire recurrent sequences of Sodium and Calcium spikes. Here, we analyze the Purkinje cell using harmonic analysis, and our experiments reveal that its output signal is comprised of three distinct frequency bands, which are combined using Amplitude and Frequency Modulation (AM/FM. We find that the three characteristic frequencies - Sodium, Calcium and Switching – occur in various combinations in all waveforms observed using whole-cell current clamp recordings. We found that the Calcium frequency can display a frequency doubling of its frequency mode, and the Switching frequency can act as a possible generator of pauses that are typically seen in Purkinje output recordings. Using a reversibly photo-switchable kainate receptor agonist, we demonstrate the external modulation of the Calcium and Switching frequencies. These experiments and Fourier analysis suggest that the Purkinje cell can be understood as a harmonic signal oscillator, enabling a higher level of interpretation of Purkinje signaling based on modern signal processing techniques.

A comparison of breast stimulation and intravenous oxytocin for the augmentation of labor.

Science.gov (United States)

Curtis, P; Resnick, J C; Evens, S; Thompson, C J

1999-06-01

Breast stimulation to augment labor has been used for centuries in tribal societies and by midwives. In recent years it has been shown to be effective in ripening the cervix, inducing labor, and as an alternative to oxytocin for the contraction stress test. This study compared the effectiveness of breast stimulation with oxytocin infusion in augmenting labor. Women admitted to the labor ward were eligible for the study if they had inadequate labor with premature rupture of the membranes and met inclusion criteria. They were assigned to oxytocin augmentation or breast stimulation (manual or pump), and were switched to oxytocin in the event of method failure. Outcomes included time to delivery, intervention to delivery, proportion of spontaneous deliveries, and Apgar scores. One hundred participants were needed in each arm of the study to demonstrate a 2- to 3-hour difference in delivery time, with a power of 80 percent. Analysis was performed on 79 women, of whom 49 were in the breast stimulation group and 30 in the oxytocin group. Sixty-five percent of the participants failed breast stimulation and were switched to oxytocin infusion. Although augmentation start to delivery was shorter for the oxytocin group (p < 0.001), no differences in total labor time occurred between the groups. Nulliparas receiving breast stimulation had more spontaneous (relative risk 1.7, p = 0.04), and fewer instrumental deliveries than those receiving oxytocin (relative risk 0.2, p = 0.02). No significant differences in adverse fetal outcomes occurred between the study groups. The small number of participants and a variety of problems with the conduct of the study prevented the formulation of reliable conclusions from the results. However, the study provided important insights into the feasibility and problems of developing a high-quality randomized trial of augmentation by breast stimulation.

Guidelines for Vehicle Robbery Prevention using Remote Blocking Signals

Directory of Open Access Journals (Sweden)

Narong Sangwaranatee

2016-01-01

Full Text Available In this paper, the radio signal remote sensing device was used to control the vehicle door switching control, which was the field trials experiment. The switching "On" and "Off" of the switching signals were used to control the vehicle door and investigated. In application, the blocking signal from the commit the remote vehicle crime in the venerable place can be protected. The results obtained have shown that the signal blocking by using another remote control over 5 meters, 10 meters and 15 meters could be achieved. The proposed models and tested results have shown that the Vehicle Brand A Model No. 1 could be blocked by 83.33 percent, while Brand A Model No.2 by 83.33 percent, Brand B Model No.1 by 40 percent, Brand B Model No.2 by 60 percent, Brand C Model No. 1 by 83.33 percent, Brand C Model No. 2 by 83.33 percent, meanwhile, the remote control for general vehicle are used radio waves with frequency 315 and 433 MHz, where the criminal will use the interference signals to form the blocking (jamming signals, the vehicle can be robbed.

Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor α signalling and results in tamoxifen insensitive proliferation

International Nuclear Information System (INIS)

Moerkens, Marja; Zhang, Yinghui; Wester, Lynn; Water, Bob van de; Meerman, John HN

2014-01-01

Tamoxifen resistance is a major problem in the treatment of estrogen receptor (ER) α -positive breast cancer patients. Although the mechanisms behind tamoxifen resistance are still not completely understood, clinical data suggests that increased expression of receptor tyrosine kinases is involved. Here, we studied the estrogen and anti-estrogen sensitivity of human breast cancer MCF7 cells that have a moderate, retroviral-mediated, ectopic expression of epidermal growth factor receptor (MCF7-EGFR). Proliferation of MCF7-EGFR and parental cells was induced by 17β-estradiol (E2), epidermal growth factor (EGF) or a combination of these. Inhibition of proliferation under these conditions was investigated with 4-hydroxy-tamoxifen (TAM) or fulvestrant at 10 -12 to 10 -6 M. Cells were lysed at different time points to determine the phosphorylation status of EGFR, MAPK 1/3 , AKT and the expression of ERα. Knockdown of target genes was established using smartpool siRNAs. Transcriptomics analysis was done 6 hr after stimulation with growth factors using Affymetrix HG-U133 PM array plates. While proliferation of parental MCF7 cells could only be induced by E2, proliferation of MCF7-EGFR cells could be induced by either E2 or EGF. Treatment with TAM or fulvestrant did significantly inhibit proliferation of MCF7-EGFR cells stimulated with E2 alone. EGF treatment of E2/TAM treated cells led to a marked cell proliferation thereby overruling the anti-estrogen-mediated inhibition of cell proliferation. Under these conditions, TAM however did still inhibit ERα- mediated transcription. While siRNA-mediated knock-down of EGFR inhibited the EGF- driven proliferation under TAM/E2/EGF condition, knock down of ERα did not. The TAM resistant cell proliferation mediated by the conditional EGFR-signaling may be dependent on the PI3K/Akt pathway but not the MEK/MAPK pathway, since a MEK inhibitor (U0126), did not block the proliferation. Transcriptomic analysis under the various E2/TAM

Confinement and diffusion modulate bistability and stochastic switching in a reaction network with positive feedback

International Nuclear Information System (INIS)

Mlynarczyk, Paul J.; Pullen, Robert H.; Abel, Steven M.

2016-01-01

Positive feedback is a common feature in signal transduction networks and can lead to phenomena such as bistability and signal propagation by domain growth. Physical features of the cellular environment, such as spatial confinement and the mobility of proteins, play important but inadequately understood roles in shaping the behavior of signaling networks. Here, we use stochastic, spatially resolved kinetic Monte Carlo simulations to explore a positive feedback network as a function of system size, system shape, and mobility of molecules. We show that these physical properties can markedly alter characteristics of bistability and stochastic switching when compared with well-mixed simulations. Notably, systems of equal volume but different shapes can exhibit qualitatively different behaviors under otherwise identical conditions. We show that stochastic switching to a state maintained by positive feedback occurs by cluster formation and growth. Additionally, the frequency at which switching occurs depends nontrivially on the diffusion coefficient, which can promote or suppress switching relative to the well-mixed limit. Taken together, the results provide a framework for understanding how confinement and protein mobility influence emergent features of the positive feedback network by modulating molecular concentrations, diffusion-influenced rate parameters, and spatiotemporal correlations between molecules

Fixed switching frequency applied in single-phase boost AC to DC converter

International Nuclear Information System (INIS)

Chen, T.-C.; Ren, T.-J.; Ou, J.-C.

2009-01-01

The fixed switching frequency control for a single-phase boost AC to DC converter to achieve a sinusoidal line current and unity power factor is proposed in this paper. The relation between the line current error and the fixed switching frequency was developed. For a limit line current error, the minimum switching frequency for a boost AC to DC converter can be achieved. The proposed scheme was implemented using a 32-bit digital signal processor TMS320C32. Simulations and experimental results demonstrate the feasibility and fast dynamic response of the proposed control strategy.

Evaluation of magnetization transfer ratios for breast tissues and breast diseases

Energy Technology Data Exchange (ETDEWEB)

Sasaki, Fumio; Murai, Hiroshi; Takeuchi, Thouru; Iwase, Takuji; Miura, Shigeto; Mastushima, Shigeru; Oosaki, Hikaru [Aichi Cancer Center, Nagoya (Japan). Hospital; Kinosada, Yasuomi

1997-03-01

To determine MTRs for normal structures and benign diseases in the breast two-dimensional magnetization transfer imaging was performed in 62 patients and in 3 young female volunteers. With regard to the MTRs of measurements in the normal breast tissues, fat tissues which is close to simple cysts in MTRs show little transfer of longitudinal magnetization. MTRs of the muscles was 15.15{+-}6.22%, which exceeded those of breast parenchyma. The breast parenchyma didn`t show the change of MTR value due to the difference of patient age and due to variable amount of fat and fibrous tissues. Breast parenchyma in the two young volunteers clearly showed biphasic change of MTR values in accordance with the menstrual cycle; little transfer value was due to hydration in the postovulatory period and high transfer value was due to dehydration in the preovulatory period. In the remaining one volunteer during lactation period, mammary parenchyma shows sever decrease in MTR, because mammary gland is loaded with massive fluid, showing a very high signal intensity on First IR and T2-weighted images. MTR values of benign breast diseases including mastopathy, fibroadenoma and phyllodes tumor had no significant difference from those of the breast parenchyma and muscle. Non-invasive ductal carcinoma was equivalent to breast parenchyma in MTR. (K.H.)

EXPRESSION AND SIGNIFICANCE OF ERK PROTEIN IN HUMAN BREAST CARCINOMA

Institute of Scientific and Technical Information of China (English)

张秀梅; 李柏林; 宋敏; 宋继谒

2004-01-01

Objective: To investigate the expression of ERK and p-ERK protein in human breast cancer and their corresponding tissue, to assess the significance of ERK signal pathway in tumorigenesis and progression of breast carcinoma. Methods: 40 breast cancer cases were used in S-P immunohistochemistry technique and Western Blot study. Results: The expression of ERK1, ERK2, and p- ERK protein levels increased remarkably in breast cancer tissues in comparison to normal tissues (P<0.01). The expression was upregulated by 1.32-, 1.53-and 4.27-fold, respectively. The overexpressions of ERK1, ERK2, and p- ERK proteins were obviously correlated with clinical stage of breast cancer. Protein levels of ERK and p-ERK were higher in stage III patients than in stage I and stage II patients (P<0.05). These proteins were strongly related with axillary lymph node metastasis of breast cancer, but not correlated with histopathological type and status of ER and PR of breast cancer. Expression of ERK1, and ERK2, protein showed a positive linear correlation. Conclusion: ERK signal transduction pathway is a key factor during human breast tumorigenesis and breast cancer progression.

Uncertainty estimation of non-ideal analog switches using programmable Josephson voltage standards for mutual inductance measurement in the joule balance

International Nuclear Information System (INIS)

Wang, Gang; Zhang, Zhonghua; Li, Zhengkun; Xu, Jinxin; You, Qiang

2016-01-01

Measurement of the mutual inductance is one of the key techniques in the joule balance to determine the Planck constant h, where a standard-square-wave compensation method was proposed to accurately measure the dc value of the mutual inductance. With this method, analog switches are used to compose an analog-switch signal generator to synthesize the excitation and compensation voltages. However, the accuracy of the compensation voltage is influenced by the non-ideal behaviors of analog-switches. In this paper, the effect from these non-ideal switches is analyzed in detail and evaluated with the equivalent circuits. A programmable Josephson voltage standard (PJVS) is used to generate a reference compensation voltage to measure the time integration of the voltage waveform generated by the analog-switch signal generator. Moreover, the effect is also evaluated experimentally by comparing the difference between the mutual inductance measured with the analog-switch signal generator and the value determined by the PJVS-analog-switch generator alternately in the same mutual inductance measurement system. The result shows that the impact of analog switches is 1.97  ×  10 −7 with an uncertainty of 1.83  ×  10 −7 (k  =  1) and confirms that the analog switch method can be used regularly instead of the PJVS in the mutual inductance measurement for the joule balance experiment. (paper)

Urokinase-type plasminogen activator receptor (uPAR) ligation induces a raft-localized integrin signaling switch that mediates the hypermotile phenotype of fibrotic fibroblasts.

Science.gov (United States)

Grove, Lisa M; Southern, Brian D; Jin, Tong H; White, Kimberly E; Paruchuri, Sailaja; Harel, Efrat; Wei, Ying; Rahaman, Shaik O; Gladson, Candece L; Ding, Qiang; Craik, Charles S; Chapman, Harold A; Olman, Mitchell A

2014-05-02

The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-linked membrane protein with no cytosolic domain that localizes to lipid raft microdomains. Our laboratory and others have documented that lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibit a hypermotile phenotype. This study was undertaken to elucidate the molecular mechanism whereby uPAR ligation with its cognate ligand, urokinase, induces a motile phenotype in human lung fibroblasts. We found that uPAR ligation with the urokinase receptor binding domain (amino-terminal fragment) leads to enhanced migration of fibroblasts on fibronectin in a protease-independent, lipid raft-dependent manner. Ligation of uPAR with the amino-terminal fragment recruited α5β1 integrin and the acylated form of the Src family kinase, Fyn, to lipid rafts. The biological consequences of this translocation were an increase in fibroblast motility and a switch of the integrin-initiated signal pathway for migration away from the lipid raft-independent focal adhesion kinase pathway and toward a lipid raft-dependent caveolin-Fyn-Shc pathway. Furthermore, an integrin homologous peptide as well as an antibody that competes with β1 for uPAR binding have the ability to block this effect. In addition, its relative insensitivity to cholesterol depletion suggests that the interactions of α5β1 integrin and uPAR drive the translocation of α5β1 integrin-acylated Fyn signaling complexes into lipid rafts upon uPAR ligation through protein-protein interactions. This signal switch is a novel pathway leading to the hypermotile phenotype of IPF patient-derived fibroblasts, seen with uPAR ligation. This uPAR dependent, fibrotic matrix-selective, and profibrotic fibroblast phenotype may be amenable to targeted therapeutics designed to ameliorate IPF.

A Repeated Signal Difference for Recognising Patterns

Directory of Open Access Journals (Sweden)

Kieran Greer

2016-08-01

Full Text Available This paper describes a new mechanism that might help with defining pattern sequences, by the fact that it can produce an upper bound on the ensemble value that can persistently oscillate with the actual values produced from each pattern. With every firing event, a node also receives an on/off feedback switch. If the node fires then it sends a feedback result depending on the input signal strength. If the input signal is positive or larger, it can store an ‘on’ switch feedback for the next iteration. If the signal is negative or smaller it can store an ‘off’ switch feedback for the next iteration. If the node does not fire, then it does not affect the current feedback situation and receives the switch command produced by the last active pattern event for the same neuron. The upper bound therefore also represents the largest or most enclosing pattern set and the lower value is for the actual set of firing patterns. If the pattern sequence repeats, it will oscillate between the two values, allowing them to be recognised and measured more easily, over time. Tests show that changing the sequence ordering produces different value sets, which can also be measured.

Human lymphoma mutations reveal CARD11 as the switch between self-antigen–induced B cell death or proliferation and autoantibody production

Science.gov (United States)

Jeelall, Yogesh S.; Wang, James Q.; Law, Hsei-Di; Domaschenz, Heather; Fung, Herman K.H.; Kallies, Axel; Nutt, Stephen L.

2012-01-01

Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell–independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo. PMID:23027925

Robust filtering and fault detection of switched delay systems

CERN Document Server

Wang, Dong; Wang, Wei

2013-01-01

Switched delay systems appear in a wide field of applications including networked control systems, power systems, memristive systems. Though the large amount of ideas with respect to such systems have generated, until now, it still lacks a framework to focus on filter design and fault detection issues which are relevant to life safety and property loss. Beginning with the comprehensive coverage of the new developments in the analysis and control synthesis for switched delay systems, the monograph not only provides a systematic approach to designing the filter and detecting the fault of switched delay systems, but it also covers the model reduction issues. Specific topics covered include: (1) Arbitrary switching signal where delay-independent and delay-dependent conditions are presented by proposing a linearization technique. (2) Average dwell time where a weighted Lyapunov function is come up with dealing with filter design and fault detection issues beside taking model reduction problems. The monograph is in...

Baicalein suppresses 17-β-estradiol-induced migration, adhesion and invasion of breast cancer cells via the G protein-coupled receptor 30 signaling pathway.

Science.gov (United States)

Shang, Dandan; Li, Zheng; Zhu, Zhuxia; Chen, Huamei; Zhao, Lujun; Wang, Xudong; Chen, Yan

2015-04-01

Flavonoids are structurally similar to steroid hormones, particularly estrogens, and therefore have been studied for their potential effects on hormone-dependent cancers. Baicalein is the primary flavonoid derived from the root of Scutellaria baicalensis Georgi. In the present study, we investigated the effects of baicalein on 17β-estradiol (E2)-induced migration, adhesion and invasion of MCF-7 and SK-BR-3 breast cancer cells. The results demonstrated that baicalein suppressed E2-stimulated wound-healing migration and cell‑Matrigel adhesion, and ameliorated E2-promoted invasion across a Matrigel-coated Transwell membrane. Furthermore, baicalein interfered with E2-induced novel G protein-coupled estrogen receptor (GPR30)-related signaling, including a decrease in tyrosine phosphorylation of epidermal growth factor receptor (EGFR) as well as phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine kinase Akt, without affecting GPR30 expression. The results also showed that baicalein suppressed the expression of GPR30 target genes, cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF) induced by E2. Furthermore, baicalein prevented GPR30-related signaling activation and upregulation of CYR61 and CTGF mRNA levels induced by G1, a specific GPR 30 agonist. The results suggest that baicalein inhibits E2-induced migration, adhesion and invasion through interfering with GPR30 signaling pathway activation, which indicates that it may act as a therapeutic candidate for the treatment of GPR30-positive breast cancer metastasis.

Electrostatically actuated resonant switches for earthquake detection

KAUST Repository

Ramini, Abdallah H.

2013-04-01

The modeling and design of electrostatically actuated resonant switches (EARS) for earthquake and seismic applications are presented. The basic concepts are based on operating an electrically actuated resonator close to instability bands of frequency, where it is forced to collapse (pull-in) if operated within these bands. By careful tuning, the resonator can be made to enter the instability zone upon the detection of the earthquake signal, thereby pulling-in as a switch. Such a switching action can be functionalized for useful functionalities, such as shutting off gas pipelines in the case of earthquakes, or can be used to activate a network of sensors for seismic activity recording in health monitoring applications. By placing a resonator on a printed circuit board (PCB) of a natural frequency close to that of the earthquake\\'s frequency, we show significant improvement on the detection limit of the EARS lowering it considerably to less than 60% of the EARS by itself without the PCB. © 2013 IEEE.

TRIM44 Is a Poor Prognostic Factor for Breast Cancer Patients as a Modulator of NF-κB Signaling.

Science.gov (United States)

Kawabata, Hidetaka; Azuma, Kotaro; Ikeda, Kazuhiro; Sugitani, Ikuko; Kinowaki, Keiichi; Fujii, Takeshi; Osaki, Akihiko; Saeki, Toshiaki; Horie-Inoue, Kuniko; Inoue, Satoshi

2017-09-08

Many of the tripartite motif (TRIM) proteins function as E3 ubiquitin ligases and are assumed to be involved in various events, including oncogenesis. In regard to tripartite motif-containing 44 (TRIM44), which is an atypical TRIM family protein lacking the RING finger domain, its pathophysiological significance in breast cancer remains unknown. We performed an immunohistochemical study of TRIM44 protein in clinical breast cancer tissues from 129 patients. The pathophysiological role of TRIM44 in breast cancer was assessed by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. TRIM44 strong immunoreactivity was significantly associated with nuclear grade ( p = 0.033), distant disease-free survival ( p = 0.031) and overall survival ( p = 0.027). Multivariate analysis revealed that the TRIM44 status was an independent prognostic factor for distant disease-free survival ( p = 0.005) and overall survival ( p = 0.002) of patients. siRNA-mediated TRIM44 knockdown significantly decreased the proliferation of MCF-7 and MDA-MB-231 cells and inhibited the migration of MDA-MB-231 cells. Microarray analysis and qRT-PCR showed that TRIM44 knockdown upregulated CDK19 and downregulated MMP1 in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-κB)-mediated transcriptional activity stimulated by tumor necrosis factor α (TNFα). Moreover, TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of the p65 subunit of NF-κB and IκBα in both MCF-7 and MDA-MB-231 cells. TRIM44 would play a role in the progression of breast cancer by promoting cell proliferation and migration, as well as by enhancing NF-κB signaling.

Design of an Ultra-wideband Pseudo Random Coded MIMO Radar Based on Radio Frequency Switches

Directory of Open Access Journals (Sweden)

Su Hai

2017-02-01

Full Text Available A Multiple-Input Multiple-Output (MIMO ultra-wideband radar can detect the range and azimuth information of targets in real time. It is widely used for geological surveys, life rescue, through-wall tracking, and other military or civil fields. This paper presents the design of an ultra-wideband pseudo random coded MIMO radar that is based on Radio Frequency (RF switches and implements a MIMO radar system. RF switches are employed to reduce cost and complexity of the system. As the switch pressure value is limited, the peak power of the transmitting signal is 18 dBm. The ultra-wideband radar echo is obtained by hybrid sampling, and pulse compression is computed by Digital Signal Processors (DSPs embedded in an Field-Programmable Gate Array (FPGA to simplify the signal process. The experiment illustrates that the radar system can detect the range and azimuth information of targets in real time.

Action of Molecular Switches in GPCRs - Theoretical and Experimental Studies

Science.gov (United States)

Trzaskowski, B; Latek, D; Yuan, S; Ghoshdastider, U; Debinski, A; Filipek, S

2012-01-01

G protein coupled receptors (GPCRs), also called 7TM receptors, form a huge superfamily of membrane proteins that, upon activation by extracellular agonists, pass the signal to the cell interior. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed. Biochemical and crystallographic methods together with molecular dynamics simulations and other theoretical techniques provided models of the receptor activation based on the action of so-called “molecular switches” buried in the receptor structure. They are changed by agonists but also by inverse agonists evoking an ensemble of activation states leading toward different activation pathways. Switches discovered so far include the ionic lock switch, the 3-7 lock switch, the tyrosine toggle switch linked with the nPxxy motif in TM7, and the transmission switch. The latter one was proposed instead of the tryptophan rotamer toggle switch because no change of the rotamer was observed in structures of activated receptors. The global toggle switch suggested earlier consisting of a vertical rigid motion of TM6, seems also to be implausible based on the recent crystal structures of GPCRs with agonists. Theoretical and experimental methods (crystallography, NMR, specific spectroscopic methods like FRET/BRET but also single-molecule-force-spectroscopy) are currently used to study the effect of ligands on the receptor structure, location of stable structural segments/domains of GPCRs, and to answer the still open question on how ligands are binding: either via ensemble of conformational receptor states or rather via induced fit mechanisms. On the other hand the structural investigations of homo- and heterodimers and higher oligomers revealed the mechanism of allosteric signal transmission and receptor

Three-tier multi-granularity switching system based on PCE

Science.gov (United States)

Wang, Yubao; Sun, Hao; Liu, Yanfei

2017-10-01

With the growing demand for business communications, electrical signal processing optical path switching can't meet the demand. The multi-granularity switch system that can improve node routing and switching capabilities came into being. In the traditional network, each node is responsible for calculating the path; synchronize the whole network state, which will increase the burden on the network, so the concept of path calculation element (PCE) is proposed. The PCE is responsible for routing and allocating resources in the network1. In the traditional band-switched optical network, the wavelength is used as the basic routing unit, resulting in relatively low wavelength utilization. Due to the limitation of wavelength continuity, the routing design of the band technology becomes complicated, which directly affects the utilization of the system. In this paper, optical code granularity is adopted. There is no continuity of the optical code, and the number of optical codes is more flexible than the wavelength. For the introduction of optical code switching, we propose a Code Group Routing Entity (CGRE) algorithm. In short, the combination of three-tier multi-granularity optical switching system and PCE can simplify the network structure, reduce the node load, and enhance the network scalability and survivability. Realize the intelligentization of optical network.

Performance Verification on UWB Antennas for Breast Cancer Detection

Directory of Open Access Journals (Sweden)

Vijayasarveswari V.

2017-01-01

Full Text Available Breast cancer is a common disease among women and death figure is continuing to increase. Early breast cancer detection is very important. Ultra wide-band (UWB is the promising candidate for short communication applications. This paper presents the performance of different types of UWB antennas for breast cancer detection. Two types of antennas are used i.e: UWB pyramidal antenna and UWB horn antenna. These antennas are used to transmit and receive the UWB signal. The collected signals are fed into developed neural network module to measure the performance efficiency of each antenna. The average detection efficiency is 88.46% and 87.55% for UWB pyramidal antenna and UWB horn antenna respectively. These antennas can be used to detect breast cancer in the early stage and save precious lives.

Mammography combined with breast dynamic contrast-enhanced-magnetic resonance imaging for the diagnosis of early breast cancer

Institute of Scientific and Technical Information of China (English)

Yakun He; Guohui Xu; Jin Ren; Bin Feng; Xiaolei Dong; Hao Lu; Changjiu He

2016-01-01

Objective The aim of this study was to investigate the application of mammography combined with breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the diagnosis of early breast cancer. Methods Mammography and DCE-MRI were performed for 120 patients with breast cancer (malignant, 102; benign; 18). Results The sensitivity of mammography for early diagnosis of breast cancer was 66.67%, specificity was 77.78%, and accuracy was 68.33%. The sensitivity of MRI for early diagnosis of breast cancer was 94.12%, specificity was 88.89%, and accuracy was 93.33%. However, the sensitivity of mammography combined with DCE-MRI volume imaging with enhanced water signal (VIEWS) scanning for early diagnosis of breast cancer was 97.06%, specificity was 94.44%, and accuracy was 96.67%. Conclusion Mammography combined with DCE-MRI increased the sensitivity, specificity, and accuracy of diagnosing early breast cancer.

Loss of Mel-18 enhances breast cancer stem cell activity and tumorigenicity through activating Notch signaling mediated by the Wnt/TCF pathway.

Science.gov (United States)

Won, Hee-Young; Lee, Jeong-Yeon; Shin, Dong-Hui; Park, Ji-Hye; Nam, Jeong-Seok; Kim, Hyoung-Chin; Kong, Gu

2012-12-01

Mel-18 has been proposed as a negative regulator of Bmi-1, a cancer stem cell (CSC) marker, but it is still unclear whether Mel-18 is involved in CSC regulation. Here, we examined the effect of Mel-18 on the stemness of human breast CSCs. In Mel-18 small hairpin RNA (shRNA)-transduced MCF-7 cells, side population (SP) cells and breast CSC surface marker (CD44(+)/CD24(-)/ESA(+))-expressing cells, which imply a CSC population, were enriched. Moreover, the self-renewal of CSCs was enhanced by Mel-18 knockdown, as measured by the ability for tumorsphere formation in vitro and tumor-initiating capacity in vivo. Similarly, Mel-18 overexpression inhibited the number and self-renewal activity of breast CSCs in SK-BR-3 cells. Furthermore, our data showed that Mel-18 blockade up-regulated the expression of the Wnt/TCF target Jagged-1, a Notch ligand, and consequently activated the Notch pathway. Pharmacologic inhibition of the Notch and Wnt pathways abrogated Mel-18 knockdown-mediated tumorsphere formation ability. Taken together, our findings suggest that Mel-18 is a novel negative regulator of breast CSCs that inhibits the stem cell population and in vitro and in vivo self-renewal through the inactivation of Wnt-mediated Notch signaling.

Surviving bacterial sibling rivalry: inducible and reversible phenotypic switching in Paenibacillus dendritiformis.

Science.gov (United States)

Be'er, Avraham; Florin, E-L; Fisher, Carolyn R; Swinney, Harry L; Payne, Shelley M

2011-01-01

Natural habitats vary in available nutrients and room for bacteria to grow, but successful colonization can lead to overcrowding and stress. Here we show that competing sibling colonies of Paenibacillus dendritiformis bacteria survive overcrowding by switching between two distinct vegetative phenotypes, motile rods and immotile cocci. Growing colonies of the rod-shaped bacteria produce a toxic protein, Slf, which kills cells of encroaching sibling colonies. However, sublethal concentrations of Slf induce some of the rods to switch to Slf-resistant cocci, which have distinct metabolic and resistance profiles, including resistance to cell wall antibiotics. Unlike dormant spores of P. dendritiformis, the cocci replicate. If cocci encounter conditions that favor rods, they secrete a signaling molecule that induces a switch to rods. Thus, in contrast to persister cells, P. dendritiformis bacteria adapt to changing environmental conditions by inducible and reversible phenotypic switching. In favorable environments, species may face space and nutrient limits due to overcrowding. Bacteria provide an excellent model for analyzing principles underlying overcrowding and regulation of density in nature, since their population dynamics can be easily and accurately assessed under controlled conditions. We describe a newly discovered mechanism for survival of a bacterial population during overcrowding. When competing with sibling colonies, Paenibacillus dendritiformis produces a lethal protein (Slf) that kills cells at the interface of encroaching colonies. Slf also induces a small proportion of the cells to switch from motile, rod-shaped cells to nonmotile, Slf-resistant, vegetative cocci. When crowding is reduced and nutrients are no longer limiting, the bacteria produce a signal that induces cocci to switch back to motile rods, allowing the population to spread. Genes encoding components of this phenotypic switching pathway are widespread among bacterial species, suggesting

A molecular-sized optical logic circuit for digital modulation of a fluorescence signal

Science.gov (United States)

Nishimura, Takahiro; Tsuchida, Karin; Ogura, Yusuke; Tanida, Jun

2018-03-01

Fluorescence measurement allows simultaneous detection of multiple molecular species by using spectrally distinct fluorescence probes. However, due to the broad spectra of fluorescence emission, the multiplicity of fluorescence measurement is generally limited. To overcome this limitation, we propose a method to digitally modulate fluorescence output signals with a molecular-sized optical logic circuit by using optical control of fluorescence resonance energy transfer (FRET). The circuit receives a set of optical inputs represented with different light wavelengths, and then it switches high and low fluorescence intensity from a reporting molecule according to the result of the logic operation. By using combinational optical inputs in readout of fluorescence signals, the number of biomolecular species that can be identified is increased. To implement the FRET-based circuits, we designed two types of basic elements, YES and NOT switches. An YES switch produces a high-level output intensity when receiving a designated light wavelength input and a low-level intensity without the light irradiation. A NOT switch operates inversely to the YES switch. In experiments, we investigated the operation of the YES and NOT switches that receive a 532-nm light input and modulate the fluorescence intensity of Alexa Fluor 488. The experimental result demonstrates that the switches can modulate fluorescence signals according to the optical input.

1.114-gb/s time/space division switch system

Science.gov (United States)

Pawelski, Robert L.; Nordin, Ronald A.; Huisman, R. F.; Kelly, S.; Payne, William A.; Veach, R. S.

1990-10-01

Advanced digital communication services11 such as Broadband ISDN High Definition Television (HDTV) and enhanced data networking are expected to require high bandwidth and fast reconfiguration time switching centers available in the 1990''s. Digital GaAs IC''s can allow the implementation of these switching centers providing these services efficiently and at a low cost. The low cost arises from the reduction in hardware power maintenance etc. when the switch is designed to operate at the incoming data rate instead of at a lower rate. In order to utilize the capacity of a high bandwidth data link time division multiplexing is employed. This is a technique where multiple digital signals are interleaved (bit byte or block) on one data link. Clearly it is advantageous to have a switch that not only has a large bandwidth but can reconfigure at the data rate so as to provide bit byte or block switching functions thus being compatible with many different transmission formats. We present an experimental Time/Space Division Switch System capable of operating at over 1 Gb/s. Both custom and commercial Gallium Arsenide (GaAs) devices are used in the design of the various system functional blocks. These functional blocks include a Time Slot Interchanger (TSI) Time Multiplexed Switch (TMS) TMS Controller Multiplexer and Demultiplexers. In addition to the system overview we discuss such issues as printed circuit board microwave interconnections and CAD tools for high speed

The Shape of Breasts Suspended in Liquid

NARCIS (Netherlands)

De Kleijn, S.C.; Rensen, W.H.J.

2007-01-01

Philips has designed an optical mammography machine. In this machine the breast is suspended into a cup in which the measurements take place. A special fluid is inserted into the cup to prevent the light from going around the breast instead of going through it but this fluid also weakens the signal.

Source of seismic signals

Energy Technology Data Exchange (ETDEWEB)

Frankovskii, B.A.; Khor' yakov, K.A.

1980-08-30

Patented is a source of seismic signals consisting of a shock generator with a basic low-voltage and auxillary high-voltage stator coils, a capacitive transformer and control switches. To increase the amplitude of signal excitation a condensor battery and auxillary commutator are introduced into the device, which are connected in parallel and serially into the circuit of the main low-voltage stator coil.

Frequency response function of motors for switching noise energy with a new experimental approach

International Nuclear Information System (INIS)

Kim, Hyunsu; Yoon, Jong-Yun

2017-01-01

Switching energy in electrical vehicles can create serious noise from the motors. However, the characteristics of switching noise in vehicle motors are not clear due to the complexity of measuring them. This study proposes a new experimental method to investigate the switching noise energy of a vehicle motor based on frequency response functions. A function generator-amplifier system is used to gen- erate the switching energy instead of the complex battery-inverter system that has previously been used to examine the noise energy characteristics. Even though newly adapted experimental method is simple, the switching noise energy was explicitly investigated under various input signals. Thus, this simple new method can be used to investigate the dynamic characteristics of noise energy in a vehicle motor

A Novel Four-Step Commutation for Bidirectional Switch Cells of AC-AC Matrix Converter

DEFF Research Database (Denmark)

Guo, Yougui; Zeng, Ping; Blaabjerg, Frede

2012-01-01

on or off of output current happens on the second and third steps. Here the second step is equal to the third one. This method is implemented with four steps by programming in VHDL language. First, the special flip-flop, 74AHC16373, is obtained by programming so as to make input sector signals, output...... sector ones and active switching time PWM ones synchronize. Second, the required switching states are flexibly realized in the form of the look-up table by programming in VHDL language for 36 switching combinations of input sectors with output ones. Third, the obtained switching states are judged whether...... they need commutation by delayers. Finally, the novel method proposed is implemented by switching sequencers. The simulation results have verified its feasibility....

Frequency response function of motors for switching noise energy with a new experimental approach

Energy Technology Data Exchange (ETDEWEB)

Kim, Hyunsu [Ensemble Center for Automotive Research, Seoul (Korea, Republic of); Yoon, Jong-Yun [Incheon National University, Incheon (Korea, Republic of)

2017-06-15

Switching energy in electrical vehicles can create serious noise from the motors. However, the characteristics of switching noise in vehicle motors are not clear due to the complexity of measuring them. This study proposes a new experimental method to investigate the switching noise energy of a vehicle motor based on frequency response functions. A function generator-amplifier system is used to gen- erate the switching energy instead of the complex battery-inverter system that has previously been used to examine the noise energy characteristics. Even though newly adapted experimental method is simple, the switching noise energy was explicitly investigated under various input signals. Thus, this simple new method can be used to investigate the dynamic characteristics of noise energy in a vehicle motor.

Trastuzumab Resistance: Role for Notch Signaling

Directory of Open Access Journals (Sweden)

Kinnari Mehta

2009-01-01

Full Text Available Epidermal growth factor receptor-2 (ErbB-2/HER2 is a potent breast oncogene that has been shown to be amplified in 20% of breast cancers. Overexpression of ErbB-2 predicts for aggressive tumor behavior, resistance to some cytotoxic and antihormonal therapies, and poor overall survival. Trastuzumab, the humanized, monoclonal antibody directed against ErbB-2 has shown tremendous efficacy and improved overall survival for women when combined with a taxane-based chemotherapy. However, resistance to trastuzumab remains a major concern, most notably in women with metastatic breast cancer. Numerous mechanisms that include overexpression of alternate receptor tyrosine kinases and/or loss of critical tumor suppressors have been proposed in the last several years to elucidate trastuzumab resistance. Here we review the many possible mechanisms of action that could contribute to resistance, and novel therapies to prevent or reverse the resistant phenotype. Moreover, we provide a critical role for Notch signaling cross-talk with overlapping or new signaling networks in trastuzumab-resistant breast.

Optical switching properties of VO2 films driven by using WDM-aligned lasers

International Nuclear Information System (INIS)

Tsai, K.Y.; Wu, F.-H.; Shieh, H.-P.D.; Chin, T.-S.

2006-01-01

Vanadium dioxide (VO 2 ) film had been demonstrated a high speed IR shutter driven by total optical modulation. However, it usually required a higher power heating laser of high power and precise optical systems to cover the probe beam on the sample with a heating beam of larger area. A new optical system, simply composed of wavelength division multiplexing (WDM), fiber lens or convex lens system, and a glass sheet with VO 2 thin film on it, was easily assembled to utilize VO 2 film as an IR shutter, implying the possibility to highly miniaturize the VO 2 -based optical shutter. A permanent low-transmittance (PLT) region forms on the film within the probe beam, resulting in a decrease in average power of the probe beam. Another ring-type switching area (switching ring) forms around the PLT region, resulting in the transmittance switching of the probe beam synchronously with the heating signal. VO 2 films can be switched with the highest rate of a continuous square heating signal of 3 mW at 120 kHz. A heating pulse of 0.7 ns and 13 mW can be used to stimulate an IR pulse with fiber lens

Forward modeling of fluctuating dietary 13C signals to validate 13C turnover models of milk and milk components from a diet-switch experiment.

Directory of Open Access Journals (Sweden)

Alexander Braun

Full Text Available Isotopic variation of food stuffs propagates through trophic systems. But, this variation is dampened in each trophic step, due to buffering effects of metabolic and storage pools. Thus, understanding of isotopic variation in trophic systems requires knowledge of isotopic turnover. In animals, turnover is usually quantified in diet-switch experiments in controlled conditions. Such experiments usually involve changes in diet chemical composition, which may affect turnover. Furthermore, it is uncertain if diet-switch based turnover models are applicable under conditions with randomly fluctuating dietary input signals. Here, we investigate if turnover information derived from diet-switch experiments with dairy cows can predict the isotopic composition of metabolic products (milk, milk components and feces under natural fluctuations of dietary isotope and chemical composition. First, a diet-switch from a C3-grass/maize diet to a pure C3-grass diet was used to quantify carbon turnover in whole milk, lactose, casein, milk fat and feces. Data were analyzed with a compartmental mixed effects model, which allowed for multiple pools and intra-population variability, and included a delay between feed ingestion and first tracer appearance in outputs. The delay for milk components and whole milk was ~12 h, and that of feces ~20 h. The half-life (t½ for carbon in the feces was 9 h, while lactose, casein and milk fat had a t½ of 10, 18 and 19 h. The (13C kinetics of whole milk revealed two pools, a fast pool with a t½ of 10 h (likely representing lactose, and a slower pool with a t½ of 21 h (likely including casein and milk fat. The diet-switch based turnover information provided a precise prediction (RMSE ~0.2 ‰ of the natural (13C fluctuations in outputs during a 30 days-long period when cows ingested a pure C3 grass with naturally fluctuating isotope composition.

Mammary Ductal Environment Is Necessary for Faithful Maintenance of Estrogen Signaling in ER+ Breast Cancer

OpenAIRE

Haricharan, Svasti; Lei, Jonathan; Ellis, Matthew

2016-01-01

In this issue of Cancer Cell, Sflomos et al. (2016) describe a robust preclinical animal model of ER+ breast cancer. The authors identify the critical role of the breast microenvironment in determining hormone response of ER+ breast cancer cells and in driving the luminal phenotype of breast cancer.

Photonic-crystal switch divider based on Ge2Sb2Te5 thin films.

Science.gov (United States)

Ma, Beijiao; Zhang, Peiqing; Wang, Hui; Zhang, Tengyu; Zeng, Jianghui; Zhang, Qian; Wang, Guoxiang; Xu, Peipeng; Zhang, Wei; Dai, Shixun

2016-11-10

A three-port phase-change photonic-crystal switch divider based on Ge2Sb2Te5 chalcogenide thin film was proposed. The chalcogenide material used was determined to have a high refractive index and fast phase-change speed by using laser radiation. The structure with a T-junction cavity was used to achieve three switch functions: switching "ON" in only one output port, switching "OFF" in both output ports, and dividing signals into two output ports. The transmission properties of the designed device at 2.0 μm were studied by the finite difference time domain method, which showed that the switch divider can achieve very high switching efficiency by optimizing T-junction cavity parameters. The scaling laws of photonic crystals revealed that the operating wavelength of the designed structure can be easily extended to another wavelength in the midinfrared region.

Energy reversible switching from amorphous metal based nanoelectromechanical switch

KAUST Repository

Mayet, Abdulilah M.; Smith, Casey; Hussain, Muhammad Mustafa

2013-01-01

We report observation of energy reversible switching from amorphous metal based nanoelectromechanical (NEM) switch. For ultra-low power electronics, NEM switches can be used as a complementary switching element in many nanoelectronic system applications. Its inherent zero power consumption because of mechanical detachment is an attractive feature. However, its operating voltage needs to be in the realm of 1 volt or lower. Appropriate design and lower Young's modulus can contribute achieving lower operating voltage. Therefore, we have developed amorphous metal with low Young's modulus and in this paper reporting the energy reversible switching from a laterally actuated double electrode NEM switch. © 2013 IEEE.

Energy reversible switching from amorphous metal based nanoelectromechanical switch

KAUST Repository

Mayet, Abdulilah M.

2013-08-01

We report observation of energy reversible switching from amorphous metal based nanoelectromechanical (NEM) switch. For ultra-low power electronics, NEM switches can be used as a complementary switching element in many nanoelectronic system applications. Its inherent zero power consumption because of mechanical detachment is an attractive feature. However, its operating voltage needs to be in the realm of 1 volt or lower. Appropriate design and lower Young\\'s modulus can contribute achieving lower operating voltage. Therefore, we have developed amorphous metal with low Young\\'s modulus and in this paper reporting the energy reversible switching from a laterally actuated double electrode NEM switch. © 2013 IEEE.

Targeting the androgen receptor in triple-negative breast cancer: current perspectives

Directory of Open Access Journals (Sweden)

Mina A

2017-09-01

Full Text Available Alain Mina,1 Rachel Yoder,2 Priyanka Sharma1 1Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Westwood, 2University of Kansas Cancer Center, Kansas City, KS, USA Abstract: Triple-negative breast cancer (TNBC is an aggressive subtype associated with frequent recurrence and metastasis. Unlike hormone receptor-positive subtypes, treatment of TNBC is currently limited by the lack of clinically available targeted therapies. Androgen signaling is necessary for normal breast development, and its dysregulation has been implicated in breast tumorigenesis. In recent years, gene expression studies have identified a subset of TNBC that is enriched for androgen receptor (AR signaling. Interference with androgen signaling in TNBC is promising, and AR-inhibiting drugs have shown antitumorigenic activity in preclinical and proof of concept clinical studies. Recent advances in our understanding of androgenic signaling in TNBC, along with the identification of interacting pathways, are allowing development of the next generation of clinical trials with AR inhibitors. As novel AR-targeting agents are developed and evaluated in clinical trials, it is equally important to establish a robust set of biomarkers for identification of TNBC tumors that are most likely to respond to AR inhibition. Keywords: triple-negative breast cancer, androgen signaling, targeted therapy, biomarkers, prognosis 

Mammary Ductal Environment Is Necessary for Faithful Maintenance of Estrogen Signaling in ER+ Breast Cancer

Science.gov (United States)

Haricharan, Svasti; Lei, Jonathan; Ellis, Matthew

2016-01-01

In this issue of Cancer Cell, Sflomos et al. (2016) describe a robust preclinical animal model of ER+ breast cancer. The authors identify the critical role of the breast microenvironment in determining hormone response of ER+ breast cancer cells and in driving the luminal phenotype of breast cancer. PMID:26977876

US findings of bilateral primary breast cancer: Retrospective study

International Nuclear Information System (INIS)

Lou Li; Cong Xinli; Yu Guofang; Li Jichang; Ma Yuxiang

2007-01-01

Background: For women with breast cancer, the contralateral breast is at high risk. The bilateral cancers may be synchronous or metachronous. If the bilateral breast cancers have similar ultrasonography (US) appearances, the US findings of the first breast cancer (index cancer) might lead to early detection of the contralateral cancer. The purpose of this study was to identify the US characteristics of bilateral breast cancer and to determine whether bilateral breast cancers have similar US appearances and whether the US findings for one breast cancer might be predictive of the contralateral breast cancer. Methods: We retrospectively reviewed the US manifestations of 58 patients with surgically proven bilateral primary breast cancer and compared the contralateral cancer with the index cancer by evaluation the margin, shape, inside echoes, posterior attenuation, calcification and color flow signals of 58 lesion pairs to investigate whether the bilateral breast cancers have similar US appearances. Results: Bilateral primary breast cancers were more located in upper outer quadrant, frequently spiculation, taller than wide shape, with irregular margin, heterogeneous internal echo and acoustic shadowing, containing microcalcification and abundant color flow signals. The most common US appearances were taller than wide shape (75.0%, 87/116), irregular margins (79.3%, 92/116) and heterogeneous internal echo (86.2%, 100/116). Of the total 58 lesion pairs, 18 (31.0%) pairs had similar US characteristics, whereas 40 (69.0%) pairs had different US characteristics. Conclusions: US signs of the index cancer do not indicate the most likely appearance of the second cancer in the contralateral breast. Evaluation of the contralateral cancer should be performed without regard for the US findings for the index cancer

Switching between intravenous and subcutaneous trastuzumab

DEFF Research Database (Denmark)

Gligorov, Joseph; Curigliano, Giuseppe; Müller, Volkmar

2017-01-01

AIM: To assess the safety and tolerability of switching between subcutaneous (SC) and intravenous (IV) trastuzumab in the PrefHer study (NCT01401166). PATIENTS AND METHODS: Patients with HER2-positive early breast cancer completed (neo)adjuvant chemotherapy and were randomised to receive four...... cycles of SC trastuzumab, via single-use injection device (SID; Cohort 1) or hand-held syringe (Cohort 2), followed by four cycles of IV, or vice versa (the crossover period presented here) as part of their 18 standard cycles of adjuvant trastuzumab treatment. Adverse events (AEs) were reported using....... Rates of clinically important events, including grade ≥3 AEs, serious AEs, AEs leading to study drug discontinuation and cardiac AEs, were low and similar between treatment arms (trastuzumab were observed. CONCLUSIONS: PrefHer revealed...

Orbit Correction for the Newly Developed Polarization-Switching Undulator

Science.gov (United States)

Obina, Takashi; Honda, Tohru; Shioya, Tatsuro; Kobayashi, Yukinori; Tsuchiya, Kimichika; Yamamoto, Shigeru

2007-01-01

A new scheme of undulator magnet arrangements has been proposed and developed as a polarization-switching radiation source, and its test-stand was installed in the 2.5-GeV Photon Factory storage ring (PF ring) in order to investigate the effects on the beam orbit. The closed orbit distortion (COD) over 200 μm was produced in a vertical direction when we switched the polarization of the radiation from the test-stand. In a horizontal direction, the COD was less than 50μm. The results agreed well with the predictions from the magnetic-field measurement on the bench. In order to suppress the CODs and realize a stable operation of the ring with the polarization-switching, we developed an orbit correction system which consists of an encoder to detect motion of magnets, a pair of beam position monitors (BPMs), signal processing parts, and a pair of steering magnets. We succeeded in suppressing the CODs to the level below 3μm using the system even when we switch the polarization at a maximum frequency of 0.8 Hz.

Switched-capacitor techniques for high-accuracy filter and ADC design

NARCIS (Netherlands)

Quinn, P.J.; Roermund, van A.H.M.

2007-01-01

Switched capacitor (SC) techniques are well proven to be excellent candidates for implementing critical analogue functions with high accuracy, surpassing other analogue techniques when embedded in mixed-signal CMOS VLSI. Conventional SC circuits are primarily limited in accuracy by a) capacitor

Spike-timing dependent plasticity in a transistor-selected resistive switching memory

International Nuclear Information System (INIS)

Ambrogio, S; Balatti, S; Nardi, F; Facchinetti, S; Ielmini, D

2013-01-01

In a neural network, neuron computation is achieved through the summation of input signals fed by synaptic connections. The synaptic activity (weight) is dictated by the synchronous firing of neurons, inducing potentiation/depression of the synaptic connection. This learning function can be supported by the resistive switching memory (RRAM), which changes its resistance depending on the amplitude, the pulse width and the bias polarity of the applied signal. This work shows a new synapse circuit comprising a MOS transistor as a selector and a RRAM as a variable resistance, displaying spike-timing dependent plasticity (STDP) similar to the one originally experienced in biological neural networks. We demonstrate long-term potentiation and long-term depression by simulations with an analytical model of resistive switching. Finally, the experimental demonstration of the new STDP scheme is presented. (paper)

Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells

International Nuclear Information System (INIS)

Camirand, Anne; Zakikhani, Mahvash; Young, Fiona; Pollak, Michael

2005-01-01

Gefitinib (Iressa, ZD 1839, AstraZeneca) blocks the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and inhibits proliferation of several human cancer cell types including breast cancer. Phase II clinical trials with gefitinib monotherapy showed an objective response of 9 to 19% in non-small-cell lung cancer patients and less than 10% for breast cancer, and phase III results have indicated no benefit of gefitinib in combination with chemotherapy over chemotherapy alone. In order to improve the antineoplastic activity of gefitinib, we investigated the effects of blocking the signalling of the insulin-like growth factor 1 receptor (IGF-1R), a tyrosine kinase with a crucial role in malignancy that is coexpressed with EGFR in most human primary breast carcinomas. AG1024 (an inhibitor of IGF-1R) was used with gefitinib for treatment of MDA468, MDA231, SK-BR-3, and MCF-7 breast cancer lines, which express similar levels of IGF-1R but varying levels of EGFR. Proliferation assays, apoptosis induction studies, and Western blot analyses were conducted with cells treated with AG1024 and gefitinib as single agents and in combination. Gefitinib and AG1024 reduced proliferation in all lines when used as single agents, and when used in combination revealed an additive-to-synergistic effect on cell growth inhibition. Flow cytometry measurements of cells stained with annexin V-propidium iodide and cells stained for caspase-3 activation indicated that adding an IGF-1R-targeting strategy to gefitinib results in higher levels of apoptosis than are achieved with gefitinib alone. Gefitinib either reduced or completely inhibited p42/p44 Erk kinase phosphorylation, depending on the cell line, while Akt phosphorylation was reduced by a combination of the two agents. Overexpression of IGF-1R in SK-BR-3 cells was sufficient to cause a marked enhancement in gefitinib resistance. These results indicate that IGF-1R signaling reduces the antiproliferative effects of

Pseudospark switches

International Nuclear Information System (INIS)

Billault, P.; Riege, H.; Gulik, M. van; Boggasch, E.; Frank, K.

1987-01-01

The pseudospark discharge is bound to a geometrical structure which is particularly well suited for switching high currents and voltages at high power levels. This type of discharge offers the potential for improvement in essentially all areas of switching operation: peak current and current density, current rise, stand-off voltage, reverse current capability, cathode life, and forward drop. The first pseudospark switch was built at CERN at 1981. Since then, the basic switching characteristics of pseudospark chambers have been studied in detail. The main feature of a pseudospark switch is the confinement of the discharge plasma to the device axis. The current transition to the hollow electrodes is spread over a rather large surface area. Another essential feature is the easy and precise triggering of the pseudospark switch from the interior of the hollow electrodes, relatively far from the main discharge gap. Nanosecond delay and jitter values can be achieved with trigger energies of less than 0.1 mJ, although cathode heating is not required. Pseudospark gaps may cover a wide range of high-voltage, high-current, and high-pulse-power switching at repetition rates of many kilohertz. This report reviews the basic researh on pseudospark switches which has been going on at CERN. So far, applications have been developed in the range of thyratron-like medium-power switches at typically 20 to 40 kV and 0.5 to 10 kA. High-current pseudospark switches have been built for a high-power 20 kJ pulse generator which is being used for long-term tests of plasma lenses developed for the future CERN Antiproton Collector (ACOL). The high-current switches have operated for several hundred thousand shots, with 20 to 50 ns jitter at 16 kV charging voltage and more than 100 kA peak current amplitude. (orig.)

Development of high power X-band semiconductor microwave switch for pulse compression systems of future linear colliders

Directory of Open Access Journals (Sweden)

Fumihiko Tamura

2002-06-01

Full Text Available We describe concepts for high power semiconductor rf switches, designed to handle signals at X-band with power level near 100 MW. We describe an abstract design methodology and derive a general scaling law for these switches. We also present a design and experimental work of a switch operating at the TE_{01} mode in overmoded circular waveguides. The switch is composed of an array of tee junction elements that have a p-i-n diode array window in the third arm.

Modulation of Cyclins, p53 and Mitogen-Activated Protein Kinases Signaling in Breast Cancer Cell Lines by 4-(3,4,5-Trimethoxyphenoxybenzoic Acid

Directory of Open Access Journals (Sweden)

Kuan-Han Lee

2014-01-01

Full Text Available Despite the advances in cancer therapy and early detection, breast cancer remains a leading cause of cancer-related deaths among females worldwide. The aim of the current study was to investigate the antitumor activity of a novel compound, 4-(3,4,5-trimethoxyphenoxybenzoic acid (TMPBA and its mechanism of action, in breast cancer. Results indicated the relatively high sensitivity of human breast cancer cell-7 and MDA-468 cells towards TMPBA with IC50 values of 5.9 and 7.9 µM, respectively compared to hepatocarcinoma cell line Huh-7, hepatocarcinoma cell line HepG2, and cervical cancer cell line Hela cells. Mechanistically, TMPBA induced apoptotic cell death in MCF-7 cells as indicated by 4',6-diamidino-2-phenylindole (DAPI nuclear staining, cell cycle analysis and the activation of caspase-3. Western blot analysis revealed the ability of TMPBA to target pathways mediated by mitogen-activated protein (MAP kinases, 5' adenosine monophosphate-activated protein kinase (AMPK, and p53, of which the concerted action underlined its antitumor efficacy. In addition, TMPBA induced alteration of cyclin proteins’ expression and consequently modulated the cell cycle. Taken together, the current study underscores evidence that TMPBA induces apoptosis in breast cancer cells via the modulation of cyclins and p53 expression as well as the modulation of AMPK and mitogen-activated protein kinases (MAPK signaling. These findings support TMPBA’s clinical promise as a potential candidate for breast cancer therapy.

Targeting progesterone metabolism in breast cancer with l-proline derived new 14-azasteroids.

Science.gov (United States)

Singh, Jyotsana; Singh, Ritesh; Gupta, Preeti; Rai, Smita; Ganesher, Asha; Badrinarayan, Preethi; Sastry, G Narahari; Konwar, Rituraj; Panda, Gautam

2017-08-15

Breast cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast cancer cells. Here, we estimated the potential of alternate targeting of breast cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Carcinogen inducibility in vivo and down-regulation of DMBT1 during breast carcinogenesis

DEFF Research Database (Denmark)

Mollenhauer, Jan; Helmke, Burkhard; Medina, Daniel

2004-01-01

unambiguous inactivating DMBT1 mutations in breast cancer. Expression analyses in the human and mouse mammary glands pointed to the necessity of DMBT1 induction. While age-dependent and hormonal effects could be ruled out, 9 of 10 mice showed induction of Dmbt1 expression after administration...... of the carcinogen 7,12-dimethybenz(alpha)anthracene prior to the onset of tumorigenesis or other histopathological changes. DMBT1 displayed significant up-regulation in human tumor-flanking tissues compared to in normal breast tissues (P displayed a switch from lumenal...

Caveolin-1 expression in benign and malignant lesions of the breast

Directory of Open Access Journals (Sweden)

Kiesel Ludwig

2007-10-01

Full Text Available Abstract Background Caveolin-1 is thought to have an important impact on both signal transduction and mediation of intracellular processes. Furthermore, it has been suggested that Caveolin-1 may contribute to certain steps of carcinogenesis in various types of cancer. We examined the potential clinical relevance of Caveolin-1 in normal, benign and malignant breast tissue specimens. Methods Using tissue microarray (TMA technology cases of invasive breast cancer, DCIS, benign breast disease (i.e. fibroadenoma, sclerosing adenosis, ductal hyperplasia and radial scar and normal breast tissue were evaluated for Caveolin-1 expression. Immunohistochemical staining with an anti-Caveolin-1-antibody was performed. Staining intensity was quantified semiquantitatively. In invasive lesions staining results were correlated with clinical and pathological data. Results No Caveolin-1 expression was observed in epithelial cells of normal breast tissue (n = 5, benign breast disease (n = 295 and DCIS (n = 108. However, Caveolin-1 expression was found in 32 of 109 cases of invasive breast carcinomas (29.4%. Caveolin-1 expression in invasive breast cancer could neither be correlated with survival parameters such as overall or disease-free survival nor with established clinical and pathological markers. Conclusion In this study we demonstrated expression of Caveolin-1 in one third of invasive breast cancers. A significant increase in Caveolin-1 expression was observed comparing invasive breast cancer to both benign breast tissue and non-invasive breast cancer. Since inhibitors of Caveolin-1 signalling are available, targeting Caveolin-1 in breast cancer may represent a potential option for future breast cancer treatment.

MOSFET analog memory circuit achieves long duration signal storage

Science.gov (United States)

1966-01-01

Memory circuit maintains the signal voltage at the output of an analog signal amplifier when the input signal is interrupted or removed. The circuit uses MOSFET /Metal Oxide Semiconductor Field Effect Transistor/ devices as voltage-controlled switches, triggered by an external voltage-sensing device.

Power requirements reducing of FBG based all-optical switching

Science.gov (United States)

Scholtz, Ľubomír.; Solanská, Michaela; Ladányi, Libor; Müllerová, Jarmila

2017-12-01

Although Fiber Bragg gratings (FBGs) are well known devices, their using as all-optical switching elements has been still examined. Current research is focused on optimization of their properties for their using in future all-optical networks. The main problem are high switching intensities needed for achieving the changes of the transmission state. Over several years switching intensities have been reduced from hundreds of GW/cm2 to tens of MW/cm2 by selecting appropriate gratings and signal parameters or using suitable materials. Two principal nonlinear effects with similar power requirements can result in the bistable transmission/reflection of an input optical pulse. In the self-phase modulation (SPM) regime switching is achieved by the intense probe pulse itself. Using cross-phase modulation (XPM) a strong pump alters the FBG refractive index experienced by a weak probe pulse. As a result of this the detuning of the probe pulse from the center of the photonic band gap occurs. Using of XPM the effect of modulation instability is reduced. Modulation instability which is the main SPM degradation mechanism. We focused on nonlinear FBGs based on chalcogenide glasses which are very often used in various applications. Thanks to high nonlinear parameters chalcogenide glasses are suitable candidates for reducing switching intensities of nonlinear FBGs.

A Switch Is Not a Switch: Syntactically-Driven Bilingual Language Control

Science.gov (United States)

Gollan, Tamar H.; Goldrick, Matthew

2018-01-01

The current study investigated the possibility that language switches could be relatively automatically triggered by context. "Single-word switches," in which bilinguals switched languages on a single word in midsentence and then immediately switched back, were contrasted with more complete "whole-language switches," in which…

Switching Phenomena in a System with No Switches

Science.gov (United States)

Preis, Tobias; Stanley, H. Eugene

2010-02-01

It is widely believed that switching phenomena require switches, but this is actually not true. For an intriguing variety of switching phenomena in nature, the underlying complex system abruptly changes from one state to another in a highly discontinuous fashion. For example, financial market fluctuations are characterized by many abrupt switchings creating increasing trends ("bubble formation") and decreasing trends ("financial collapse"). Such switching occurs on time scales ranging from macroscopic bubbles persisting for hundreds of days to microscopic bubbles persisting only for a few seconds. We analyze a database containing 13,991,275 German DAX Future transactions recorded with a time resolution of 10 msec. For comparison, a database providing 2,592,531 of all S&P500 daily closing prices is used. We ask whether these ubiquitous switching phenomena have quantifiable features independent of the time horizon studied. We find striking scale-free behavior of the volatility after each switching occurs. We interpret our findings as being consistent with time-dependent collective behavior of financial market participants. We test the possible universality of our result by performing a parallel analysis of fluctuations in transaction volume and time intervals between trades. We show that these financial market switching processes have properties similar to those of phase transitions. We suggest that the well-known catastrophic bubbles that occur on large time scales—such as the most recent financial crisis—are no outliers but single dramatic representatives caused by the switching between upward and downward trends on time scales varying over nine orders of magnitude from very large (≈102 days) down to very small (≈10 ms).

Estrogen and progesterone signalling in the normal breast and its implications for cancer development.

Science.gov (United States)

Hilton, Heidi N; Clarke, Christine L; Graham, J Dinny

2018-05-05

The ovarian hormones estrogen and progesterone are master regulators of the development and function of a broad spectrum of human tissues, including the breast, reproductive and cardiovascular systems, brain and bone. Acting through the nuclear estrogen (ER) and progesterone receptors (PR), both play complex and essential coordinated roles in the extensive development of the lobular alveolar epithelial structures of the normal breast during puberty, the normal menstrual cycle and pregnancy. The past decade has seen major advances in understanding the mechanisms of action of estrogen and progesterone in the normal breast and in the delineation of the complex hierarchy of cell types regulated by ovarian hormones in this tissue. There is evidence for a role for both ER and PR in driving breast cancer, and both are favourable prognostic markers with respect to outcome. In this review, we summarize current knowledge of the mechanisms of action of ER and PR in the normal breast, and implications for the development and management of breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

ECG fiducial point extraction using switching Kalman filter.

Science.gov (United States)

Akhbari, Mahsa; Ghahjaverestan, Nasim Montazeri; Shamsollahi, Mohammad B; Jutten, Christian

2018-04-01

In this paper, we propose a novel method for extracting fiducial points (FPs) of the beats in electrocardiogram (ECG) signals using switching Kalman filter (SKF). In this method, according to McSharry's model, ECG waveforms (P-wave, QRS complex and T-wave) are modeled with Gaussian functions and ECG baselines are modeled with first order auto regressive models. In the proposed method, a discrete state variable called "switch" is considered that affects only the observation equations. We denote a mode as a specific observation equation and switch changes between 7 modes and corresponds to different segments of an ECG beat. At each time instant, the probability of each mode is calculated and compared among two consecutive modes and a path is estimated, which shows the relation of each part of the ECG signal to the mode with the maximum probability. ECG FPs are found from the estimated path. For performance evaluation, the Physionet QT database is used and the proposed method is compared with methods based on wavelet transform, partially collapsed Gibbs sampler (PCGS) and extended Kalman filter. For our proposed method, the mean error and the root mean square error across all FPs are 2 ms (i.e. less than one sample) and 14 ms, respectively. These errors are significantly smaller than those obtained using other methods. The proposed method achieves lesser RMSE and smaller variability with respect to others. Copyright © 2018 Elsevier B.V. All rights reserved.

49 CFR 1242.12 - Administration-signals (account XX-19-04).

Science.gov (United States)

2010-10-01

... 49 Transportation 9 2010-10-01 2010-10-01 false Administration-signals (account XX-19-04). 1242.12... Structures § 1242.12 Administration—signals (account XX-19-04). Separate common administration—signals... (XX-17-19) Switching (XX-18-19) ...

Tissue architecture and breast cancer: the role of extracellular matrix and steroid hormones

Energy Technology Data Exchange (ETDEWEB)

Hansen, R K; Bissell, M J

2000-06-01

The changes in tissue architecture that accompany the development of breast cancer have been the focus of investigations aimed at developing new cancer therapeutics. As we learn more about the normal mammary gland, we have begun to understand the complex signaling pathways underlying the dramatic shifts in the structure and function of breast tissue. Integrin-, growth factor-, and steroid hormone-signaling pathways all play an important part in maintaining tissue architecture; disruption of the delicate balance of signaling results in dramatic changes in the way cells interact with each other and with the extracellular matrix, leading to breast cancer. The extracellular matrix itself plays a central role in coordinating these signaling processes. In this review, we consider the interrelationships between the extracellular matrix, integrins, growth factors, and steroid hormones in mammary gland development and function.

Optical switching based on the manipulation of microparticles in a colloidal liquid using strong scattering force

International Nuclear Information System (INIS)

Liu Jin; Liu Zheng-Qi; Feng Tian-Hua; Dai Qiao-Feng; Wu Li-Jun; Lan Sheng

2010-01-01

This paper demonstrates the realization of an optical switch by optically manipulating a large number of polystyrene spheres contained in a capillary. The strong scattering force exerted on polystyrene spheres with a large diameter of 4.3 μm is employed to realize the switching operation. A transparent window is opened for the signal light when the polystyrene spheres originally located at the beam centre are driven out of the beam region by the strong scattering force induced by the control light. The switching dynamics under different incident powers is investigated and compared with that observed in the optical switch based on the formation of optical matter. It is found that a large extinction ratio of ∼ 30 dB and fast switching-on and switching-off times can be achieved in this type of switch. (classical areas of phenomenology)

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

Science.gov (United States)

Zeng, Chenjie; Guo, Xingyi; Long, Jirong; Kuchenbaecker, Karoline B; Droit, Arnaud; Michailidou, Kyriaki; Ghoussaini, Maya; Kar, Siddhartha; Freeman, Adam; Hopper, John L; Milne, Roger L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Agata, Simona; Ahmed, Shahana; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arason, Adalgeir; Arndt, Volker; Arun, Banu K; Arver, Brita; Bacot, Francois; Barrowdale, Daniel; Baynes, Caroline; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Blot, William J; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Carpenter, Jane; Chang-Claude, Jenny; Choi, Ji-Yeob; Claes, Kathleen B M; Clarke, Christine; Cox, Angela; Cross, Simon S; Czene, Kamila; Daly, Mary B; de la Hoya, Miguel; De Leeneer, Kim; Devilee, Peter; Diez, Orland; Domchek, Susan M; Doody, Michele; Dorfling, Cecilia M; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Dwek, Miriam; Dworniczak, Bernd; Egan, Kathleen; Eilber, Ursula; Einbeigi, Zakaria; Ejlertsen, Bent; Ellis, Steve; Frost, Debra; Lalloo, Fiona; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; Friedlander, Michael; Friedman, Eitan; Gambino, Gaetana; Gao, Yu-Tang; Garber, Judy; García-Closas, Montserrat; Gehrig, Andrea; Damiola, Francesca; Lesueur, Fabienne; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Giles, Graham G; Godwin, Andrew K; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Hartikainen, Jaana M; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Hogervorst, Frans B L; Verhoef, Senno; Hendricks, Carolyn B; Hillemanns, Peter; Hollestelle, Antoinette; Hulick, Peter J; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Joly Beauparlant, Charles; Jones, Michael; Kabisch, Maria; Kang, Daehee; Karlan, Beth Y; Kauppila, Saila; Kerin, Michael J; Khan, Sofia; Khusnutdinova, Elza; Knight, Julia A; Konstantopoulou, Irene; Kraft, Peter; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Le Marchand, Loic; Lee, Chuen Neng; Lee, Min Hyuk; Lester, Jenny; Li, Jingmei; Liljegren, Annelie; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mai, Phuong L; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; McGuffog, Lesley; Meindl, Alfons; Menegaux, Florence; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Newcomb, Polly A; Nord, Silje; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olswold, Curtis; Osorio, Ana; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Peeters, Stephanie; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Presneau, Nadege; Radice, Paolo; Rahman, Nazneen; Ramus, Susan J; Rashid, Muhammad Usman; Rennert, Gad; Rhiem, Kerstin; Rudolph, Anja; Salani, Ritu; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Schoemaker, Minouk J; Schürmann, Peter; Seynaeve, Caroline; Shen, Chen-Yang; Shrubsole, Martha J; Shu, Xiao-Ou; Sigurdson, Alice; Singer, Christian F; Slager, Susan; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Swerdlow, Anthony; Szabo, Csilla I; Tchatchou, Sandrine; Teixeira, Manuel R; Teo, Soo H; Terry, Mary Beth; Tessier, Daniel C; Teulé, Alex; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tung, Nadine; Turnbull, Clare; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Ven den Berg, David; Vijai, Joseph; Wang-Gohrke, Shan; Weitzel, Jeffrey N; Whittemore, Alice S; Winqvist, Robert; Wong, Tien Y; Wu, Anna H; Yannoukakos, Drakoulis; Yu, Jyh-Cherng; Pharoah, Paul D P; Hall, Per; Chenevix-Trench, Georgia; Dunning, Alison M; Simard, Jacques; Couch, Fergus J; Antoniou, Antonis C; Easton, Douglas F; Zheng, Wei

2016-06-21

Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P association signals at

Breast cancer lung metastasis: Molecular biology and therapeutic implications.

Science.gov (United States)

Jin, Liting; Han, Bingchen; Siegel, Emily; Cui, Yukun; Giuliano, Armando; Cui, Xiaojiang

2018-03-26

Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.

Mammary Development and Breast Cancer: A Wnt Perspective

Science.gov (United States)

Yu, Qing Cissy; Verheyen, Esther M.; Zeng, Yi Arial

2016-01-01

The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how its various components contribute to breast carcinoma pathology. PMID:27420097

Switching between intravenous and subcutaneous trastuzumab: safety results from the PrefHer trial

OpenAIRE

Gligorov, Joseph; Curigliano, Giuseppe; Müller, Volkmar; Knoop, Ann; Jenkins, Valerie; Verma, Sunil; Osborne, Stuart; Lauer, Sabine; Machackova, Zuzana; Fallowfield, Lesley; Pivot, Xavier

2017-01-01

Aim: To assess the safety and tolerability of switching between subcutaneous (SC) and intravenous (IV) trastuzumab in the PrefHer study (NCT01401166).\\ud \\ud Patients and methods: Patients with HER2-positive early breast cancer completed (neo)adjuvant chemotherapy and were randomised to receive four cycles of SC trastuzumab, via single-use injection device (SID; Cohort 1) or hand-held syringe (Cohort 2), followed by four cycles of IV, or vice versa (the crossover period presented here) as par...

Breast ultrasound tomography with total-variation regularization

Energy Technology Data Exchange (ETDEWEB)

Huang, Lianjie [Los Alamos National Laboratory; Li, Cuiping [KARMANOS CANCER INSTIT.; Duric, Neb [KARMANOS CANCER INSTIT

2009-01-01

Breast ultrasound tomography is a rapidly developing imaging modality that has the potential to impact breast cancer screening and diagnosis. A new ultrasound breast imaging device (CURE) with a ring array of transducers has been designed and built at Karmanos Cancer Institute, which acquires both reflection and transmission ultrasound signals. To extract the sound-speed information from the breast data acquired by CURE, we have developed an iterative sound-speed image reconstruction algorithm for breast ultrasound transmission tomography based on total-variation (TV) minimization. We investigate applicability of the TV tomography algorithm using in vivo ultrasound breast data from 61 patients, and compare the results with those obtained using the Tikhonov regularization method. We demonstrate that, compared to the Tikhonov regularization scheme, the TV regularization method significantly improves image quality, resulting in sound-speed tomography images with sharp (preserved) edges of abnormalities and few artifacts.

Voltage-Driven Conformational Switching with Distinct Raman Signature in a Single-Molecule Junction.

Science.gov (United States)

Bi, Hai; Palma, Carlos-Andres; Gong, Yuxiang; Hasch, Peter; Elbing, Mark; Mayor, Marcel; Reichert, Joachim; Barth, Johannes V

2018-04-11

Precisely controlling well-defined, stable single-molecule junctions represents a pillar of single-molecule electronics. Early attempts to establish computing with molecular switching arrays were partly challenged by limitations in the direct chemical characterization of metal-molecule-metal junctions. While cryogenic scanning probe studies have advanced the mechanistic understanding of current- and voltage-induced conformational switching, metal-molecule-metal conformations are still largely inferred from indirect evidence. Hence, the development of robust, chemically sensitive techniques is instrumental for advancement in the field. Here we probe the conformation of a two-state molecular switch with vibrational spectroscopy, while simultaneously operating it by means of the applied voltage. Our study emphasizes measurements of single-molecule Raman spectra in a room-temperature stable single-molecule switch presenting a signal modulation of nearly 2 orders of magnitude.

Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival.

Science.gov (United States)

Pai, Vaibhav P; Marshall, Aaron M; Hernandez, Laura L; Buckley, Arthur R; Horseman, Nelson D

2009-01-01

The breast microenvironment can either retard or accelerate the events associated with progression of latent cancers. However, the actions of local physiological mediators in the context of breast cancers are poorly understood. Serotonin (5-HT) is a critical local regulator of epithelial homeostasis in the breast and other organs. Herein, we report complex alterations in the intrinsic mammary gland serotonin system of human breast cancers. Serotonin biosynthetic capacity was analyzed in human breast tumor tissue microarrays using immunohistochemistry for tryptophan hydroxylase 1 (TPH1). Serotonin receptors (5-HT1-7) were analyzed in human breast tumors using the Oncomine database. Serotonin receptor expression, signal transduction, and 5-HT effects on breast cancer cell phenotype were compared in non-transformed and transformed human breast cells. In the context of the normal mammary gland, 5-HT acts as a physiological regulator of lactation and involution, in part by favoring growth arrest and cell death. This tightly regulated 5-HT system is subverted in multiple ways in human breast cancers. Specifically, TPH1 expression undergoes a non-linear change during progression, with increased expression during malignant progression. Correspondingly, the tightly regulated pattern of 5-HT receptors becomes dysregulated in human breast cancer cells, resulting in both ectopic expression of some isoforms and suppression of others. The receptor expression change is accompanied by altered downstream signaling of 5-HT receptors in human breast cancer cells, resulting in resistance to 5-HT-induced apoptosis, and stimulated proliferation. Our data constitutes the first report of direct involvement of 5-HT in human breast cancer. Increased 5-HT biosynthetic capacity accompanied by multiple changes in 5-HT receptor expression and signaling favor malignant progression of human breast cancer cells (for example, stimulated proliferation, inappropriate cell survival). This occurs

Tissue architecture and breast cancer: the role of extracellular matrix and steroid hormones

Science.gov (United States)

Hansen, R K; Bissell, M J

2010-01-01

The changes in tissue architecture that accompany the development of breast cancer have been the focus of investigations aimed at developing new cancer therapeutics. As we learn more about the normal mammary gland, we have begun to understand the complex signaling pathways underlying the dramatic shifts in the structure and function of breast tissue. Integrin-, growth factor-, and steroid hormone-signaling pathways all play an important part in maintaining tissue architecture; disruption of the delicate balance of signaling results in dramatic changes in the way cells interact with each other and with the extracellular matrix, leading to breast cancer. The extracellular matrix itself plays a central role in coordinating these signaling processes. In this review, we consider the interrelationships between the extracellular matrix, integrins, growth factors, and steroid hormones in mammary gland development and function. PMID:10903527

LMI-based adaptive reliable H∞ static output feedback control against switched actuator failures

Science.gov (United States)

An, Liwei; Zhai, Ding; Dong, Jiuxiang; Zhang, Qingling

2017-08-01

This paper investigates the H∞ static output feedback (SOF) control problem for switched linear system under arbitrary switching, where the actuator failure models are considered to depend on switching signal. An active reliable control scheme is developed by combination of linear matrix inequality (LMI) method and adaptive mechanism. First, by exploiting variable substitution and Finsler's lemma, new LMI conditions are given for designing the SOF controller. Compared to the existing results, the proposed design conditions are more relaxed and can be applied to a wider class of no-fault linear systems. Then a novel adaptive mechanism is established, where the inverses of switched failure scaling factors are estimated online to accommodate the effects of actuator failure on systems. Two main difficulties arise: first is how to design the switched adaptive laws to prevent the missing of estimating information due to switching; second is how to construct a common Lyapunov function based on a switched estimate error term. It is shown that the new method can give less conservative results than that for the traditional control design with fixed gain matrices. Finally, simulation results on the HiMAT aircraft are given to show the effectiveness of the proposed approaches.

Method for in-vivo NMR measurements in the human breast to screen for small breast cancer in an otherwise healthy breast

International Nuclear Information System (INIS)

Rollwitz, W.L.

1986-01-01

A method is described of conducting a noninvasive female breast cancer test comprising the steps of: (a) forming an inhomogeneous magnetic field between the poles of a magnet wherein the magnetic field defines a specific volume between the poles wherein the specific volume has a specified magnetic field intensity H/sub o/ for NMR testing and the specific volume extends outwardly to an edge defined by the outer edge of the female breast; (b) moving incrementally the specific volume from a beginning point toward an ending point to scan a breast between the pole pieces of the magnet and thereby move the specific volume through the breast the movement being with N examinations located along the breast at different locations wherein each specific volume has the defined thickness and outward extent; (c) periodically interrogating by a transmitted pulse from a coil into the breast portion located in the specific volume for NMR response wherein the NMR response is dependent on hydrogen in the water, and the water has two states, one state in cancer cells and the other state in healthy tissue, and the cancer cells provide a different NMR response compared with water in the healthy tissue, the step of interrogating including first and second NMR interrogations of specific breast volumes forming NMR responses; (d) wherein the magnetic field intensity in the specific volume and the pulse from the coil cause an NMR response from water in the body tissue making up the breast portion; and (e) determining cancer cell anomalies arising from cancer cells in the breast as indicated by comparison of the NMR water responses to form difference signals

A Physical Mechanism and Global Quantification of Breast Cancer.

Directory of Open Access Journals (Sweden)

Chong Yu

Full Text Available Initiation and progression of cancer depend on many factors. Those on the genetic level are often considered crucial. To gain insight into the physical mechanisms of breast cancer, we construct a gene regulatory network (GRN which reflects both genetic and environmental aspects of breast cancer. The construction of the GRN is based on available experimental data. Three basins of attraction, representing the normal, premalignant and cancer states respectively, were found on the phenotypic landscape. The progression of breast cancer can be seen as switching transitions between different state basins. We quantified the stabilities and kinetic paths of the three state basins to uncover the biological process of breast cancer formation. The gene expression levels at each state were obtained, which can be tested directly in experiments. Furthermore, by performing global sensitivity analysis on the landscape topography, six key genes (HER2, MDM2, TP53, BRCA1, ATM, CDK2 and four regulations (HER2⊣TP53, CDK2⊣BRCA1, ATM→MDM2, TP53→ATM were identified as being critical for breast cancer. Interestingly, HER2 and MDM2 are the most popular targets for treating breast cancer. BRCA1 and TP53 are the most important oncogene of breast cancer and tumor suppressor gene, respectively. This further validates the feasibility of our model and the reliability of our prediction results. The regulation ATM→MDM2 has been extensive studied on DNA damage but not on breast cancer. We notice the importance of ATM→MDM2 on breast cancer. Previous studies of breast cancer have often focused on individual genes and the anti-cancer drugs are mainly used to target the individual genes. Our results show that the network-based strategy is more effective on treating breast cancer. The landscape approach serves as a new strategy for analyzing breast cancer on both the genetic and epigenetic levels and can help on designing network based medicine for breast cancer.

Nonlinear Raman spectroscopy of liquid crystals: orientational alignment and switching behaviour in a ferroelectric liquid crystal mixture

Science.gov (United States)

Grofcsik, Andras

Picosecond inverse Raman spectroscopy has been employed to probe the alignment behaviour and switching characteristics of a 6 mum thick ferroelectric liquid crystal based on a host mixture of fluorinated phenyl biphenylcarboxylates and a chiral dopant. Optical bistability is observed in the Raman signal on application of dc electric fields of opposite polarity. For particular polarities of the applied field, the Raman signals display a cos4theta dependence on the angle of rotation around the beam direction. Reorientational rate constants of 300 mus and 590 mus are observed for the aromatic core at the high-voltage limit for the rise and decay of the 1600 cm-1 Raman signal on application of a switching ac electric field.

1H-MRS evaluation of breast lesions by using total choline signal-to-noise ratio as an indicator of malignancy: a meta-analysis.

Science.gov (United States)

Wang, Xin; Wang, Xiang Jiang; Song, Hui Sheng; Chen, Long Hua

2015-05-01

The aim of this study was to evaluate the diagnostic performance of the use of total choline signal-to-noise ratio (tCho SNR) criteria in MRS studies for benign/malignant discrimination of focal breast lesions. We conducted (1) a meta-analysis based on 10 studies including 480 malignant breast lesions and 312 benign breast lesions and (2) a subgroup meta-analysis of tCho SNR ≥ 2 as cutoff for malignancy based on 7 studies including 371 malignant breast lesions and 239 benign breast lesions. (1) The pooled sensitivity and specificity of proton MRS with tCho SNR were 0.74 (95 % CI 0.69-0.77) and 0.76 (95 % CI 0.71-0.81), respectively. The PLR and NLR were 3.67 (95 % CI 2.30-5.83) and 0.25 (95 % CI 0.14-0.42), respectively. From the fitted SROC, the AUC and Q* index were 0.89 and 0.82. Publication bias was present (t = 2.46, P = 0.039). (2) Meta-regression analysis suggested that neither threshold effect nor evaluated covariates including strength of field, pulse sequence, TR and TE were sources of heterogeneity (all P value >0.05). (3) Subgroup meta-analysis: The pooled sensitivity and specificity were 0.79 and 0.72, respectively. The PLR and NLR were 3.49 and 0.20, respectively. The AUC and Q* index were 0.92 and 0.85. The use of tCho SNR criteria in MRS studies was helpful for differentiation between malignant and benign breast lesions. However, pooled diagnostic measures might be overestimated due to publication bias. A tCho SNR ≥ 2 as cutoff for malignancy resulted in higher diagnostic accuracy.

49 CFR 231.16 - Steam locomotives used in switching service.

Science.gov (United States)

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Steam locomotives used in switching service. 231... RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.16 Steam..., buffer block, footboard, brake pipe, signal pipe, steam-heat pipe or arms of uncoupling lever shall...

Optimal control of switching time in switched stochastic systems with multi-switching times and different costs

Science.gov (United States)

Liu, Xiaomei; Li, Shengtao; Zhang, Kanjian

2017-08-01

In this paper, we solve an optimal control problem for a class of time-invariant switched stochastic systems with multi-switching times, where the objective is to minimise a cost functional with different costs defined on the states. In particular, we focus on problems in which a pre-specified sequence of active subsystems is given and the switching times are the only control variables. Based on the calculus of variation, we derive the gradient of the cost functional with respect to the switching times on an especially simple form, which can be directly used in gradient descent algorithms to locate the optimal switching instants. Finally, a numerical example is given, highlighting the validity of the proposed methodology.

Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.

Science.gov (United States)

Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

2015-09-29

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.

Paris saponin-induced autophagy promotes breast cancer cell apoptosis via the Akt/mTOR signaling pathway.

Science.gov (United States)

Xie, Zhan-Zhi; Li, Man-Mei; Deng, Peng-Fei; Wang, Sheng; Wang, Lei; Lu, Xue-Ping; Hu, Liu-Bing; Chen, Zui; Jie, Hui-Yang; Wang, Yi-Fei; Liu, Xiao-Xiao; Liu, Zhong

2017-02-25

Paris saponins possess anticancer, anti-inflammatory, and antiviral effects. However, the anticancer effect of Paris saponins has not been well elucidated and the mechanisms underlying the potential function of Paris saponins in cancer therapy are needed to be further identify. In this study, we report that saponin compounds isolated from Paris polyphylla exhibited antitumor activity against breast cancer cell lines, MCF-7 and MDA-MB-231. Paris saponin XA-2 induced apoptosis in both cell lines, as evidenced by the activation of caspases and cleavage of Poly (ADP-ribose) polymerase. The ability of XA-2 to induce autophagy was confirmed by acridine orange staining, accumulation of autophagosome-bound Long chain 3 (LC3)-II, and measurement of autophagic flux. XA-2-induced autophagy was observed to promote apoptosis by the combined treatment of breast cancer cell lines with XA-2 and autophagy inhibitors 3-methyladenine and bafilomycin A1, respectively. Moreover, we report a decrease in the levels of Akt/mTOR signaling pathway proteins, such as the phosphorylated forms of Akt, mTOR, P70S6K, and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). Taken together, these results provide important insights explaining the anticancer activity of Paris saponins and the potential development of XA-2 as a new therapeutic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Breast imaging using the Twente photoacoustic mammoscope (PAM): new clinical measurements

Science.gov (United States)

Heijblom, Michelle; Piras, Daniele; Ten Tije, Ellen; Xia, Wenfeng; van Hespen, Johan; Klaase, Joost; van den Engh, Frank; van Leeuwen, Ton; Steenbergen, Wiendelt; Manohar, Srirang

2011-07-01

Worldwide, yearly about 450,000 women die from the consequences of breast cancer. Current imaging modalities are not optimal in discriminating benign from malignant tissue. Visualizing the malignancy-associated increased hemoglobin concentration might significantly improve early diagnosis of breast cancer. Since photoacoustic imaging can visualize hemoglobin in tissue with optical contrast and ultrasound-like resolution, it is potentially an ideal method for early breast cancer imaging. The Twente Photoacoustic Mammoscope (PAM) has been developed specifically for breast imaging. Recently, a large clinical study has been started in the Medisch Spectrum Twente in Oldenzaal using PAM. In PAM, the breast is slightly compressed between a window for laser light illumination and a flat array ultrasound detector. The measurements are performed using a Q-switched Nd:YAG laser, pulsed at 1064 nm and a 1 MHz unfocused ultrasound detector array. Three-dimensional data are reconstructed using a delay and sum reconstruction algorithm. Those reconstructed images are compared with conventional imaging and histopathology. In the first phase of the study 12 patients with a malignant lesion and 2 patients with a benign cyst have been measured. The results are used to guide developments in photoacoustic mammography in order to pave the way towards an optimal technique for early diagnosis of breast cancer.

Improvement of out-of-band Behaviour in Switch-Mode Amplifiers and Power Supplies by their Modulation Topology

DEFF Research Database (Denmark)

Knott, Arnold

2010-01-01

Switch-mode power electronics is disturbing other electronic circuits by emission of electromagnetic waves and signals. To allow transmission of information, a set of regulatory rules (electromagnetic compatibility (EMC)) were created to limit this disturbance. To fulfill those rules in power...... electronics, shielding and filtering is required, which is limiting the size reduction. The motivation for this project was to find alternative ways to avoid trouble with interference of switch-mode power electronics and transmission and receiver circuits. An especial focus is given to audio power amplifiers....... After a historical overview and description of interaction between power electronics and electromagnetic compatibility (chapter 1), the thesis will first show the impact of the high frequency signals on the audio performance of switch-mode audio power amplifiers (chapter 2). Therefore the work of others...

Synchronization of Switched Neural Networks With Communication Delays via the Event-Triggered Control.

Science.gov (United States)

Wen, Shiping; Zeng, Zhigang; Chen, Michael Z Q; Huang, Tingwen

2017-10-01

This paper addresses the issue of synchronization of switched delayed neural networks with communication delays via event-triggered control. For synchronizing coupled switched neural networks, we propose a novel event-triggered control law which could greatly reduce the number of control updates for synchronization tasks of coupled switched neural networks involving embedded microprocessors with limited on-board resources. The control signals are driven by properly defined events, which depend on the measurement errors and current-sampled states. By using a delay system method, a novel model of synchronization error system with delays is proposed with the communication delays and event-triggered control in the unified framework for coupled switched neural networks. The criteria are derived for the event-triggered synchronization analysis and control synthesis of switched neural networks via the Lyapunov-Krasovskii functional method and free weighting matrix approach. A numerical example is elaborated on to illustrate the effectiveness of the derived results.

Common genomic signaling among initial DNA damage and radiation-induced apoptosis in peripheral blood lymphocytes from locally advanced breast cancer patients

DEFF Research Database (Denmark)

Henríquez-Hernández, Luis Alberto; Pinar, Beatriz; Carmona-Vigo, Ruth

2013-01-01

PURPOSE: To investigate the genomic signaling that defines sensitive lymphocytes to radiation and if such molecular profiles are consistent with clinical toxicity; trying to disclose the radiobiology mechanisms behind these cellular processes. PATIENTS AND METHODS: Twelve consecutive patients...... suffering from locally advanced breast cancer and treated with high-dose hyperfractionated radiotherapy were recruited. Initial DNA damage was measured by pulsed-field gel electrophoresis and radiation-induced apoptosis was measured by flow cytometry. Gene expression was assessed by DNA microarray. RESULTS...

Characterization of Heregulin-Stimulated Signal Transduction Pathways to the Nucleus

National Research Council Canada - National Science Library

Wilson, Kristin

2000-01-01

... 40% of breast cancers and correlates with a poor prognosis for women with breast cancer. Mapping the molecular determinants of the heregulin/ErbB2 signaling pathway will be important in determining viable cellular targets for therapeutic intervention...

cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction

Energy Technology Data Exchange (ETDEWEB)

Son, Jieun; Lee, Jong-Ho; Kim, Ha-Neui; Ha, Hyunil, E-mail: hyunil74@hotmail.com; Lee, Zang Hee, E-mail: zang1959@snu.ac.kr

2010-07-23

Research highlights: {yields} CREB is highly expressed in advanced breast cancer cells. {yields} Tumor-related factors such as TGF-{beta} further elevate CREB expression. {yields} CREB upregulation stimulates metastatic potential of breast cancer cells. {yields} CREB signaling is required for breast cancer-induced bone destruction. -- Abstract: cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cells and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-{beta}. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.

Neoadjuvant chemotherapy for breast cancer: correlation between the baseline MR imaging findings and responses to therapy

International Nuclear Information System (INIS)

Uematsu, Takayoshi; Yuen, Sachiko; Kasami, Masako

2010-01-01

To retrospectively evaluate the magnetic resonance (MR) imaging findings of breast cancer before neoadjuvant chemotherapy (NAC) and to compare findings of chemosensitive breast cancer with those of chemoresistant breast cancer. The MR imaging findings before NAC in 120 women undergoing NAC were reviewed. The MR imaging findings were compared with the pathological findings and responses. A complete response (pCR) and marked response were achieved in 12 and 35% of 120 breast cancers in 120 women respectively. Breast cancers with a pCR or marked response were classified as chemosensitive breast cancer. The remaining 64 breast cancers (53%) were classified as chemoresistant breast cancer. Large tumour size, a lesion without mass effect, and very high intratumoural signal intensity on T2-weighted MR images were significantly associated with chemoresistant breast cancer. Lesions with mass effect and washout enhancement pattern were significantly associated with chemosensitive breast cancer. Areas with very high intratumoural signal intensity on T2-weighted images corresponded pathologically to areas of intratumoural necrosis. Several MR imaging features of breast cancer before NAC can help predict the efficacy of NAC. (orig.)

Neoadjuvant chemotherapy for breast cancer: correlation between the baseline MR imaging findings and responses to therapy

Energy Technology Data Exchange (ETDEWEB)

Uematsu, Takayoshi; Yuen, Sachiko [Shizuoka Cancer Center Hospital, Breast Imaging and Breast Intervention Section, Naga-izumi, Shizuoka (Japan); Kasami, Masako [Shizuoka Cancer Center Hospital, Department of Pathology, Naga-izumi, Shizuoka (Japan)

2010-10-15

To retrospectively evaluate the magnetic resonance (MR) imaging findings of breast cancer before neoadjuvant chemotherapy (NAC) and to compare findings of chemosensitive breast cancer with those of chemoresistant breast cancer. The MR imaging findings before NAC in 120 women undergoing NAC were reviewed. The MR imaging findings were compared with the pathological findings and responses. A complete response (pCR) and marked response were achieved in 12 and 35% of 120 breast cancers in 120 women respectively. Breast cancers with a pCR or marked response were classified as chemosensitive breast cancer. The remaining 64 breast cancers (53%) were classified as chemoresistant breast cancer. Large tumour size, a lesion without mass effect, and very high intratumoural signal intensity on T2-weighted MR images were significantly associated with chemoresistant breast cancer. Lesions with mass effect and washout enhancement pattern were significantly associated with chemosensitive breast cancer. Areas with very high intratumoural signal intensity on T2-weighted images corresponded pathologically to areas of intratumoural necrosis. Several MR imaging features of breast cancer before NAC can help predict the efficacy of NAC. (orig.)

Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.

Science.gov (United States)

Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu

2018-04-01

Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen

A square wave is the most efficient and reliable waveform for resonant actuation of micro switches

Science.gov (United States)

Ben Sassi, S.; Khater, M. E.; Najar, F.; Abdel-Rahman, E. M.

2018-05-01

This paper investigates efficient actuation methods of shunt MEMS switches and other parallel-plate actuators. We start by formulating a multi-physics model of the micro switch, coupling the nonlinear Euler-Bernoulli beam theory with the nonlinear Reynolds equation to describe the structural and fluidic domains, respectively. The model takes into account fringing field effects as well as mid-plane stretching and squeeze film damping nonlinearities. Static analysis is undertaken using the differential quadrature method (DQM) to obtain the pull-in voltage, which is verified by means of the finite element model and validated experimentally. We develop a reduced order model employing the Galerkin method for the structural domain and DQM for the fluidic domain. The proposed waveforms are intended to be more suitable for integrated circuit standards. The dynamic response of the micro switch to harmonic, square and triangular waveforms are evaluated and compared experimentally and analytically. Low voltage actuation is obtained using dynamic pull-in with the proposed waveforms. In addition, global stability analysis carried out for the three signals shows advantages of employing the square signal as the actuation method in enhancing the performance of the micro switch in terms of actuation voltage, switching time, and sensitivity to initial conditions.

Ultra-fast all-optical plasmonic switching in near infra-red spectrum using a Kerr nonlinear ring resonator

Science.gov (United States)

Nurmohammadi, Tofiq; Abbasian, Karim; Yadipour, Reza

2018-03-01

In this paper, an all-optical plasmonic switch based on metal-insulator-metal (MIM) nanoplasmonic waveguide with a Kerr nonlinear ring resonator is introduced and studied. Two-dimensional simulations utilizing the finite-difference time-domain algorithm are used to demonstrate an apparent optical bistability and significant switching mechanisms (in enabled-low condition: T(ON/OFF) =21.9 and in enabled-high condition: T(ON/OFF) =24.9) of the signal light arisen by altering the pump-light intensity. The proposed all-optical switching demonstrates femtosecond-scale feedback time (90 fs) and then ultra-fast switching can be achieved. The offered all-optical switch may recognize potential significant applications in integrated optical circuits.

Determinants of cell-to-cell variability in protein kinase signaling.

Science.gov (United States)

Jeschke, Matthias; Baumgärtner, Stephan; Legewie, Stefan

2013-01-01

Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity') and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s) or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability.

Switch Reference in Mbya Guarani: A Fair-Weather Phenomenon.

Science.gov (United States)

Dooley, Robert A.

Switch reference, in which certain clauses contain a signal indicating whether that clause has the same or a different subject, is examined in Mbya Guarani. It is found that most cases can be covered by a grammatical rule stated in terms of the grammatical subjects of the two clauses involved, yielding "same subject" and "different…

Mammary Ductal Environment Is Necessary for Faithful Maintenance of Estrogen Signaling in ER⁺ Breast Cancer.

Science.gov (United States)

Haricharan, Svasti; Lei, Jonathan; Ellis, Matthew

2016-03-14

In this issue of Cancer Cell, Sflomos et al. (2016) describe a robust preclinical animal model of ER⁺ breast cancer. The authors identify the critical role of the breast microenvironment in determining hormone response of ER⁺ breast cancer cells and in driving the luminal phenotype of breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

MRI of the breast - histopathologic correlation

International Nuclear Information System (INIS)

Heywang, S.H.; Fenzl, G.; Hahn, D.; Beck, R.; Krischke, I.; Bassermann, R.; Nathrath, W.; Eiermann, W.

1987-01-01

132 solid breast masses have been examined at our institution by MR and have consequently been histopathologically correlated. T1- and T2-weighted SE and multiecho sequences have been evaluated visually. It was found that signal intensities of tissues on T2-weighted images correlated with the contents of fibrosis, cells or water. Thus in some lesions (which consisted of different tissue components), a characteristic internal structure was visible on T2-weighted images, reflecting their histopathologic structure. Corresponding to their different composition, differences of signal intensity have also been noted between those fibroadenomas with a high contents of fibrosis and all other well-circumscribed breast lesions (fibroadenomas, carcinomas). However, for the majority of lesions with irregular contours a discrimination based on signal intensities or calculated T1- and T2-values did not seem possible. This overlap can also be explained by the macroscopically similar composition (amount of fibrosis, water or cells) of benign and malignant irregular lesions. (orig.)

Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormonesensitive early breast cancer: a case study

International Nuclear Information System (INIS)

Bryce, Jane; Bauer, Martina; Hadji, Peyman

2012-01-01

In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI) is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms. We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+) breast cancer. A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly. The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia. Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication

The Breast Cancer to Bone (B2B) Metastases Research Program: a multi-disciplinary investigation of bone metastases from breast cancer.

Science.gov (United States)

Brockton, Nigel T; Gill, Stephanie J; Laborge, Stephanie L; Paterson, Alexander H G; Cook, Linda S; Vogel, Hans J; Shemanko, Carrie S; Hanley, David A; Magliocco, Anthony M; Friedenreich, Christine M

2015-07-10

Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone. The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood samples are collected and detailed epidemiologic data is collected by in-person interview and self-administered questionnaires. Additional self-administered questionnaires and blood samples are completed at specified follow-up intervals (24, 48 and 72 months). Vital status is obtained prior to each follow-up through record linkages with the Alberta Cancer Registry. Recurrences are identified through medical chart abstractions. Each of the four projects applies specific methods and analyses to assess the impact of serum vitamin D and cytokine concentrations, tumour transcript and protein expression, serum metabolomic profiles and in vitro cell signalling on breast cancer bone metastases. The B2B Research Program will address key issues in breast cancer bone metastases including the association between lifestyle factors (particularly a comprehensive assessment of vitamin D status) inflammation and bone metastases, the significance or primary tumour gene expression in tissue tropism, the

The Breast Cancer to Bone (B2B) Metastases Research Program: a multi-disciplinary investigation of bone metastases from breast cancer

International Nuclear Information System (INIS)

Brockton, Nigel T.; Gill, Stephanie J.; Laborge, Stephanie L.; Paterson, Alexander H. G.; Cook, Linda S.; Vogel, Hans J.; Shemanko, Carrie S.; Hanley, David A.; Magliocco, Anthony M.; Friedenreich, Christine M.

2015-01-01

Bone is the most common site of breast cancer distant metastasis, affecting 50–70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone. The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood samples are collected and detailed epidemiologic data is collected by in-person interview and self-administered questionnaires. Additional self-administered questionnaires and blood samples are completed at specified follow-up intervals (24, 48 and 72 months). Vital status is obtained prior to each follow-up through record linkages with the Alberta Cancer Registry. Recurrences are identified through medical chart abstractions. Each of the four projects applies specific methods and analyses to assess the impact of serum vitamin D and cytokine concentrations, tumour transcript and protein expression, serum metabolomic profiles and in vitro cell signalling on breast cancer bone metastases. The B2B Research Program will address key issues in breast cancer bone metastases including the association between lifestyle factors (particularly a comprehensive assessment of vitamin D status) inflammation and bone metastases, the significance or primary tumour gene expression in tissue tropism, the

Six-port optical switch for cluster-mesh photonic network-on-chip

Science.gov (United States)

Jia, Hao; Zhou, Ting; Zhao, Yunchou; Xia, Yuhao; Dai, Jincheng; Zhang, Lei; Ding, Jianfeng; Fu, Xin; Yang, Lin

2018-05-01

Photonic network-on-chip for high-performance multi-core processors has attracted substantial interest in recent years as it offers a systematic method to meet the demand of large bandwidth, low latency and low power dissipation. In this paper we demonstrate a non-blocking six-port optical switch for cluster-mesh photonic network-on-chip. The architecture is constructed by substituting three optical switching units of typical Spanke-Benes network to optical waveguide crossings. Compared with Spanke-Benes network, the number of optical switching units is reduced by 20%, while the connectivity of routing path is maintained. By this way the footprint and power consumption can be reduced at the expense of sacrificing the network latency performance in some cases. The device is realized by 12 thermally tuned silicon Mach-Zehnder optical switching units. Its theoretical spectral responses are evaluated by establishing a numerical model. The experimental spectral responses are also characterized, which indicates that the optical signal-to-noise ratios of the optical switch are larger than 13.5 dB in the wavelength range from 1525 nm to 1565 nm. Data transmission experiment with the data rate of 32 Gbps is implemented for each optical link.

Superconducting Switch for Fast On-Chip Routing of Quantum Microwave Fields

Science.gov (United States)

Pechal, M.; Besse, J.-C.; Mondal, M.; Oppliger, M.; Gasparinetti, S.; Wallraff, A.

2016-08-01

A switch capable of routing microwave signals at cryogenic temperatures is a desirable component for state-of-the-art experiments in many fields of applied physics, including but not limited to quantum-information processing, communication, and basic research in engineered quantum systems. Conventional mechanical switches provide low insertion loss but disturb operation of dilution cryostats and the associated experiments by heat dissipation. Switches based on semiconductors or microelectromechanical systems have a lower thermal budget but are not readily integrated with current superconducting circuits. Here we design and test an on-chip switch built by combining tunable transmission-line resonators with microwave beam splitters. The device is superconducting and as such dissipates a negligible amount of heat. It is compatible with current superconducting circuit fabrication techniques, operates with a bandwidth exceeding 100 MHz, is capable of handling photon fluxes on the order of 1 05 μ s-1 , equivalent to powers exceeding -90 dBm , and can be switched within approximately 6-8 ns. We successfully demonstrate operation of the device in the quantum regime by integrating it on a chip with a single-photon source and using it to route nonclassical itinerant microwave fields at the single-photon level.

Effect of gadolinium injection on diffusion-weighted imaging with background body signal suppression (DWIBS) imaging of breast lesions.

Science.gov (United States)

Moschetta, Marco; Telegrafo, Michele; Rella, Leonarda; Stabile Ianora, Amato Antonio; Angelelli, Giuseppe

2014-12-01

Diffusion-weighted imaging with background body signal suppression (DWIBS) provides both qualitative and quantitative imaging of breast lesions and are usually performed before contrast material injection (CMI). This study aims to assess whether the administration of gadolinium significantly affects DWIBS imaging. 200 patients were prospectively evaluated by MRI with STIR, TSE-T2, pre-CMI DWIBS, contrast enhanced THRIVE-T1 and post-CMI DWIBS sequences. Pre and post-CMI DWIBS were analyzed searching for the presence of breast lesions and calculating the ADC value. ADC values of ≤1.44×10(-3) mm(2)/s were considered suspicious for malignancy. This analysis was then compared with the histological findings. Sensitivity, specificity, diagnostic accuracy (DA), positive predictive value (PPV) and negative (NPV) were calculated for both sequences and represented by ROC analysis. Pre and post-CMI ADC values were compared by using the paired t test. In 150/200 (59%) patients, pre and post-CMI DWIBS indicated the presence of breast lesions, 53 (35%) with ADC values of >1.44×10(-3) mm(2)/s and 97 (65%) with ADC≤1.44×10(-3) mm(2)/s. Pre-CMI and post-DWIBS sequences obtained the same sensitivity, specificity, DA, PPV and NPV values of 97%, 83%, 89%, 79% and 98%. The mean ADC value of benign lesions was 1.831±0.18×10(-3) mm(2)/s before and 1.828±0.18×10(-3) mm(2)/s after CMI. The mean ADC value of the malignant lesions was 1.146±0.16×10(-3) mm(2)/s before and 1.144±0.16×10(-3) mm(2)/s after CMI. No significant difference was found between pre and post CMI ADC values (p>0.05). DWIBS imaging is not influenced by CMI. Breast MR protocol could be modified by placing DWIBS after dynamic contrast enhanced sequences in order to maximize patient cooperation. Copyright © 2014 Elsevier Inc. All rights reserved.

Note: Switching crosstalk on and off in Kelvin probe force microscopy

International Nuclear Information System (INIS)

Polak, Leo; Wijngaarden, Rinke J.; Man, Sven de

2014-01-01

In Kelvin Probe Force Microscopy (KPFM) electronic crosstalk can occur between the excitation signal and probe deflection signal. Here, we demonstrate how a small modification to our commercial instrument enables us to literally switch the crosstalk on and off. We study in detail the effect of crosstalk on open-loop KPFM and compare with closed-loop KPFM. We measure the pure crosstalk signal and verify that we can correct for it in the data-processing required for open-loop KPFM. We also demonstrate that open-loop KPFM results are independent of the frequency and amplitude of the excitation signal, provided that the influence of crosstalk has been eliminated

Dynamic Breast Magnetic Resonance Imaging without Complications in a Patient with Dual-Chamber Demand Pacemaker

International Nuclear Information System (INIS)

Sardanelli, F.; Lupo, P.; Esseridou, A.; Fausto, A.; Quarenghi, M.

2006-01-01

Mammography and ultrasound indicated a cancer of the right breast in a 77-year-old woman with a dual-chamber demand pacemaker. The patient was not pacemaker-dependent. She underwent breast 1.5T magnetic resonance imaging (MRI) (dynamic gradient echo sequence with Gd-DOTA 0.1 mmol/kg). Before the patient entered the MR room, the configuration of the device was changed (the response to magnet was switched from asynchronous to off and the rate-responsive algorithm was disabled). No relevant modifications of heart rhythm or rate were observed during the MR examination. No symptom was reported. Immediately after the examination, the pacemaker interrogation showed neither program changes nor alert warnings. MRI detected a bifocal cancer in the right breast which allowed tailored breast-conserving treatment to be initiated. Histopathology confirmed a bifocal invasive ductal carcinoma

Dynamic Breast Magnetic Resonance Imaging without Complications in a Patient with Dual-Chamber Demand Pacemaker

Energy Technology Data Exchange (ETDEWEB)

Sardanelli, F.; Lupo, P.; Esseridou, A.; Fausto, A.; Quarenghi, M. [Policlinico San Donato, San Donato Milanese, Milan (Italy). Depts. of Radiology, Arrhythmia and Electrophysiology Center

2006-02-15

Mammography and ultrasound indicated a cancer of the right breast in a 77-year-old woman with a dual-chamber demand pacemaker. The patient was not pacemaker-dependent. She underwent breast 1.5T magnetic resonance imaging (MRI) (dynamic gradient echo sequence with Gd-DOTA 0.1 mmol/kg). Before the patient entered the MR room, the configuration of the device was changed (the response to magnet was switched from asynchronous to off and the rate-responsive algorithm was disabled). No relevant modifications of heart rhythm or rate were observed during the MR examination. No symptom was reported. Immediately after the examination, the pacemaker interrogation showed neither program changes nor alert warnings. MRI detected a bifocal cancer in the right breast which allowed tailored breast-conserving treatment to be initiated. Histopathology confirmed a bifocal invasive ductal carcinoma.

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Science.gov (United States)

Suzuki, H; Toyota, M; Caraway, H; Gabrielson, E; Ohmura, T; Fujikane, T; Nishikawa, N; Sogabe, Y; Nojima, M; Sonoda, T; Mori, M; Hirata, K; Imai, K; Shinomura, Y; Baylin, S B; Tokino, T

2008-01-01

Although mutation of APC or CTNNB1 (β-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a β-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. PMID:18283316

Switching Loss Reduction in the Three-Phase Quasi-Z-Source Inverters Utilizing Modified Space Vector Modulation Strategies

DEFF Research Database (Denmark)

Abdelhakim, Ahmed; Davari, Pooya; Blaabjerg, Frede

2018-01-01

Several single-stage topologies have been introduced since kicking off the three-phase Z-source inverter (ZSI), and among these topologies, the quasi-ZSI (qZSI) is the most common one due to its simple structure and continuous input current. Furthermore, different modulation strategies, utilizing...... multiple reference signals, have been developed as well. However, prior art modulation methods have some demerits, such as the complexity of generating the gate signals, the increased number of switch commutations with continuous commutation at high current level during the entire fundamental cycle...... the generation of the gate signals by utilizing only three reference signals, and achieving a single switch commutation at a time. These modulation strategies are analyzed and compared to the conventional ones, where a reduced-scale 1 kVA three-phase qZSI is designed and simulated using these different...

Aberrantly methylated DNA as a biomarker in breast cancer

DEFF Research Database (Denmark)

Kristiansen, Søren; Jørgensen, Lars Mønster; Guldberg, Per

2013-01-01

hypermethylation events, their use as tumor biomarkers is usually not hampered by analytical signals from normal cells, which is a general problem for existing protein tumor markers used for clinical assessment of breast cancer. There is accumulating evidence that DNA-methylation changes in breast cancer patients...... occur early during tumorigenesis. This may open up for effective screening, and analysis of blood or nipple aspirate may later help in diagnosing breast cancer. As a more detailed molecular characterization of different types of breast cancer becomes available, the ability to divide patients...... as a versatile biomarker tool for screening, diagnosis, prognosis and monitoring of breast cancer. Standardization of methods and biomarker panels will be required to fully exploit this clinical potential....

Adaptive Backstepping-Based Neural Tracking Control for MIMO Nonlinear Switched Systems Subject to Input Delays.

Science.gov (United States)

Niu, Ben; Li, Lu

2018-06-01

This brief proposes a new neural-network (NN)-based adaptive output tracking control scheme for a class of disturbed multiple-input multiple-output uncertain nonlinear switched systems with input delays. By combining the universal approximation ability of radial basis function NNs and adaptive backstepping recursive design with an improved multiple Lyapunov function (MLF) scheme, a novel adaptive neural output tracking controller design method is presented for the switched system. The feature of the developed design is that different coordinate transformations are adopted to overcome the conservativeness caused by adopting a common coordinate transformation for all subsystems. It is shown that all the variables of the resulting closed-loop system are semiglobally uniformly ultimately bounded under a class of switching signals in the presence of MLF and that the system output can follow the desired reference signal. To demonstrate the practicability of the obtained result, an adaptive neural output tracking controller is designed for a mass-spring-damper system.

Digital switched hydraulics

Science.gov (United States)

Pan, Min; Plummer, Andrew

2018-06-01

This paper reviews recent developments in digital switched hydraulics particularly the switched inertance hydraulic systems (SIHSs). The performance of SIHSs is presented in brief with a discussion of several possible configurations and control strategies. The soft switching technology and high-speed switching valve design techniques are discussed. Challenges and recommendations are given based on the current research achievements.

Enhancement of resistive switching properties in Al2O3 bilayer-based atomic switches: multilevel resistive switching

Science.gov (United States)

Vishwanath, Sujaya Kumar; Woo, Hyunsuk; Jeon, Sanghun

2018-06-01

Atomic switches are considered to be building blocks for future non-volatile data storage and internet of things. However, obtaining device structures capable of ultrahigh density data storage, high endurance, and long data retention, and more importantly, understanding the switching mechanisms are still a challenge for atomic switches. Here, we achieved improved resistive switching performance in a bilayer structure containing aluminum oxide, with an oxygen-deficient oxide as the top switching layer and stoichiometric oxide as the bottom switching layer, using atomic layer deposition. This bilayer device showed a high on/off ratio (105) with better endurance (∼2000 cycles) and longer data retention (104 s) than single-oxide layers. In addition, depending on the compliance current, the bilayer device could be operated in four different resistance states. Furthermore, the depth profiles of the hourglass-shaped conductive filament of the bilayer device was observed by conductive atomic force microscopy.

MRI of breast tumors with emphasis on histopathologic correlation

International Nuclear Information System (INIS)

Kuwabara, Masako

1991-01-01

Breast MR imaging is now expected as the third most important diagnostic modality. The author investigated relationship between signal intensity of T2 weighted images (T2WI) and various pathological findings of 51 mass lesions in 51 female patients. T2WI were not effective in differentiation between malignant and benign lesions. High signal intensity areas defined visually well correlated with pathological tissues with large water content such as necrosis, edema, cyst, and dilatated ducts. There was also good correlation between low signal intensity areas and pathological tissue with less water content such as fibrosis, scar, and hyalinization. Signal intensity measured by tumor/fat ratio had no correlation with water content. It probably indicates that visually defined signal intensity is more reliable than the measured ratio. In conclusion, it is warrented to say that T2WI is a good tool for investigating secondary changes of breast tumors and helpful in diangosis of high intensity tumors described above. (author)

Analog and mixed-signal electronics

CERN Document Server

Stephan, Karl

2015-01-01

A practical guide to analog and mixed-signal electronics, with an emphasis on design problems and applications This book provides an in-depth coverage of essential analog and mixed-signal topics such as power amplifiers, active filters, noise and dynamic range, analog-to-digital and digital-to-analog conversion techniques, phase-locked loops, and switching power supplies. Readers will learn the basics of linear systems, types of nonlinearities and their effects, op-amp circuits, the high-gain analog filter-amplifier, and signal generation. The author uses system design examples to motivate

Optical switching and photoluminescence in erbium-implanted vanadium dioxide thin films

Energy Technology Data Exchange (ETDEWEB)

Lim, Herianto, E-mail: mail@heriantolim.com; Stavrias, Nikolas; Johnson, Brett C.; McCallum, Jeffrey C. [School of Physics, University of Melbourne, Parkville, Victoria 3010 (Australia); Marvel, Robert E.; Haglund, Richard F. [Department of Physics and Astronomy, Vanderbilt University, Nashville, Tennessee 37240 (United States)

2014-03-07

Vanadium dioxide (VO{sub 2}) is under intensive consideration for optical switching due to its reversible phase transition, which features a drastic and rapid shift in infrared reflectivity. Classified as an insulator–to–metal transition, the phase transition in VO{sub 2} can be induced thermally, electrically, and optically. When induced optically, the transition can occur on sub-picosecond time scales. It is interesting to dope VO{sub 2} with erbium ions (Er{sup 3+}) and observe their combined properties. The first excited-state luminescence of Er{sup 3+} lies within the wavelength window of minimal transmission-loss in silicon and has been widely utilized for signal amplification and generation in silicon photonics. The incorporation of Er{sup 3+} into VO{sub 2} could therefore result in a novel photonic material capable of simultaneous optical switching and amplification. In this work, we investigate the optical switching and photoluminescence in Er-implanted VO{sub 2} thin films. Thermally driven optical switching is demonstrated in the Er-implanted VO{sub 2} by infrared reflectometry. Photoluminescence is observed in the thin films annealed at ∼800 °C or above. In addition, Raman spectroscopy and a statistical analysis of switching hysteresis are carried out to assess the effects of the ion implantation on the VO{sub 2} thin films. We conclude that Er-implanted VO{sub 2} can function as an optical switch and amplifier, but with reduced switching quality compared to pure VO{sub 2}.

Clinical and ultrasonographic features of male breast tumors: A retrospective analysis.

Science.gov (United States)

Yuan, Wei-Hsin; Li, Anna Fen-Yau; Chou, Yi-Hong; Hsu, Hui-Chen; Chen, Ying-Yuan

2018-01-01

The purpose of this study was to determine clinical and ultrasonographic characteristics of male breast tumors. The medical records of male patients with breast lesions were retrieved from an electronic medical record database and a pathology database and retrospectively reviewed. A total of 112 men (125 breast masses) with preoperative breast ultrasonography (US) were included (median age, 59.50 years; age range, 15-96 years). Data extracted included patient age, if the lesions were bilateral, palpable, and tender, and the presence of nipple discharge. Breast lesion features on static US images were reviewed by three experienced radiologists without knowledge of physical examination or pathology results, original breast US image interpretations, or surgical outcomes. The US features were documented according to the BI-RADS (Breast Imaging-Reporting and Data System) US lexicons. A forth radiologist compiled the data for analysis. Of the 125 breast masses, palpable tender lumps and bilateral synchronous masses were more likely to be benign than malignant (both, 100% vs 0%, P nipples were common in malignant lesions (P nipple, irregular shape, the presence of an echogenic halo, predominantly internal vascularity, and rich color flow signal on color Doppler ultrasound were significantly related to malignancy (all, P < 0.05). An echogenic halo and the presence of rich color flow signal were independent predictors of malignancy. Specific clinical and US characteristics of male breast tumors may help guide treatment, and determine if surgery or conservative treatment is preferable.

Intentional preparation of auditory attention-switches: Explicit cueing and sequential switch-predictability.

Science.gov (United States)

Seibold, Julia C; Nolden, Sophie; Oberem, Josefa; Fels, Janina; Koch, Iring

2018-06-01

In an auditory attention-switching paradigm, participants heard two simultaneously spoken number-words, each presented to one ear, and decided whether the target number was smaller or larger than 5 by pressing a left or right key. An instructional cue in each trial indicated which feature had to be used to identify the target number (e.g., female voice). Auditory attention-switch costs were found when this feature changed compared to when it repeated in two consecutive trials. Earlier studies employing this paradigm showed mixed results when they examined whether such cued auditory attention-switches can be prepared actively during the cue-stimulus interval. This study systematically assessed which preconditions are necessary for the advance preparation of auditory attention-switches. Three experiments were conducted that controlled for cue-repetition benefits, modality switches between cue and stimuli, as well as for predictability of the switch-sequence. Only in the third experiment, in which predictability for an attention-switch was maximal due to a pre-instructed switch-sequence and predictable stimulus onsets, active switch-specific preparation was found. These results suggest that the cognitive system can prepare auditory attention-switches, and this preparation seems to be triggered primarily by the memorised switching-sequence and valid expectations about the time of target onset.

Diode array pumped, non-linear mirror Q-switched and mode-locked ...

Indian Academy of Sciences (India)

A non-linear mirror consisting of a lithium triborate crystal and a dichroic ... effects such as all-optical switching [7,8], nearly degenerate four-wave mixing [9,10], .... is driven by a radio frequency signal of 27.2MHz with a modulation available in.

Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation

Directory of Open Access Journals (Sweden)

Olivia Alder

2014-10-01

Full Text Available Summary: Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines. : It is unclear how key transcription factors are critical for both lineage specification during embryonic development and maintenance of a differentiated, adult phenotype. By profiling the enhancer occupancy of the key transcription factors HNF4A and FOXA2 during mouse liver development, Alder et al. have found that YAP1 can influence enhancer interactions and target gene expression levels. Enhancer switching enables HNF4A and FOXA2 to fulfill distinct roles during organ development.

AR Expression in Breast Cancer CTCs Associates with Bone Metastases.

Science.gov (United States)

Aceto, Nicola; Bardia, Aditya; Wittner, Ben S; Donaldson, Maria C; O'Keefe, Ryan; Engstrom, Amanda; Bersani, Francesca; Zheng, Yu; Comaills, Valentine; Niederhoffer, Kira; Zhu, Huili; Mackenzie, Olivia; Shioda, Toshi; Sgroi, Dennis; Kapur, Ravi; Ting, David T; Moy, Beverly; Ramaswamy, Sridhar; Toner, Mehmet; Haber, Daniel A; Maheswaran, Shyamala

2018-04-01

Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER) + breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER + breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients. Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. Mol Cancer Res; 16(4); 720-7. ©2018 AACR . ©2018 American Association for Cancer Research.

Default mode network abnormalities during state switching in attention deficit hyperactivity disorder.

Science.gov (United States)

Sidlauskaite, J; Sonuga-Barke, E; Roeyers, H; Wiersema, J R

2016-02-01

Individuals with attention deficit hyperactivity disorder (ADHD) display excess levels of default mode network (DMN) activity during goal-directed tasks, which are associated with attentional disturbances and performance decrements. One hypothesis is that this is due to attenuated down-regulation of this network during rest-to-task switching. A second related hypothesis is that it may be associated with right anterior insula (rAI) dysfunction - a region thought to control the actual state-switching process. These hypotheses were tested in the current fMRI study in which 19 adults with ADHD and 21 typically developing controls undertook a novel state-to-state switching paradigm. Advance cues signalled upcoming switches between rest and task periods and switch-related anticipatory modulation of DMN and rAI was measured. To examine whether rest-to-task switching impairments may be a specific example of a more general state regulation deficit, activity upon task-to-rest cues was also analysed. Against our hypotheses, we found that the process of down-regulating the DMN when preparing to switch from rest to task was unimpaired in ADHD and that there was no switch-specific deficit in rAI modulation. However, individuals with ADHD showed difficulties up-regulating the DMN when switching from task to rest. Rest-to-task DMN attenuation seems to be intact in adults with ADHD and thus appears unrelated to excess DMN activity observed during tasks. Instead, individuals with ADHD exhibit attenuated up-regulation of the DMN, hence suggesting disturbed re-initiation of a rest state.

Real-time 2.5  Gbit/s spatial circuit switching on W-band wireless links

DEFF Research Database (Denmark)

Rodríguez, Sebastián; Morales Vicente, Alvaro; Gallardo, Omar

2017-01-01

A spatial circuit switching system based on a beam steering application for W-band wireless links is proposed and experimentally demonstrated. The system enables two simultaneous transmissions of a 2.5 Gbit∕s data signal over a carrier of 81 GHz, while allowing the receiver to dynamically switch...... between them. The performance of the system is tested with the real-time measurements of the BER, achieving values below the FEC limit for 7% of overhead and serving to prove the viability of wireless spatial circuit switching in the next generation of wireless access networks....

BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer.

Science.gov (United States)

Shields, Sarah; Conroy, Emer; O'Grady, Tony; McGoldrick, Alo; Connor, Kate; Ward, Mark P; Useckaite, Zivile; Dempsey, Eugene; Reilly, Rebecca; Fan, Yue; Chubb, Anthony; Matallanas, David Gomez; Kay, Elaine W; O'Connor, Darran; McCann, Amanda; Gallagher, William M; Coppinger, Judith A

2018-03-20

Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.

Characterization of ERAS, a putative novel human oncogene, in skin and breast

Energy Technology Data Exchange (ETDEWEB)

Peña Avalos, B.L. de la

2014-07-01

Most human tumors have mutations in genes of the RAS small GTPase protein family. RAS works as a molecular switch for signaling pathways that modulate many aspects of cell behavior, including proliferation, differentiation, motility and death. Oncogenic mutations in RAS prevent GTP hydrolysis, locking RAS in a permanently active state, being the most common mutations in HRAS, KRAS and NRAS. The human RAS family consists of at least 36 different genes, many of which have been scarcely studied. One of these relatively unknown genes is ERAS (ES cell-expressed RAS), which is a constitutively active RAS protein, localized in chromosome X and expressed only in embryonic cells, being undetectable in adult tissues. New high throughput technologies have made it possible to screen complete cancer genomes for identification of mutations associated to cancer. Using the Sleeping Beauty (SB) transposon system, ERAS was identified as a putative novel oncogene in non-melanoma skin and breast cancers. The major aim of this project is to determine the general characteristics of ERAS as a putative novel human oncogene in skin and breast cells. Forced expression of ERAS results in drastic changes in cell shape, proliferation and motility. When ERAS is overexpressed in skin and breast human cells it is mainly localized in the cytoplasmic membrane. ERAS activates the phosphatidylinositol-3-OH kinase (PI3K) pathway but not the mitogen-activated protein kinase (MAPK) pathway. ERAS-expressing cells suffer spontaneous morphologic and phenotypic EMT-like changes, including cytoskeleton reorganization, vimentin and N-cadherin up-regulation and down-regulation of E-cadherin, which can be associated with increased malignancy, and invasive and metastatic potential. Our results suggest that inappropriate expression of ERAS lead to transformation of human cells. (Author)

Burst switching without guard interval in all-optical software-define star intra-data center network

Science.gov (United States)

Ji, Philip N.; Wang, Ting

2014-02-01

Optical switching has been introduced in intra-data center networks (DCNs) to increase capacity and to reduce power consumption. Recently we proposed a star MIMO OFDM-based all-optical DCN with burst switching and software-defined networking. Here, we introduce the control procedure for the star DCN in detail for the first time. The timing, signaling, and operation are described for each step to achieve efficient bandwidth resource utilization. Furthermore, the guidelines for the burst assembling period selection that allows burst switching without guard interval are discussed. The star all-optical DCN offers flexible and efficient control for next-generation data center application.

Dynamical modeling and experiment for an intra-cavity optical parametric oscillator pumped by a Q-switched self-mode-locking laser

Science.gov (United States)

Wang, Jing; Liu, Nianqiao; Song, Peng; Zhang, Haikun

2016-11-01

The rate-equation-based model for the Q-switched mode-locking (QML) intra-cavity OPO (IOPO) is developed, which includes the behavior of the fundamental laser. The intensity fluctuation mechanism of the fundamental laser is first introduced into the dynamics of a mode-locking OPO. In the derived model, the OPO nonlinear conversion is considered as a loss for the fundamental laser and thus the QML signal profile originates from the QML fundamental laser. The rate equations are solved by a digital computer for the case of an IOPO pumped by an electro-optic (EO) Q-switched self-mode-locking fundamental laser. The simulated results for the temporal shape with 20 kHz EO repetition and 11.25 W pump power, the signal average power, the Q-switched pulsewidth and the Q-switched pulse energy are obtained from the rate equations. The signal trace and output power from an EO QML Nd3+: GdVO4/KTA IOPO are experimentally measured. The theoretical values from the rate equations agree with the experimental results well. The developed model explains the behavior, which is helpful to system optimization.

Switched Cooperative Driving Model towards Human Vehicle Copiloting Situation: A Cyberphysical Perspective

Directory of Open Access Journals (Sweden)