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Bone metastases are a common occurrence in several malignancies, including breast, prostate, and lung. Once established in bone, tumors are responsible for significant morbidity and mortality1. Thus, there is a significant need to understand the molecular mechanisms controlling the establishment, growth and activity of tumors in bone. Several in vivo models have been established to study these events and each has specific benefits and limitations. The most commonly used model utilizes intracardiac inoculation of tumor cells directly into the arterial blood supply of athymic (nude) BalbC mice. This procedure can be applied to many different tumor types (including PC-3 prostate cancer, lung carcinoma, and mouse mammary fat pad tumors); however, in this manuscript we will focus on the breast cancer model, MDA-MB-231. In this model we utilize a highly bone-selective clone, originally derived in Dr. Mundy's group in San Antonio2, that has since been transfected for GFP expression and re-cloned by our group3. This clone is a bone metastatic variant with a high rate of osteotropism and very little metastasis to lung, liver, or adrenal glands. While intracardiac injections are most commonly used for studies of bone metastasis2, in certain instances intratibial4 or mammary fat pad injections are more appropriate. Intracardiac injections are typically performed when using human tumor cells with the goal of monitoring later stages of metastasis, specifically the ability of cancer cells to arrest in bone, survive, proliferate, and establish tumors that develop into cancer-induced bone disease. Intratibial injections are performed if focusing on the relationship of cancer cells and bone after a tumor has metastasized to bone, which correlates roughly to established metastatic bone disease. Neither of these models recapitulates early steps in the metastatic process prior to embolism and entry of tumor cells into the circulation. If monitoring primary tumor growth or metastasis from the primary site to bone, then mammary fat pad inoculations are usually preferred; however, very few tumor cell lines will consistently metastasize to bone from the primary site, with 4T1 bone-preferential clones, a mouse mammary carcinoma, being the exception 5,6.
This manuscript details inoculation procedures and highlights key steps in post inoculation analyses. Specifically, it includes cell culture, tumor cell inoculation procedures for intracardiac and intratibial inoculations, as well as brief information regarding weekly monitoring by x-ray, fluorescence and histomorphometric analyses.
18 Related JoVE Articles!
Three Dimensional Cultures: A Tool To Study Normal Acinar Architecture vs. Malignant Transformation Of Breast Cells
Institutions: University of Michigan Comprehensive Cancer Center, University of Michigan Comprehensive Cancer Center.
Invasive breast carcinomas are a group of malignant epithelial tumors characterized by the invasion of adjacent tissues and propensity to metastasize. The interplay of signals between cancer cells and their microenvironment exerts a powerful influence on breast cancer growth and biological behavior1
. However, most of these signals from the extracellular matrix are lost or their relevance is understudied when cells are grown in two dimensional culture (2D) as a monolayer. In recent years, three dimensional (3D) culture on a reconstituted basement membrane has emerged as a method of choice to recapitulate the tissue architecture of benign and malignant breast cells. Cells grown in 3D retain the important cues from the extracellular matrix and provide a physiologically relevant ex vivo
. Of note, there is growing evidence suggesting that cells behave differently when grown in 3D as compared to 2D4
. 3D culture can be effectively used as a means to differentiate the malignant phenotype from the benign breast phenotype and for underpinning the cellular and molecular signaling involved3
. One of the distinguishing characteristics of benign epithelial cells is that they are polarized so that the apical cytoplasm is towards the lumen and the basal cytoplasm rests on the basement membrane. This apico-basal polarity is lost in invasive breast carcinomas, which are characterized by cellular disorganization and formation of anastomosing and branching tubules that haphazardly infiltrates the surrounding stroma. These histopathological differences between benign gland and invasive carcinoma can be reproduced in 3D6,7
. Using the appropriate read-outs like the quantitation of single round acinar structures, or differential expression of validated molecular markers for cell proliferation, polarity and apoptosis in combination with other molecular and cell biology techniques, 3D culture can provide an important tool to better understand the cellular changes during malignant transformation and for delineating the responsible signaling.
Medicine, Issue 86, pathological conditions, signs and symptoms, neoplasms, three dimensional cultures, Matrigel, breast cells, malignant phenotype, signaling
Quantification of Breast Cancer Cell Invasiveness Using a Three-dimensional (3D) Model
Institutions: University of Western Ontario, University of Western Ontario, Lawson Health Research Institute.
It is now well known that the cellular and tissue microenvironment are critical regulators influencing tumor initiation and progression. Moreover, the extracellular matrix (ECM) has been demonstrated to be a critical regulator of cell behavior in culture and homeostasis in vivo
. The current approach of culturing cells on two-dimensional (2D), plastic surfaces results in the disturbance and loss of complex interactions between cells and their microenvironment. Through the use of three-dimensional (3D) culture assays, the conditions for cell-microenvironment interaction are established resembling the in vivo
microenvironment. This article provides a detailed methodology to grow breast cancer cells in a 3D basement membrane protein matrix, exemplifying the potential of 3D culture in the assessment of cell invasion into the surrounding environment. In addition, we discuss how these 3D assays have the potential to examine the loss of signaling molecules that regulate epithelial morphology by immunostaining procedures. These studies aid to identify important mechanistic details into the processes regulating invasion, required for the spread of breast cancer.
Medicine, Issue 88, Breast cancer, cell invasion, extracellular matrix (ECM), three-dimensional (3D) cultures, immunocytochemistry, Matrigel, basement membrane matrix
A Matrigel-Based Tube Formation Assay to Assess the Vasculogenic Activity of Tumor Cells
Institutions: University of Massachusetts, University of Massachusetts, University of Massachusetts.
Over the past several decades, a tube formation assay using growth factor-reduced Matrigel has been typically employed to demonstrate the angiogenic activity of vascular endothelial cells in vitro1-5
. However, recently growing evidence has shown that this assay is not limited to test vascular behavior for endothelial cells. Instead, it also has been used to test the ability of a number of tumor cells to develop a vascular phenotype6-8
. This capability was consistent with their vasculogenic behavior identified in xenotransplanted animals, a process known as vasculogenic mimicry (VM)9
. There is a multitude of evidence demonstrating that tumor cell-mediated VM plays a vital role in the tumor development, independent of endothelial cell angiogenesis6, 10-13
. For example, tumor cells were found to participate in the blood perfused, vascular channel formation in tissue samples from melanoma and glioblastoma patients8, 10, 11
. Here, we described this tubular network assay as a useful tool in evaluation of vasculogenic activity of tumor cells. We found that some tumor cell lines such as melanoma B16F1 cells, glioblastoma U87 cells, and breast cancer MDA-MB-435 cells are able to form vascular tubules; but some do not such as colon cancer HCT116 cells. Furthermore, this vascular phenotype is dependent on cell numbers plated on the Matrigel. Therefore, this assay may serve as powerful utility to screen the vascular potential of a variety of cell types including vascular cells, tumor cells as well as other cells.
Cancer Biology, Issue 55, tumor, vascular, endothelial, tube formation, Matrigel, in vitro
Ultrasound Imaging-guided Intracardiac Injection to Develop a Mouse Model of Breast Cancer Brain Metastases Followed by Longitudinal MRI
Institutions: University of Texas Southwestern Medical Center.
Breast cancer brain metastasis, occurring in 30% of breast cancer patients at stage IV, is associated with high mortality. The median survival is only 6 months. It is critical to have suitable animal models to mimic the hemodynamic spread of the metastatic cells in the clinical scenario. Here, we are introducing the use of small animal ultrasound imaging to guide an accurate injection of brain tropical breast cancer cells into the left ventricle of athymic nude mice. Longitudinal MRI is used to assessing intracranial initiation and growth of brain metastases. Ultrasound-guided intracardiac injection ensures not only an accurate injection and hereby a higher successful rate but also significantly decreased mortality rate, as compared to our previous manual procedure. In vivo
high resolution MRI allows the visualization of hyperintense multifocal lesions, as small as 310 µm in diameter on T2
-weighted images at 3 weeks post injection. Follow-up MRI reveals intracranial tumor growth and increased number of metastases that distribute throughout the whole brain.
Medicine, Issue 85, breast cancer brain metastasis, intracardiac injection, ultrasound imaging, MRI, MDA-MB231/Br-GFP cells
An In Vitro System to Study Tumor Dormancy and the Switch to Metastatic Growth
Institutions: University of Haifa, National Cancer Institute.
Recurrence of breast cancer often follows a long latent period in which there are no signs of cancer, and metastases may not become clinically apparent until many years after removal of the primary tumor and adjuvant therapy. A likely explanation of this phenomenon is that tumor cells have seeded metastatic sites, are resistant to conventional therapies, and remain dormant for long periods of time 1-4
The existence of dormant cancer cells at secondary sites has been described previously as quiescent solitary cells that neither proliferate nor undergo apoptosis 5-7
. Moreover, these solitary cells has been shown to disseminate from the primary tumor at an early stage of disease progression 8-10
and reside growth-arrested in the patients' bone marrow, blood and lymph nodes 1,4,11
. Therefore, understanding mechanisms that regulate dormancy or the switch to a proliferative state is critical for discovering novel targets and interventions to prevent disease recurrence. However, unraveling the mechanisms regulating the switch from tumor dormancy to metastatic growth has been hampered by the lack of available model systems.
in vivo and ex vivo
model systems to study metastatic progression of tumor cells have been described previously 1,12-14
. However these model systems have not provided in real time and in a high throughput manner mechanistic insights into what triggers the emergence of solitary dormant tumor cells to proliferate as metastatic disease. We have recently developed a 3D in vitro
system to model the in vivo
growth characteristics of cells that exhibit either dormant (D2.OR, MCF7, K7M2-AS.46) or proliferative (D2A1, MDA-MB-231, K7M2) metastatic behavior in vivo
. We demonstrated that tumor cells that exhibit dormancy in vivo
at a metastatic site remain quiescent when cultured in a 3-dimension (3D) basement membrane extract (BME), whereas cells highly metastatic in vivo
readily proliferate in 3D culture after variable, but relatively short periods of quiescence. Importantly by utilizing the 3D in vitro
model system we demonstrated for the first time that the ECM composition plays an important role in regulating whether dormant tumor cells will switch to a proliferative state and have confirmed this in in vivo
. Hence, the model system described in this report provides an in vitro
method to model tumor dormancy and study the transition to proliferative growth induced by the microenvironment.
Medicine, Issue 54, Tumor dormancy, cancer recurrence, metastasis, reconstituted basement membrane extract (BME), 3D culture, breast cancer
In vivo Bioluminescence Imaging of Tumor Hypoxia Dynamics of Breast Cancer Brain Metastasis in a Mouse Model
Institutions: University of Texas Southwestern Medical Center , University of Texas Southwestern Medical Center , Kyoto University Graduate School of Medicine.
It is well recognized that tumor hypoxia plays an important role in promoting malignant progression and affecting therapeutic response negatively. There is little knowledge about in situ, in vivo,
tumor hypoxia during intracranial development of malignant brain tumors because of lack of efficient means to monitor it in these deep-seated orthotopic tumors. Bioluminescence imaging (BLI), based on the detection of light emitted by living cells expressing a luciferase gene, has been rapidly adopted for cancer research, in particular, to evaluate tumor growth or tumor size changes in response to treatment in preclinical animal studies. Moreover, by expressing a reporter gene under the control of a promoter sequence, the specific gene expression can be monitored non-invasively by BLI. Under hypoxic stress, signaling responses are mediated mainly via the hypoxia inducible factor-1α (HIF-1α) to drive transcription of various genes. Therefore, we have used a HIF-1α reporter construct, 5HRE-ODD-luc, stably transfected into human breast cancer MDA-MB231 cells (MDA-MB231/5HRE-ODD-luc). In vitro
HIF-1α bioluminescence assay is performed by incubating the transfected cells in a hypoxic chamber (0.1% O2
) for 24 hr before BLI, while the cells in normoxia (21% O2
) serve as a control. Significantly higher photon flux observed for the cells under hypoxia suggests an increased HIF-1α binding to its promoter (HRE elements), as compared to those in normoxia. Cells are injected directly into the mouse brain to establish a breast cancer brain metastasis model. In vivo
bioluminescence imaging of tumor hypoxia dynamics is initiated 2 wks after implantation and repeated once a week. BLI reveals increasing light signals from the brain as the tumor progresses, indicating increased intracranial tumor hypoxia. Histological and immunohistochemical studies are used to confirm the in vivo
imaging results. Here, we will introduce approaches of in vitro
HIF-1α bioluminescence assay, surgical establishment of a breast cancer brain metastasis in a nude mouse and application of in vivo
bioluminescence imaging to monitor intracranial tumor hypoxia.
Medicine, Issue 56, bioluminescence imaging (BLI), tumor hypoxia dynamics, hypoxia inducible factor-1α (HIF-1α), breast cancer brain metastasis
A Mouse Tumor Model of Surgical Stress to Explore the Mechanisms of Postoperative Immunosuppression and Evaluate Novel Perioperative Immunotherapies
Institutions: Ottawa Hospital Research Institute, University of Ottawa, University of Ottawa, The Second Hospital of Shandong University, University of Tabuk, Ottawa General Hospital.
Surgical resection is an essential treatment for most cancer patients, but surgery induces dysfunction in the immune system and this has been linked to the development of metastatic disease in animal models and in cancer patients. Preclinical work from our group and others has demonstrated a profound suppression of innate immune function, specifically NK cells in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Relatively few animal studies and clinical trials have focused on characterizing and reversing the detrimental effects of cancer surgery. Using a rigorous animal model of spontaneously metastasizing tumors and surgical stress, the enhancement of cancer surgery on the development of lung metastases was demonstrated. In this model, 4T1 breast cancer cells are implanted in the mouse mammary fat pad. At day 14 post tumor implantation, a complete resection of the primary mammary tumor is performed in all animals. A subset of animals receives additional surgical stress in the form of an abdominal nephrectomy. At day 28, lung tumor nodules are quantified. When immunotherapy was given immediately preoperatively, a profound activation of immune cells which prevented the development of metastases following surgery was detected. While the 4T1 breast tumor surgery model allows for the simulation of the effects of abdominal surgical stress on tumor metastases, its applicability to other tumor types needs to be tested. The current challenge is to identify safe and promising immunotherapies in preclinical mouse models and to translate them into viable perioperative therapies to be given to cancer surgery patients to prevent the recurrence of metastatic disease.
Medicine, Issue 85, mouse, tumor model, surgical stress, immunosuppression, perioperative immunotherapy, metastases
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Institutions: Northwestern University, Northwestern University, Northwestern University.
Our laboratory has developed a novel orthotopic implantation model of human prostate cancer (PCa). As PCa death is not due to the primary tumor, but rather the formation of distinct metastasis, the ability to effectively model this progression pre-clinically is of high value. In this model, cells are directly implanted into the ventral lobe of the prostate in Balb/c athymic mice, and allowed to progress for 4-6 weeks. At experiment termination, several distinct endpoints can be measured, such as size and molecular characterization of the primary tumor, the presence and quantification of circulating tumor cells in the blood and bone marrow, and formation of metastasis to the lung. In addition to a variety of endpoints, this model provides a picture of a cells ability to invade and escape the primary organ, enter and survive in the circulatory system, and implant and grow in a secondary site. This model has been used effectively to measure metastatic response to both changes in protein expression as well as to response to small molecule therapeutics, in a short turnaround time.
Medicine, Issue 79, Urogenital System, Male Urogenital Diseases, Surgical Procedures, Operative, Life Sciences (General), Prostate Cancer, Metastasis, Mouse Model, Drug Discovery, Molecular Biology
Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells
Institutions: Sheba Medical Center, Tel-Aviv University, Tel-Aviv University, Tel-Aviv University, Ecole Superieure de Biotechnologie Strasbourg, Tel-Aviv University.
Phenanthrene derivatives acting as potent PARP1 inhibitors prevented the bi-focal clustering of supernumerary centrosomes in multi-centrosomal human cancer cells in mitosis. The phenanthridine PJ-34 was the most potent molecule. Declustering of extra-centrosomes causes mitotic failure and cell death in multi-centrosomal cells. Most solid human cancers have high occurrence of extra-centrosomes. The activity of PJ-34 was documented in real-time by confocal imaging of live human breast cancer MDA-MB-231 cells transfected with vectors encoding for fluorescent γ-tubulin, which is highly abundant in the centrosomes and for fluorescent histone H2b present in the chromosomes. Aberrant chromosomes arrangements and de-clustered γ-tubulin foci representing declustered centrosomes were detected in the transfected MDA-MB-231 cells after treatment with PJ-34. Un-clustered extra-centrosomes in the two spindle poles preceded their cell death. These results linked for the first time the recently detected exclusive cytotoxic activity of PJ-34 in human cancer cells with extra-centrosomes de-clustering in mitosis, and mitotic failure leading to cell death. According to previous findings observed by confocal imaging of fixed cells, PJ-34 exclusively eradicated cancer cells with multi-centrosomes without impairing normal cells undergoing mitosis with two centrosomes and bi-focal spindles. This cytotoxic activity of PJ-34 was not shared by other potent PARP1 inhibitors, and was observed in PARP1 deficient MEF harboring extracentrosomes, suggesting its independency of PARP1 inhibition. Live confocal imaging offered a useful tool for identifying new molecules eradicating cells during mitosis.
Cancer Biology, Issue 78, Medicine, Cellular Biology, Molecular Biology, Biomedical Engineering, Anatomy, Physiology, Genetics, Neoplastic Processes, Pharmacologic Actions, Live confocal imaging, Extra-centrosomes clustering/de-clustering, Mitotic Catastrophe cell death, PJ-34, myocardial infarction, microscopy, imaging
Therapeutic Gene Delivery and Transfection in Human Pancreatic Cancer Cells using Epidermal Growth Factor Receptor-targeted Gelatin Nanoparticles
Institutions: Northeastern University.
More than 32,000 patients are diagnosed with pancreatic cancer in the United States per year and the disease is associated with very high mortality 1
. Urgent need exists to develop novel clinically-translatable therapeutic strategies that can improve on the dismal survival statistics of pancreatic cancer patients. Although gene therapy in cancer has shown a tremendous promise, the major challenge is in the development of safe and effective delivery system, which can lead to sustained transgene expression.
Gelatin is one of the most versatile natural biopolymer, widely used in food and pharmaceutical products. Previous studies from our laboratory have shown that type B gelatin could physical encapsulate DNA, which preserved the supercoiled structure of the plasmid and improved transfection efficiency upon intracellular delivery. By thiolation of gelatin, the sulfhydryl groups could be introduced into the polymer and would form disulfide bond within nanoparticles, which stabilizes the whole complex and once disulfide bond is broken due to the presence of glutathione in cytosol, payload would be released 2-5
. Poly(ethylene glycol) (PEG)-modified GENS, when administered into the systemic circulation, provides long-circulation times and preferentially targets to the tumor mass due to the hyper-permeability of the neovasculature by the enhanced permeability and retention
. Studies have shown over-expression of the epidermal growth factor receptor (EGFR) on Panc-1 human pancreatic adenocarcinoma cells 7
. In order to actively target pancreatic cancer cell line, EGFR specific peptide was conjugated on the particle surface through a PEG spacer.8
Most anti-tumor gene therapies are focused on administration of the tumor suppressor genes, such as wild-type p53 (wt-p53), to restore the pro-apoptotic function in the cells 9
. The p53 mechanism functions as a critical signaling pathway in cell growth, which regulates apoptosis, cell cycle arrest, metabolism and other processes 10
. In pancreatic cancer, most cells have mutations in p53 protein, causing the loss of apoptotic activity. With the introduction of wt-p53, the apoptosis could be repaired and further triggers cell death in cancer cells 11
Based on the above rationale, we have designed EGFR targeting peptide-modified thiolated gelatin nanoparticles for wt-p53 gene delivery and evaluated delivery efficiency and transfection in Panc-1 cells.
Bioengineering, Issue 59, Gelatin Nanoparticle, Gene Therapy, Targeted Delivery, Pancreatic Cancer, Epidermal Growth Factor Receptor, EGFR
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Institutions: Cedars-Sinai Medical Center.
Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors.
Chemistry, Issue 88, Cancer treatment, personalized medicine, polymalic acid, nanodrug, biopolymer, targeting, host compatibility, biodegradability
In vivo Dual Substrate Bioluminescent Imaging
Institutions: Case Western Reserve University .
Our understanding of how and when breast cancer cells transit from established primary tumors to metastatic sites has increased at an exceptional rate since the advent of in vivo
bioluminescent imaging technologies 1-3
. Indeed, the ability to locate and quantify tumor growth longitudinally in a single cohort of animals to completion of the study as opposed to sacrificing individual groups of animals at specific assay times has revolutionized how researchers investigate breast cancer metastasis. Unfortunately, current methodologies preclude the real-time assessment of critical changes that transpire in cell signaling systems as breast cancer cells (i)
evolve within primary tumors, (ii)
disseminate throughout the body, and (iii)
reinitiate proliferative programs at sites of a metastatic lesion. However, recent advancements in bioluminescent imaging now make it possible to simultaneously quantify specific spatiotemporal changes in gene expression as a function of tumor development and metastatic progression via
the use of dual substrate luminescence reactions. To do so, researchers take advantage for two light-producing luciferase enzymes isolated from the firefly (Photinus pyralis
) and sea pansy (Renilla reniformis
), both of which react to mutually exclusive substrates that previously facilitated their wide-spread use in in vitro
cell-based reporter gene assays 4
. Here we demonstrate the in vivo
utility of these two enzymes such that one luminescence reaction specifically marks the size and location of a developing tumor, while the second luminescent reaction serves as a means to visualize the activation status of specific signaling systems during distinct stages of tumor and metastasis development. Thus, the objectives of this study are two-fold. First, we will describe the steps necessary to construct dual bioluminescent reporter cell lines, as well as those needed to facilitate their use in visualizing the spatiotemporal regulation of gene expression during specific steps of the metastatic cascade. Using the 4T1 model of breast cancer metastasis, we show that the in vivo
activity of a synthetic Smad Binding Element (SBE) promoter was decreased dramatically in pulmonary metastasis as compared to that measured in the primary tumor 4-6
. Recently, breast cancer metastasis was shown to be regulated by changes within the primary tumor microenvironment and reactive stroma, including those occurring in fibroblasts and infiltrating immune cells 7-9
. Thus, our second objective will be to demonstrate the utility of dual bioluminescent techniques in monitoring the growth and localization of two unique cell populations harbored within a single animal during breast cancer growth and metastasis.
Medicine, Issue 56, firefly luciferase, Renilla Luciferase, breast cancer, metastasis, Smad
Adaptation of Semiautomated Circulating Tumor Cell (CTC) Assays for Clinical and Preclinical Research Applications
Institutions: London Health Sciences Centre, Western University, London Health Sciences Centre, Lawson Health Research Institute, Western University.
The majority of cancer-related deaths occur subsequent to the development of metastatic disease. This highly lethal disease stage is associated with the presence of circulating tumor cells (CTCs). These rare cells have been demonstrated to be of clinical significance in metastatic breast, prostate, and colorectal cancers. The current gold standard in clinical CTC detection and enumeration is the FDA-cleared CellSearch system (CSS). This manuscript outlines the standard protocol utilized by this platform as well as two additional adapted protocols that describe the detailed process of user-defined marker optimization for protein characterization of patient CTCs and a comparable protocol for CTC capture in very low volumes of blood, using standard CSS reagents, for studying in vivo
preclinical mouse models of metastasis. In addition, differences in CTC quality between healthy donor blood spiked with cells from tissue culture versus patient blood samples are highlighted. Finally, several commonly discrepant items that can lead to CTC misclassification errors are outlined. Taken together, these protocols will provide a useful resource for users of this platform interested in preclinical and clinical research pertaining to metastasis and CTCs.
Medicine, Issue 84, Metastasis, circulating tumor cells (CTCs), CellSearch system, user defined marker characterization, in vivo, preclinical mouse model, clinical research
Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer
Institutions: Wistar Institute, University of Pennsylvania, Geisel School of Medicine at Dartmouth, University of Pennsylvania, University of Pennsylvania, University of Pennsylvania.
Breast cancer is a heterogeneous disease involving complex cellular interactions between the developing tumor and immune system, eventually resulting in exponential tumor growth and metastasis to distal tissues and the collapse of anti-tumor immunity. Many useful animal models exist to study breast cancer, but none completely recapitulate the disease progression that occurs in humans. In order to gain a better understanding of the cellular interactions that result in the formation of latent metastasis and decreased survival, we have generated an inducible transgenic mouse model of YFP-expressing ductal carcinoma that develops after sexual maturity in immune-competent mice and is driven by consistent, endocrine-independent oncogene expression. Activation of YFP, ablation of p53, and expression of an oncogenic form of K-ras was achieved by the delivery of an adenovirus expressing Cre-recombinase into the mammary duct of sexually mature, virgin female mice. Tumors begin to appear 6 weeks after the initiation of oncogenic events. After tumors become apparent, they progress slowly for approximately two weeks before they begin to grow exponentially. After 7-8 weeks post-adenovirus injection, vasculature is observed connecting the tumor mass to distal lymph nodes, with eventual lymphovascular invasion of YFP+ tumor cells to the distal axillary lymph nodes. Infiltrating leukocyte populations are similar to those found in human breast carcinomas, including the presence of αβ and γδ T cells, macrophages and MDSCs. This unique model will facilitate the study of cellular and immunological mechanisms involved in latent metastasis and dormancy in addition to being useful for designing novel immunotherapeutic interventions to treat invasive breast cancer.
Medicine, Issue 85, Transgenic mice, breast cancer, metastasis, intraductal injection, latent mutations, adenovirus-Cre
Analysis of Cell Migration within a Three-dimensional Collagen Matrix
Institutions: Witten/Herdecke University.
The ability to migrate is a hallmark of various cell types and plays a crucial role in several physiological processes, including embryonic development, wound healing, and immune responses. However, cell migration is also a key mechanism in cancer enabling these cancer cells to detach from the primary tumor to start metastatic spreading. Within the past years various cell migration assays have been developed to analyze the migratory behavior of different cell types. Because the locomotory behavior of cells markedly differs between a two-dimensional (2D) and three-dimensional (3D) environment it can be assumed that the analysis of the migration of cells that are embedded within a 3D environment would yield in more significant cell migration data. The advantage of the described 3D collagen matrix migration assay is that cells are embedded within a physiological 3D network of collagen fibers representing the major component of the extracellular matrix. Due to time-lapse video microscopy real cell migration is measured allowing the determination of several migration parameters as well as their alterations in response to pro-migratory factors or inhibitors. Various cell types could be analyzed using this technique, including lymphocytes/leukocytes, stem cells, and tumor cells. Likewise, also cell clusters or spheroids could be embedded within the collagen matrix concomitant with analysis of the emigration of single cells from the cell cluster/ spheroid into the collagen lattice. We conclude that the 3D collagen matrix migration assay is a versatile method to analyze the migration of cells within a physiological-like 3D environment.
Bioengineering, Issue 92, cell migration, 3D collagen matrix, cell tracking
Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging, Volumetric Computed Tomography and Ultrasound
Institutions: German Cancer Research Center, Heidelberg, Germany, German Cancer Research Center, Heidelberg, Germany.
Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo
assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques.
For this purpose, we injected 105
MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg1
. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula1
. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US).
MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified2-4
. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions5,6
. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated, respectively. DCE-US allows for real-time imaging of vascularization in bone metastases after injection of microbubbles7
In conclusion, in a model of site-specific breast cancer bone metastases multi-modal imaging techniques including MRI, VCT and US offer complementary information on morphology and functional parameters of angiogenesis in these skeletal lesions.
Cancer Biology, Issue 66, Medicine, Physiology, Physics, bone metastases, animal model, angiogenesis, imaging, magnetic resonance imaging, MRI, volumetric computed tomography, ultrasound
Non-enzymatic, Serum-free Tissue Culture of Pre-invasive Breast Lesions for Spontaneous Generation of Mammospheres
Institutions: George Mason University, Virginia Surgery Associates.
Breast ductal carcinoma in situ
(DCIS), by definition, is proliferation of neoplastic epithelial cells within the confines of the breast duct, without breaching the collagenous basement membrane. While DCIS is a non-obligate precursor to invasive breast cancers, the molecular mechanisms and cell populations that permit progression to invasive cancer are not fully known. To determine if progenitor cells capable of invasion existed within the DCIS cell population, we developed a methodology for collecting and culturing sterile human breast tissue at the time of surgery, without enzymatic disruption of tissue.
Sterile breast tissue containing ductal segments is harvested from surgically excised breast tissue following routine pathological examination. Tissue containing DCIS is placed in nutrient rich, antibiotic-containing, serum free medium, and transported to the tissue culture laboratory. The breast tissue is further dissected to isolate the calcified areas. Multiple breast tissue pieces (organoids) are placed in a minimal volume of serum free medium in a flask with a removable lid and cultured in a humidified CO2
incubator. Epithelial and fibroblast cell populations emerge from the organoid after 10 - 14 days. Mammospheres spontaneously form on and around the epithelial cell monolayer. Specific cell populations can be harvested directly from the flask without disrupting neighboring cells. Our non-enzymatic tissue culture system reliably reveals cytogenetically abnormal, invasive progenitor cells from fresh human DCIS lesions.
Cancer Biology, Issue 93, Breast, ductal carcinoma in situ, epidermal growth factor, mammosphere, organoid, pre-invasive, primary cell culture, serum-free, spheroid
Monitoring Tumor Metastases and Osteolytic Lesions with Bioluminescence and Micro CT Imaging
Institutions: Caliper Life Sciences.
Following intracardiac delivery of MDA-MB-231-luc-D3H2LN cells to Nu/Nu mice, systemic metastases developed in the injected animals. Bioluminescence imaging using IVIS Spectrum was employed to monitor the distribution and development of the tumor cells following the delivery procedure including DLIT reconstruction to measure the tumor signal and its location.
Development of metastatic lesions to the bone tissues triggers osteolytic activity and lesions to tibia and femur were evaluated longitudinally using micro CT. Imaging was performed using a Quantum FX micro CT system with fast imaging and low X-ray dose. The low radiation dose allows multiple imaging sessions to be performed with a cumulative X-ray dosage far below LD50. A mouse imaging shuttle device was used to sequentially image the mice with both IVIS Spectrum and Quantum FX achieving accurate animal positioning in both the bioluminescence and CT images. The optical and CT data sets were co-registered in 3-dimentions using the Living Image 4.1 software. This multi-mode approach allows close monitoring of tumor growth and development simultaneously with osteolytic activity.
Medicine, Issue 50, osteolytic lesions, micro CT, tumor, bioluminescence, in vivo, imaging, IVIS, luciferase, low dose, co-registration, 3D reconstruction

domain: literature


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From the cities of Coastal Virginia to Richmond, find wonderful displays of lights sure to delight your family.
Fireside chats, hot cocoa, festive decorations, and twinkling lights. Spend these special days in Virginia with the ones you love.
Appalachian Trail, Rockbridge Co.
Art in Lexington: A Gallery Tour!
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Brushy Hills Hike
Campbell House, The
Seven mile nature trail follows the Maury River from Lexington to Buena Vista along the old railroad bed, now owned and managed by the Virginia Mil...
Hiking to the Devil's Marbleyard requires considerable strenuous uphill walking. The Lexington Visitor Center can provide you with a map and ...
Free fun for the whole family! Participate in this high-tech treasure hunt using GPS coordinates to locate hidden geocaches. GPS units available on ...
The George C. Marshall Museum profiles our first 5-star general, US Army Chief of Staff during World War II, the "organizer of victory".&...
House Mountain Trails
A blast from the past! Authentic 1950's drive-in movie theater. Bring the entire family, including pets, for an evening of fun at the country's&nbs...
The construction on the Chapel began in 1867 at the request of Robert E. Lee, who served as president from 1865-1870 of what was once Washington Co...
The Lenfest Center for the Arts, home of the department of theater, music and art and is a multi-use facility designed and equipped to accommodate ...
Lexington's entire downtown is listed on the State and National register of Historic Places. As the Rockbridge County seat, it has long been the ...
Moore's Creek Dam
A unique exhibition dedicated to all who have worn a uniform in the service of their country. American, British, European and Asian countries repre...
North Mountain Trail
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domain: geography


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Gadgets add stress, rob your sleep
Only recently, Germany's employment ministry banned its managers from calling or emailing staff out of hours except in emergencies, to prevent employees from burning out.
But in India, there's no escaping the 'beep' from the boss at unearthly hours, giving executives here more than heartburn. Dheeraj Gosain (34), who handles business development for an HR consultancy firm, is a proud owner of an iPhone, iPad, iPod and an Android phone.
But he now wants to be rid of these - and get his peace and freedom back. "Staying updated is a pain," he says. He could be having a candle light dinner with his spouse, when an urgent email from his boss pops up. Or he could be with his family on a holiday and a client demands an immediate solution over email. "There is always fear hanging on your head," he says.
"It is like advancing a bomb blast. The worst thing is, you can't do anything but respond, taking your mind off your leisure time and spoiling it. These gadgets have sabotaged and hijacked our personal lives," Gosain says.
Gosain's peers across functions and industries share his feelings. Smart gadgets, from iPhones, iPads, BlackBerrys to Android phones, have no doubt helped managers to pass on information and instructions to their subordinates on a real-time basis. But they have also ended up wrecking worklife balance. "There is a shift in company culture. Even though firms say they care for their people, with salaries going u
However, he says, it is a two-way street. "People put up with it as they are paid fantastically and don't want to lose a certain lifestyle," he adds. Arecent global study, 'Well-being of the Mobile Workforce', by commercial Wi-Fi network provider iPass and the Institute of Work Psychology (Sheffield University, England ) suggests that besides the loss of work-life balance, "connected" professionals suffer sleep disorders, higher stress levels and reduced productivity gains.
The study covered over 5,600 mobile enterprise employees at 1,100 companies worldwide. Nearly 26% of respondents spent 15 to 20 hours extra hours working every week, as their management and co-workers expected them to stay connected, even on a vacation. Varun Patel (name changed), a senior IT audit professional in an international IT firm, testifies to this.
Till recently, he would be wide awake every few hours, checking his emails. "It was affecting me personallyand professionally," he says. He now has a new job and a boss who does not send him such emails. Professionals lay the blame on the insensitivity of those using the gadgets.
Anil Shah (name changed), a senior executive at an international firm's media division, says he experienced this just a few months ago while on vacation with his family. A senior executive called him, promising to keep the conversation short. But he took 45 minutes to explain how urgent his requirement was and asked if Shah could deliver it by the end of the day. "I ended up devoting a complete day on this, reviewing reports and replying to mails, out of a five-day holiday, leaving my family complaining about a wasted vacation through the rest of the year," says Shah.
"If it is so important, why don't people plan for it in advance," he asks. Gangjee has dealt with many cases of anxiety-related to the overuse of gadgets. "It is also the reason for sleep deprivation, which leads to short-term memory loss, besides a drop in productivity as you can't take proper decisions if your mind is not relaxed," he says.
The problem is exacerbated by dependence on gadgets, to the extent that people's self-image and identity now depends on phones. "That's the reason people pick up their phones in the middle of birthday celebrations, believing that if they don't respond, people will stop calling and they will cease to be important to others," says Gangjee.
However, work-life balance or the lack of it is not in the smartphone but in an individual's mind, says Adil Malia, president, HR, Essar Group.
"People tend to respond to every call or email as they feel it can be important (which is not always true), and to be on top of competition," he says. All that people need to do is mark an absent notification to let callers know that they are not available except for exceptional situations, he says.
"Organisations don't instruct professionals to use smartphones, you choose to use one. People don't want you to check emails in the middle of the night. It's about your discipline," says Pratik Kumar, executive vice president, HR, Wipro.
Smartphones come with different kinds of alerts — lights, blips, and even timings to switch them off, he says. "It's like saying, 'ban cars to stop drunken driving'. That's not the solution," says Rituparna Chakraborty, co-founder & SVP, Team-Lease Services. Never go overboard to make yourself available, she says.
"If you set an expectation, you have to act accordingly." Ultimately, you don't let the device control you; you're the boss here.

domain: news


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The city of Shivpuri is also a municipality in the Shivpuri district located in the Indian state of Madhya Pradesh. It falls within the Gwalior Division of the state. Shivpuri functions as the administrative headquarter of the eponymous district. Shivpuri district shares a border with Rajasthan towards the west. It consists of nine tehsils. Shivpuri functioned as the summer capital of the Scindia rulers of Gwalior. Shivpuri is a popular tourist attraction, especially in the monsoon season when it has a number of lakes and minor waterfalls. The lush greenery and the thick dense forests in and around the city makes is a scenic place to explore. Places of tourist attraction near this city are Chhatari ornate marble memorials, Ban Ganga Dham, Chintaharan Mandir, Mohineshwar Dham, etc.
Incorporated in 1911, the Central Bank of India was the first commercial bank which was entirely owned and managed by Indians. Sir Sorabji Pochkhanawala, founded the Bank as a result of his dream realization about the bank. The first Chairman was Sir Pherozesha Mehta of this pure swadeshi Bank. In fact, Sir Sorabji Pochkhanawala felt so proud about this bank that he proclaimed CBI as the "countrys asset and property of the nation." He also said that "CBI has been made on peoples faith and considers itself as the peoples bank." During the last 106 years of history, the Bank has faced challenges and threats. The CBI successfully transformed every threat into an opportunity of business and excelled over its competitors in the Banking industry. The Central Bank of India can be honestly mentioned as an all India bank, due to stretch of its vast network across all the 29 States and 6 Union Territories of India. Among the public sector banks, the Central Bank of India holds a very significant place on account of its 4715 Branches, 1 Extension counters, along with 10 Satellite Offices as on January 2018, at various centers throughout the length and breadth of the country.


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Why Catholics Must Care
October 12 @ 7:00 pm - 8:30 pmFree
Fr. Andrew Linn will give a 1/2 hour talk on “Why Catholics Must Care” at St. Monica – Donovan Hall in Whitefish Bay!
Hear the difference of knowing the resources and making the connections for those in need. Hear the difference Catholics can make for the Women’s Care Center and other organizations. Most of all, understand how you can change Milwaukee!
Sheryl Laird, Director of the Women’s Care Center, will share for a few minutes, information on how church involvement makes a difference at the WCC. Hear the wonderful news of the lives saved and women with little hope empowered and served with compassion!
Refreshments and a networking opportunity will follow provided by Catholics4Life! Join with others from across the Milwaukee archdiocese and be inspired to help mom’s, dad’s and babies have life and have it more abundantly!

domain: sociology


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To make the base, melt the butter and sugar in a saucepan over a gentle heat and stir in the crushed biscuit.
Press the mixture evenly in to the base of loose-bottomed cake tin. Place in the fridge to chill.
To make the filling, place the cheese in a large mixing bowl. Beat in the egg yolks, half the caster sugar, the lemon zest and juice, the cream and the marmalade.
Put the gelatine and water into a small heatproof bowl over a pan of simmering water and stir until dissolved.
Beat the gelatine mix into the cheese mixture then put to one side.
Whisk the egg whites until stiff, then whisk in the remaining caster sugar. Fold into the cheese mixture then spoon into the prepared tin. Chill for 3 to 4 hours.
Remove the cheesecake from the tin when set. Warm the marmalade, mandarin slices and ginger together in a small pan then carefully tip over the cheesecake and chill again before serving.
For best results allow to chill for 4 hours.
Tell us about it.Upload your recipe
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domain: food


The V12 Vantage was an unprecedented engineering achievement. Combining a V12 engine with the lightest Aston Martin sports-car in a package of pure aggression.
15kg lighter than V12 Vantage. 573PS of power. 620Nm of peak torque. With enhanced low and mid-range power the new-generation AM28 engine pushes the V12 Vantage S to a top speed of 205mph, creating the fastest series production model we’ve ever made.


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Camere da letto
In Primo Piano
Regole della casa
Feste/eventi non ammessi
Politica di Cancellazione
Non è previsto nessun rimborso per cancellazioni fatte quando il pagamento è già stato effettuato.
Great location for watching the northern lights. Good proximity to the sights on the southern side!
Awesome house for our group of six! The owner supplied us with a 20 page guide to the sights you don’t want to miss while in Iceland. Without this, I’m sure we would have missed some things!
Overall, awesome experience. The house was a perfect location for our trip. We took the advice of the homeowner who sends a guidebook to help plan some of our day trips. Saw the northern lights our first night there while enjoying the hot tub & bottle of sparkling wine left by the homeowner.
Very clean lovely home with all the amenities. In fact, the homeowners go above & beyond to make your trip enjoyable. Would highly recommend.
very relaxing stay
This house was ideal for our Family trip to Iceland. Peaceful surroundings, all the most important sights of the golden circle (and more besides) easy to reach and enough space for everybody (7 persons/ 3 generations). We especially liked "our" own hot tub and the Barbecue.
Thanks for this Relaxing Holidays.
A most wonderful cabin stay for enjoying Iceland
From beginning to end everything was excellent. Communication, cabin, convenience, and hospitality.
It was a birthday trip and we arrived to a very thoughtful message and a bottle of lovely Prosecco in the fridge. Not to mention a few Icelandic delicacies. Such a lovely arrival and thoughtful gesture. The cabin itself is full of character, warmth, and good energy. It could not have been better.
All I can say is do not think twice about staying at Stefan & Helga’s cabin. They each were so thoughtful and responsive whenever we had any needs.
If you want a comforting, quiet & comfortable place to stay on your trip to Iceland, you now know where to stay.
Great location; lovely home by lake w/2.5 baths & hot tub
We thoroughly enjoyed our stay! It felt as though a good friend had opened their
vacation home to us. This refined cabin has interesting personal souvenirs around, but because it’s not someone’s main residence, we (Mom, Dad & teen) felt much more comfortable than when we've stayed at an AirBnB with the homeowners’ personal effects everywhere.
It was perfect for our needs: we wanted to experience Icelandic life more than from a hotel, we wanted more scheduling freedom, and we wished to be closer to the Golden Circle- those 12 hour tours from Reykjavík were so unappealing. So we rented a car and house, shopped in grocery stores, cooked some meals, did laundry (reducing our travel clothing by half) and were closer to the main attractions. (Driving is as in America, on the right, driver’s seat on the left.) We were even greeted with some classic Icelandic foods upon our arrival with descriptions-what a perfect touch! Just the sort of experience we were looking for.
The wooden (even the ceilings!) home is lovely and spacious The pictures do not do it justice. There’s an eat-in kitchen with an induction cooktop and combo microwave/ convection/conventional oven ( fascinating), good-sized den with sofas, table & satellite TV, & a large dining room table. The teen’s bedroom was just a bed and dresser, but there are ample rooms for spreading out - there’s a Florida room, a large sitting room off the MBR, a game room with a table and a glass ceiling( for watching the Northern Lights?), and a delightful small loft playroom for little ones upstairs. The master has a beautiful nice-sized en suite bathroom with a vanity, seat & magnifying mirror, plenty of counter/cabinet space for stuff, a shower with detachable head. We appreciated 2.5 bathrooms. The laundry room w/ W/D has a counter for folding clothes. We had a relaxing experience in the hot tub on a cold night seeing thousands of stars!
One day our plans through, so we zipped to Reykjavík ( about an hour’s drive) and visited the Perlan Museum. The home is also about an hour away from Gullfoss waterfall. Vík is about 2 hours away . We definitely preferred going on half day trips on our own schedule. We stayed at the home 5 nights.
I will say that we when we first were driving to the home that we did not follow the directions to a T, and had to backtrack a bit. The house itself is not directly off the highway. Once we got there and put the house on our GPS, we were fine.
Beautiful home and location!
This house was perfect for our group of 6 adults.. would be great for families as well. The location was perfect for day trips around the southern region or to Reykjavik.
This house has so much charm and character and sits on a beautiful lake. The hot tub was wonderful and made a perfect viewing place to watch the Northern Lights which made a grand appearance on our last night!
Helga and Stefan were easy to reach when we had questions and were very accommodating. Our group members all highly recommended this home for Iceland vacations.

domain: travel


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R o b e r t = G i b b i n g s - - 1 8 8 9 - 1 9 5 8
Established in a career as an illustrator and printmaker, Gibbings' purchase and directorship from 1924-33 of the Golden Cockerel Press was of profound importance to the evolution of English 20th-century book design. He controlled every detail of the design and manufacture of seventy-two books. Forty-eight were illustrated with wood engravings, nineteen by his work, nine by Eric Gill, and the balance by thirteen other artists. Gibbings continued his prolific
output as a freelance engraver and in 1938 was made art director for the Penguin series of illustrated Classics. In this position he commissioned work by the leading wood engravers of the period. His own later wood engravings may be seen in books such as Sweet Thames Run Softly (Dent 1940), Coming Down the Seine (Dent 1953), Till I End My Song (Dent 1957).
Edition 200. Signed in pencil and initialed in the block, lower right.
Image size 9 x 8 1/2 inches (228 x 216 mm); sheet size 14 x 11 1/2 inches (356 x 292 mm).
A fine, black impression, on cream Japan, with full margins (1 1/2 to 3 inches). Glue remains in the top left and right sheet corners, verso, well away from the image, otherwise in excellent condition.
The 1936 Presentation Print of The Woodcut Society of Kansas City. Illustrated in James Swann: In Quest of a Printmaker, Czestochowski, 1990.
Collections: British Museum, Nelson-Atkins Museum of Art.

domain: artistic


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Sarajevo forward Matthias Fanimo has trained his sights on a Celtic revenge mission.
The English-born star is desperate to right wrongs from last season’s Champions League qualifiers following two defeats from Celtic over two legs.
The 26-year-old scored the winning goal for his side in the last round of Europa League qualifying as they dispatched Montenegrin champions Buducnost Podgorica.
Celtic made light work of the Bosnians in 2019 but Fanimo is buoyant heading into Thursday's clash.
He said: “It is going to be a very good game. The club played Celtic last year twice, over two legs, and obviously lost both games, but it is a new season, and anything can happen.”
Sarajevo have won five on the bounce following their exit from this year’s Champions League qualifiers at the hands of Belarussian champions Dinamo Brest, bagging 14 goals along the way.
And Fanimo is confident his sustain will sustain that impressive form when the Premiership champions come to town.
He said: “It’s a new team here compared to the one from last season and everyone is pretty confident going into this game against Celtic.
"My own confidence levels are really good going into the game and it will definitely be a good test for myself going up against this calibre of opposition.”
His goal in the last round saw him take his tally to three goals in ten matches this season and Fanimo would love to knock in the winner against Celtic on Thursday.
He said: “It would be amazing to score the winning goal again.
"But it would be equally as special if any of the lads scored the winner that took us through to the Europa League group stages, I honestly would be just as happy.
"A win against Celtic would just mean everything to the players. After the last round everyone was just so ecstatic and over the moon, hopefully we can use the confidence from the win in the last game and really go and do something in this match.”
Regarded as one of the quickest footballers in Europe, Fanimo’s speed is something Celtic must be wary of come Thursday night.
Indeed, he once clocked a pace recorded as one of the 10 quickest ever seen on a football pitch, placing him in esteemed company alongside the likes of Kylian Mbappe.
But, as Fanimo is quick to stress, there's much more to his game.
He said: “That is a strong attribute to my game, but I do have many other attributes alongside my pace.
"Hopefully, we can use my speed to our advantage throughout the match on Thursday to try and exploit Celtic.”
The Bosnian FA allowed for Sarajevo’s match at the weekend to be postponed for extra preparations going into the game against Neil Lennon’s side.
Fanimo is hopeful the extra rest and work on the training field will prove the difference after the whistle blows.
He said: “Hopefully, it pays off. In the last month or two we have been completely slammed with games every three days, so this is the first time we have had a longer break in between matches.
"It will be interesting to see if the decision pays off but for us, I hope that it is to our advantage and it pays off well.”
Playing for AFC Hornchurch in 2018, Fanimo took a leap of faith in his career when opportunity arose on the continent.
He ditched the UK to ply his trade across Europe, initially in Slovenia and now Bosnia.
Fanimo admits there was a tricky settling in period but now feels the move is starting to pay off.
He said: “I had quite an interesting transition period where I went from the seventh tier in England to Slovenia.
"I had to adjust to moving to another country and getting back into the swing of full-time football.”
Fanimo has enjoyed his spell in Europe so far and is confident he made the right choice.
He said: “So far it has been really good, I've got no complaints at all about playing in Europe. Hopefully, for myself personally, more good things come from being out here.
"When I left West Ham and I had so many injuries there, a lot of clubs were reluctant to take the chance on me. A fresh start was definitely needed.”


Custom designed for clients, this rock cutter comes in various sizes to cut samples of any shape.
- 3 phase, 10 hp motor, 36 inch blade.
- SS Clamp with 18 anchor points for holding sample of any shape.
- Hand wheel operation for operator safety.
- Can cut up to 1 ft x 1 ft x 1 ft sample size.
- Circulating fluid tank which provides the blade with lubricant.
Geological samples and thin sections need to have their surfaces polished to ensure that the features are seen clearly.
- 1.5 hp motor with variable speed from 100 – 900 rpm
- Dual wheels – customized grit size
- Recirculating fluid tank for coolant.
- Removable bottom tray for easy cleaning
- Stainless steel construction to prevent rusting.


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This is the third year the gala will be held at the Circus Club. For many years, the league's major fundraiser was a garden tour. The difficulties of staffing and finding homeowners willing to open their gardens to the public led members to look for a new format, which has proved a winner.
Andrea Palmer of Menlo Park and Jane Hartman of Burlingame are co-chairs of this year's gala, which begins at 5 p.m. During the cocktail hour, guests will visit tables with floral displays for sale, as well as auction items, ranging from "secret packages" to gourmet dinners in private homes. A mime and strolling musicians will add to the Parisian atmosphere.
During dinner in a "Paris Bistro," a live auction will feature such items as a photographic safari in South Africa.
Proceeds from the event benefit the San Francisco Symphony and its education and community outreach programs, including "Concerts for Kids." For 22 years, the league's docents have prepared students in the second- and third-grade in the Ravenswood School District with weeks of music listening and training before attending "Concerts for Kids" performed by the San Francisco Symphony. The children's concert tickets and bus transportation are paid for by the Mid-Peninsula League.
Tickets to the benefit are $190 per person with reservations due by May 10. For more information, call 321-3718.


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About Bear Trap
This is the novel the FBI and CIA don’t want you to read. After being delayed for over a year it’s finally available.
Tonight, ruthless Russian Spetsnaz soldiers are marauding the Alaskan wilderness killing everyone who has the misfortune to stumble across their path. Why have they violated America’s sovereignty?
About the Author
Bob’s career path has been one of service. After college he flew helicopters for the Marine Corps in Asia. Then he became a police officer. After 9/11 he joined the Guard and flew in OIF II. While there he accepted an intelligence officer position with NGA. Now he uses those experiences to inform his writing.
About Hope Is Dead
Murder has come to Mayberry! Bodies are dropping in this sleepy backwater county. After the Sheriff’s only detective is found dead in a burned-out trailer it’s up to new Deputy Zack Goodson and his training officer, Mark Langford, to stop this vicious unknown predator before he destroys more innocent lives.
Latest Blog Post
Thank you for taking the time to read a little about me and my books. I have always loved reading military and police thrillers and action/adventure novels. When I was in high school, I was a member of the Military Book Club. I read everything I could get my hands on about military pilots…Read More


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Klépierre, the European pure play leader in shopping centers with more than 100 malls in 16 countries, has received two MAPIC Awards at the 22nd MAPIC Awards ceremony, which took place during a gala dinner at the Palais des Festivals in Cannes. Klépierre’s Hoog Catharijne extension was named “Best Urban Retail Project” while the Group’s Prado mall, to open next year in Marseille, garnered “Best Futura Shopping Center.”
Created in 1996, the MAPIC Awards reward excellence, innovation and creativity in the retail real estate industry, recognizing the finest retailers and retail real estate projects. Winners are selected by an independent international jury of retail real estate professionals, which, this year, was presided by Primark Property Director, Tom Meager.
“It is a source of great pride for Klépierre to have the most prominent professionals of our industry pay tribute to two of our flagship projects this year. Hoog Catharijne embodies our vision of how malls must evolve and get more modern by mixing an unprecedented offer of retail, high street restaurants, offices hosting international headquarters and two hotels. Prado, which is fully integrated in the urban scheme, was designed with the idea of creating a social place marked by a spirit of openness, dynamism and benevolence, in an innovative and iconic architecture,” declared Jean-Marc Jestin, Chairman of the Klépierre Management Board. “I would personally like to express my thanks to the MAPIC Awards jury for this distinction, which is an honor for the whole Klépierre Group. I would also like to take this opportunity to thank all our staff members and partners involved in the winning and finalist projects.”
Source : Company


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Get flash to fully experience Pearltrees
<img src="http://makezineblog.files.wordpress.com/2010/06/banner_diy_wedding.gif?w=629&h=100" width="629" height="100" border="0" alt="CRAFT: DIY Wedding" />
Yesterday you learned about Alexander Calder , his circus, his stabiles, and his mobiles. Today, try your hand at creating a mobile, just like Calder. Supplies Needed: Construction Paper Scissors Hole Punch Thread (or yarn for younger children) Sticks White Glue This is a great project for older kids who are learning about weight and balance, though, with a little help, younger children can also enjoy creating mobile art. Gather your materials.
Alexander Calder mobiles have become popular among modernists and those into modern design, art, and midcentury modern style. There is something extremely compelling in Calder's work, and in the look and style of his mobiles. I cannot take my eyes off the moving art, the arms that gracefully move at the slightest breeze. I am in awe of the peaceful nature of Alexander Calder mobiles, and the hangning mobiles of other artists today.
Edit Edited by Andy, Imperatrix, Jack Herrick, Krystle C. and 12 others The sculptor Alexander Calder said "To most people who look at a mobile, it's no more than a series of flat objects that move.
From the December 1954 issue of Popular Science , "How to make an abstract mobile," instructions which were preceded by "How to Make a Christmas Tree Mobile": You can really express yourself in an abstract mobile. Unlike the Christmas-tree mobile, which is a literal mobile designed to represent a definite object, the abstract mobile gives the builder free rein, unlimited as to size, shape, or mood. The design and balance of an abstract mobile can make it move dreamily, solemnly, or wittily--like the difference between an exuberant fountain and a lazy, meandering stream. From this photo in Hanns Reich's 1962 book Children and their Fathers , it looks like there's at least one dad who really expressed himself: How to make an abstract mobile, Popular Science December 1954 [google magazines via dinosaurs + robots , which has helpfully large scans]
First thing to do is to find the objects that will hang from your mobile... they should be small and light for a simple mobile (although, keep in mind, that there are some really cool mobiles made with huge plates of welded steel)... but to start, keep it simple. For the one I made for my daughter, I used little alphabet blocks into which i sunk a tiny screw-eye (sold for attaching wire to the back of picture frames). For this instructable, I used tea-bags because they were handy. Next thing is to find some hanging wire.

domain: design


How can cities make the best use of CCTV while at the same time guaranteeing individual rights and freedom, particularly in terms of data protection? This was the main theme of the conference organised on February 18, 2011, in Prague (Czech Republic) by the crime prevention department of the Czech Ministry of the Interior, in partnership with Efus. The date had been chosen to coincide with the trade fair on security equipments Pragoalarm/Pragosec, which took place in the Czech capital from February 17 to February 19.
The Interior Ministry had invited around 70 representatives from various cities and regions of the country to discuss issues of data protection. Efus presented its project “Citizens, cities and video surveillance” and the Charter for a democratic use of video surveillance (http://cctvcharter.eu/). Two Efus members and project partners, the cities of Rotterdam and Brno, presented their experience, and explained why they had signed the Charter.
The representatives of the Czech Office for personal data protection, Dr Miroslava Matusova , expressed her satisfaction with the Interior Ministry’s decision to hold the conference. She also voiced her support for Efus initiative in favour of a responsible use of CCTV, stressing the importance of data protection. She said that much efforts had already been made to guarantee protection, but that much remained to be done.
The Czech Republic has heavily invested in video surveillance since 1996, with 173 cities being now equipped thanks in large part to state funding. Public financing is still available to cities wishing to install a CCTV system. However, the official in charge of CCTV at the Interior Ministry, Tomas Konicek, said that public financing depends on the type of system chosen by applicants, and in particular the guarantees it offers in terms of data protection. “Keep in mind these issues,” he said. “They are necessary when designing your system and when applying for national funds.”
Indeed, the guidelines for applicants issued by the Czech Interior Ministry go beyond the guarantees required by law. For instance, cities must submit a thorough analysis of their security issues, demonstrate why they deem CCTV necessary, and detail for which purpose.
The conference also focused on the overall efficiency of video surveillance, with many speakers stressing that it is not a “magic bullet”, but merely a tool among others. There was a unanimous consensus on the importance of taking into account the human factor, and of accompanying any CCTV system with a coherent set of preventive measures.
The experience of the cities of Brno, Sokolov, Zlin (Czech Republic), and Bratislava (Slovakia) were presented, raising other issues such as citizens’ participation in prevention schemes, technical requirements, CCTV operators’ training, and follow-up procedures when an incident is detected.
Efus is confident that this conference will encourage more Czech cities and regions to join their European counterparts who have already signed the Charter for a responsible use of video surveillance.
All the documents of the conference will be available shortly for download at this link to the Czech Interior Ministry’s website.


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The Ironic Elements of Ovid’s Metamorphoses
Ovid’s Metamorphoses is one of the greatest works of early Roman literature. Consisting of 15 books, Metamorphoses tells the stories of the myths of creation in early Roman and Greek culture. The work has been very influential in western literature and art, with many later authors and artists referencing or alluding to Ovid’s tales.
The Metamorphoses is often lauded for its poetic style, which is highly descriptive and lyrical. This, combined with the element of surprise in many of the stories, creates a work that is both beautiful and entertaining. However, beneath the surface there are also a number of ironic elements at play. In this essay, I will discuss three of the most prominent examples of irony in Metamorphoses: Ovid’s view of love, the use of humor, and the transformation theme.
2. Ovid’s Metamorphoses: main characteristics
2.1 Characteristics of the work
Ovid’s Metamorphoses consists of 15 books, each containing a number of shorter poems or ‘episodes’. The episodes are often connected by common themes or characters, but they can also stand alone as individual tales.
The work as a whole covers a wide range of topics, from the beginnings of the world to the deification of Julius Caesar. However, a large portion of Metamorphoses is devoted to stories about love, often featuring gods and mortals as lovers. These stories frequently end in tragedy, but they are also interspersed with moments of comedy and light relief.
2. 2 Themes
The Metamorphoses deals with a number of important themes, including love, religion, and mortality. However, one of the most significant themes is transformation. This is evident not only in the many stories about characters undergoing physical transformations, but also in the way that Ovid uses transformation as a metaphor for other forms of change such as aging or death.
2. 3 Style
Ovid’s style is highly poetic and descriptive, making use of metaphors and similes to bring his stories to life. He also employs a great deal of wordplay, which helps to create an atmosphere of light-hearted fun amidst the more serious moments. For example, in the story of Pygmalion and Galatea (Book X), Ovid describes Pygmalion’s statue as being ‘like a real woman…but more beautiful’ (X.185-186). This play on words highlights the contrast between art and reality that is at the heart of the story.
3. The ironic elements in Metamorphoses
3.1 Ovid’s view on love
One example of irony in Metamorphoses can be found in Ovid’s attitude towards love. Although he frequently writes about love affairs between gods and mortals (such as Jupiter and Europa or Apollo and Daphne), he never idealizes these relationships. On the contrary, he often emphasizes the negative consequences that can result from loving someone who is too far above or below you in terms of social status or power.
For instance, in the story of Pygmalion and Galatea (Book X), Pygmalion falls in love with a statue that he has carved himself. Although his love is eventually reciprocated by the statue (who is transformed into a real woman), their relationship is ultimately unhappy because Pygmalion is unable to accept her as an equal. Similarly, in the story of Orpheus and Eurydice (Book XI), Orpheus goes to the underworld to try and rescue his wife from the clutches of death. However, he fails in his task and ultimately loses her forever.
Ovid’s emphasis on the negative aspects of love is ironic because it contradicts the popular view of love as a positive force that can overcome all obstacles. By presenting love as a source of pain and suffering, Ovid highlights the darker side of this emotion.
3. 2 The use of humor
Another example of irony in Metamorphoses can be found in Ovid’s use of humor. Although the work contains many light-hearted moments, these are often undermined by an underlying sense of irony or mockery. For instance, in the story of Midas and Saturn (Book XI), Midas is granted the power to turn anything he touches into gold. However, this gift quickly turns into a curse when Midas discovers that he can no longer eat or drink. In the end, he has to beg for Saturn to take back his ‘gift’, highlighting the foolishness of Midas’ greed.
Similarly, in the story of Daedalus and Icarus (Book VIII), Daedalus uses his ingenuity to fashion a pair of wings made out of wax. He then escapes from imprisonment on Crete by flying away with his son Icarus. However, Icarus gets too close to the sun and his wings melt, causing him to plunge to his death in the sea below. This tragic ending serves as a warning against over-reaching oneself and highlights the dangers of hubris.
3. 3 The transformation theme
The final example of irony in Metamorphoses can be found in the way that Ovid uses transformation as a metaphor for other forms of change. Although transformation is often presented as a positive force (for example, when Zeus transforms Io into a cow to save her from Hera’s wrath), it can also have negative consequences (such as when Dionysus transforms Pentheus into a wild beast as punishment for his lack of faith).
This ambivalent attitude towards transformation is evident in the story of Echo and Narcissus (Book III). Echo falls in love with Narcissus, but he rejects her because he only loves himself. As punishment, Hera transforms Echo into a being who can only repeat the words of others. However, this transformation ultimately leads to Echo’s downfall because she is unable to declare her love for Narcissus before he dies. In this way, Ovid suggests that transformation can be both a blessing and a curse.
In conclusion, Metamorphoses is a work that is full of irony. Ovid’s view of love as a source of pain and suffering, his use of humor to highlight the dark side of human nature, and his ambivalent attitude towards transformation all serve to create a work that is both thought-provoking and entertaining.

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Morphology changes induced by laser irradiation on disperse red 13 films prepared by physical vapor deposition
(Synthetic Metals, 2003-04-04) [Trabalho apresentado em evento]
Surface morphology changes induced by argon laser irradiation (514 nm) on disperse red 13 (DR13) films prepared by physical vapor deposition (PVD) were investigated. Atomic force microscopy was used to characterize the ...

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Women’s Hockey vs. Minnesota State Mankato Mavericks
Maria Stoa, Contributing Writer
October 14, 2011
Filed under Sports
Colonials (2-0) Mavericks (3-1)
Robert Morris and Minnesota State are meeting for only the sixth time in the Colonials history, and the women’s hockey team is 2-2-1 against the Mavericks all time. The last time they played against Minnesota State, it was on December 3, 2011 and RMU won 2-1. Assistant captain, Brianna Delaney had a goal and an assist.
The next day, on December 4, 2011, the two teams tied 2-2 after an overtime period was played. Brianna Delaney again contributed, this time with a two-goals in the game.
The Colonials are off to a great start as they got their 2011-2012 season started with a weekend sweep over Lindenwood, and outscored their opponent in two games by a total of 15-2. Many players had a multipoint weekend, with freshman Rebecca Vint scoring 3 goals and adding 2 assists, and Freshman Katie Fergus also scoring 3 goals and contributing 2 assists.
Sophomore Thea Imbrongo had one goal and three assists, while junior Cobina Delaney had two goals and two assists. Senior assistant captain Brianna Delaney had 2 goals and 2 assists.
“It was a good weekend, and many players got points,” Brianna Delaney explained. “The scoring was not all coming from the same group of people.”
MSU is off to a great start as well on September 30 MSU got a win against Lindenwood University. It was a close game but MSU came out on top with a 4-3 win.
The next day MSU also earned a home sweep against Lindenwood winning 10-2. On October 7, forward Nicole Germaine’s first goal of the season couldn’t have came at a better time as she put a rebound away with 49 seconds left in overtime, giving MSU the 3-2 win over eighth-ranked Mercyhurst. The win improved MSU’s record to 3-0.
On October 8 MSU’s winning streak was snapped against Mercyhurst after a goal was scored with two minutes remaining in the game, which gave the Lakers a 5-4 win over MSU.
Not only is RMU looking to keep their winning streak going and improve upon their 2-0 record but Brianna Delaney will be looking to break the all time point record in RMU women’s ice hockey history. Sara O’Malley was the all time point leader with 97 points, however on October 8, 2011 vs. Lindenwood University Brianna Delaney scored two goals and added one assist bringing her to 97 points.
Her teammates are excited for her to accomplish this milestone.
“It is really exciting that Bri is going to break the record at the beginning of her senior year when Sara only broke it her last few games of her senior year,” explained senior Captain, Paige Pietrangelo.


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Fiction Workshop — Susan Gregg GilmorePosted: March 8, 2009
The 7th Council for the Written Word Spring Fiction Workshop is now one for the history books. Lingering, however, are a few memories and tidbits that I hope to hold onto. First of all, the image in my mind of the venue — the Westview Clubhouse — it was beautiful … something out of a Southern movie … tall, expansive, white, with columns and gardens and oak floors that look ancient, but they’re not. Our workshop was held in Townsend Hall, upstairs. Secondly, it did my heart good to see Bill Peach carrying out the trash afterward and Jim Taulman vacuuming the burgundy carpet in that huge room. Once again, Susie Dunham made magic with two 8-foot tables; she filled them with Krispy Kreme doughnuts, trail mix, and a silver platter of red and green grapes … and also a mix of Gerbera daisies. Currie Powers, Susan Lentz, and I waved our wands to put the other details in place, and Laurie Kay made name tags that matched the cover of our speaker’s book — Looking for Salvation at the Dairy Queen by Susan Gregg Gilmore.
Some words of wisdom for writers from Susan:
You must spend TIME IN THE CHAIR. When you spend time there, the story takes you over and fills your head. Maybe you’ll write, maybe you’ll just think. Doesn’t matter. Spend time in the chair.
Susan’s journalism experience helped her to tell a story in a tight space, to know the importance of word choice, to use words that pull the reader in quickly, to know the importance of editing.
Write … edit, edit, edit … then it begins to sing.
First impressions matter, matter, matter. The first sentence should captivate the reader.
Think about how you can paint your story for the reader.
Four dozen writers. A speaker with a heart for her art. A good workshop.