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4th Principal Investigators Meeting Abstracts
4th Principal Investigators Meeting
Innovative Molecular Analysis Technologies Program
June 16-18, 2003
Hilton San Diego Resort
San Diego, California
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Daniel Kenan, M.D., Ph.D.
Duke University
Differential Gene Expression in Endothelial Cells by RNP-tag Analysis
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Daniel J. Kenan,1 Barbara D. Lipes,1 Luiz Penalva,2 Christopher D. Kontos,3 and Jack D. Keene2
1Department of Pathology, 2Department of Molecular Genetics and Microbiology, 3Department of Cardiology, Duke University Medical Center
Despite the central role of endothelial cells (ECs) in cancer biology, relatively little is known about the molecular perturbations that occur in tumor endothelium and their relationship to disease. Tumor ECs are particularly difficult to study because their behavior is influenced by characteristics of the tumor microvascular environment that cannot be recapitulated ex vivo, including EC functional interactions with adjacent stromal and tumor cells and their dependence on blood flow and extracellular matrix for stable differentiation. This project seeks to develop a robust technology platform enabling analysis of tumor EC gene expression within native tissues. The technology is based on the ability to co-immunoprecipitate RNA binding proteins together with their associated mRNA species from cell and tissue extracts. The primary implementation of the technology will engineer a transgenic mouse expressing an epitope-tagged poly(A) binding protein under control of an endothelium-specific promoter. Anti-epitope tag antibodies can then be used to recover endothelium mRNAs from both normal and tumor transgenic tissue extracts. Recovered mRNAs can be detected and quantitated in high-throughput fashion using microarray technologies. In addition, the mRNAs will be used as input for construction of SAGE and EST libraries that will serve to validate the microarray data as well as to guide the construction of EC-targeted custom microarrays. Human homologues will be identified for any genes that are differentially expressed in murine tumor endothelium, and the homologues will be validated for specificity of expression in human tumor endothelium. The technology will be used to study murine and human EC gene expression in a variety of tumors and normal tissues across a range of anatomic sites. Detected alterations in tumor EC gene expression that may affect disease progression or that can serve as diagnostic markers or therapeutic targets will be validated in ECs from different tumor and tissue types. This project will generate reagents, information, and technologies that are likely to lead to improved detection and treatment of cancer.
Gerard McGarrity, Ph.D.
Intronn, Inc.
Real-Time in vivo Imaging of Gene Expression by SMaRTTM (Spliceosome Mediated RNA Trans-Splicing)
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M. Puttaraju,1 S. Bhaumik,2 L.G. Mitchell,1 G. McGarrity,1 G. Temple,1 and S.S. Gambhir2
1Intronn Inc., and 2The Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, UCLA School of Medicine
Objectives: Spliceosome-mediated RNA trans-splicing (SMaRT) is a novel technology to reprogram genes at the level of mRNA splicing. We have previously reported imaging of gene expression in live cells and animals by trans-splicing of a bioluminescence reporter gene, synthetic Renilla luciferase (hRluc) (AMI, 4:S17, 2002). Here, we report our recent developments to improve the efficiency of SMaRTTM for real-time imaging.
Methods: To measure the maximal level of signal generated through RNA trans-splicing, different sizes of hemi-reporter "mini-gene targets" consisting of a part of the hRluc sequence as "5' exon" coupled to the coding sequence for human papilloma virus (HPV16) E7 and the intronic sequences immediately upstream were constructed, here referred to as HPV-LucT. Two pre-trans-splicing molecules (PTMs) were engineered, consisting of a "binding domain" complementary to the HPV-LucT followed by 3' splice elements (branch point sequence, polypyrimidine tract, and acceptor AG dinucleotide) and two different lengths (255nt and 50nt) of hRluc sequence as a "3' exon." Transient transfections of N2a/293T cells were done with appropriate combinations of HPV-LucT and PTMs capable of regenerating, via trans-splicing of 5' and 3' hRluc exons, the active luciferase. Recovered luciferase (hRL) signal was measured using cell extracts and a luminometer. Confirmation of intact hRluc mRNA and protein was further assessed with RT-PCR and Western blotting.
in vivo delivery of different PTMs were performed by tail vein injection of transferrin-polyethylineamine (Tf-PEI)-PTM complexes (Mol. Ther. In Press) into nude mice (N=2) bearing transiently transfected HPV-LucTN2a cells (5x106 cells) implanted subcutaneously. The mice were imaged 24 hours later, using a cooled charge-coupled device (CCD) camera (PNAS 99:377-382, 2002) after tail vein injection of the substrate coelenterazine (60 µg/mouse). Control tumors consisting of N2a cells (5x106 cells) were implanted in the same mice.
Results: Cis-splicing of HPV-LucT3 produced no detectable luciferase signal in cell culture. Depending on the PTM exon size, we obtained ~5-15% restoration of hRluc. Smaller PTMs repaired HPV-LucT more efficiently and showed significantly (P0‹.05) higher hRL activity than larger PTMs. Statistically significant (P‹0.05) signals were also generated in vivo from HPV-T3N2a-implanted cells (6.9E+03 p/s/cm2/sr), in comparison to control N2a implanted cells (3.0E+03 p/s/cm2/sr) in the same mouse, when imaged under cooled CCD camera.Conclusions: These results indicate that variations in size of the 3'-hemireporter gene within a PTM can significantly influence its trans-splicing efficiency, both in vitro and in vivo . We have shown previously that variations in size and sequence of PTM binding domains, as well as in choice of PTM 3' splice elements, can markedly affect the efficiency and specificity of the trans-splicing reaction (Mol. Ther. 4:105-114, 2001). These results taken together indicate that multiple features of a PTM are potentially important in trans-splicing reactions. We are currently developing a high-throughput genetic screen to discover and define the most optimal combinations of PTM elements for molecular imaging and therapy.
Further, this study demonstrates the feasibility of imaging of mRNA repair, both in vitro and in vivo . This approach should eventually allow imaging of endogenous mRNA in living subjects, potentially imaging the expression of a wide variety of endogenous genes.
Alvin Beitz, Ph.D.
University of Minnesota
Use of 2-D Gel/Mass Spectrometry and Oligonucleotide DNA Microarrays To Study Tumor Protein Production in vivo and in vitro
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Alvin J. Beitz, Mary Baddorf, and Daryl Hoskins
Department of Veterinary Pathobiology, University of Minnesota
Our lab is interested in determining what factors are secreted by tumors in vivo and how tumor cells change when they grow in an in situ environment as compared to an in vitro culture. To study this we have developed an in vivo microperfusion procedure to directly sample tumor secreted proteins and peptides in a mouse hindpaw fibrosarcoma model. We are comparing samples of tumor secreted proteins isolated in vivo with those found in tumor homogenates and with those isolated from tumor cells in vitro . Proteins in microperfusion or homogenate samples are isolated on 2-D gels and subsequently trypsinized and identified using mass spectrometry. Early results on homogenates of the foot tumor show that while the 2-D gel electrophoresis is going very well, the MALDI-TOF identification of proteins remains unreliable at the present time. Because of the limitations we have encountered with MALDI-TOF, we are currently starting to utilize MALDI-MS/MS and ESI-MS/MS procedures rather than MALDI-TOF in order to increase the reliability of protein identification.
In addition mRNA is being isolated from tumor cells in vivo and in vitro and message expression analyzed using Affymetrix microarrays. We have found a number of tumor cell mRNAs that are significantly up-regulated in vivo compared to the cells in culture. These include P lysozyme; cathepsin S; chemokine receptor 5; small inducible cytokine B subfamily, member 9; guanylate nucleotide binding protein 1, Fc receptor, IgG low affinity Iib; and transforming growth factor, beta-induced, 68 kDa; and chemokine receptor 1. Additional genes that were up- or down-regulated will be reported at the meeting. By comparing mRNA expression with protein expression, we hope to elucidate the effects of the tumor environment on protein production and secretion.
David Morris, Ph.D.
University of Washington
Translating a Transcriptome: High-Throughput Analysis of mRNA Translation
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David R. Morris,1 Vivian L. MacKay,1 Xiaohong Li,2 Kyle A. Serikawa,1 Xie L. Xu,2 G. Lynn Law,1 Lue Ping Zhao,2 and Roger Bumgarner3
Departments of 1Biochemistry and 3Microbiology, University of Washington; and 2Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
A transcriptome provides the database from which a cell assembles its unique collection of proteins. However, translation of individual mRNA species into their encoded proteins can be regulated, sometimes resulting in discordance between the level of an mRNA and the abundance of its protein product. We have developed a methodology, translation state array analysis or TSAA, that simultaneously assesses the level of an mRNA and its association with the translational machinery. Detailed descriptions through TSAA of the translational behavior of 4931 transcripts of Saccharomyces cerevisiae show that, indeed, there is a striking diversity across the constellation of mRNA molecules. Transcripts of different genes can vary from complete engagement with polysomes to total sequestration in mRNP particles. Of those mRNAs primarily located in polysomes, the average ribosome spacing on the message can vary by more than an order of magnitude. Thus, this spectrum of translational behavior provides an extraordinary dynamic range of regulation, exclusive of actual transcript levels. These diverse translational properties do not show a strong correlation with global mRNA properties such as transcript abundance, codon bias, initiator AUG context, or estimated lengths of the untranslated regions. For example, abundant mRNAs tend on average to be better translated than the population as a whole, but some representatives of this class, such as the mRNA products of GCN4 and HAC1, are located only to a minor extent in polysomes. On the other hand, low-abundance mRNAs often localize greater than 90% in polysomes, examples being the CDC28, CLB3, and ADE1 products. These results are consistent with each mRNA having its own set of unique structural properties that confer its specific translation activity. The information garnered from this analysis allows one to estimate relative rates of protein production across the transcriptome and provides new insights into this additional level of gene expression control.
Zuyi Wang, Ph.D.
Catholic University of America
Machine Learning for Molecular Analysis of Cancer
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Yue Wang,1 Zuyi Wang,2 Javed Khan,3 Robert Clarke,4 Junying Zhang,5 and Jianhua Xuan5
1Virginia Polytechnic Institute and State University, 2Children's National Medical Center, 3National Cancer Institute, 4Georgetown University Medical Center, 5The Catholic University of America
The challenge of cancer treatment has been to target specific therapies to pathogenetically distinct cancer types, to maximize efficacy, and to minimize toxicity. However, cancers with similar histopathological appearance can follow significantly different clinical courses and show different responses to therapy. The recent development of gene microarrays provides an opportunity to take a genome-wide approach to predict clinical heterogeneity in cancer treatment and potentially discover new diagnostic and therapeutic targets. Such global views are also likely to reveal previously unrecognized patterns of gene regulation and generate new hypotheses warranting further study. This talk will first present our comprehensive framework aimed at developing a statistically principled, model-supported, and visually insightful machine-learning approach for microarray gene expression data analysis. The discussion will then focus on pheno/gene cluster discovery by VISual Data Analyzer (VISDA) and pheno-classification/ prediction by adaptive multilayer perceptron neural networks (wFC-DCA-MLP).
Dale Larson, M.S.
Harvard Medical School
Surface Plasmon Enhanced Microscopy; A New Technology with Optical Resolution of 10 nm
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Dale Larson
Harvard Medical School
SPEM is a new scanning microscopy technology with optical resolution that rivals electron microscopy. SPEM is based on a novel photonics device invented in the Technology and Engineering Center at Harvard Medical School that produces a small, bright source of propagating light. The device acts as a "photonic funnel"; light is collected over a large area (relative to the aperture) and is emitted through the aperture with an effective concentration of approximately 3X (300%). The device can be produced to provide either a single light source or an array of independent light sources. Devices are currently being fabricated with 35-nm to 150-nm apertures, and apertures around 5-nm to 10-nm are expected in the near future.
This photonics device forms the basis for a new scanning microscopy technology, SPEM, where an array of nanometric light sources illuminate a sample to excite fluorescently labeled molecules. The coordinates of the fluorescence are recorded and the device is stepped (step size on the order of the aperture size) over one position and fluorescence is excited and recorded again. When the scan is completed the coordinates where fluorescence was measured are used to assemble an ultra-high-resolution image. The first application of SPEM will be for tissue samples embedded in either OCT or paraffin. Multi-spectral imaging using either quantum dots or fluorophores is enhanced with SPEM because the small excitation area dramatically simplifies deconvolution of emission spectra from multiple sources by limiting the number of labeled molecules that can be in the small area.
Advantages of SPEM include:
- Resolution of <=50nm, and possibly down to 5-nm
- Fast scanning due to the array format (using a hexagonal array with ~1,000 to 10,000 apertures)
- Fast scanning due to increased irradiance
- Reduced background fluorescence because only a fraction of the sample is illuminated for each step
- Compatibility with current immunohistochemical practices
- Can be designed as an accessory to existing inverted microscopes
Ion image (50kX magnification) of a three-aperture linear array (150-nm apertures with center-to-center spacing of 350 nm). The 2-µm square is used to normalize the emission from the apertures in the array.
Emission from the three-aperture linear array (1.4 numerical aperture oil immersion lens) showing partially collimated light.
Bruce Mayer, Ph.D.
University of Connecticut
SH2 Profiling: Classifying Tumor Cells on the Basis of Global Tyrosine Phosphorylation State
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Kazuya Machida1, Gonzalo Rivera1, Irina Nurieyeva1, Peter Nollau2, and Bruce J. Mayer1
1University of Connecticut Health Center, and 2Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
Signals that regulate cell proliferation, differentiation, and motility are often transmitted via activation of tyrosine kinases, and amplification or mutational activation of tyrosine kinases is often seen in human cancers. Src Homology 2 (SH2) and PhosphoTyrosine Binding (PTB) domains are small, modular protein domains that bind specifically to tyrosine-phosphorylated peptides. Over a hundred different SH2 and PTB domains are known in humans; each of these domains binds to a different spectrum of tyrosine-phosphorylated peptides. We are developing methods that use SH2 and PTB domain binding to probe the global tyrosine phosphorylation state of cells and are exploring whether such patterns can provide the basis for classification of tumor cells.
We have used a far-Western blot-based SH2 profiling method to analyze both tumor-derived cell lines and primary human cancer samples. The method provides a wealth of information and has the potential to serve as the basis for both class discovery and class assignment. It can also highlight specific tyrosine-phosphorylated proteins that correlate with clinically relevant parameters and which can subsequently be identified. Prospective studies are currently under way to profile tumor samples from patients with hematological malignancies and carcinoma of the breast. Over 30 SH2 or PTB domain probes are currently available in the laboratory, and ongoing studies are aimed at further improving the sensitivity of the SH2 domain probes and decreasing background. We have also found that SH2 domains can be used to probe sections of paraffin-embedded, formalin-fixed tumor specimens, opening the door to large-scale retrospective studies to establish whether patterns of SH2 binding significantly correlate with clinical outcomes.
We have also been seeking to develop high-throughput, quantitative SH2 profiling assays that can be used for the rapid analysis of small amounts of tissue. Toward this end we have tested reverse-phase protein arrays, which show promise for quantitating relative levels of SH2-binding sites in large number of samples simultaneously. We have also begun development of a one-tube multiplexed SH2 profiling assay, in which the binding of tens or hundreds of SH2 domains to a protein sample could be quantitated at one time. For such assays, each protein binding domain must bear a unique, quantifiable tag; current efforts involve in vivo biotinylation of probes and their subsequent labeling with unique oligonucleotides tags coupled to streptavidin. Quantitation of DNA-tagged probes can be performed by established PCR-based methods with high throughput. SH2 profiling of tumor samples is expected to allow meaningful classification that will aid in development of therapies tailored to the individual patient.
Martin Stanton, Ph.D.
Archemix Corporation
Nucleic Acid-Based Biosensors as Tools for Cancer Research and Drug Discovery
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Dilara Grate, Anthony Keefe, Chunhua Wang, Jeff Kurz, Thomas McCauley, Scott Lewis, Markus Kurz, Ryan Boomer, Stefan Gross, Sharon Cload, Alicia Ferguson, Nobuko Hamaguchi, and Martin Stanton
Archemix Corp., Cambridge, MA
Current methods that profile genome-wide RNA or protein levels typically do not provide information concerning levels of the actual bioactive forms of proteins in biological samples. The ability to detect post-translational protein modifications, such a protein phosphorylation, represents a significant advance over existing techniques for expression profiling. Archemix has developed a variety of nucleic acid-based biosensors, including aptamers and allosteric ribozymes (RiboReportersTM) that are capable of monitoring the post-translational state of proteins important in the development and progression of disease. We have created both solution-phase and chip-based biosensors for specific, multiplex detection of isoforms of cancer-associated proteins (e.g., MAP kinases, VEGF, IMPDH, bFGF) in complex biological matrices such as serum and cell extracts.
Dan Jay, Ph.D.
Tufts University
Functional Proteomics To Identify Proteins in Cancer Cell Invasion
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Brenda K. Eustace1, Takashi Sakurai1, Jean K. Stewart1,Leodovico Ilag2, and Daniel G. Jay1
1Department of Physiology, Tufts University School of Medicine, and 2Xerion Pharmaceuticals AG, Martinsried, Germany
We have developed a novel functional proteomic screen to identify proteins involved in cancer cell invasion. The screen uses a direct protein inactivation technique named fluorophore-assisted light inactivation (FALI). We have used FALI with both monoclonal (mAb) and recombinant single-chain variable fragment antibodies (scFv) directed randomly against components of the surface proteome of HT-1080 fibrosarcoma cells. These binders were used with FALI to directly inactivate the bound proteins in cells. The cells were then tested for their ability to invade a thin Matrigel layer in an in vitro invasion assay. Antibodies that showed a significant effect on invasion with FALI were used for immunoprecipitation and mass spectrometry to identify the bound protein.
Several interesting proteins have been identified in this screen. These targets include proteins with previously characterized roles in invasion, which act as a validation of our screen, as well as those with uncharacterized roles. One of these proteins that had not been previously shown to function in invasion has been further validated using FALI with commercial antibodies and pharmacological inhibition. We have also begun to elucidate a potential mechanism of action for this validated protein target.
Our findings show novel and important functions for specific surface proteins in cancer cell invasion. Surface proteins are particularly amenable to therapeutic intervention using function blocking antibodies or pharmacological agents, and thus the information from this screen can be directly used to suggest new therapies. This FALI screening strategy also has wide applicability as a method to identify functionally important proteins in a variety of disease processes.
Bernard Futscher, Ph.D.
Univeristy of Arizona
Epigenomic Changes During Leukemia Cell Differentiation: Analysis of Histone Acetylation and Cytosine Methylation using CpG Island Microarrays
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Marcela Nouzova, Nicholas Holtan, Jose Munoz-Rodriguez, Nirav Merchant, Susan Millar, R. Ben Isett, and Bernard Futscher
Arizona Cancer Center, College of Pharmacy, University of Arizona
Aberrations to the normal levels and patterns of 5-methylcytosine and histone acetylation are a common feature of human cancers. These aberrations are known to disrupt the orderly expression of genes and participate in the transformed phenotype. Microarray technology offers an opportunity to measure and analyze these epigenetic changes on a genome-wide scale. To this end, we have sequence-validated a human CpG island library containing 6,800 genomic clones. These sequenced clones were first processed through FAKtory, a configurable, GUI-based software that provides a configurable DNA fragment pipeline of processing stages through which DNA traces must pass. Afterward, finished CpG island sequences were subjected to BLAST analysis to the HTGs, nr, and UCSC DNA-sequence databases. Approximately 5,000 unique clones were identified a vast majority with characteristics consistent with CpG islands. Almost all redundant clones were of mitochondrial genome, or either interspersed or satellite repetitive sequence origin. All clones were arrayed onto glass slides for 2-color fluorescence hybridization experiments that assessed cytosine methylation and histone acetylation states.
To test and validate these CpG island arrays, we used a well-described model of all-trans-retinoic acid (ATRA)-induced differentiation of human acute promyelocytic leukemia cells (NB4). Cytosine methylation and histone acetylation states were determined for normal peripheral blood mononuclear cells, untreated, undifferentiated NB4 cells, and ATRA-differentiated NB4 cells. CpG island microarray hybridization results show that the untreated NB4 cells have increased methylation of their CpG islands compared to PBLs, but ATRA had no detectable effect on NB4 cytosine methylation levels during the differentiation process. Cytosine methylation differences between NB4 and normal peripheral blood mononuclear cells detected by microarray profiling were confirmed by bisulfite sequencing. To assess changes in chromatin structure, DNA isolated from chromatin immunoprecipitations from the various cells were used to probe the CpG island microarrays. While ATRA did not induce changes in genomic methylation levels, it did induce complex changes in histone acetylation throughout the genome of ATRA-treated NB4 cells. First, a number of single copy CpG islands associated with genes displayed increased levels of histone acetylation including the known target, RAR beta. Second, increased levels of histone H4 acetylation were seen in the high copy alpha satellite sequences, suggesting that high copy elements localized to centromeric regions become preferentially acetylated during leukemic cell differentiation. Third, histone acetylation changes observed occurred independently of changes in 5-methylcytosine. Histone acetylation changes detected by microarray profiling were confirmed by ChIP -PCR analysis. In summary, CpG island microarrays can be used to provide a genome-wide assessment of epigenetic changes in cancer and normal cells.
Vincent Gau, Ph.D.
Genefluidics, Inc.
Rapid Molecular Detection of PML/RAR Using Electrochemical Sensorarray
[ Expand Abstract ]
Vincent Gau
GeneFluidics, Inc., Monterey Park, CA
We propose a series of pilot experiments to test the hypothesis that a totally integrated, rapid detection system for the screening of the PML/RARalpha translocation in raw blood samples using a MEMS-based electrochemical sensor array, which is superior in some applications over existing technology. The ultimate goal of these studies is the development of an inexpensive, user-friendly system capable of diagnosing PML/RARalpha translocation cases in less than one hour. The challenge of this task is in modifying the present sensor design and protocol so minor alterations in genetic code can be detected using the ultra sensitive, highly specific sensor array.
Acute promyelocytic leukemia (APL) comprises a distinct subset of acute myeloid leukemia (AML), and represents 10-15% of all AML cases (Stone and Mayer, 1990). In general, patients with APL tend to be younger than patients with other types of AML, with 90 percent of cases occurring between the ages of 15 and 60 (Avvisati et al, 1991). In addition, patients with APL are much more likely to suffer from disseminated intravascular coagulation (DIC) at the time of presentation, which increases the risk of life-threatening bleeding (reviewed in Tallman and Kwaan, 1992). Treatment in the past consisted of chemotherapy, which unfortunately worsened the DIC frequently, and early hemorrhagic death was common. Within the last fifteen years a vitamin A derivative, all-trans retinoic acid (ATRA), has been documented to promptly resolve DIC, and to significantly increase the complete remission rate and overall survival of APL patients (Huang et. al., 1988, Sun et. al., 1992, Castaigne et. al., 1990, Warrell et. al., 1991, Chen et. al., 1991). Additionally, there is evidence that administration of ATRA decreases the incidence of early hemorrhagic death (Visani et. al., 2000).
John Welsh, Ph.D.
Sidney Kimmel Cancer Center.
Vertical Coverage Arrays in Analyzing Transcription
[ Expand Abstract ]
Rosana Risques, Gaelle Rondeau, Martin Judex, Michael McClelland, and John Welsh
Sidney Kimmel Cancer Center, San Diego, CA
Vertical arrays are microarrays whose spotted elements consist of low-complexity representations (LCRs) of mRNA populations from different sources. For example, these LCRs can be made from control and treatment groups, normal and tumor samples, etc. The concept behind the invention is to be able to place thousands of experimental samples on a single chip so that the expression behavior of genes can be explored in response to many variables. LCRs are used to limit the sequence complexity in any single spot, thereby increasing the representation of its member sequences and decreasing background hybridization. LCRs can be made in various ways. We have focused on LCR preparation using RNA arbitrarily primed polymerase chain reaction (RAP-PCR). RAP-PCR works either by subjecting RNA to reverse transcription using oligo-d(T)20, followed by arbitrary priming where arbitrarily chosen primers are used in low-stringency PCR, or by subjecting RNA to reverse transcription with initial use of an arbitrary primer followed by low-stringency PCR. Either strategy samples the mRNA population according to the sequence of the arbitrary primer. With 30 arbitrary primers or primer pairs, it is possible to detect most of the transcripts in a cell. When LCRs prepared in this way are immobilized on a glass slide, they can be hybridized with a fluorescently labeled probe and the resulting fluorescent signal reports the relative abundance of the transcript in the mRNA population from which the LCR was derived. We devised this approach in order to be able to determine the response of several hundred exemplar genes to several hundred drugs, so that we can choose those drugs that are most likely to perturb other genes regulated by the same transcription factor as the exemplars. These drugs will then be used in standard microarray experiments to identify genes that are likely to be controlled by the transcription factor. We have demonstrated the efficacy of the vertical array approach.
Jean-Pierre Issa, M.D.
University of Texas at M. D. Anderson Cancer Center
Methylated CpG Island Amplification for Methylation Profiling of Cancer
[ Expand Abstract ]
Jean-Pierre Issa, Rajan Mannari, and Xuqi Chen
Department of Leukemia, and The University of Texas at M. D. Anderson Cancer Center
DNA methylation within promoter-associated CpG islands is a common mechanism of gene silencing in cancer and targets many critical processes involved in tumor development and invasion as well as DNA repair. Methylation profiling refers to the assessment of the methylation status of multiple genes in cancer. Such profiling is increasingly recognized as useful in tumor classification and identifies biologically and clinically distinct subgroups. In practice, methylation profiling is limited by available technology, and most large-scale studies have focused on a small number of genes. Methylated CpG island amplification (MCA) was developed to overcome such limitations. In this technique, amplicons specific for methylated CpG islands are generated by methylation-sensitive restriction enzyme digestion and ligation of PCR adaptors in the vicinity of methylated islands. This allows amplification of a large number of CpG islands simultaneously (theoretically, 70% of all islands). These amplicons can either be spotted on slides and probed with gene-specific probes, or can be labeled and used to probe filters or slides spotted with a large number of target CpG islands. A limiting step, then, is the identification of specific targets of hypermethylation in cancer.
Using MCA coupled with representational difference analysis, we have been cloning promoter-associated CpG islands in various cancer cell lines. In an initial study, we had isolated 33 clones differentially methylated in colon cancer, but the number and identity of associated genes were unknown. Reanalysis of these using BLAT searches of the most recent release of the human genome sequence identifies 19 sequences that are located in the 5' promoter area of genes. In current MCA/RDA experiments using leukemia and colon cancer cell lines, we have identified an additional 27 promoter-associated CpG islands hypermethylated in cancer. Finally, a preliminary review of genes known to be hypermethylated in cancer revealed 30 commonly inactivated genes, the methylation of which could be detected by MCA, bringing the total of testable targets to over 75. These studies then provide the tools for initiating MCA-based methylation profiling of human cancers.
Jan Schnitzer, M.D.
Sidney Kimmel Cancer Center
Vascular Proteomics: Mapping Targets on Endothelia and Caveolae in vivo for Organ- and Tumor-Directed Delivery and Transcytosis
[ Expand Abstract ]
Jan E. Schnitzer
Sidney Kimmel Cancer Center, San Diego, CA
The future of cancer detection and treatment lies in the development of technologies to facilitate the targeted delivery of drugs and genes specifically to their intended sites of action inside tumors in order to enhance efficacy by creating higher drug concentrations in the tumor tissue while reducing drug toxicity by minimizing exposure to other organs. Unfortunately, the effectiveness of modern anticancer immunotherapy using antibodies against tumor cell surface antigens coupled to toxins has been disappointing because the tumor endothelium effectively blocks access to their intended target sites on the tumor cells. An alternative strategy for the therapy of solid tumors is to target agents to the endothelium of tumor blood vessels rather than to the tumor cells themselves to cause infarction of the tumor by rapid and selective destruction of the vasculature supplying the tumor. A new addition to the vascular targeting strategy that has become apparent from our recent work is the potential utility of a vesicular transport pathway (caveolae) discovered in endothelium for selectively overcoming this key cell barrier to facilitate directed delivery to underlying tumor tissue cells.
We have developed a novel identification technology platform and targeting strategy for discovering accessible in vivo targets in normal and neoplastic tissues. Using novel subfractionation techniques for purifying luminal endothelial cell plasma membrane and caveolae directly from tissue, we have produced in different tumors and tissues high-resolution proteomic maps of the endothelial cell surface directly in contact with the circulating blood. Multiple protein separation techniques coupled with MS and database analysis directly establishes the molecular heterogeneity of this interface among tissues and has produced an extensive database including organ-, tumor- and caveolae-specific protein targets. Antibodies targeting caveolae in a specific vascular bed rapidly accumulate in a single tissue at levels up to 89% of IV dose in 30 min. Immunoconjugates increase tissue-specific drug delivery by 200-fold and allow transcellular delivery to improve localized bio-efficacy.
Subfractionation coupled with MS analysis also unmasks 5 key tumor-induced targets expressed at the endothelial cell surface that are not readily detected by standard proteomic or genomic analysis. Tissue staining with antibodies raised to corresponding peptides confirms tumor induction at the endothelial cell surface of various rat, rabbit, monkey, and human tumors, including lung, prostate, liver, brain, and breast. One target, TE3, concentrates in caveolae and appears quite tumor specific. Biodistribution studies reveals significant accumulation of IV-injected TE3 antibody in solid tumors within 1-2 hours. Gamma scintigraphy using radiolabeled TE3 antibodies injected IV permits rapid visualization of chemically induced primary tumors in rats as well as metastatic rat lung tumors in vivo . Thus, tumors can affect their vasculature to express a distinct molecular signature that can be identified using our novel profiling strategy. Profiling accessible functional targets is an important logical step not only for achieving site-directed pharmacodelivery in vivo but also for overcoming the normally restrictive endothelial cell barrier to transport drugs and possibly even genes to their intended targets, the underlying tissue cells. Such targeting vectors may improve molecular imaging of tumors and help re-engineer past therapies showing considerable promise in vitro but failing clinically because of poor delivery and systemic side effects.
Ie-Ming Shih, M.D., Ph.D.
Johns Hopkins University
Assessment of Plasma DNA Levels, Allelic Imbalance and CA-125 as Diagnostic Tests for Cancer
[ Expand Abstract ]
Hsueh-Wei Chang1,Shing M. Lee3, Steven N. Goodman3, Gad Singer1, Sarah K. R. Cho1, Lori J. Sokoll1, Fredrick J. Montz2, Richard Roden1, Zhen Zhang1, Daniel W. Chan1,3, Robert J. Kurman1,2, and Ie-Ming Shih1,2
1Department of Pathology, 2Department of Gynecology and Obstetrics, and 3the Oncology Center, The Johns Hopkins Medical Institutions
Background: Tumor-released DNA in blood represents a promising molecular marker for cancer diagnosis.
Methods: We first addressed whether measurement of plasma DNA concentration was a feasible screening method for ovarian and other cancers. Second, using ovarian cancer as an example, we performed digital single-nucleotide polymorphism (SNP) analysis to precisely determine allelic status in plasma DNA and to evaluate the potential of this new technology for detection of ovarian cancers. We contrasted this with the combination of plasma DNA concentration and serum CA125 levels.
Results: Based on data from 330 patients, the area under the receiver-operating characteristic (ROC) curve for plasma DNA concentration was 0.90 for neoplastic versus healthy patients and 0.74 for neoplastic versus non-neoplastic patients. Given 100% specificity, the highest sensitivity achieved was 57%. Of the 330 patients, digital SNP analysis was performed on 54 ovarian cancer patients and 31 non-neoplastic disease controls. Allelic imbalance (AI) in at least one SNP in plasma DNA was found in 87% (95% CI: 60%-98%) of stage I/II and 95% (95% CI: 83%-99%) of stage III/IV patients and none in 31 patients without neoplastic disease (specificity 100%, CI: 89% to 100%). For the 63 patients with serum CA125 data, DNA plasma concentration added information to serum CA125 levels by increasing the area under the ROC curve from 0.78 to 0.84.
Conclusion: Measurement of plasma DNA levels may not be sensitive or specific enough for use as a cancer screening or diagnostic tool, even in conjunction with CA125, but detection of allelic imbalance in plasma DNA using the digital SNP analysis holds a great promise for the detection of cancer.
Branimir Sikic, M.D.
Stanford University
Gene Expression Profiling of Unknown Primary Cancers
[ Expand Abstract ]
No Abstract Available.


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Total Points: 125,128,677,196,329,549,824.00
Manuel Charr to David Haye: "I am officially challenging you!"
Heavyweight contender Manuel Charr has targeted David Haye in order to fast track a rematch with WBC heavyweight champion Vitali Klitschko. I will do whatever it takes to make this fight happen, said Charr. I can only hope that Vitali doesnt retire. I heard that David Haye wants to fight him, too. Well, David, we both have the same goal so let us find out in the ring who should have the right to challenge Klitschko. I am hereby officially challenging you for an elimination bout!
Another chance to secure a title shot would be winning the WBC World Cup which is supposed to start in May. The WBC is looking for eight contenders for the World Cup, states Charr. I am honored to be on the short list. The winner of the tournament will become the mandatory challenger for the world championship. The only problem is the World Cup is scheduled for a whole year which means that Charr in case he wins the tournament would be world title challenger in 2014 when Vitali Klitschko will most probably be retired. But the Diamond Boy desperately wants to face Klitschko again to show the world that he can beat the best heavyweight fighter in the world. Thats why I am calling out David Haye. I am not ducking anybody and only looking for the biggest challenge out there. David, if youre reading this, come on and fight me! Im ready and only waiting for you lets get it on!
Undisputed Champion
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Rep Power: 18
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Total Points: 1,101,120,123.73
There's an 8 page thread on this about halfway down the page...
Undisputed Champion
Join Date: Sep 2009
Location: North Tulsa, Oklahoma
Posts: 14,051
Quoted: 735 Post(s)
Rep Power: 54
Points: 101,000,006,080,828,096.00
Bank: 6,872,815.98
Total Points: 101,000,006,087,700,912.00
Join Date: Sep 2006
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Rep Power: 26
Points: 20,157,261,019.41
Bank: 57,504,572,510.51
Total Points: 77,661,833,529.92
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Barring a setback, Chicago Bulls guard and reigning NBA MVP Derrick Rose, who missed his 12th consecutive game Thursday with a strained groin, will play Sunday when the Bulls take on the New York Knicks, the Chicago Tribune reported.
"I'm dying to play, but we're being smart," Rose told the newspaper. "I guess a couple of more days rest will be good for me."
Chicago (42-13) has been without Rose for 22 games this season but is 8-4 in the latest stretch and 15-7 overall in his absence. The Bulls defeated the Boston Celtics, 93-86, Thursday to snap a two-game losing streak, the first time this season they had lost back-to-back games.
According to the Tribune, Rose—who returned to full practice only Wednesday—likely will play Sunday in what could be a preview of a first-round NBA playoff series with the Knicks, who are 1½ games ahead of the Milwaukee Bucks for the Eastern Conference's final playoff spot.
Rose took contact in that midweek practice for the first time since the most recent injury and afterward was optimistic he would be able to play this weekend.
He was a game-time scratch Thursday by coach Tom Thibodeau after participating fully in the morning's shootaround and working out before the game.
Thibodeau said the opponent doesn't factor into the decision to play or sit Rose.
"If he's healthy and can play, he'll play," Thibodeau said. "If he's not, he will not play. We just have to be smart about it. You're cautious because of where you are in the season too. He has to be healthy. We're not going to rush him back just to have him back."
To that end, Rose admitted Thursday that he still was feeling a little discomfort in the groin, saying he's "not able to run at full speed."
When he returns, that won't be the case.
"I'm not going to hold back at all," Rose said, according to the Tribune. "My game is to be aggressive and try to get people going."
Rose did say he is "a little bit" concerned about reinjuring the groin, "but every day it's improving, the less I think about it. I'm running more, feeling better. I know it will be different if it's a game-type experience."
Rose said he isn't concerned about being affected by the injury during what could be a long playoff run for the Bulls.
"I should be fine," Rose said. "Taking all this rust off with all the other injuries I had, being nicked up. They're gone. The only thing I'm worried about is my groin."
Rose last played March 12 in a victory against the Knicks. C.J. Watson has started at point guard in place of Rose.


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2 posts tagged with cats by tessalations999.
Displaying 1 through 2 of 2.
Bored cat wants to play!
Cat question! I have two cats, one 18 years and the other 1 year. The younger male cat seems bored and wants to play all the time, but the other cat never plays and likes to be left alone. We live in an 800 square foot apartment, and the cats both need to stay indoors because of the neighborhood. Any ideas of how to help the younger cat have enough stimulation? Should we get another cat, or is 3 cats in a small apartment crazy? Thank you!
Old cat and new kitten strategy
Old cat, new kitten filter: Does anyone have experience introducing an older cat to a new kitten? My cat is 17 years old, female indoor. Any advice/ best practices?
Page: 1


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Despite Scrutiny, Betting Still Rampant
By Sandip G - CHENNAI
Published: 19th April 2014 08:02 AM
Last Updated: 19th April 2014 08:24 AM
Despite the recent crackdown on betting in the city and beefed-up police surveillance subsequent to the IPL spot-fixing and betting scandals last year, punters seem to be unperturbed and are apparently still operating smoothly and nonchalantly.
According a source, while notorious ones like Kitty were detained and released, new ones have surfaced. "It's going full-swing. In fact, the amount of money invested has doubled in this edition. Crores change hands for every match. It's not like new ones have just come out of somewhere. They have been there for a while. It's not a one-man institution. A lot of people are involved in this. Even if a few are arrested, others still operate," a highly placed source informed TNIE.
Take for instance, a Chennai-based gambler plying his trade under the alibi "MM". "Originally from outside the city, he has been making a killing this season. He owns a big transport company. But his betting centre is in the outskirts and he keeps moving. He is not the only one, there are several others too," he explained.
Surprisingly, they are least discreet about it. "There are no reasons for them to be scared of anybody. A few years ago, there was CB-CID and they were extra vigilant. But now they are no longer here, the punters operate without any fear. It's business as usual for them," he stated.
Like in the previous years, they operate through cell phones. "Everything is operated through cell-phone with out-station SIM cards. Most of these cards are purchased under false names from different corners of the country, so it's very difficult to track them down," he said.
It doesn't matter that the first phase is held in the United Arab Emirates or it's coinciding with the general elections. "Nothing really matters for them. It's a big nexus and will continue despite these scandals. Last year the issue surfaced because a lot of big names were involved," he furthered.
Meanwhile, the punters back Chennai Super Sings to win the league. "Given their consistent, CSK are the favourites, followed by Royal Challengers Bangalore and Mumbai Indians. The odds, though, keep changing," he said.
Disclaimer: We respect your thoughts and views! But we need to be judicious while moderating your comments. All the comments will be moderated by the NIE editorial. Abstain from posting comments that are obscene, defamatory or inflammatory, and do not indulge in personal attacks. Try to avoid outside hyperlinks inside the comment. Help us delete comments that do not follow these guidelines.


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ScriptSpot is a diverse online community of artists and developers who come together to find and share scripts that empower their creativity with 3ds Max. Our users come from all parts of the world and work in everything from visual effects to gaming, architecture, students or hobbyists.
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text:
1213 isn't the most up to date but it should work nonetheless. Do you have a second USB device you can try so we can rule that out? It could be that the multiple partitions you have setup are causing the issue or it could be the drive may not be compatible with Dios Mios at all (USB loading GameCube and Wii games have different compatibility). If it turns out the drive doesn't work with DM you may want to try Devolution.Quote:
Originally Posted by michaeltr91


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Published on 16.05.13 in Vol 15, No 5 (2013): May
Works citing "Internet Use Among Older Adults: Association With Health Needs, Psychological Capital, and Social Capital"
According to Crossref, the following articles are citing this article (DOI 10.2196/jmir.2333):
(note that this is only a small subset of citations)
- Gordon NP, Hornbrook MC. Differences in Access to and Preferences for Using Patient Portals and Other eHealth Technologies Based on Race, Ethnicity, and Age: A Database and Survey Study of Seniors in a Large Health Plan. Journal of Medical Internet Research 2016;18(3):e50CrossRef
- Dickinson C, Dow J, Gibson G, Hayes L, Robalino S, Robinson L. Psychosocial intervention for carers of people with dementia: What components are most effective and when? A systematic review of systematic reviews. International Psychogeriatrics 2016;:1CrossRef
- Vošner HB, Bobek S, Kokol P, Krečič MJ. Attitudes of active older Internet users towards online social networking. Computers in Human Behavior 2016;55:230CrossRef
- Lifshitz R, Nimrod G, Bachner YG. Internet use and well-being in later life: a functional approach. Aging & Mental Health 2016;:1CrossRef
- Kim MJ, Lee C, Preis MW. Seniors' loyalty to social network sites: Effects of social capital and attachment. International Journal of Information Management 2016;36(6):1020CrossRef
- Szanton SL, Roberts L, Leff B, Walker JL, Seplaki CL, Soones T, Thorpe RJ, Ornstein KA. Home but still engaged: participation in social activities among the homebound. Quality of Life Research 2016;25(8):1913CrossRef
- Gazibara T, Kurtagic I, Kisic-Tepavcevic D, Nurkovic S, Kovacevic N, Gazibara T, Pekmezovic T. Computer and online health information literacy among Belgrade citizens aged 66–89 years. Health Promotion International 2016;31(2):335CrossRef
- Romano MF, Sardella MV, Alboni F, Russo L, Mariotti R, Nicastro I, Barletta V, Di Bello V. Is the Digital Divide an Obstacle to e-Health? An Analysis of the Situation in Europe and in Italy. Telemedicine and e-Health 2015;21(1):24CrossRef
- Mouton A, Cloes M. Efficacy of a web-based, center-based or combined physical activity intervention among older adults. Health Education Research 2015;30(3):422CrossRef
- Khazaal Y, Achab S, Billieux J, Thorens G, Zullino D, Dufour M, Rothen S. Factor Structure of the Internet Addiction Test in Online Gamers and Poker Players. JMIR Mental Health 2015;2(2):e12CrossRef
- Fischer SH, David D, Crotty BH, Dierks M, Safran C. Acceptance and use of health information technology by community-dwelling elders. International Journal of Medical Informatics 2014;83(9):624CrossRef
- Banbury A, Roots A, Nancarrow S. Rapid review of applications of e-health and remote monitoring for rural residents. Australian Journal of Rural Health 2014;22(5):211CrossRef
- Kowalski C, Kahana E, Kuhr K, Ansmann L, Pfaff H. Changes Over Time in the Utilization of Disease-Related Internet Information in Newly Diagnosed Breast Cancer Patients 2007 to 2013. Journal of Medical Internet Research 2014;16(8):e195CrossRef
- Henriquez-Camacho C, Losa J, Miranda JJ, Cheyne NE. Addressing healthy aging populations in developing countries: unlocking the opportunity of eHealth and mHealth. Emerging Themes in Epidemiology 2014;11(1)CrossRef
According to Crossref, the following books are citing this article (DOI 10.2196/jmir.2333):
- DuBenske LL, Mayer DK, Gustafson DH. Oncology Informatics. 2016. :181CrossRef
- Seçkin G. Emotions, Technology, and Health. 2016. :41CrossRef


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Boogie Monster Dance Kit
by Josie Bissett & Illustrated by Kevan J. Atteberry
Item #4570
This complete dance kit includes one Boogie Monster book, one pair of Boogie Legs Leggings, and one full-length Boogie Monster Boogie music CD by Recess Monkey. Everything is packaged in a colorful reusable box with a magnetic closure. Makes a great gift for parents, grandparents, and children (ages 3–8).


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ATLANTIC CITY — Most city government offices are closed in Atlantic City.
Today is first of 10 furlough days ordered by Mayor Lorenzo Langford to help balance the budget. The furlough does not include the police and fire departments
City Hall, the Atlantic City Free Public Library and other government-run buildings will reopen Tuesday.
The next furlough day will be Aug. 16.
More Atlantic City news:


text:
LINDEN — A Linden fire captain was arrested last week on drug charges after city police raided his home and allegedly found marijuana and prescription painkillers.
But the 55-year-old says the charges are trumped up and that he'll be vindicated when he has his day in court.
Louis A. Gazzo is charged with possessing marijuana, drug paraphernalia and Percocet, a painkiller, Linden police Lt. James Sarnicki said. He was taken into custody last Friday after detectives searched his home on Summit Terrace.
His son, 21-year-old Anthony Gazzo, and another Linden man, 23-year-old Michael Terpilowski, were also charged with drug counts, police said.
The elder Gazzo defended himself today. "I'm a 30-year decorated fire captain. I don't do drugs," he said.
He said the marijuana wasn't his. The painkillers — which he said are Oxycodone, not Percocet — were prescribed to him by a doctor.
"It was either when I threw my back out, when I had my colon surgery or when I pulled my ACL. Or it could even have been when I pulled a tendon in my ankle," he said. "I've been in the hospital three or four times in the last 10 years."
Gazzo earned $105,760 in 2010, public records show. He said he filed for retirement this year.
Mayor Richard Gerbounka, while noting Gazzo hasn't been convicted of anything, said his arrest shows that no one gets special treatment there.
"It goes to show you that, no matter who is violating the law, the City of Linden will take the appropriate criminal action against them regardless of who they may be."


text:
Whether or not the Flyers win their libel suit against WIP (610-AM) and host Craig Carton, they have accomplished something.
Taking on the station publicly, standing up for team captain Eric Lindros, has certainly closed any gap that might have existed between the organization and No. 88, who will be working on a new contract with the Flyers this summer as he approaches the final season of his original six-year deal.
Lindros emerged after yesterday's practice to tell reporters he was ``feeling a lot better today.'' He had been asked about the bruise on his hip that kept him out of Wednesday's 3-1 loss to New Jersey, but he might have been talking about more than that.


text:
Low-Cost Kitchen Crafts
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Funky Salt and Pepper Shakers
By: Kreinik
We are adding the craft to your Craft Projects.
The project was added to your Craft Projects.
Click here to view your Craft Projects.
Add some to your kitchen table with these funky salt and pepper shakers embellished with beads and fiber. You can match the threads to your kitchen color scheme.
- Salt and pepper shakers
- Treasure Tape, 3/4" roll
- Kreinik holographic thread colors in 1/8" Ribbon size
- Flat-backed cabochons (optional)
- Micro beadlets; we used gold Beadlets from Kreinik (also available are clear beads and silver beads)
- Shallow pan or tray
Lay a strip of double-sided Treasure Tape on each shaker. Remove the red liner to expose the top sticky surface.
Begin decorating with thread: lay the 1/8" Ribbon in desired pattern. See our photo for inspiration.
Place any flat-backed buttons or cabochons in open sticky areas.
- Then place your shakers in a shallow pan or tray and cover all remaining sticky areas with the gold micro beads.
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- "18 Projects Every Crafter Wants" free eBook


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HourlyMore than 30 hrs/week
Start DateJanuary 4, 2013
Looking for a dedicated phone rep who will prospect leads needing potential credit repair as well court local affiliates like realtors, car dealers, furniture dealers soliciting prospects needing credit to qualify for large purchases.
Daily Tasks
- Contact consumers selling our PERFORMANCE oriented credit service where they pay per deletion
- Developing and securing new affiliates to bring clients into our service
- Finding, Qualifying, Evaluating Leads
- Must have own dialer, phone, minutes
- Ability to record phone calls
- Must be able to deliver reporting, and manage CRM input
Extra Consideration given to those with lead sources, social media marketing experience, previous credit agency sales experience, ability to close sales.
Skills: marketing
About the Client
United States
Palm Bay 06:22 PM
Jobs Posted
39% Hire Rate, 1 Open Job
Over $50,000
Total Spent
106 Hires, 1 Active
Avg Hourly Rate Paid
4,136 Hours


text:
Top Definition
Your Penis.. A quote from Borat film "Please,Touch my crum"
Borat "Touch my crum..Please, I'll touch your's"
מאת benuk 8 בנובמבר, 2006
Trending Now
Can you define these popular missing words?
An allergic reaction to the oral ingestion of semen can result in crums, low viscosity diarrhea.
"I've got to get my boyfriend to stop cumming in my mouth because every morning I'm filling up the toilet with tons of crums"
מאת VagFingaz 29 באוקטובר, 2009
Someone who is such a lowly human being they do not deserve your time of day.
Jim - "Hey mate, can I borrow $5 for another rum and coke?"
Peter - "Fuck off crum"
Peter - "Fuck off crum"
מאת Manets 24 בינואר, 2009
Crum is the alcohol mixture of cream soda^ and rum*. One shot of rum mixed with a bottle of cream soda will make the rum almost tasteless. Typically a 1/3 glass of rum and the rest cream soda will make for an enjoyable harder mixture know as a Pro-V mixture. Ice is not necessarily needed but is preferred.
* Clear brands of Rum are typically used (BACARDI®)
^ IBC® cream soda is the preferred brand.
* Clear brands of Rum are typically used (BACARDI®)
^ IBC® cream soda is the preferred brand.
I needed a quick drunkenness, after mixing a Crum on the rocks my problems melted away.
מאת captian 10 באוקטובר, 2007
Someone who is so useless that they can be compared to a crum of bread. A crum is someone who resides in their house all the time and refuses to participate in any galas or events.
Mike "Hey Dom lets go get that chick to come over tonight to my crib"
Dom "Not even worth it bro, that girl is a crum, she ain't leavin her house for a million dollars"
Dom "Not even worth it bro, that girl is a crum, she ain't leavin her house for a million dollars"
מאת thekooker 5 בדצמבר, 2010
It's when you cry and cum at the same time. A feeling of eternal happiness.
Every Christopher Nolan film will for sure make you crum.
I just crummed.
Crumming is my speciality.
I just crummed.
Crumming is my speciality.
מאת Jonye 3 בדצמבר, 2014
Your entire package consisting of one wang and two balls in a sac.
Timo- "Wow Eric you have a tight crum"
Eric- "Thanks Timo, its the briefs ;)"
Eric- "Thanks Timo, its the briefs ;)"
מאת Frederick Crumster 21 באוקטובר, 2009


text:
I'm worried that pregnancy will be impossible for me because my cycle is so irregular. I've been tracking my periods for over 2 years and right now, my average cycle lasts 56 days so it's really difficult to pin-point when I'm ovulating and when's the best time for us as most online tracking tools aren't designed for cycles this long.
We haven't been "preventing" pregnancy for over a year and nothing's happened. Mind you, we haven't been using my BBT or anything like that either so I can continue living in denial thinking our timing has just been off. I'm looking forward to using the tools on here to help me track my ovulating cycle but I'm really worried and looking for some info/help.
I asked my doctor about it and he said it was normal, that some women simply have a longer cycle than others and I made another appointment to discuss fertility but it seems like an eternity until then...


text:
Top 100 DJs
He may have been dethroned after two years at the top of the poll but Hardwell's bigger than ever. Robbert van de Corput's 2015 was a very good year even by his bombastic standards.
It's incredible to think that Martin Garrix isn't legally allowed to drink alcohol at the EDM festivals he's been a fixture at the past few years.
"I think it's a really odd phenomenon," Armin van Buuren says matter-of-factly down the phone line.
"It's like you're driving a Ferrari at full speed, and that's fun and I love that energy; that adrenaline," Steve Aoki tells DJ Mag over the phone from his car, but not while driving (we hope).
The ushering in of 'future house' as the "saviour of EDM" last year felt a little premature, but a 22-place climb for Oliver Heldens (Highest House DJ)...
Alesso obviously puts as much time and effort into making EDM/pop tunes as he does his hair.
Willem van Hanegem and Ward van der Harst's mix-up of trance, electro and progressive house elements have seen them reach out and connect to a wide audience of dance music fans across the world....
Dash Berlin have been everywhere this past year.
Before trying their hand at dance music, Canadian duo DVBBS (pronounced 'Dubs'), made up of brothers Alexandre and Christopher van den Hoef, were members of a local rock band.
It's official, Axwell and Ingrosso are married. Not legally of course — even if civil partnerships (unlike some US States) are accepted in Sweden.
For Nicky Romero, 2015 was another typically hectic year.
"Turbulent" is Blasterjaxx's adjective of choice to describe their year, speaking to DJ Mag all the way from Shanghai.
Like the prom queen that snubs her most persistent suitor year after year, Diplo has declined DJ Mag's gracious advances yet again, opting instead to let us speculate...
Fadil El Ghoul, aka R3HAB, has been on a quick ascent to join his EDM colleagues at the festival main stages, and for proof of his studio prowess, you only need to glance at the tracklist for his...
We think Zedd must have been destined for success from an early age; born to a guitarist father and pianist mother, young Anton was classically trained in several instruments.
With releases on Dutch imprint Spinin' Records, remixes for the likes of Avicii, and a huge collaboration alongside Tiesto, American EDM producer and...
Australian sisters NERVO are big news. While some have questioned the lack of women in the Top 100 DJs poll, these DJ and production siblings have consistently placed in the upper reaches.
Known as much for his personality both online and onstage as he is for his massively successful productions, Toronto native Joel Zimmerman, aka Deadmau5, maintains his place in the DJ Mag Top 100...
Dannic is an artist who...
This year, Dyro (real name Jordy Van Egmond) has gone big.
Deorro, born Erick Orrosquieta, started out DJing when he was just 14.
Once the mainstay of our Top 10, trance is no longer the dominant sound of the world's big-room clubs.
The dawn of future house in 2014 heralded a new age for EDM, it seemed.
Flying solo and loving it, former Swedish House Mafia man Steve Angello has mostly positive things to say about the state of the scene as he sees it.
Despite only forming in 2011, VINAI are a duo very much setting the EDM world on fire right now.
Alok is a poster boy for Brazil's love of deep mid-tempo forms of house and techno — albeit with a pop twist. It's a subcultural penchant often outshone by the garish lights of EDM.
What do you get when you lock Skrillex and Diplo in a studio together? A wildly successful bass child, apparently.
Tom Swoon only discovered Deadmau5 and Daft Punk around five years ago but his early efforts at unofficial remixes soon led to his bootleg of...
What sets Shogun apart from other US DJs is his work ethic; Andrew Chen is known to spend 12...
Koen Bauweraerts, better known as Belgian producer Coone, is one of the elder statesmen of hardstyle.
The duo of Ruben Den Boer and Victor Pool, aka Vicetone,inject a strong affinity with melody into their main stage EDM productions, and describe the past year as the "...
From the moment Richie Hawtin crossed the river from Windsor, Ontario, to the techno heartland of Detroit, Michigan, the techno savant set in motion a journey that would see the British-born...
2015 has been a big one for Steve and Ruben, aka the notorious Wolfpack.
Dutch hardstyle producer Brennan Heart has had one of those years. "I thought 2014 was madness, but 2015 topped it… crazy", he sighs.
While at one time Major Lazer seemed destined to be a Diplo side-project devoted to futuristic versions of Jamaican dancehall, made alongside UK producer Switch, it's become very much the Mad...
Inspired as much by video games as he is the sounds of Wolfgang Gartner, it's delightful how Porter Robinson has captured the imagination of the EDM community.
For Markus Schulz, life imitates art. Or rather, fantasy. The self-styled unicorn-slayer of trance has found his moniker has presented some surreal encounters in recent years.
Swedish producer Eric Prydz is a chameleon.
"I wish I had more time to do everything I have in my mind. I wish the days had 48 hours," Diego Miranda tells DJ Mag.
It's not only America that's currently experiencing a dance music epiphany.
Danny Avila is a DJ who proves that age really is just a number.
It's been business as usual for Kura (aka Rúben de Almeida Barbeiro) in 2015, having placed 42nd in last year's DJ Mag Top 100 DJs poll.
Dillon Francis chooses not to talk to us when we try and get in touch, something we can only attribute to him being too busy (ie.
Asaf Borger, aka Borgore, is something of a musical chameleon.
Every year Daft Punk are voted into the Top 100 DJs poll, and every year we have to write a profile for a duo that haven't DJ'd properly since 2001 at London's Fabric.
When he first emerged in the mid-'90s, Umek was associated with the loop techno sound.
A Maltese duo who juggle the emotive thrills of trance with their love for chillout vibes, Cyprian Cassar and Joven Grech have been working together as Tenishia...
Hardstyle has never been more popular than it is right now. One man who's helped bring the genre to unforeseen heights is the inventively named Radical Redemption.
Unlike the vast majority of DJs on this list, Frontliner is a man who plays by his own rules.
By now you'll know the singular synth strokes of 'Tsunami', a UK No.1 and the reason its producer shot to fame in 2013.
Apparently Netsky, or Boris Daenen, was too busy for DJ Mag's interview.
Together Bizzey (Leonardo Roelandschap), Nizzle (Nils Rondhuis) and Jim Aasgier make up Yellow Claw, a grouping whose sonic output is a diverse...
Dutch house titan and last month's DJ Mag cover star Chuckie is going through something of a reinvention.
Will Sparks is a truly passionate guy. He's passionate about his city, about his music and most of all, about his fans.
Da Tweekaz have had quite a year.
The Dutch DJ, real name Quinten van den Berg, has climbed a further six places in the Top 100 DJs poll this year.
Andre Tanneberger, aka ATB, has come a long way since his UK No.1, '9PM (Till I Come)'.
Makj is the alias of US DJ/producer Mackenzie Johnson.
Last year, Kaskade's management made a song and dance about him answering a few simple questions for our poll.
From his early UK chart success with 'Out Of The Blue' under his System F alias to creating a raft of timeless trance anthems alongside Tiesto as Gouryella, Rotterdam's Ferry Corsten has been...


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Defensively Invoking Treaties in American Courts: Jurisdictional Challenges Under the U.N. Drug Trafficking Convention by Foreign Defendants Kidnapped Abroad by U.S. Agents
Thomas M. McDonnell
Pace University School of Law
William & Mary Law Review, Vol. 37, 1996
This article unravels the non-self-executing treaty doctrine, examines the invocation of a treaty as a defense to governmental action, and develops a test for when an individual (rather than a government) may assert a treaty defensively in state or federal courts. Lastly, this Article applies this test to state-sponsored kidnapping and the U.N. Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. The parties to this treaty, whIch was sponsored by the United States, barred one country's law enforcement agents from operating without permission on another country's soil and rejected a provision requiring a country to extradite its own citizens. This article demonstrates that, had the Convention been in effect when the Supreme Court decided United States v. Alvarez-Machain, the Court would have been constrained, even under its flawed reasoning in interpreting the extradition treaty at issue there, to have recognized the challenge to the trial court's personal jurisdiction brought by the Mexlcan physician abducted from Guadalajara by paid agents of the United States.
Number of Pages in PDF File: 112
Date posted: December 27, 2008
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Hotels in Mississauga, Ontario
Search & Compare Mississauga Hotels
Trending now in Mississauga
- Most bookedSandman Signature Mississauga Hotel
228 people looked at this hotel in the last hour
Most recent review
"This hotel is nice and clean, seems like it has been recently upgraded, My room looked new and comfortable. It has a nice view to the airport runway (which is a big plus for me). The lady at reception was not that nice but she was not rude. I am thinking of staying again here next time."
G, Sep 2016, US
168 people looked at this hotel in the last hour
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"The hotel is undergoing renovations. Check in staff did there best to apologise for this. Thankful for the breakfast but the staff there was rude to many people. They just stood there then told people off for not throwing out the disposable dishes. "
A Traveller, Sep 2016, CA
- TownePlace Suites by Marriott Mississauga-Arpt Corp CtrNo Guest Reviews yet
164 people looked at this hotel in the last hour
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"Room had everything basic for guests requirements. Very practical essentials were available."
C, Sep 2016, CA
156 people looked at this hotel in the last hour
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"We were pleasantly surprised of how very quiet it was at night. Breakfast was good and a nice open, clean room."
A Traveller, Sep 2016, CA
146 people looked at this hotel in the last hour
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"Good Hilton hotel with everything you need before an early flight out of Toronto."
C, Sep 2016, GB
140 people looked at this hotel in the last hour
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"The room had a microwave, fridge and extra sink with counter top, great for preparing a gluten and lactose free snack."
A Traveller, Sep 2016, AU
114 people looked at this hotel in the last hour
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"My peace of mind when traveling is worth the expense. Two nights and a week of parking for approx. $560. Worth it. "
M, Sep 2016, CA
105 people looked at this hotel in the last hour
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"The room was clean and location next to the airport was great. My only reproach about this hotel is that the bathroom was the smallest bathroom I have had in a hotel in a long time (door almost hits toilet seat) and I travel a lot. Besides size of bathroom, they do not give you shampoos, soaps & ..."
A Traveller, Sep 2016, US
75 people looked at this hotel in the last hour
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"Great location to the Pearson Airport. Easy to find from the terminals. The hotel was clean, unique and really comfortable. "
A Traveller, Sep 2016, CA
61 people looked at this hotel in the last hour
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"We were flying out at 830am on an international flight so we had to leave the hotel at 520am, the service for shuttle was on time, only downfall was there were no trolleys for luggage from room to lobby as people tend to take them and not return them to lobby.The staff were great, informative, we..."
A Traveller, Sep 2016, AU
Map of Mississauga hotels
- Mississauga Hershey Centre
- The International Centre
- Square One Shopping Mall
- University of Toronto Mississauga
- Mississauga Convention Centre
- Erin Mills Town Centre
- Dixie Outlet Mall
- Heartland Town Centre
- Red Rose Convention Centre
- Mississauga Celebration Square
- Mississauga Grand Banquet and Convention Centre
- Iceland Arena
- Playdium
- Living Arts Centre
- Mississauga Civic Centre
- Toronto Golf Club
- Jack Darling Memorial Park
- Hershey Sport Zone
- Rattray Marsh Conservation Area
- Derrydale Golf Course
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If you are looking for Mississauga hotels in a particular area, you can use the search feature at the top of the page to search by neighborhood, landmark, address or zip code, or you can search by using the built-in map feature. You can also browse hotels in Mississauga by type, amenities, and star-rating so that you can find the best hotel. Currently, top rated hotels in Mississauga are:
- Custom-Made Luxury Suite-By Elite Suites
- Maplewood Furnished Suites
- Goodwood Suites
- Alt Hotel Toronto Airport
- Homewood Suites by Hilton Toronto-Mississauga
The location of your Mississauga hotel is important. If you are traveling to Mississauga, &StateorCountry for business, you may want to consider getting a hotel close to the airport or near your meeting venue. By doing so, you can really cut down on transportation costs and time. You may also want to book a hotel that offers free wifi just in case you need to get some work done.
If you are traveling for vacation, figure out which attractions or landmarks you want to see and book a hotel that is within close proximity. Although hotels near attractions might cost a little more, you may find that spending those extra few dollars is worth the convenience. You can even find hotels that align with your interests. For example, if you are looking for a relaxing vacation, a spa hotel may be the perfect choice for you.
You'll also want to determine which type of accommodations will suit your needs before booking a hotel in Mississauga. If you're traveling with the kiddos, a family friendly hotel will offer larger rooms and more sleeping arrangements. For those traveling for an extended period of time, booking a hotel suite with a kitchenette is a smart move and will feel a little more like home. If you are budget conscience and just need a place to rest your head, a hostel or motel may be all you need.
If you are looking to score the best discounts and deals, use the filter to sort by price from low to high. You can book a hotel in Mississauga for as low as $49 per night. If you are looking to cut down on expenses, look for hotels that include free breakfast and parking. Some hotels even offer free shuttle service to and from nearby places. You can also sort by star rating, proximity, and guest rating.
Before you book, check out user reviews. Hotels.com has 17317 reviews in Mississauga. We show reviews from Expedia and TripAdvisor so you know that you are reading genuine, reliable reviews. Be sure to download the Hotels.com app so you can book your reservations on the go, view amenities, and save the hotels you want to view and compare later.


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Golden Dragon Acrobats
The best of a time-honored tradition, some 25 centuries old, meets modern movement and expression in a gorgeous, innovative acrobatic performance. The Golden Dragons are recognized throughout the United States and abroad as one of the premiere Chinese acrobatic companies touring today.
Performing Arts Type
- Theatre
- Dance


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Remember the space race and the Apollo era when humans got to walk on the Moon, space was the final frontier and we were all just decades away from living a life much like an episode of a campy sci-fi flick? For most of us, it's all in the past and we know full well that lunar landings were about national pride and political incentives first and foremost. But some people still can't let go and have spent the last 30 years calling for a brand new commitment to space travel and exploration through flashy appeals to our imaginations.
So we can create a million jobs in a dire recession by committing ourselves to space? That's all well and good, but exactly how are we going to do that? Yes, there's something about creating new types of space vehicles, but how will it generate 20,000 jobs? To who are all of these launch vehicles going to be sold and what's the demand for them? Is there a target market in mind for these machines? When it comes to asteroid mining, how is it going to be done, who's going to do it and just how many jobs will it create? And the same can be said for today's ideas of space tourism since relying on a new flavor of the month for wealthy thrill seekers isn't as much of a business model as a speculative little venture that could be tossed aside when enough people have flown and it's become a bore.
This is not to say that space travel or space exploration can't create jobs. In fact, having a huge infrastructure aimed at exploring the cosmos would create a lot of high tech, well paid jobs but only if all this exploration can ultimately pay for itself. What good is investing money into a new launch vehicle if it doesn't get used all that much? All ideas and projections which rely on NASA having a nearly bottomless wallet stuffed with tax receipts and an unlimited scope in its quests to explore other planets and map the universe, are little more than a gamble. The budget gods giveth and the budget gods can also taketh. Without a major incentive and with national pride's place on our priority lists being replaced with the economy, NASA isn't about to go out and buy new launch vehicles without a very good reason to do so.
Of course the groups of space enthusiasts think they've listed good reasons that range from a new set of technological leaps to political competitions. And they have. But the problem is that this is all they've done. Anyone can give a laundry list and urge us to do something. The really big problem is the details and establishing a realistic way that space exploration pays for itself. It's not enough to draw up a potential Mars habitat and declare that doing this will generate lots of jobs. Sure it will but what's the payback? Why should we spend tens of billions of dollars on a project that can't pay for itself? What do you get with a flood of investment in a venture which doesn't have a tangible payoff? You get a bubble and after three of those taking ever bigger hits to our economy, one would think we'd want to stop doing that.
I've always been fascinated by space and I'm all for space travel. But in order to create a lasting commitment to space travel and exploration, there needs to be something more to the pitch. If we could have some more details, stats and strategic analyses, it would be a good start. Barely masked desires of going into space for the sheer thrill of going into space and living our sci-fi dream, aren't an economic panacea and shouldn't be pitched like one. Answering a crisis made by a bubble by getting us to invest billions into another one didn't work last time and it's highly unlikely to work in the future. It's great that we have people thinking about how to get us to the final frontier but right now, it's time for a little tough love. Undermining their mission by trying to get us to invest in a space bubble is not going to help them win many fans.


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Dec. 27, 6:30 pm, ESPN
Three Reasons Why You Have To Watch This Bowl
1. Two teams in the 1992 Final Four are now battling in a bowl game that has surprisingly become terrific over the last several years. The matchups might not have always seemed scintillating, but the Belk – formerly the Meineke Car Care and Continental Tire – has come up with four straight games decided by a touchdown or less and five of the last six.
2. This is Duke's first bowl game since losing to Wisconsin in the 1995 Hall of Fame, and it's just the third post-season appearance since 1960. The team might have died down the stretch, but it still managed to come up with the wins needed to finally get back over the hump.
3. Cincinnati was really, really close to being the Big East representative in the BCS losing to Louisville in overtime and to Rutgers by seven. The Bearcats destroyed the rest of the Big East, winning all of its five conference games by double digits.
And Why You Shouldn't Care A Lick: Cincinnati comes into the game winning four of its last five helped by one of the nation's best defenses. The Bearcats haven't allowed more than 17 points since early November. Meanwhile, Duke has lost its last four games and five of its last six thanks to a defense that that hasn't allowed fewer than 42 points since mid-October.
Three Names To Drop To Make Every Man Want You And Every Woman Fear You:
1. RB George Winn, Sr. Cincinnati – The team needed a steady star to carry the offense, and Winn became it with five 100-yard games on the way to 1,204 yards and 12 touchdowns.
2. WR Jamison Crowder, Soph. Duke. – Connor Vernon is the bigger name, but Crowder had the better year. On fire by the end of the season, he caught seven passes for 167 yards against Clemson and closed out with eight grabs for 203 yards and two touchdowns against Miami.
3. LB Greg Blair, Sr. Cincinnati – One of the Big East's most underappreciated players, the sure-thing tackler came up with 19 stops against Louisville and finished up the season with 123 tackles. He's the best player on a strong defense.
Gut-Reaction Pick That Might Change In The Next Few Days On A Whim: Cincinnati 41 … Duke 17


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Today was my second day at James Gettys Elementary school. I was excited to see the students and was hoping that they would like the recipe for this week. Our theme was apples and I talked to kids about how apples are in a lot of desserts. The dessert we made today was called apple pie in a cup. It was a simple version that kids could do in a short period of time. Most of the students liked the recipe and had a lot to say. One of the girls in the class brought her apron from home which I thought was really cute. Some of the roles I played in this lesson was to show them how to dice an apple, tell them when to mix certain ingredients, and clean up the kitchen after we finished cooking. Overall, I am very pleased with my lesson. It went very smooth and took the whole time. Before the students left, we gave them a survey on how they felt and we received many good ratings for this recipe.


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Aeropostale (NASDAQOTH: AROPQ ) is going south of the border.
On Monday, the clothing chain announced it is signing a licensing agreement with local Mexican department store operator Distribuidora Liverpool. Aeropostale will begin opening store-in-store shops within Liverpool department stores this summer. Simultaneously, Aeropostale will begin opening standalone stores, beginning in the Sante Fe Mall in Mexico City this summer.
CEO Thomas P. Johnson explained the move by calling Mexico "a pivotal market," and praising Liverpool for its "incredible insight and experience into the consumer as the operator of Mexico's largest and preeminent department store."
For its part, Liverpool Commercial Director Graciano Guichard Gonzalez said that company is "excited to capitalize on the popularity and recognition of the Aeropostale brand in Mexico."
Investors were less excited. Aeropostale shares dropped 0.4% in Monday trading, closing at $13.75.


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Holy Cross Germantown Hospital provides expert care for complicated pregnancies like Desma's.
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My older son waved me off this summer when I tried to congratulate him for his good grade on a United States History Advanced Placement exam.
"Half the kids in the class got a 5," he said, referring to the top possible score.
The opposite happened when I had a serious talk with my younger son about a low mark on his AP exam for a social studies course at Nature Coast Technical High School.
He replied that "lots of kids got a 1" — not just a failing grade, but a full notch below failure.
My sons are different, of course, different in how hard they study and how they deal with praise and criticism.
Still, I suspected there might be something to what they said about these classes, and, after reviewing AP scores in all subjects at all of Hernando County's public high schools, I found there absolutely was.
I also found plenty of information — along with what I saw of these classes from my second-deck seat as a parent — to confirm what I've long believed about standardized tests.
No, AP tests, which give students a chance to earn college credits for rigorous courses, aren't at the heart of the testing debate.
Still, I think that, like the Florida Comprehensive Assessment Test, they give a generally accurate picture of the skill and commitment of teachers. I also think the complaining we hear from teachers about being made to "teach to the test" is mostly resistance to being held accountable — and that we need more accountability in schools, not less.
I'm naming my son's history teacher at Springstead High School, John Imhof, because he deserves to be singled out. In fact, I'll go further. Considering the number of kids he's teaching, how well he's teaching them, how crucial his subject is to building scholarship and citizenship, I'd say he's doing some of the most important work in the county.
Fifty-two of his students took the AP exam, and my son was almost right — nearly half of them, 23, received the highest mark, 5. Only three scored lower than a 3 — the level usually required to earn college credit. The average score of students in his classes was 4.19.
This was the second-highest average in the county, behind only a Chinese language course that had just three students. My other son's teacher, on the other hand, ended up with one of the lowest averages, 1.76.
I'm not naming her, or even the exact subject she taught, because public embarrassment isn't the kind of accountability I have in mind, and because neither she nor Nature Coast is alone in producing miserably low scores.
In fact, the school's overall average AP score was second-highest in the county, though with its very low rates of AP enrollment, they should be a lot higher. But parents would also be well advised to steer their kids clear of AP microeconomics or biology courses at Central High School or U.S. history at Hernando High.
I'm focusing on just one of these bad teachers, my son's, because she's the one I know most about. To achieve such a low average, many of her students did, in fact, get 1's — 12 of 21 students tested. There wasn't a single 5 and only two 4's.
Many of you will assume that Imhof had better material to work with, and it's true that Springstead's International Baccalaureate program attracts many of the county's top students.
But only about half of his students last year were in IB, said Springstead principal Susan Duval. And school superintendent Bryan Blavatt confirmed my impression that the district's elementary and middle school magnet pipeline deposits most of its kids at Nature Coast. That helps explain why it has the lowest percentage among county high schools of students eligible for free or reduced-price lunches, which correlates to higher scores.
So, no doubt Nature Coast kids could produce plenty of good marks with proper instruction.
The problem is, in my son's class, they didn't get it.
He almost never brought home reading assignments. And when I asked his teacher about this, I got only vague emails in reply. His rare writing assignments were impressively called "projects," even though they generally involved a few scrawled paragraphs. When I told my son this wasn't acceptable, that he needed to work a lot harder in an AP class, he told me he was doing fine. And he was, by his teacher's standards. His year-end grade was a B.
My other son? Reading almost nightly, spending weekends outlining chapters of his textbook, regularly writing essays that looked fine to me but that never seemed good enough for his teacher, who returned them covered with corrections and suggestions.
It was a lot of work for my son, but more for Imhof, a popular teacher with large classes.
The payoff is not just that my son scored well enough on his AP exam to earn college credit or impress admissions offices, though that's one of the best things AP exams can do for students and for this community — send the message that our schools are capable of world-class instruction.
No, the real payoff is that my son and his classmates know how to write, know how to think clearly and know how to recognize pseudo-historical junk when they hear it.
Likewise, my main concern about my younger son isn't the black mark on his academic record. It's the blown opportunity to learn about other cultures and economies, a lifetime's worth of context that would be helpful in just about any field.
I'll be honest. The whole thing infuriated me, especially the minimal consequences. His teacher missed out on some bonus money the state awards teachers for each passing grade on AP exams. But she makes the same base salary as Imhof, about $41,000 a year. She is still teaching and, incredibly, still teaching AP.
Joe Clifford, the principal at Central High, told me that he's set on improving his school's poor AP record, and this year he hired a new AP coordinator.
Duval, the Springstead principal, explained how good AP programs bring in more money through state stipends awarded for passing grades, and that these pay for more training, which raises the level of instruction in all of the school's classes.
What's going on with AP at Nature Coast? Do bad teachers get a warning? Do they have access to extra training?
I don't know because principal Toni-Ann Noyes didn't call me back. Maybe it's just habit. She rarely returns calls from reporters in this office.
Or maybe she just doesn't like being held accountable.