USING A TREATMENT PACKAGE TO TEACH REQUEST BEHAVIOR TO YOUNG CHILDREN WITH COMPLEX COMMUNICATION NEEDS

Three preschoolers with limited or no verbal language were taught to request preferred objects using an adapted Picture Exchange Communication System (Bondy & Frost, 1998) and elements of peer mediated instruction and intervention (Neitzel, 2008) (PECS/PMII). These two interventions have been established as evidence based practices, but have not previously been taught and implemented by one adult and a preschool child in a preschool classroom. Same-aged peers were the communicative partners for the picture exchange. A teacher served as the facilitator of the exchanges. A multiple probe (days) across participants design was utilized to determine the effectiveness of the intervention. The percentage of successful exchanges/requests made by the target child using the adapted PECS/PMII method was evaluated to determine the effectiveness of the intervention when implemented by a same-aged peer. The target children not only made requests to the criterion level, two of the three increased their appropriate verbal responses. The same-aged peers were able to effectively implement the steps for PECS phase 1

Prostate Cancer Molecular Aspects to Direct Visualization Utilizing a Bioreactor

Prostate cancer is the most common cancer in males, and the second leading cause of cancer deaths in American men. Most of the mortality associated with this disease is a result of widespread dissemination of tumors cells from the primary tumor mass. In order for metastasis to occur, the cancer cell must overcome multiple barrier which include development, neovascularization, intravastion, adherence or attachment, extravasation, and ectopic growth. As dissemination from the primary tumor mass is a rate-limiting step during metastasis, tumor cells undergo an epithelial to mesenchymal transition (EMT) to acquire enhanced invasiveness and increased motility. A key step within EMT is a loss of cadherin mediated cell-cell adhesion. Unfortunately, current understanding of the regulatory mechanism of this decreased cell-cell adhesion is poorly understood. Herein this work utilizes the LHRH antagonist Cetrorelix to investigate the regulation of E-cadherin expression in invasive prostate cancer cells. We provide direct evidence that E-cadherin expression can be reinstated upon abrogation of EGFR signaling via LHRH antagonist Cetrorelix or specific inhibitors of EGFR signaling thereby limiting the invasiveness of these cells. In concert, we developed a microscale liver perfusion culture system that provides a tissue-relevant environment to assess metastasis behavior of human prostate cancer cell line DU-145 in the liver capillary bed as a model system. This system offers the currently unavailable features of real time observation of in vivo microenvironment with the manipulation of in vitro cultures. Within this system we were able to observe three dimensional growth and invasion of prostate cancer cells juxtaposed to hepatic tissue, revealing an exceptionally defined cell border at the interface of prostate cancer cells and hepatic tissue. Although not completed defined within this system, we hypothesize that exists heterotypic cell-communication between prostate cancer cells and hepatocytes.The very distinct cell border observed within our liver microreactor, coupled with our previous findings of reexpression of E-cadherin expression lead us to investigate the involvement of E-cadherin in this heterotypic communication. Consequently, prostate cancer cells utilize E-cadherin at the point of initial adherence to parenchymal hepatocytes (heterotypic interaction) and throughout the development of the metastatic tumor mass (homotypic interaction). Our observed expression pattern of E-cadherin has not been reported before. These findings constitute a new paradigm in the adhesiveness or lack there of in cancer cells during tumor invasion. The differentiation or redifferentiation (EMT) of the cancer cell during the pathophysiological events of metastasis is likely a characteristic of adaptability to the microenvironment. The term epithelial mesenchymal transition (EMT) only summates the dedifferentiation of epithelial cells to escape the primary tumor, although we have provided evidence of phenotypic reversion. Therefore we provide the impetus that Epithelial Mesenchymal Transition (EMT) should be renamed "Meschenymal Epithelial reverting Transition (MErT)" to underscore the dynamics of the cancer cell progression

Data Discovery and Anomaly Detection Using Atypicality: Theory

A central question in the era of 'big data' is what to do with the enormous amount of information. One possibility is to characterize it through statistics, e.g., averages, or classify it using machine learning, in order to understand the general structure of the overall data. The perspective in this paper is the opposite, namely that most of the value in the information in some applications is in the parts that deviate from the average, that are unusual, atypical. We define what we mean by 'atypical' in an axiomatic way as data that can be encoded with fewer bits in itself rather than using the code for the typical data. We show that this definition has good theoretical properties. We then develop an implementation based on universal source coding, and apply this to a number of real world data sets.Comment: 40 page

EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells

<p>Abstract</p> <p>Background</p> <p>Lung cancer remains a leading cause of cancer death among both men and women in the United States. Treatment modalities available for this malignancy are inadequate and thus new drugs with improved pharmacological profiles and superior therapeutic indices are being continually explored. Noscapinoids constitute an emerging class of anticancer agents that bind tubulin but do not significantly alter the monomer/polymer ratio of tubulin. EM011, a rationally-designed member of this class of non-toxic agents, is more potent than the lead molecule, noscapine.</p> <p>Results</p> <p>Here we report that EM011 inhibited proliferation of a comprehensive panel of lung cancer cells with IC₅₀'s ranging from 4-50 μM. In A549 human non-small cell lung cancer cells, the antiproliferative activity was mediated through blockage of cell-cycle progression by induction of a transient but robust mitotic arrest accompanied by activation of the spindle assembly checkpoint. The mitotically-arrested A549 cells then override the activated mitotic checkpoint and aberrantly exit mitosis without cytokinesis resulting in pseudo G1-like multinucleated cells that either succumb directly to apoptosis or continue another round of the cell-cycle. The accumulated enormous DNA perhaps acts as genotoxic stress to trigger cell death. EM011-induced apoptotic cell death in A549 cells was associated with a decrease of the Bcl2/BAX ratio, activation of caspase-3 and cleavage of PARP. Furthermore, EM011 induced downregulation of survivin expression over time of treatment. Abrogation of survivin led to an increase of cell death whereas, overexpression caused decreased apoptosis.</p> <p>Conclusion</p> <p>These <it>in vitro </it>data suggest that EM011 mediates antiproliferative and proapoptotic activity in non-small cell A549 lung cancer cells by impeding cell-cycle progression and attenuating antiapoptotic signaling circuitries (viz. Bcl2, survivin). The study provides evidence for the potential usefulness of EM011 in chemotherapy of lung cancer.</p

Side population rather than CD133+ cells distinguishes enriched tumorigenicity in hTERT-immortalized primary prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Subpopulations of cancer cells with the capacity of generating solid tumors have been characterized. In various cancer types, including prostate cancer cells, a side population (SP) and CD133-expressing cells have been proposed as containing a population cancer cells with stem-like ability. Therefore the aim of this work was to determine, in prostate cancer cell lines, the frequency and tumorigenic potential of SP and CD133+ cells.</p> <p>Results</p> <p><it>In vitro </it>2D colony-forming assay and sphere-forming assay, Flow cytometry analysis and magnetic cell sorting were utilized to sort CD133+, CD133- and Side population (SP) cells. Our findings indicate that CD44 and integrin α-6 are uniformly expressed in the hTERT cell lines; however, CD133 is expressed only in a small population (< 0.1%). FACS-sorted CD133+ and CD133- cells exhibited similar tumorigenicity <it>in vitro </it>and <it>in vivo</it>. Additionally, for the hTERT cells, SP rather than CD133 expression showed an 8-fold enhanced tumorigenic potential. The data suggest that SP cells, rather than those with CD133 marker, contain the rare population of CSC capable of producing prostate tumors.</p> <p>Conclusion</p> <p>Collectively, our data suggest that although CD133 is expressed only in a small population of hTERT-immortalized prostate cancer cells, it is not likely to be associated with stem cells, as CD133- and CD133+ cells exhibited similar tumorigenicity. However, SP isolated cells, appear to be enriched with tumorigenic stem-like cells capable of generating palpable tumors.</p

Complement C3 variant and the risk of age-related macular degeneration

Background: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.Methods: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.Results: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9 x 10(sup -5)) and the Scottish group (244 cases and 351 controls, P=5.0 x 10(sup -5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.Conclusions: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease

Tumor-Stromal Interactions Influence Radiation Sensitivity in Epithelial- versus Mesenchymal-Like Prostate Cancer Cells

HS-27a human bone stromal cells, in 2D or 3D coultures, induced cellular plasticity in human prostate cancer ARCaPE and ARCaPM cells in an EMT model. Cocultured ARCaPE or ARCaPM cells with HS-27a, developed increased colony forming capacity and growth advantage, with ARCaPE exhibiting the most significant increases in presence of bone or prostate stroma cells. Prostate (Pt-N or Pt-C) or bone (HS-27a) stromal cells induced significant resistance to radiation treatment in ARCaPE cells compared to ARCaPM cells. However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in both ARCaPE- and ARCaPM-cocultured cells. Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin. These cell adhesion molecules such as E-cadherin and integrin alpha v in cancer cells induce cell survival signals and mediate resistance to cancer treatments such as radiation

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

Lack of immune system cells or impairment in differentiation of immune cells is the basis for many chronic diseases. Metabolic changes could be the root cause for this immune cell impairment. These changes could be a result of altered transcription, cytokine production from surrounding cells, and changes in metabolic pathways. Immunity and mitochondria are interlinked with each other. An important feature of mitochondria is it can regulate activation, differentiation, and survival of immune cells. In addition, it can also release signals such as mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS) to regulate transcription of immune cells. From current literature, we found that mitochondria can regulate immunity in different ways. First, alterations in metabolic pathways (TCA cycle, oxidative phosphorylation, and FAO) and mitochondria induced transcriptional changes can lead to entirely different outcomes in immune cells. For example, M1 macrophages exhibit a broken TCA cycle and have a pro-inflammatory role. By contrast, M2 macrophages undergo β-oxidation to produce anti-inflammatory responses. In addition, amino acid metabolism, especially arginine, glutamine, serine, glycine, and tryptophan, is critical for T cell differentiation and macrophage polarization. Second, mitochondria can activate the inflammatory response. For instance, mitochondrial antiviral signaling and NLRP3 can be activated by mitochondria. Third, mitochondrial mass and mobility can be influenced by fission and fusion. Fission and fusion can influence immune functions. Finally, mitochondria are placed near the endoplasmic reticulum (ER) in immune cells. Therefore, mitochondria and ER junction signaling can also influence immune cell metabolism. Mitochondrial machinery such as metabolic pathways, amino acid metabolism, antioxidant systems, mitochondrial dynamics, mtDNA, mitophagy, and mtROS are crucial for immune functions. Here, we have demonstrated how mitochondria coordinate to alter immune responses and how changes in mitochondrial machinery contribute to alterations in immune responses. A better understanding of the molecular components of mitochondria is necessary. This can help in the development of safe and effective immune therapy or prevention of chronic diseases. In this review, we have presented an updated prospective of the mitochondrial machinery that drives various immune responses

Identification of Distinct Heterogenic Subtypes and Molecular Signatures Associated with African Ancestry in Triple Negative Breast Cancer Using Quantified Genetic Ancestry Models in Admixed Race Populations

Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n = 42) and European American (EA, n = 33) women. RNA sequencing data were analyzed to measure changes in genome-wide expression, and we utilized logistic regressions to identify ancestry-associated gene expression signatures. Using SNVs identified from our RNA sequencing data, global ancestry was estimated. We identified 156 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated in TCGA data. In AA patients, there was a higher incidence of basal-like two tumors and altered TP53, NFB1, and AKT pathways. The distinct distribution of TNBC subtypes and altered oncologic pathways show that the ethnic variations in TNBCs are driven by shared genetic ancestry. Thus, to appreciate the molecular diversity of TNBCs, tumors from patients of various ancestral origins should be evaluated

Phage Ligands for Identification of Mesenchymal-Like Breast Cancer Cells and Cancer-Associated Fibroblasts

Epithelial to mesenchymal transition (EMT) is believed to be crucial for primary tumors to escape their original residence and invade and metastasize. To properly define EMT, there is a need for ligands that can identify this phenomenon in tumor tissue and invivo. A phage-display selection screening was performed to select novel binding phage peptides for identification of EMT in breast cancer. Epithelial breast cancer cell line, MCF-7 was transformed to mesenchymal phenotype by TGF-β treatment and was used for selection. Breast fibroblasts were used for subtractive depletion and breast cancer metastatic cell lines MDA-MB-231, T47D-shNMI were used for specificity assay. The binding peptides were identified, and their binding capacities were confirmed by phage capture assay, phage-based ELISA, immunofluorescence microscopy. The phage peptide bearing the 7-amino acid sequence, LGLRGSL, demonstrated selective binding to EMT phenotypic cells (MCF-7/TGF-β and MDA-MB-231) as compared to epithelial subtype, MCF-7, T47D and breast fibroblasts (Hs578T). The selected phage was also able to identify metastatic breast cancer tumor in breast cancer tissue microarray (TMA). These studies suggest that the selected phage peptide LGLRGSL identified by phage-display library, showed significant ability to bind to mesenchymal-like breast cancer cells/ tissues and can serve as a novel probe/ligand for metastatic breast cancer diagnostic and imaging