bluuebunny/crossref_metadata_2025 huggingface dataset:
GLOBAL AND PARTIAL PHASE SYNCHRONIZATIONS IN ARRAYS OF PIECEWISE LINEAR TIME-DELAY SYSTEMS
Authors: SURESH R. , SENTHILKUMAR D. V. , LAKSHMANAN M. , KURTHS J.
Published: August 2012

In this paper, we report the phenomena of global and partial phase synchronizations in linear arrays of unidirectionally coupled piecewise linear time-delay systems. In particular, in a linear array with open end boundary conditions, global phase synchronization (GPS) is achieved by a sequential synchronization of local oscillators in the array as a function of the coupling strength (a second order transition). Several phase synchronized clusters are also formed during the transition to GPS at intermediate values of the coupling strength, as a prelude to full scale synchronization. On the other hand, in a linear array with closed end boundary conditions (ring topology), partial phase synchronization (PPS) is achieved by forming different groups of phase synchronized clusters above some threshold value of the coupling strength (a first order transition) where they continue to be in a stable PPS state. We confirm the occurrence of both global and partial phase synchronizations in two different piecewise linear time-delay systems using various qualitative and quantitative measures in three different frameworks, namely, using explicit phase, recurrence quantification analysis and the framework of localized sets.
CONTEXT-FREE REWRITING SYSTEMS AND WORD-HYPERBOLIC STRUCTURES WITH UNIQUENESS
Authors: CAIN ALAN J. , MALTCEV VICTOR
Published: August 2012

This paper proves that any monoid presented by a confluent context-free monadic rewriting system is word-hyperbolic. This result then applied to answer a question asked by Duncan and Gilman by exhibiting an example of a word-hyperbolic monoid that does not admit a word-hyperbolic structure with uniqueness (that is, in which the language of representatives maps bijectively onto the monoid).
SIEVE METHODS IN GROUP THEORY III: Aut(Fn)
Authors: LUBOTZKY ALEXANDER , MEIRI CHEN
Published: August 2012

Let π : Aut (Fn) → Aut (ℤn) be the epimorphism induced by the isomorphism [Formula: see text] and define [Formula: see text]. We prove that the subset of [Formula: see text] consisting of all non-irreducible with irreducible powers and all non-hyperbolic elements is exponentially small.
REDUCTION OF GAIT ABNORMALITIES IN TYPE 2 DIABETIC PATIENTS DUE TO PHYSICAL ACTIVITY: A QUANTITATIVE EVALUATION BASED ON STATISTICAL GAIT ANALYSIS
Authors: AGOSTINI VALENTINA , DE LUCA RICCARDO , MANSIN LUCIANO CORGIAT , KNAFLITZ MARCO
Published: August 2012

The aim of this study is the objective assessment of gait abnormalities in diabetic patients and the quantification of the benefits of physical activity in improving gait quality. Patients were equipped with foot-switches and knee goniometers and were asked to walk at their natural pace for 2.5 min. A statistical gait analysis was performed extracting from hundreds of strides the "atypical" cycles, i.e., the cycles which do not show the usual sequence of gait phases (heel contact, flat foot contact, push off, swing), the duration of the heel contact phase, and the knee kinematics in the sagittal plane. A sample population of 27 non-neuropathic type 2 diabetic patients was examined before and after attending a light-intensity physical activity program that lasted for four months. A fuzzy classifier was used to assign a score to the gait abnormalities of each patient in baseline conditions and after the program completion. More than 50% of the subjects showed a significant reduction in their gait abnormalities and on average, the most frequent improvements were the reduction of atypical cycles and heel contact duration. Furthermore, we found that in basal conditions, the left side is more affected by gait abnormalities than the right (P < 0.003).
A THEORETICAL STUDY ON THE INFRARED SPECTRA, THERMODYNAMIC FUNCTIONS, AND DETONATION PARAMETERS FOR THE –CN, –NC, –NNO2and –ONO2DERIVATIVES OF HNS
Authors: WANG GUI-XIANG , GONG XUE-DONG , LIU YAN , XIAO HE-MING
Published: August 2012

The cyano (–CN), isocyano (–NC), nitramine (–NNO2), and nitrate (–ONO2) derivatives of HNS has been studied in this work at the B3LYP/6-31G* level of density functional theory. Their IR spectra were predicted and assigned by vibrational analysis. Based on the frequencies scaled by 0.96 and the principle of statistic thermodynamics, the thermodynamic functions were evaluated. It is found that the thermodynamic functions linearly increase with the number of – CN , – NC , – NNO2, and – ONO2groups, as well as the temperature. The contribution of various substitutents to the thermodynamic functions has the order of – ONO2> –NNO2> –NC > –CN . Detonation properties were evaluated using the modified Kamlet–Jacobs equations based on the calculated densities and heats of formation. Compared with the commonly used explosives (RDX and HMX), 3,3′,5-trinitramine-2,2′,4,4′,6,6′-Hexanitrostilbene, 3,3′,5,5′-tetranitramine-2,2′, 4,4′,6,6′-Hexanitrostilbene, 3,3′,5-trinitrate-2,2′,4,4′,6,6′-Hexanitrostilbene, and 3,3′,5,5′-tetranitrate-2,2′, 4,4′,6,6′-Hexanitrostilbene have better detonation performance and may be potential candidates of high energy density compounds.
MORPHOLOGICAL PROPERTIES OF PYRROLE AND PHENYLENE ROD–COIL DIBLOCK COPOLYMERS BY DISSIPATIVE PARTICLE DYNAMICS
Authors: YILDIRIM EROL , YURTSEVER MINE
Published: August 2012

Poly (para-phenylene)s (PPP) and polypyrroles (PPy) are important members of the conducting polymers. Rod–coil type diblock copolymers formed by coupling of PPP and PPy rigid blocks with polycaprolactone (PCL), polystyrene (PS) and polymethylmethacrylate (PMMA) coil blocks were modeled and morphological properties have been studied by a coarse grained simulation method at the mesoscale. Geometry optimizations and the atomic charge calculations were done quantum mechanically to obtain the input parameters for the mesoscale dynamics simulations. The accurate mixing energies and the Flory–Huggins interaction parameters between the monomers of polymers were calculated and used to study the phase behaviors and the morphologies of the copolymers as a function of type and weight percentages of the blocks by Dissipative Particle Dynamics (DPD) simulations. We showed that the methodology employed took into account not only the interaction parameter and chain length of the blocks but also the chemical structure of the polymers and it could be used to produce the phase diagram of the copolymers which has importance for the industrial applications of such materials. Among the studied copolymers, the most suitable one for thin layer applications was predicted to be PPP–b–PCL in which PPP forms lamellar and cylindrical phases in the PCL matrix if amount of PPP rod block is below 50 wt%.
Emotion-Aware Assistive System for Humanistic Care Based on the Orange Computing Concept
Authors: Wang Jhing-Fa , Chen Bo-Wei , Fan Wei-Kang , Li Chih-Hung
Published: August 2012

Mental care has become crucial with the rapid growth of economy and technology. However, recent movements, such as green technologies, place more emphasis on environmental issues than on mental care. Therefore, this study presents an emerging technology called orange computing for mental care applications. Orange computing refers to health, happiness, and physiopsychological care computing, which focuses on designing algorithms and systems for enhancing body and mind balance. The representative color of orange computing originates from a harmonic fusion of passion, love, happiness, and warmth. A case study on a human-machine interactive and assistive system for emotion care was conducted in this study to demonstrate the concept of orange computing. The system can detect emotional states of users by analyzing their facial expressions, emotional speech, and laughter in a ubiquitous environment. In addition, the system can provide corresponding feedback to users according to the results. Experimental results show that the system can achieve an accurate audiovisual recognition rate of 81.8% on average, thereby demonstrating the feasibility of the system. Compared with traditional questionnaire-based approaches, the proposed system can offer real-time analysis of emotional status more efficiently.
Bacterial Foraging‐Tabu Search Metaheuristics for Identification of Nonlinear Friction Model
Authors: Sarasiri Nuapett , Suthamno Kittiwong , Sujitjorn Sarawut
Published: August 2012

This paper proposes new metaheuristic algorithms for an identification problem of nonlinear friction model. The proposed cooperative algorithms are formed from the bacterial foraging optimization (BFO) algorithm and the tabu search (TS). The paper reports the search comparison studies of the BFO, the TS, the genetic algorithm (GA), and the proposed metaheuristics. Search performances are assessed by using surface optimization problems. The proposed algorithms show superiority among them. A real‐world identification problem of the Stribeck friction model parameters is presented. Experimental setup and results are elaborated.
Highlights for the Management of a Child with Hypertension
Authors: Seikaly Mouin G.
Published: August 2012

Over the past several decades, childhood hypertension has undergone a considerable conceptual change, as hypertension is a predictor of future development of cardiovascular disease in adults. Childhood hypertension has distinctive features that distinguish it from hypertension in adults. Pediatric hypertension is often secondary. It is widely believed that therapeutic intervention at an early age favorably modifies the long-term outcome of hypertension. Despite its significance as a cause for morbidity, childhood hypertension is underdiagnosed and less studied with many basic issues remaining contentious.
Complete Response of Liver Metastasis of Gastric Cancer Treated by S-1 Chemoradiotherapy: A Case Report
Authors: Miyazawa Tomonori , Ebe Kazuyu , Koide Norihiko , Fujita Nobuhiro
Published: August 2012

This paper presents a case of suspected liver metastasis of gastric cancer and a virtual complete response to S-1 chemoradiotherapy. A 69-year-old man underwent distal gastrectomy for gastric cancer in 2008. Multiple liver metastases occurred in 2009. He underwent 15 courses of S-1 therapy and radiation therapy (37.5 Gy). Abdominal computed tomography showed virtual complete disappearance of liver metastasis after chemoradiotherapy. Hence, this case was interpreted as a complete response. No sign of recurrence was noted 18 months after complete response was confirmed. S-1 chemoradiotherapy is likely to be effective in treating patients with liver metastases of gastric cancer.
Sponge Farming Trials: Survival, Attachment, and Growth of Two Indo-Pacific Sponges,Neopetrosiasp. andStylissa massa
Authors: Schiefenhövel Karin , Kunzmann Andreas
Published: August 2012

Sponges, an important part of the reef ecosystem, are of commercial value for public aquaria, pharmacology and chemistry. With the growing demand for sponges, natural resources are at risk of being overexploited. Growing of sponges in artificial or semi natural farms is an alternative. In this study different farming methods were tested on two Indo-Pacific sponge species,Neopetrosiasp. andStylissa massa. Survival, growth and attachment ability were observed with different substrates (suspended ropes, coral boulders and artificial substrate), two types of aquaria with different water volume and two different field sites in Indonesia. The two species responded differently to their individual locations and environmental stresses. Survival, growth and attachment rates ofNeopetrosiasp. at the field site are depending on the cultivation method, we found highest volume increment (27–35%) for a horizontal line in the field. Whereas the volume increase forS. massadid not show any differences for the different transplantation methods,Neopetrosiasp. generally showed higher rates thanS. massa. Further aquaria experiments, for example, on nutrient supply, should be tested to receive more detailed data about sponges, particularly because almost all fragments of both species showed a decline or steady state in mean length.
A Concept for Selection of Codon-Suppressor tRNAs Based on Read-Through Ribosome Display in anIn VitroCompartmentalized Cell-Free Translation System
Authors: Ogawa Atsushi , Hayami Masayoshi , Sando Shinsuke , Aoyama Yasuhiro
Published: August 2012

Here is presented a concept forin vitroselection of suppressor tRNAs. It uses a pool of dsDNA templates in compartmentalized water-in-oil micelles. The template contains a transcription/translation trigger, an amber stop codon, and another transcription trigger for the anticodon- or anticodon loop-randomized gene for tRNASer. Upon transcription are generated two types of RNAs, a tRNA and a translatable mRNA (mRNA-tRNA). When the tRNA suppresses the stop codon (UAG) of the mRNA, the full-length protein obtained upon translation remains attached to the mRNA (read-through ribosome display) that contains the sequence of the tRNA. In this way, the active suppressor tRNAs can be selected (amplified) and their sequences read out. The enriched anticodon (CUA) was complementary to the UAG stop codon and the enriched anticodon-loop was the same as that in the natural tRNASer.
A Hybrid Power Series Artificial Bee Colony Algorithm to Obtain a Solution for Buckling of Multiwall Carbon Nanotube Cantilevers Near Small Layers of Graphite Sheets
Authors: Noghrehabadi Aminreza , Ghalambaz Mohammad , Ghalambaz Mehdi , Ghanbarzadeh Afshin
Published: August 2012

A hybrid power series and artificial bee colony algorithm (PS-ABC) method is applied to solve a system of nonlinear differential equations arising from the distributed parameter model of multiwalled carbon nanotube (MWCNT) cantilevers in the vicinity of thin and thick graphite sheets subject to intermolecular forces. The intermolecular forces are modeled using van der Waals forces. A trial solution of the differential equation is defined as sum of two polynomial parts. The first part satisfies the boundary conditions and does contain two adjustable parameters. The second part is constructed as not to affect the boundary conditions, which involves adjustable parameters. The ABC method is applied to find adjustable parameters of trial solution (in first and second part). The obtained results are compared with numerical results as well as analytical solutions those reported in the literature. The results of the presented method represent a remarkable accuracy in comparison with numerical results. The minimum initial gap and the detachment length of the actuator that does not stick to the substrate due to the intermolecular forces, as important parameters in pull-in instability of MWCNT actuator, are evaluated by obtained power series.
Periodic Solutions in Shifts δ± for a Nonlinear Dynamic Equation on Time Scales
Authors: Çetin Erbil , Topal F. Serap
Published: August 2012

Let 𝕋 ⊂ ℝ be a periodic time scale in shifts δ±. We use a fixed point theorem due to Krasnosel′skiĭ to show that nonlinear delay in dynamic equations of the form , has a periodic solution in shifts δ±. We extend and unify periodic differential, difference, h‐difference, and q‐difference equations and more by a new periodicity concept on time scales.
Atherosclerosis in Juvenile Idiopathic Arthritis
Authors: Jednacz Ewa , Rutkowska-Sak Lidia
Published: August 2012

Atherosclerosis is a chronic inflammatory disease of the arteries. Clinical consequences of the atherosclerotic process occur in the adult population, however atherosclerotic process begins in childhood. The classic risk factors for atherosclerosis include obesity, dyslipidaemia, age, gender or family history. In recent years, attention has been drawn to the similarity between atherosclerotic inflammatory processes and inflammatory changes in the course of systemic connective tissue disease, in particular systemic lupus etythematosus (SLE) or rheumatoid arthritis (RA). There is also observed the similarity of the pathogenetic background of development of atherosclerosis and juvenile idiopathic arthritis (JIA). Elevated levels of pro-inflammatory cytokines are observed in the course of juvenile idiopathic arthritis. Also homocysteine concentrations, which may play a significant role in the development of atherosclerotic lesions, are observed higher in patients with JIA. Some studies revealed higher carotid intima-media thickness (IMT) index values in children with JIA. In view of the fact that atherosclerotic process begins as early as in childhood, the introduction of appropriate preventive measures in children is a matter of utmost importance.
Genetic Innovation in Vertebrates: Gypsy Integrase Genes and Other Genes Derived from Transposable Elements
Authors: Chalopin Domitille , Galiana Delphine , Volff Jean-Nicolas
Published: August 2012

Due to their ability to drive DNA rearrangements and to serve as a source of new coding and regulatory sequences, transposable elements (TEs) are considered as powerful evolutionary agents within genomes. In this paper, we review the mechanism of molecular domestication, which corresponds to the formation of new genes derived from TE sequences. Many genes derived from retroelements and DNA transposons have been identified in mammals and other vertebrates, some of them fulfilling essential functions for the development and survival of their host organisms. We will particularly focus on the evolution and expression of Gypsy integrase (GIN) genes, which have been formed from ancient event(s) of molecular domestication and have evolved differentially in some vertebrate sublineages. What we describe here is probably only the tip of the evolutionary iceberg, and future genome analyses will certainly uncover new TE-derived genes and biological functions driving genetic innovation in vertebrates and other organisms.
Diet and Aging
Authors: Ribarič Samo
Published: August 2012

Nutrition has important long-term consequences for health that are not only limited to the individual but can be passed on to the next generation. It can contribute to the development and progression of chronic diseases thus effecting life span. Caloric restriction (CR) can extend the average and maximum life span and delay the onset of age-associated changes in many organisms. CR elicits coordinated and adaptive stress responses at the cellular and whole-organism level by modulating epigenetic mechanisms (e.g., DNA methylation, posttranslational histone modifications), signaling pathways that regulate cell growth and aging (e.g., TOR, AMPK, p53, and FOXO), and cell-to-cell signaling molecules (e.g., adiponectin). The overall effect of these adaptive stress responses is an increased resistance to subsequent stress, thus delaying age-related changes and promoting longevity. In human, CR could delay many diseases associated with aging including cancer, diabetes, atherosclerosis, cardiovascular disease, and neurodegenerative diseases. As an alternative to CR, several CR mimetics have been tested on animals and humans. At present, the most promising alternatives to the use of CR in humans seem to be exercise, alone or in combination with reduced calorie intake, and the use of plant-derived polyphenol resveratrol as a food supplement.
Regular Physical Exercise as a Strategy to Improve Antioxidant and Anti-Inflammatory Status: Benefits in Type 2 Diabetes Mellitus
Authors: Teixeira de Lemos Edite , Oliveira Jorge , Páscoa Pinheiro João , Reis Flávio
Published: August 2012

Over the last 30 years the combination of both a sedentary lifestyle and excessive food availability has led to a significant increase in the prevalence of obesity and aggravation of rates of metabolic syndrome and type 2 diabetes mellitus (T2DM). Several lines of scientific evidence have been demonstrating that a low level of physical activity and decreased daily energy expenditure leads to the accumulation of visceral fat and, consequently, the activation of the oxidative stress/inflammation cascade, which underlies the development of insulin resistant T2DM and evolution of micro, and macrovascular complications. This paper focuses on the pathophysiological pathways associated with the involvement of oxidative stress and inflammation in the development of T2DM and the impact of regular physical exercise (training) as a natural antioxidant and anti-inflammatory strategy to prevent evolution of T2DM and its serious complications.
Abstract 1081: Expression of TGFβ3 and its effects on migratory and invasive behavior in prostate cancer cells: Involvement of PI3K/Akt pathway
Authors: Walker Lindsey , Millena Ana Cecilia , Strong Nicole , Khan Shafiq
Published: August 2012

Transforming Growth Factor-β (TGFβ) is a secreted protein that is involved in the regulation of many cellular processes and has been implicated as a factor in cancer cell invasion and metastasis. Studies have indicated that different TGFβ isoforms may exert differential effects on cancer cells during different stages of the disease, however very little is known about the expression patterns of the 3 isoforms in prostate cancer. Non-traditional signaling pathways including PI3-kinase have been associated with TGFβ-mediated effects on cancer cell invasion and metastasis. Whether or not TGFβ isoforms play a differential role in migration and invasion of prostate cancer, and act through PI3-Kinase, has not been investigated. In the present study, we have carried out expression analysis of TGFβ isoforms and signaling components in cell line models representing different stages of prostate cancers and studied the differential effects of specific isoforms on migratory, invasive behavior and induction of the PI3-Kinase and MAPK/ERK pathways. TGFβ1 and TGF-β3 were expressed in all cell lines, with TGFβ3 increasing in metastatic cell lines. TGFβ1 and TGFβ3 induced motility and invasive behavior in PC3 cells, with TGFβ3 being more potent in inducing invasive behavior. TGF-β3 caused a significant increase in the phosphorylation of AKT (pAKT), a downstream target of PI3-Kinase, in PC3 cells. LY294002, a PI3-kinase inhibitor, blocked this induced migration and phosphorylation of AKT. Inhibitors of TGFβRI (SB431524) and Smad-3 (SIS3) blocked TGF-β induced motility and TGFβ isoform induced pAKT. There was no differential isoform effect on the phosphorylation of ERK (pERK). PD98059, a MAPK/ERK inhibitor, did inhibit any TGFβ induced migration and pERK, but did not affect isoform induced pAKT. Furthermore, TGFβ isoforms may be differentially phosphorylating Smad-2 and Smad-3 in PC3 cells. Based on these results, we conclude that TGFβ3 is expressed in metastatic prostate cancer cell lines and is involved in induction of invasive behavior in these cells. Furthermore, these effects of TGFβ3 are mediated via the PI3-Kinase pathway and are TGFβRI and Smad-3 dependent. Grant support: MBRS-RISE 2R25GM060414, NIH 1P20MD002285-02 and RCMI G12RR03602

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1081. doi:1538-7445.AM2012-1081
Abstract 1085: TGFBR2-dependent alterations of glycosylation in MSI colorectal cancer
Authors: Lee Jennifer , Schoenig Kai , Ball Claudia R. , Glimm Hanno , Kopitz Juergen , Gebert Johannes
Published: August 2012

Aberrant glycosylation is a common feature of many malignancies including colorectal cancers. About 15% of colorectal cancers show the microsatellite instability (MSI) phenotype that is associated with a high frequency of biallelic frameshift mutations in the exon 3 coding mononucleotide microsatellite of the Transforming growth factor beta receptor 2 (TGFBR2) gene. If and how disruption of normal TGFBR2 signaling in these MSI colorectal cancer cells is linked to altered glycan pattern is largely unexplored. To address this issue we used the TGFBR2-deficient MSI colon carcinoma cell line HCT116 as a model system. Stable clones enabling doxycycline-inducible expression of wildtype TGFBR2 transgene were generated by recombinase-mediated cassette exchange (RMCE). In two independent clones dox-inducible expression of wildtype TGFBR2 protein and functional reconstitution of TGFBR2-mediated signal transduction as recognized by target gene regulation (SMAD7, SERPINE, c-myc) and Phospho-SMAD2 analysis was confirmed by Western blot and qRT-PCR analysis. Metabolic labeling experiments using the sialic acid precursor 3H-N-acetyl-mannosamine revealed a significant decline of 30% and hence newly synthesized sialoglycoproteins in TGFBR2 expressing cells. Therefore, our findings demonstrate that this model system can be used as a versatile tool to study TGFBR2-dependent effects. Furthermore, our data reveal a TGFBR2 gene-dependent aberrant glycosylation pattern in the MSI colon cell line HCT116.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1085. doi:1538-7445.AM2012-1085
Abstract 1095: Comprehensive miRNA profiling of taxane-resistant human breast and ovarian cancer cell lines using the SmartChip real-time PCR system
Authors: Duran George E. , Wang Cindy Y. , Francisco E. Brian , Wong Kee , Robinson Nicole , Sikic Branimir I.
Published: August 2012

MiRNAs are post-transcriptional regulators of cell proliferation, tissue differentiation, embryonic development and apoptosis. We profiled the expression of miRNAs in a panel of taxane-resistant human breast and ovarian cancer cell lines using the recently developed WaferGen SmartChip System. Four breast cancer cell lines (MCF-7, BT-549, MDA-MB-231 and T-47D) and four ovarian cancer cell lines (1A9/A2780, ES-2, MES-OV and OVCAR-3) were selected for resistance to either docetaxel or paclitaxel alone or co-selected with taxane in the presence of the P-glycoprotein inhibitor, PSC-833 (valspodar, 2 µM). All of the variants established by exposure to taxanes alone are MDR1/ABCB1(+), whereas the resistance observed in the co-selected variants is not transporter-mediated. We have previously reported elevated class III β-tubulin (TUBB3) content, reduced BRCA1 and elevated CDKN1A (p21) in the majority of the non-MDR1 taxane variants relative to parental controls. For miRNA profiling, total RNA was analyzed using the SmartChip Human MicroRNA Panel version 2.0 containing 1,150 unique real-time PCR reactions in quadruplicate for a total of ∼4,600 reactions per sample. Following ligation to a miRNA cloning linker (Integrated DNA Technology, Coraville, IA), the equivalent of 500 ng of starting RNA per sample was added to a one-step cDNA and real-time PCR cocktail (Applied Biosystems, Foster City, CA). The total volume per reaction was 100 nL containing an equivalent of 96 pg of RNA. Forty cycles of real-time PCR were performed on the SmartChip Cycler and a quality screen was performed to remove any outlier data. MiRNA profiling is complete and an analysis of these data revealed a clear separation between the two sets of non-MDR1 variants based on tumor type (breast vs. ovarian), and selection conditions (non-MDR1 vs. parental). We observed reduced miR-200 family expression in the majority of these taxane-resistant variants, consistent with published findings that miR-200c directly targets and suppresses TUBB3. Furthermore, Significance Analysis of Microarrays (SAM) software identified reduced miR-635, miR-296-3P, and let-7B in both MDR1(+) and MDR1(-) variants of breast origin, and elevated let-7 family (let-7B, let-7F and let-7I) and reduced miR-1225-5P and miR-4286 in the ovarian cell lines relative to parental controls. The functional significance of these observations will be studied by introducing miRNA inhibitors or mimics specific to key alterations with the goal of sensitizing cells to taxanes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1095. doi:1538-7445.AM2012-1095
Abstract 1096: Loss of miR-200 family of microRNAs confers resistance to tamoxifen in human breast cancer cells
Authors: Manavalan Tissa T. , Klinge Carolyn M.
Published: August 2012

MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level. MiR-200 family includes two clusters i.e. miR-200 a/200b/ 429 and miR-200c/141 encoded on chromosome 1 and chromosome 12, respectively. Previous studies have demonstrated that miR-200 family targets ZEB1, a transcription factor that promotes epithelial-to-mesenchymal transition (EMT). Previous reports demonstrated a loss of miR-200a, b and c in MDA-MB-231 breast cancer cells resulted in EMT. These studies also showed a concomitant increase in ZEB1 protein. We observed lower miR-200a, b and c expression in estrogen-independent LCC1 and endocrine-resistant LCC2, LCC9, and LY2 compared to the parental, endocrine-sensitive MCF-7 human breast cancer cell line. We found that ZEB1 protein is expressed in tamoxifen-resistant LY2 cells but not in tamoxifen-sensitive MCF-7 cells. LY2 cells did not express E-cadherin, a ZEB1 target which is also a marker for epithelial phenotype. This is the first demonstration that LY2 cells have undergone EMT as part of their endocrine-resistant phenotype. These studies indicate that loss of miR-200 and a corresponding increase in ZEB1 protein is an indicator of tamoxifen-resistance in breast cancer cells. Further, in concordance with higher miR-221/222, there was decreased expression of estrogen receptor alpha (ERα) mRNA and protein in LY2 cells when compared to MCF-7 cells. We hypothesize that ERα expression is decreased in cells that have undergone EMT and this subsequently leads to endocrine-resistance and an invasive phenotype. Future studies will determine whether re-expression of ERα or knockdown of ZEB1 restores TAM-sensitivity in LY2 cells. By evaluating the expression of E-cadherin, it will be possible to determine whether restoration of ERα or knockdown of ZEB1 can revert cells from a mesenchymal to an epithelial phenotype. If validated, loss of miR-200 could be used as a marker of poor prognosis in TAM-resistant breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1096. doi:1538-7445.AM2012-1096
Abstract 1100: RNA aptamers as highly specific inhibitors of three human RTKs including Axl, EGFR and PDGFR
Authors: Esposito Carla Lucia , Camorani Simona , Iaboni Margherita , Condorelli Gerolama , de Franciscis Vittorio , Cerchia Laura
Published: August 2012

Aptamers are single-stranded oligonucleotides able to bind with high affinity to specific protein or non-protein targets by folding into complex tertiary structures. They have proven useful as reagents for identifying cell surface proteins and for cell typing. Further, their high specificity and low toxicity render them a valid alternative to antibodies for in vivo targeted recognition as therapeutics or delivery agents for nanoparticles, small interfering RNAs, chemotherapeutics and molecular imaging probes. We have generated aptamers as biologically active ligands for cancer cell surface proteins. The approach has been applied to different tumor systems with the generation of different 2′fluoro-pyrimidines containing RNA aptamers that specifically bind to the ectodomain of human receptor tyrosine kinases (RTKs). Three of these aptamers (named GL21, CL4 and M4) bind at high affinity and high specificity to Axl, EGFR and PDGFR, respectively. Following binding, the aptamers hamper ligand-dependent receptor dimerization and autophosphorylation. All the selected aptamers bind to the correspondent protein target with Kd values in the order of 10 nM and show excellent correlation between cell surface binding and the expression of the target on the cell surface. The anti-Axl GL21 aptamer strongly inhibits cell migration and invasion in vitro, reduces the number of colonies in soft agar colony formation assay and interferes with spheroid formation by malignant glioma U87MG cells. Furthermore, it strongly inhibits tumor growth in mouse xenograft models of human cancer. The anti-EGFR CL4 aptamer strongly induces apoptosis of EGFR-positive cells and at low doses it works even on cells that are resistant to the most frequently used EGFR-inhibitors, as gefitinib and cetuximab. In addition, the combined treatment of cetuximab with the aptamer shows clear synergy in vitro and in vivo. Moreover, we demonstrated that GL21 and M4 aptamer not only bind to Axl and PDGFR, respectively, but also internalize within the target cell thus they can be used as cargoes for tissue specific internalization. The generation of RNA-chimeras (aptamer/miRNA) is on going in our laboratory.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1100. doi:1538-7445.AM2012-1100
Abstract 1107: MicroRNA-182 acts as a chemosensitizer in GBM by repressing Bcl2L12
Authors: Kouri Fotini M. , Wu Yongfei , Chin Lynda , Stegh Alexander H.
Published: August 2012

Glioblastoma Multiforme (GBM) is the most prevalent and aggressive brain tumor, exhibiting high mortality rate and increased resistance to current forms of treatment. GBM development has been linked to deregulation of several signaling cascades involved in cell proliferation and apoptosis. Bcl2-Like 12 (Bcl2L12) is a multi-functional glioma oncoprotein, which is over-expressed in the majority of GBM and regulates tumor progression and resistance to therapy-induced apoptosis. We identified, Bcl2L12 as a potent inhibitor of post-mitochondrial caspases and the p53 tumor suppressor. To dissect the cellular mechanisms that regulate Bcl2L12 expression and function, we interrogated whether Bcl2L12 is under the control of microRNAs (miRs). In silico analysis of 272 primary GBM samples of the TCGA dataset aimed to identify miRs displaying expression levels that anti-correlate with Bcl2L12 mRNA abundance, as such candidates represent potential Bcl2L12-targeting miRs. This approach revealed a significant anti-correlation between Bcl2L12 mRNA and miR-182 expression, preferentially in the proneural subtype, a GBM class with established low Bcl2L12 genomic amplification and mRNA expression and a longer survival compared to patients with mesenchymal, neural or classical tumors. Enforced expression of miR182 in various glioma cell lines confirmed robust downregulation of Bcl2L12 mRNA and protein levels, identified the miR-182 binding site within the 3′UTR of Bcl2L12, and documented that miR-mediated downregulation of Bcl2L12 is highly specific for miR182, but not for other related miRs, such as miR-96 and miR-183. Transfection of pre-miR-182 significantly sensitized cells to various anti-glioma therapeutics, via enhancement of effector caspase activation. Furthermore, it was demonstrated that p53 regulates miR-182 levels. Taken together, our studies confirmed a Bcl2L12- miR-182 axis on genetic and biological levels, and identified miR182 as a potential therapeutic agent to halt GBM progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1107. doi:1538-7445.AM2012-1107
Abstract 1109: Pleiotropic actions of miR-153 support colorectal cancer progression through enhanced invasion and platinum based chemotherapy resistance
Authors: Mirnezami Alex H. , Zhang Lei , Pickard Karen , Jenei Veronika , Bullock Marc , Strefford John , Mitter Richard , Kelly Gavin , Primrose John N. , Thomas Gareth , Packham Graham
Published: August 2012

Background & Aims MicroRNAs (miRNA) contribute to carcinogenesis, however comparatively less is understood about their role in cancer progression. The aim of this study was to evaluate miRNA expression during progression of colorectal cancer (CRC) and to identify novel miRNA functions. Methods and results Using miRNA microarray profiling of a human cellular model of CRC progression, we have found highly expressed levels of miR-153 in more advanced tumour stages. MiR-153 upregulation was further verified by qRT-PCR. Subsequently, using laser capture microdissected human CRC tumour epithelium and real-time PCR based TaqMan® profiling, we have demonstrated that miR-153 is upregulated in primary human CRC compared with normal colonic epithelium (p<0.0001), and over-expressed in more advanced CRC stages than early stage disease (p<0.005). We show that miR-153 upregulation leads to increased CRC invasiveness using in vitro transwell invasion assays, and to more closely recreate and model in vivo circumstances, we examined the effect of stably transfected GFP-tagged miR-153 over-expression in CRC using a 3-dimensional organotypic co-culture of SW480 cells and human ex-vivo colonic fibroblast cells. Ectopic expression of miR-153 but not control miRNA resulted in increased invasion of CRC into the underlying stroma of organotypic cultures. Further in vitro functional analysis demonstrated that miR-153 over-expression also promotes chemotherapy resistance to Oxaliplatin and Cisplatin. Upregulation of miR-153 but not scrambled miRNA reduced abundance of activated Caspase 3 indicating that miR-153 is functioning as an anti-apoptotic factor in this context. Mechanistic dissection of the above functional effects show that miR-153 induces CRC invasiveness through increased MMP9 production, while resistance to platinum based chemotherapy is mediated through a direct inhibitory effect on the Forkhead box O3 (FOXO3a) transcription factor. Conclusions This is the first demonstration that over-expressed miR-153 has a significant and dual role in CRC progression, promoting both increased invasiveness and chemotherapy resistance. These findings suggest that strategies to suppress miR-153 may prove useful in advanced CRC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1109. doi:1538-7445.AM2012-1109
Abstract 1112: Identification of microRNA-based therapeutic candidates using a unique lentiviral microRNA overexpression library
Authors: van Noort Paula I. , Babae Negar , Poell Jos B. , Bourajjaj Meriem , Vidic Suzana , van Beijnum Judy R. , van Haastert Rick J. , Schultz Iman , de Gunt Thijs , van Hooij Onno , Verhaegh Gerald W. , Gommans Willemijn M. , Cerisoli Francesco , Verheul Mark , Schiffelers Raymond M. , Griffioen Arjan W. , Schalken Jack A. , Berezikov Eugene , Cuppen Edwin , Schaapveld Roel QJ , Prevost Gregoire P.
Published: August 2012

microRNA (miRNA) genes transcribed by RNA polymerase II generate small noncoding miRNAs of 18 to 24 nucleotides after maturation process. The mature miRNAs and their associated isomirs specifically bind to different mRNA transcripts, resulting in down regulation of multiple genes within the cell in a highly multiplexed way. miRNA expression profiles differ between human cell types suggesting cell-specific impacts of each miRNA on the regulation of different biological processes. Comparison of miRNA profiles of tumor samples and adjacent normal tissues showed that some miRNAs are up- or down- regulated and suggested their implication during tumor progression. However, such a miRNA profiling approach is not sufficient to identify the respective role of each miRNA gene during the tumorigenesis. Here, to assess the individual role of each miRNA gene and its different isomirs in a specific cell environment, we have constructed a lentiviral miRNA expression library containing more than 1100 human known and novel miRNA precursors. The arrayed layout of our library allowed high-throughput screens with a large spectrum of functional read-outs using either normal or tumor cells. To exemplify this approach, the results of three different screens will be presented; i.e. identification of miRNAs that inhibit the BRAF pathway, miRNAs that inhibit tumor angiogenesis and miRNAs that stimulate the mesenchymal to epithelial transition. In addition, beyond this hit identification step, we will present detailed characterization of the role of the identified miRNAs in tumor progression by means of molecular and cellular functional assays. Combining our unique miRNA expression library with a functional screening platform has allowed the identification and the further characterization of several miRNAs able to significantly impact on tumor behavior supporting the therapeutic interest of some candidates.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1112. doi:1538-7445.AM2012-1112
Abstract 1114: Loss of OPA1 expression results in apoptosis for cells overexpressing c-Myc
Authors: Graves J. Anthony , Cherok Edward P.
Published: August 2012

c-Myc (Myc) is a transcription factor that controls the expression of a vast array of genes that function in many essential cellular pathways, and high levels of Myc have been implicated in the development of many human cancers. One pathway that Myc controls is mitochondrial biogenesis. We have previously shown that Myc does this is in part via the regulation of the expression of proteins involved in mitochondrial fusion, including Opa1, whose levels are increased upon the over-expression of Myc. This results in a highly interconnected mitochondrial network in cells with high levels of Myc. This fused mitochondrial network is present despite the fact that Myc also increases the expression of proteins involved in mitochondrial fission as well. We sought to understand how Myc controls the expression of Opa1 and to determine if the high levels of mitochondrial fusion in Myc over-expressing cells are important in cellular transformation. We hypothesized that the increased mitochondrial fusion driven by the Myc-mediated increase in Opa1 may reduce apoptosis. Rat fibroblasts with inducible Myc expression were transfected with an OPA1-specific shRNA. These cells were characterized by a series of assays that measured different aspects of mitochondrial structure and function. After only 48h of Myc induction, mitochondrial mass increased by approximately two-fold compared to control cells; however, when Opa1 levels were reduced in this background (Myc+/Opa-), mitochondrial mass was decreased four-fold. The cells with decreased Opa1 expression but minimal Myc activity (Myc-/Opa-) had a punctate appearance to the mitochondria, which became even more dramatic in Myc+/Opa- cells. This was likely related to the ability of Myc to increase the proteins involved in fission. There was an approximate 50% decrease in the ability to perform oxidative phosphorylation (OXPHOS) when Myc-/Opa- cells were compared to Myc+/Opa- cells. This was consistent with the four-fold decrease in net ATP levels when Myc-/Opa- cells were compared to Myc+/Opa- cells. Finally, prolonged activation of Myc in cells with decreased expression of OPA1 leads to apoptosis. After 48 hours of Myc induction the Myc+/Opa- cells the cells gradually began to die and cultures were nearly devoid of viable cells within 10 days, whereas Myc-/Opa- cells remained almost completely viable. We believe that the unopposed mitochondrial fission in Myc+/Opa- cells results in an increase susceptibility to an early apoptotic death. The mechanisms involved in this phenomenon are being explored, as is the possibility of exploiting this consequence of Opa1 reduction as a means of selectively eliminating tumor cells that display Myc over-expression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1114. doi:1538-7445.AM2012-1114
Abstract 1115: p32 is a downstream effector of c-Myc induced glutamine addiction
Authors: Fogal Valentina , Chao Ying S. , Pastorino Sandra , Wang Lucia , Jian Pengfei , Mukthavaram Rajesh , Gallagher Matthew , Summitt IlaSri B. , Kesari Santosh
Published: August 2012

Genetic alterations of oncogenes and tumor suppressor genes are the main drivers not only of deregulated cell proliferation but also altered cancer cell metabolism. Compared with normal cells, malignant cells exhibit enhanced utilization of glucose and glutamine. As such, efforts to understand the molecular basis of the addiction to these two nutrients is likely to lead to the identification of new drug targets for the specific killing of cancer cells. A major player in tumor cell addiction to glutamine is the c-Myc oncogene. By stimulating the expression of glutamine transporters and glutaminase, this transcription factor promotes glutamine oxidation through the mitochondria. This rewiring of glutamine metabolism must be sustained by efficient mitochondrial function. The mitochondrial p32 protein was previously demonstrated to be critical in mitochondria metabolism by maintaining oxidative phosphorylation, yet the factors regulating its expression are not clear. Deregulated c-Myc is a frequent feature of gliomas and recent discoveries suggest the importance of metabolic alterations, in particular glutamine addiction, in the pathogenesis of these cancers. Interestingly, medulloblastoma can be clustered into six subgroups based on gene signature and the c-Myc amplified subgroup exhibits high p32 expression. In the present study, we hypothesized that p32 may be a downstream effector of c-Myc induced glutamine addiction. Using a c-Myc and estrogen receptor fusion protein construct in immortalized fibroblast, we demonstrated that p32 expression was up regulated upon c-Myc nuclear translocation. shRNA mediated stable knock-down of p32 in glioma cell lines and patient-derived tumor initiating cells impaired cell proliferation and tumorigenic potential in mouse models. Furthermore, attenuation of p32 expression reduced glioma cells sensitivity to glutamine deprivation and abrogated c-Myc induced glutamine consumption. Additional work is underway to determine whether c-Myc and p32 work in the same or parallel pathways to confer glutamine addiction on glioma cells and to establish the implications of this co-operation on tumor metabolism in vivo.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1115. doi:1538-7445.AM2012-1115