bluuebunny/crossref_metadata_2025 huggingface dataset:
Architecture and Optimization of a Low-Frequency Maglev Energy Harvester
Authors: Kecik Krzysztof
Published: May 2019

Low-frequency harvesters are attractive due to their availability in the ambient environment. The paper presents the design, analysis and optimization of the magnetic levitation harvester. A new nonlinear model of the electromechanical coupling, depending on the magnet position versus coil is proposed. Additionally, the influence of magnetic suspension (stiffness), load resistance and magnet-coil configuration on the foldover effect is shown.
On 1-absorbing primary ideals of commutative rings
Authors: Badawi Ayman , Celikel Ece Yetkin
Published: May 2019

Let [Formula: see text] be a commutative ring with nonzero identity. In this paper, we introduce the concept of 1-absorbing primary ideals in commutative rings. A proper ideal [Formula: see text] of [Formula: see text] is called a [Formula: see text]-absorbing primary ideal of [Formula: see text] if whenever nonunit elements [Formula: see text] and [Formula: see text], then [Formula: see text] or [Formula: see text] Some properties of 1-absorbing primary ideals are investigated. For example, we show that if [Formula: see text] admits a 1-absorbing primary ideal that is not a primary ideal, then [Formula: see text] is a quasilocal ring. We give an example of a 1-absorbing primary ideal of [Formula: see text] that is not a primary ideal of [Formula: see text]. We show that if [Formula: see text] is a Noetherian domain, then [Formula: see text] is a Dedekind domain if and only if every nonzero proper 1-absorbing primary ideal of [Formula: see text] is of the form [Formula: see text] for some nonzero prime ideal [Formula: see text] of [Formula: see text] and a positive integer [Formula: see text]. We show that a proper ideal [Formula: see text] of [Formula: see text] is a 1-absorbing primary ideal of [Formula: see text] if and only if whenever [Formula: see text] for some proper ideals [Formula: see text] of [Formula: see text], then [Formula: see text] or [Formula: see text]
A Review on Energy and Exergy Analysis of Two-Stage Vapour Compression Refrigeration System
Authors: Chowdhury Shounak , Roy Ranendra , Mandal Bijan Kumar
Published: May 2019

This paper presents a review on energy and exergy analysis of two-stage vapour compression refrigeration (VCR) system. The use of alternative refrigerants instead of conventional refrigerants has also been addressed. The governing equations for the energetic and exergetic analysis of two-stage VCR system have been identified and presented. Several experimental and numerical investigations and their findings on the performance of the two-stage VCR system available in the literature have been discussed in brief. Some of the results have also been reproduced as case studies.
A reassessment of the proposed ‘Lairg Impact Structure’ and its potential implications for the deep structure of northern Scotland
Authors: Simms Michael J. , Ernstson Kord
Published: May 2019

The Lairg Gravity Low may represent a buried impact crater
c
. 40 km across that was the source of the 1.2 Ga Stac Fada Member ejecta deposit but the gravity anomaly is too large to represent a simple crater and there is no evidence of a central peak. Reanalysis of the point Bouguer gravity data reveals a ring of positive anomalies around the central low, suggesting that it might represent the eroded central part of a larger complex crater. The inner or peak rings of complex craters show a broadly consistent 2:1 relationship between ring diameter and total crater diameter, implying that the putative Lairg crater may be as much as 100 km across. This would place the crater rim within a few kilometres of the Stac Fada Member outcrop, a location inconsistent with the thickness and clast size of the ejecta deposit. We propose that the putative impact crater originally lay further east, substantially further from the Stac Fada Member than today, and was translocated westwards to its present location beneath Lairg during the Caledonian Orogeny. This model requires that a deep-seated thrust fault, analogous to the Flannan and Outer Isles thrusts, exists beneath the Moine Thrust in north–central Scotland.
Water deprivation does not augment sympathetic or pressor responses to sciatic afferent nerve stimulation in rats or to static exercise in humans
Authors: Watso Joseph C. , Babcock Matthew C. , Robinson Austin T. , Migdal Kamila U. , Wenner Megan M. , Stocker Sean D. , Farquhar William B.
Published: May 2019

Excess dietary salt intake excites central sympathetic networks, which may be related to plasma hypernatremia. Plasma hypernatremia also occurs following water deprivation (WD). The purpose of this study was to test the hypothesis that WD induces hypernatremia and consequently augments sympathetic and pressor responses to sympathoexcitatory stimuli in rats and humans. Sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses to sciatic afferent nerve stimulation (2–20 Hz) and chemical stimulation of the rostral ventrolateral medulla (RVLM) were assessed in rats after 48 h of WD and compared with normally hydrated control rats (CON). In a parallel randomized-crossover human experiment ( n = 13 healthy young adults), sympathetic (microneurography) and pressor (photoplethysmography) responses to static exercise were compared between 16-h WD and CON conditions. In rats, plasma [Na+] was significantly higher in WD versus CON [136 ± 2 vs. 144 ± 2 (SD) mM, P < 0.01], but sciatic afferent nerve stimulation produced similar increases in renal SNA [5 Hz, 174 ± 34 vs. 169 ± 49% (SD), n = 6–8] and mean ABP [5 Hz, 21 ± 6 vs. 18 ± 7 (SD mmHg, n = 6–8]. RVLM injection of l-glutamate also produced similar increases in SNA and ABP in WD versus CON rats. In humans, WD increased serum [Na+] [140.6 ± 2.1 vs. 142.1 ± 1.9 mM (SD), P = 0.02] but did not augment sympathetic [muscle SNA: change from baseline (Δ) 6 ± 7 vs. 5 ± 7 (SD) bursts/min, P = 0.83] or mean ABP [Δ 12 ± 5 vs. 11 ± 8 (SD) mmHg, P = 0.73; WD vs. CON for all results] responses during the final minute of exercise. These findings suggest that despite eliciting relative hypernatremia, WD does not augment sympathetic or pressor responses to sciatic afferent stimulation in rats or to static exercise in humans.

NEW & NOTEWORTHY Excess dietary salt intake excites central sympathetic networks, which may be related to plasma hypernatremia. Plasma hypernatremia also occurs following water deprivation (WD). We sought to determine whether plasma hypernatremia/hyperosmolality induced by WD augments sympathetic and pressor responses to sympathoexcitatory stimuli. Our findings suggest that WD does not augment sympathetic or pressor responses to sciatic afferent nerve stimulation in rats or to static exercise in humans.
Muscle thixotropy—where are we now?
Authors: Lakie Martin , Campbell Kenneth S.
Published: May 2019

Relaxed skeletal muscle has an inbuilt resistance to movement. In particular, the resistance manifests itself as a substantial stiffness for small movements. The stiffness is impermanent, because it forms only when the muscle is stationary for some time and is reduced upon active or passive movement. Because the resistance to movement increases with time at rest and is reduced by movement, this behavior has become known as muscle thixotropy. In this short review, we describe the phenomenon of thixotropy and illustrate its significance in postural control with particular emphasis on human standing. We show how thixotropy came to be unambiguously associated with muscle mechanics and we review present knowledge of the molecular basis of thixotropic behavior. Specifically, we examine how recent knowledge about titin, and about the control of cross-bridge cycling, has impacted on the role of non-cross-bridge mechanisms and cross-bridge mechanisms in explaining thixotropy. We describe how thixotropic changes in muscle stiffness that occur during transitions from posture to movement can be tracked by analyzing physiological tremor. Finally, because skeletal muscle contains sensory receptors, and because some of these receptors are themselves thixotropic, we outline some of the consequences of muscle thixotropy for proprioception.
An ASVSF‐SLAM Algorithm with Time‐Varying Noise Statistics Based on MAP Creation and Weighted Exponent
Authors: Tian Yingzhong , Suwoyo Heru , Wang Wenbin , Li Long
Published: May 2019

The probability‐based filtering method has been extensively used for solving the simultaneous localization and mapping (SLAM) problem. Generally, the standard filter utilizes the system model and prior stochastic information to approximate the posterior state. However, in the real‐time situation, the noise statistics properties are relatively unknown, and the system is inaccurately modeled. Thus the filter divergence might occur in the integration system. Moreover, the expected accuracy might be challenging to be reached due to the absence of the responsive time‐varying of both the process and measurement noise statistic which naturally can enlarge the uncertainty in the continuous system. Consequently, the traditional strategy needs to be improved aiming to provide an ability to estimate those properties. In order to accomplish this issue, the new adaptive filter is proposed in this paper, termed as an adaptive smooth variable structure filter (ASVSF). Sequentially, the improved SVSF is derived and implemented; the process and measurement noise statistics are estimated by utilizing the maximum a posteriori (MAP) creation and the weighted exponent concept, and the covariance correction step is added based on the divergence suppression concept. In this paper the ASVSF is applied to overcome the SLAM problem of an autonomous mobile robot; henceforth it is abbreviated as an ASVSF‐SLAM algorithm. It is simulated and compared to the classical algorithm. The simulation results demonstrated that the proposed algorithm has better performance, stability, and effectiveness.
The Value of Intravoxel Incoherent Motion (IVIM) Magnetic Resonance Imaging in the Evaluation of the Osteosarcoma Response to Preoperative Neoadjuvant Chemotherapy in Teens
Authors: Zuo Houdong
Published: May 2019

Purpose. To investigate the value of intravoxel incoherent motion (IVIM) magnetic resonance imaging in the evaluation of the osteosarcoma (OS) response to preoperative neoadjuvant chemotherapy (NAC) in teens. Methods. Eighteen consecutive osteosarcoma patients (12 males and 6 females) diagnosed by histopathology were enrolled. All enrolled patients received NAC and underwent MRI examinations before and after 2 cycles of NAC. The volume (V), apparent diffusion coefficient (ADC), (slow) diffusion coefficient (D), pseudo-perfusion (fast) diffusion coefficient (D⁎or D star), and perfusion fractions (f) of the OS before and after NAC were measured and analysed. The sensitivity and the specificity of the ADC, D, D⁎ and f values and the correlation between changes in volume (ΔV) and the IVIM-derived parameters (ΔADC, ΔD, ΔD⁎ and Δf) were also calculated and analysed. Paired Student’s t-tests, receiver operating characteristic (ROC) curves, and Spearman correlation analyses were used. Results. The mean volume of the OS after NAC decreased significantly (61.55±9.3 cm3 vs 40.26±4.1 cm3) (P<0.05). After NAC, the ADC (1.21±0.09 × 10-3 mm2/s vs 1.73±0.11 × 10-3 mm2/s) and D (1.14±0.09 × 10-3 mm2/s vs 1.63±0.1 × 10-3 mm2/s) values increased and f (28.58±1.37% vs 20.93±1.16%) values decreased significantly (P<0.05), while D⁎ (9.17±0.98 × 10-3 mm2/s vs 8.94±0.13 × 10-3 mm2/s) values changed slightly (P>0.05). The AUC values of ADC (0.938) and D (0.943) were higher than those of D⁎ (0.574) and f (0.765). The sensitivity and specificity of ADC (0.778, 1) and D (0.944, 0.833) values were superior to those of D⁎ (0.278, 0.722) and f (0.5, 0.944) values. No significant correlations were found between the ΔV and ΔADC, ΔD, ΔD⁎ and Δf values (P>0.05). Conclusion. IVIM-derived parameters ADC and D have the potential to be imaging biomarkers for evaluation of the therapeutic response to NAC in OS patients.
Effects of Mnemonic Strategy Training on Brain Activity and Cognitive Functioning of Left-Hemisphere Ischemic Stroke Patients
Authors: Batista Alana X. , Bazán Paulo R. , Conforto Adriana B. , Martin Maria da Graça M. , Simon Sharon. S. , Hampstead Benjamin , Figueiredo Eberval Gadelha , Miotto Eliane C.
Published: May 2019

Memory dysfunction is one of the main cognitive impairments caused by stroke, especially associative memory. Therefore, cognitive training, such as face-name mnemonic strategy training, could be an important intervention for this group of patients. The goal of this study was to evaluate the behavioral effects of face-name mnemonic strategy training, along with the neural substrate behind these effects, in the left frontoparietal lobe stroke patients. Volunteers underwent 2 sessions of functional magnetic resonance imaging (fMRI) during face-name association task: one prior and the other after the cognitive training. The fMRI followed a block design task with three active conditions: trained face-name pairs, untrained face-name pairs, and a couple of repeated face-name pairs. Prior to each fMRI session, volunteers underwent neuropsychological assessment. Training resulted in better performance on delayed memory scores of HVLT-R, and on recognition on a generalization strategy task, as well as better performance in the fMRI task. Also, trained face-name pairs presented higher activation after training in default-mode network regions, such as the posterior cingulate cortex, precuneus, and angular gyrus, as well as in lateral occipital and temporal regions. Similarly, untrained face-name pairs also showed a nonspecific training effect in the right superior parietal cortex, right supramarginal gyrus, anterior intraparietal sulcus, and lateral occipital cortex. A correlation between brain activation and task performance was also found in the angular gyrus, superior parietal cortex, anterior intraparietal sulcus, and lateral occipital cortex. In conclusion, these results suggest that face-name mnemonic strategy training has the potential to improve memory performance and to foster brain activation changes, by the recruitment of contralesional areas from default-mode, frontoparietal, and dorsal attention networks as a possible compensation mechanism.
Endodontic Sealers Modified with Silver Vanadate: Antibacterial, Compositional, and Setting Time Evaluation
Authors: Vilela Teixeira Ana Beatriz , de Carvalho Honorato Silva Caroline , Alves Oswaldo Luiz , Cândido dos Reis Andréa
Published: May 2019

The incorporation of nanoparticles into endodontic sealers aims at increasing antimicrobial activity of the original material. Aim. The aim of this study is to incorporate the nanostructured silver vanadate decorated with silver nanoparticles (AgVO3, at 2.5%, 5%, and 10%) into three endodontic sealers and evaluate the antibacterial activity of freshly sealers, surface topography and chemical composition, and setting time. Material and Methods. The AgVO3 was incorporated into AH Plus, Sealer 26, and Endomethasone N at concentrations 0%, 2.5%, 5%, and 10% (in mass). The antibacterial activity of freshly sealers was assessed by direct contact with Enterococcus faecalis and CFU/mL count (n=10), surface topography, and chemical composition were measured by SEM/EDS, and the setting time was measured by Gillmore needle (n=10). The Kruskal-Wallis and Dunn statistical tests were applied (α=0.05). Results. All groups of sealers evaluated inhibited E. faecalis (p>0.05). The incorporation of AgVO3 altered the atomic proportions between components of the endodontic sealers, and the percentage of silver (Ag) and vanadium (V) increased proportionally to the concentrations of AgVO3. Topography analysis showed differences in components distribution on the surface of the specimens. The sealers incorporated with AgVO3 of AH Plus presented a lower setting time than the control group (p<0.05). For Sealer 26 and Endomethasone N, the incorporation of AgVO3 increased the setting time in relation to control group (p<0.05). Conclusions. The modification of endodontic sealers by AgVO3 increased the atomic percentage of Ag and V proportionally to the concentration of the nanomaterial and changed the atomic percentage of the sealer components and setting times. It cannot be affirmed that the AgVO3 promote differences in the antimicrobial activity of freshly sealers, and further investigations of the antimicrobial activity of the set sealers should be carried out.
On the Folding Mechanics of Square Columns with Double‐Surfaced Gradients
Authors: Zhou Junxian , Qin Ruixian , Chen Bingzhi
Published: May 2019

The implementation of graded thicknesses in structural designs is an efficient strategy for improving the energy absorption performance of thin‐walled columns. In this study, the mechanical responses of square columns with double‐surfaced gradients under axial crushing forces were analytically and numerically investigated. A mathematical expression for the mean crushing force on a novel tube design is derived according to the super folding element method by introducing two novel parameters: the average thickness of the efficient energy absorbing region (EEAR) and global average thickness. The analytical predictions show good agreement with the simulation results that were obtained using the nonlinear finite element program ANSYS/LS‐DYNA. The results demonstrate that a greater coefficient of average thickness of the EEAR versus global average thickness improves the energy absorption efficiency. However, increasing this coefficient largely depends on the sectional material distribution law. To explore the effects of this law on crushing responses, three different material distribution types were investigated. A significant improvement in specific energy absorption (approximately 30%) was obtained for a double‐surfaced column with an optimized material distribution type compared to that of a square column with a uniform thickness.
A Noninvasive 3D Body Scanner and Software Tool towards Analysis of Scoliosis
Authors: Roy Susmita , Grünwald Alexander T. D. , Alves-Pinto Ana , Maier Robert , Cremers Daniel , Pfeiffer Daniela , Lampe Renée
Published: May 2019

Purpose. Children with neurological disorders, such as cerebral palsy (CP), have a high risk of developing scoliosis during growth. The fast progression of scoliosis implies in several cases frequent clinical and X-ray examinations. We present an ionizing radiation-free, noncontacting method to estimate the trajectory of the vertebral column and to potentially facilitate medical diagnosis in cases where an X-ray examination is not indicated. Methods. A body scanner and corresponding analysis software tools have been developed to get 3D surface scans of patient torsos and to analyze their spinal curvatures. The trajectory of the vertebral column has been deduced from the body contours at different transverse sectional planes along the vertical torso axis. In order to verify the present methods, we have analyzed twenty-five torso contours, extracted from computer tomography (CT) images of patients who had a CT scan for other medical reasons, but incidentally also showed a scoliosis. The software tools therefore process data from the body scanner as well as X-ray or CT images. Results. The methods presented show good results in the estimations of the lateral deviation of the spine for mild and moderate scoliosis. The partial mismatch for severe cases is associated with a less accurate estimation of the rotation of the vertebrae around the vertical body axis in these cases. In addition, distinct torso contour shapes, in the transverse sections, have been characterized according to the severity of the scoliosis. Conclusion. The hardware and software tools are a first step towards an ionizing radiation-free analysis of progression of scoliosis. However, further improvements of the analysis methods and tests on a larger number of data sets with diverse types of scoliosis are necessary, before its introduction into clinical application as a supplementary tool to conventional examinations.
Identify the Key Active Ingredients and Pharmacological Mechanisms of Compound XiongShao Capsule in Treating Diabetic Peripheral Neuropathy by Network Pharmacology Approach
Authors: Yu Meixiang , Song Xin , Yang Wanhua , Li Ziwei , Ma Xiaoqin , Hao Chenxia
Published: May 2019

Compound XiongShao Capsule (CXSC), a traditional herb mixture, has shown significant clinical efficacy against diabetic peripheral neuropathy (DPN). However, its multicomponent and multitarget features cause difficulty in deciphering its molecular mechanisms. Our study aimed to identify the key active ingredients and potential pharmacological mechanisms of CXSC in treating DPN by network pharmacology and provide scientific evidence of its clinical efficacy. CXSC active ingredients were identified from both the Traditional Chinese Medicine Systems Pharmacology database, with parameters of oral bioavailability ≥ 30% and drug-likeness ≥ 0.18, and the Herbal Ingredients’ Targets (HIT) database. The targets of those active ingredients were identified using ChemMapper based on 3D-structure similarity and using HIT database. DPN-related genes were acquired from microarray dataset GSE95849 and five widely used databases (TTD, Drugbank, KEGG, DisGeNET, and OMIM). Next, we obtained candidate targets with therapeutic effects against DPN by mapping active ingredient targets and DPN-related genes and identifying the proteins interacting with those candidate targets using STITCH 5.0. We constructed an “active ingredients-candidate targets-proteins” network using Cytoscape 3.61 and identified key active ingredients and key targets in the network. We identified 172 active ingredients in CXSC, 898 targets of the active ingredients, 110 DPN-related genes, and 38 candidate targets with therapeutic effects against DPN. Three key active ingredients, namely, quercetin, kaempferol, and baicalein, and 25 key targets were identified. Next, we input all key targets into ClueGO plugin for KEGG enrichment and molecular function analyses. The AGE-RAGE signaling pathway in diabetic complications and MAP kinase activity were determined as the main KEGG pathway and molecular function involved, respectively. We determined quercetin, kaempferol, and baicalein as the key active ingredients of CXSC and the AGE-RAGE signaling pathway and MAP kinase activity as the main pharmacological mechanisms of CXSC against DPN, proving the clinical efficacy of CXSC against DPN.
Single Nucleotide Polymorphisms ofCBX4andCBX7Decrease the Risk of Hepatocellular Carcinoma
Authors: Tan Chao , Bei Chunhua , Zhu Xiaonian , Zhang Ying , Qin Linyuan , Tan Shengkui
Published: May 2019

Background. The chromobox (CBX) proteins CBX2, CBX4, CBX6, CBX7, and CBX8, also known as Polycomb (Pc) proteins, are canonical components of the Polycomb repressive complex 1 (PRC1). Abundant evidence indicates that abnormal expression of Pc proteins is associated with a variety of tumors, but their role in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. In the present study, we performed a case-control study to investigate the relationship between single nucleotide polymorphisms (SNPs) ofCBXgenes and HCC.Methods. Nine SNPs onCBXgenes (rs7217395, rs2036316 ofCBX2; rs3764374, rs1285251, rs2289728 ofCBX4; rs7292074 ofCBX6; and rs710190, rs139394, rs5750753 ofCBX7) were screened and genotyped using MassARRAY technology in 334 HCC cases and 321 controls. The association between SNPs and their corresponding gene expressions was analyzed through bioinformatics methods using the Ensembl database and Blood eQTL browser online tools.Results. The results indicated that rs2289728 (G>A) ofCBX4(P= 0.03, OR = 0.56, 95% CI: 0.33-0.94) and rs139394 (C>A) ofCBX7(P= 0.02, OR = 0.55, 95% CI: 0.33-0.90) decreased the risk of HCC. Interaction between rs2036316 and HBsAg increased the risk of HCC (P= 0.02, OR = 6.88, 95% CI: 5.20-9.11), whereas SNP-SNP interaction between rs710190 and rs139394 reduced the risk of HCC (P= 0.03, OR = 0.33, 95% CI: 0.12-0.91). Gene expression analyses showed that the rs2289728 A allele and the rs139394 A allele significantly reducedCBX4andCBX7expression, respectively.Conclusion. Our findings suggest thatCBX4rs2289728 andCBX7rs139394 are protective SNPs against HCC. The two SNPs may reduce the risk of HCC while suppressing the expression ofCBX4andCBX7.
A Seamless Gene Deletion Method and Its Application for Regulation of Higher Alcohols and Ester in Baijiu Saccharomyces cerevisiae
Authors: Li Ping , Ge Junling , Gao Yingying , Wang Jianhui , Zhang Cuiying , Xiao Dongguang
Published: May 2019

The security of engineering Saccharomyces cerevisiae is becoming more focused on industrial production in consideration of the public concern regarding genetically modified organisms. In this work, a rapid and highly efficient system for seamless gene deletion in S. cerevisiae was developed through two-step integration protocol combined with endonuclease I-SCEI expression. The factors affecting the frequency of the second homologous recombination were optimized, and studies indicated that the mutant strains with 500 bp direct repeats and that have been incubating in galactose (0.5 g/100 mL) medium at 30°C and 180 r/min for 24 h permit high frequency (6.86 × 10−4) of the second homologous recombination. Furthermore, DNA sequence assays showed only self-DNA in native location without any foreign genes after deletion using this method. The seamless gene deletion method was applied to the construction of the engineering strains with BAT2 (encoding aminotransferase) deletion and ATF1 (alcohol acetyltransferases) overexpression. The mutants exhibited significant effects on higher alcohol reduction and ester improvement after Baijiu fermentation. The engineered strains can be used in industrial production in security, thereby meeting the requirements of modern science and technology.
The Promoter-Associated Noncoding RNA pncCCND1_B Assembles a Protein–RNA Complex to Regulate Cyclin D1 Transcription in Ewing Sarcoma
Authors: Palombo Ramona , Frisone Paola , Fidaleo Marco , Mercatelli Neri , Sette Claudio , Paronetto Maria Paola
Published: May 2019

Most Ewing sarcomas are characterized by the in-frame chromosomal translocation t(11;22) generating the EWS–FLI1 oncogene. EWS–FLI1 protein interacts with the RNA helicase DHX9 and affects transcription and processing of genes involved in neoplastic transformation, including CCND1 (the cyclin D1 gene), which contributes to cell-cycle dysregulation in cancer. In this study, we found that CCND1 expression is significantly higher in patients with Ewing sarcoma compared with other sarcomas and that the pncCCND1_B RNA, a previously uncharacterized CCND1 promoter-associated noncoding (pnc) transcript, is expressed in Ewing sarcoma cells. PncCCND1_B interacted with the RNA-binding protein Sam68 and repressed CCND1 expression. Notably, knockdown of Sam68 affected pncCCND1_B subcellular localization and cyclin D1 expression. Pharmacologic impairment of DHX9/EWS–FLI1 interaction promoted RNA-dependent association of Sam68 with DHX9 and recruitment of Sam68 to the CCND1 promoter, thus repressing it. Conversely, mitogenic stimulation of Ewing sarcoma cells with IGF1 impaired Sam68/DHX9 interaction and positively regulated CCND1 expression. These studies uncover a fine-tuned modulation of the proto-oncogene CCND1 in Ewing sarcoma cells via alternative complexes formed by DHX9 with either EWS–FLI1 or pncCCND1_B-Sam68.

Significance:

A pncRNA-based mechanism represses expression of CCND1 through the formation of a protein–RNA complex and provides new therapeutic opportunities for patients with Ewing sarcoma.
Abstract CN08-04: Novel topoisomerase I inhibitors in development
Authors: Pommier Yves G.
Published: May 2019

Camptothecins are effective against previously resistant tumors. Because camptothecins are presently the only class of topoisomerase I (Top1) inhibitors approved for cancer treatment, and because camptothecins have limitations including dose-limiting toxicity, chemical instability, and are susceptible to drug efflux transporter, we developed the indenoisoquinolines. Like camptothecins, the indenoisoquinolines selectively trap Top1-DNA cleavage complexes and have been co-crystallized with the Top1-DNA cleavage complexes. Indenoisoquinolines show antitumor activity in animal models. They have several advantages over the camptothecins: 1) They are synthetic and chemically stable (unlike camptothecins); 2) The Top1 cleavage sites trapped by the indenoisoquinolines have different genomic locations than camptothecins, implying differential targeting of cancer cell genomes; 3) The Top1 cleavage complexes trapped by indenoisoquinolines are more stable than for camptothecins, indicative of prolonged drug action; and 4) They are less or not substrates for the multidrug resistance efflux pumps (ABCG2 and MDR-1). Among the more than 400 indenoisoquinolines synthesized and evaluated, three have been retained as leads for clinical development by the NCI: NSC 706744, NSC 725776 (Indimitecan) and NSC 724998 (Indotecan). The trapping of Top1 cleavage complexes by indenoisoquinolines in cells results in the rapid and sustained phosphorylation of histone H2AX (referred to as -H2AX). We will also discuss the other class of non-camptothecin Top1 inhibitors GENZ644283 (see abstract by D. Sooryakumar) and the use of -H2AX as a pharmacodynamic biomarker for the clinical development of the non-camptothecin Top1 inhibitors.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN08-04.
Abstract ED01-04: Beyond IHC: Quantitative measurement of protein analytes on tissue slides
Authors: Rimm David L. , Welsh Allison , Anagnostou Valsamo , Bai Yalai
Published: May 2019

The large number and elusive nature of analytical and pre-analytic variables associated with immunohistochemistry (IHC) have relegated the technique to a semi-quantitative or qualitative status. However, as companion diagnostics become more critical to patient management, there is new motivation to move IHC to a fully quantitative assay. Toward this goal, we have developed the AQUA® method of quantitative immunofluorescence (QIF) to measure critical analytes in breast tissue. Using a series of cell lines which are standardized to recombinant protein quantified on western blot, we have measured estrogen receptor in three separate cohorts of breast cancer cases. The quantitative approach reveals a cutpoint of 50pg/ug total protein and suggests that conventional IHC may have a misclassification rate of around 15%. Furthermore, when comparing the misclassified cases, it appears that QIF classification predicts outcome more accurately than the conventional methods. As accurate as QIF is, it does not address preanalytical variables, most significantly including cold ischemic time, or the time between surgical removal of the tissue sample and fixation. A series of QIF methods for antibody validation may allow neutralization of this variable in assessment of tumor tissue. In summary, measurement of protein on a pathology slide can now be achieved with accuracy and reproducibility of nucleic acid assays or ELISA assays. Combining QIF with rigorous methods of standardization and antibody validation allows companion diagnostic tests to be done on very small tissue fragments.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):ED01-04.
Abstract PL05-01: Translational pharmacogenomics
Authors: Mousses Spyro
Published: May 2019

Neoplasia appears to develop stochastically through a series of variable genetic events that drive multiple cycles of cellular adaptation and selection. This pathological cellular evolution produces variable cancer genomes that are characterized with structural complexity and clonal heterogeneity. Most importantly for drug discovery and development, common recurrent genetic events appear to be only the ‘tip of the iceberg’, and the next generation of genomic technologies are now revealing that most functionally relevant genetic aberrations are in fact not common or recurrent. Given this challenge of cellular and molecular heterogeneity, we have begun to explore new paradigms for translating genomic information into pharmacologically relevant insights to guide drug discovery and development. This presentation will introduce new technologies and integrated strategies to generate the necessary type of information from cancer genomes, and introduce a new ‘biointelligence’ based strategy for interpreting individual cancer genomes to gain insights into contextual dependencies and pharmacologically relevant vulnerabilities. In support of this new approach to genomics, emerging evidence is suggesting that the highly variable genetic events do converge on higher level concepts that represent shared pharmacologically tractable contexts of vulnerability. Finally, a scientific vision will be presented for practically applying these integrated pharmacogenomic strategies; a) in research to accelerate cancer drug discovery and development, and b) directly into clinical practice to support more precise medical genomics.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PL05-01.
Abstract A09: A next generation sequencing based microsatellite instability assay suitable for routine risk stratification in colorectal cancer
Authors: Alhilal Ghanim , Redford Lisa , Alonso Angel , Moreno Sira , Arends Mark , Oniscu Anca , O'Brien Ottilia , Needham Stephanie , Burn John , Jackson Michael , Santibanez-Koref Mauro
Published: May 2019

3-5% of CRCs show microsatellite instability (MSI) caused by germline defects in mismatch repair genes (MMR) predisposing to Lynch syndrome. In addition, 12% of sporadic CRCs show MSI. Currently, MSI is tested using a fragment analysis based assay not suitable for high throughput testing with suboptimal sensitivity and specificity. Knowledge of microsatellite instability affects prognosis (MSI is a positive prognostic factor in stage II CRC), risk stratification (for the affected and at risk relatives in Lynch syndrome), prediction of lymph node involvement (lymph node metastasis is unlikely in stage I MSI positive CRC) and treatment of CRCs (MMR deficient tumours showed observable benefit from PD-1 blocking agent pembrolizumab). For all these important benefits, MSI testing is now recommended for all newly diagnosed CRCs. As a result, development of a high throughput approach is desirable. We have developed and validated a high throughput sequence based MSI assay.

In this study, we tested 17 short (7-12bp) mononucleotide markers (previously identified by our team via an in silico analyses of whole genome sequencing data). These 17 markers were able to discriminate between MSI-high (MSI-H) and microsatellite stable (MSS) cases. To define the optimal parameters to discriminate between MSI-H and MSS samples, we tested these 17 markers across a panel of 141 CRC samples. This allowed us to define a scoring scheme for the 17 markers using allelic imbalance based on a linked SNP (called weighted scoring scheme), which achieved 96% sensitivity and 100% specificity. This scoring scheme was then validated using an independent cohort of 70 CRCs without knowing their MSI status. The assay achieved a 100% sensitivity and specificity.

We provide here a high throughput tool to detect microsatellite instability that is less costly, uses short mononucleotide markers (eliminating the need to test matched normal tissue) and is validated on formalin fixed paraffin embedded (FFPE) samples (similar to routine samples). The ability to test the microsatellite instability status in all the newly diagnosed CRC cases would have a great clinical impact on prognosis, risk stratification and treatment of CRCs.

Citation Format: Ghanim Alhilal, Lisa Redford, Angel Alonso, Sira Moreno, Mark Arends, Anca Oniscu, Ottilia O'Brien, Stephanie Needham, John Burn, Michael Jackson, Mauro Santibanez-Koref. A next generation sequencing based microsatellite instability assay suitable for routine risk stratification in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A09.
Abstract B17: Comprehensive colorectal cancer risk prediction to inform personalized screening and intervention
Authors: Jeon Jihyoun , Berndt Sonja I. , Brenner Hermann , Campbell Peter T. , Chan Andrew T. , Chang-Claude Jenny , Du Mengmeng , Giles Graham , Gong Jian , Gruber Stephen B. , Harrison Tabitha A. , Hoffmeister Michael , LeMarchand Loic , Li Li , Potter John D. , Rennert Gad , Schoen Robert E. , Slattery Martha L. , White Emily , Woods Michael O. , Peters Ulrike , Hsu Li
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR17) of the Conference Proceedings.

Citation Format: Jihyoun Jeon, Sonja I. Berndt, Hermann Brenner, Peter T. Campbell, Andrew T. Chan, Jenny Chang-Claude, Mengmeng Du, Graham Giles, Jian Gong, Stephen B. Gruber, Tabitha A. Harrison, Michael Hoffmeister, Loic LeMarchand, Li Li, John D. Potter, Gad Rennert, Robert E. Schoen, Martha L. Slattery, Emily White, Michael O. Woods, Ulrike Peters, Li Hsu. Comprehensive colorectal cancer risk prediction to inform personalized screening and intervention. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B17.
Abstract B19: Effect of cancer risk and patient preferences on net benefit of lung cancer screening: A Personalized Lung Cancer Screening Model
Authors: Cao Pianpian , Caverly Tanner , Hayward Rodney , Meza Rafael
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR16) of the Conference Proceedings.

Citation Format: Pianpian Cao, Tanner Caverly, Rodney Hayward, Rafael Meza. Effect of cancer risk and patient preferences on net benefit of lung cancer screening: A Personalized Lung Cancer Screening Model. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B19.
Abstract A35: Somatic mutation profile of a panel of oncogenes and tumor suppressor genes in colorectal cancer in a Brazilian population
Authors: Santos Wellington , Evangelista Adriane Feijó , Durães Ronilson , Matsushita Marcus , Reis Rui Manuel , Guimarães Denise Peixoto
Published: May 2019

Colorectal cancer (CRC) is the third most frequent cancer worldwide and the fourth leading cause of death due to cancer. The development of this disease usually occurs due to the progression of precursor lesions in the normal intestinal mucosa to tumor. Environment, age, lifestyle, and genetic background are considered risk factors for the development and progression of CRC. The molecular abnormalities involved in the progression of CRC have been well characterized, including mutations, microsatellite instability, and epigenetic changes. Although the molecular profile of colorectal cancer is well known in developed countries, in the Brazilian population information is still very limited. Therefore, in the present study we intended to characterize the mutation profile of a Brazilian population and associate this with their clinicopathologic features. A total of 61 colorectal cancer cases of different stages were included. DNA was extracted from frozen fresh tumors and sequenced using a panel of 298 genes by next-generation sequencing (NGS). The mean age of patients was 63 years old; 57.4% were male. Three patients had CRC in stage 0, 16 in stage I, 29 in stage II, 10 in stage III, and three in stage IV. Considering only nonsynonymous alterations, we found on average 7.24 mutations per patient. The majority were missense (61.8%), followed by nonsense (15.2%) and frameshift mutations (10.9%). The genes most frequently mutated were APC (78.7%), TP53 (72.1%), KRAS (60.7%), PIK3CA (14.8%), and FBXW7 (14.8%). Alterations in tumor suppressor genes such as APC and TP53 were found throughout the entire gene. On the other hand, oncogenes such as KRAS had alterations in hotspots of the gene. In conclusion, the frequency of alterations in genes sequenced in our population was similar to that found in the international literature for other populations.

Citation Format: Wellington Santos, Adriane Feijó Evangelista, Ronilson Durães, Marcus Matsushita, Rui Manuel Reis, Denise Peixoto Guimarães. Somatic mutation profile of a panel of oncogenes and tumor suppressor genes in colorectal cancer in a Brazilian population [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A35.
Abstract A60: Full-length transcripts identification from deep transcriptomic analysis of Bothrops jararaca venom gland
Authors: Messias Elisa Alves , Eguchi Flavia Coltri , Sorroche Bruna Pereira , Oliveira Angela Das Neves , Arantes Lidia Maria Rebolho Batista , Carvalho Ana Carolina De , Azevedo Anita mitico tanaka , Grego Kathleen Fernandes , Melendez Matias Eliseo , Carvalho Andre Lopes
Published: May 2019

Introduction: Head and neck cancer is a collective term defined by topographic and anatomic features to describe malignant tumors of the upper aerodigestive tract. Despite the different strategies used in the treatment of head and neck squamous cell carcinoma (HNSCC), the overall survival rate is around 50% and the main reason for treatment failure is the frequent development of loco-regional recurrences, which affect around 30% of HNSCC patients. The increase in cancer diagnosis makes it necessary to search for alternative sources to inhibit tumor progression, as well as the development of more efficient drugs. Identification of natural resources as therapeutic potential may lead to the development of new antitumor treatments.

Objectives: The aim was to identify transcripts expressed in venom glands of the Bothrops jararaca snake with therapeutic potential for head and neck squamous cell carcinoma (HNSCC) tumors.

Materials and Methods: The mRNA library from B. jararaca was sequenced using Illumina NextSeq 500 platform (76 bp unpaired-end) and NextSeq 500/550 Mid Output v2 kit (150 cycles). Library was constructed using TruSeq Stranded mRNA LT Sample Prep Kit (Illumina). De novo assembly of the B. jararaca transcriptome was performed using Velvet software to assemble the transcriptome contigs.

Results: The RNA-seq of B. jararaca venom gland generated 4,401,692 raw reads. The de novo Velvet assembly produced 3,498,133 contigs, which matched against NCBI-Blastn transcripts. From these contigs were identified 3,638 full-length transcripts, from which were selected two potential therapeutic genes, Fosfolipases A2 1 and Fosfolipases A2 2.

Conclusions: In conclusion, this transcriptome sequencing identified two potential therapeutic transcripts, Fosfolipases A2 1 and Fosfolipases A2 2, which will be analyzed in HNSCC cell lines.

Citation Format: Elisa Alves Messias, Flavia Coltri Eguchi, Bruna Pereira Sorroche, Angela Das Neves Oliveira, Lidia Maria Rebolho Batista Arantes, Ana Carolina De Carvalho, Anita mitico tanaka Azevedo, Kathleen Fernandes Grego, Matias Eliseo Melendez, Andre Lopes Carvalho. Full-length transcripts identification from deep transcriptomic analysis of Bothrops jararaca venom gland [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A60.
Abstract B09: Exploring IKKβ as an antiangiogenic therapeutic target in KRAS-induced lung cancer
Authors: Carneiro-Lobo Tatiana C. , Santos Edmilson Ozorio dos , Scalabrini Luiza Coimbra , Cardeal Laura B. , Baldwin Albert S. , Giordano Ricardo José , Basseres Daniela S.
Published: May 2019

Activating mutations in KRAS are prevalent in cancer, but therapies targeted to oncogenic RAS have so far failed. An alternative route for blocking RAS-driven oncogenic pathways is to target downstream effectors of RAS involved in promoting the oncogenic phenotype. One of the critical characteristics required for tumors to grow and progress is the ability of tumor cells to drive angiogenesis. Interestingly, oncogenic RAS promotes angiogenesis by upregulating the proangiogenic IL-8 cytokine, an NF-κB target gene, and we have shown that NF-κB activation by KRAS requires the IKKβ kinase. Interestingly, IKKβ targeting only minimally affects KRAS-mutant cell growth in vitro, nonetheless it significantly reduces KRAS-induced lung tumor growth in situ. Therefore, we hypothesized that IKKβ inhibition would reduce KRAS-induced lung tumor growth by impairing angiogenesis. To test this hypothesis, we targeted IKKβ in KRAS-mutant lung cancer cell lines A549 and H358, both by RNAi and by treatment with Compound A (CmpdA), a highly specific IKKβ inhibitor. Both approaches reduced expression and secretion of IL-8 and VEGF, another NF-κB-regulated proangiogenic growth factor. Moreover, conditioned media from IKKβ-targeted lung cells reduced endothelial cell migration and tube formation in vitro. Furthermore, siRNA-mediated IKKβ inhibition reduced xenograft tumor growth and angiogenesis in vivo. Finally, we determined that IKKβ inhibition can affect endothelial cell function independently of cancer cells as well, as CmpdA treatment directly reduced endothelial cell migration and reduced pathologic retinal angiogenesis in a mouse model of neonatal retinopathy. Taken together, these results suggest that IKKβ inhibition therapy may be an important general antiangiogenic therapy and may reduce KRAS-induced lung tumor angiogenesis, thereby providing a clinical therapeutic benefit for lung cancer patients harboring KRAS mutations.

Citation Format: Tatiana C. Carneiro-Lobo, Edmilson Ozorio dos Santos, Luiza Coimbra Scalabrini, Laura B. Cardeal, Albert S. Baldwin, Ricardo José Giordano, Daniela S. Basseres. Exploring IKKβ as an antiangiogenic therapeutic target in KRAS-induced lung cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B09.