bluuebunny/crossref_metadata_2025 huggingface dataset:
Recombinant sclerostin antagonizes effects of ex vivo mechanical loading in trabecular bone and increases osteocyte lacunar size
Authors: Kogawa M. , Khalid K. A. , Wijenayaka A. R. , Ormsby R. T. , Evdokiou A. , Anderson P. H. , Findlay D. M. , Atkins G. J.
Published: October 2017

Sclerostin has emerged as an important regulator of bone mass. We have shown that sclerostin can act by targeting late osteoblasts/osteocytes to inhibit bone mineralization and to upregulate osteocyte expression of catabolic factors, resulting in osteocytic osteolysis. Here we sought to examine the effect of exogenous sclerostin on osteocytes in trabecular bone mechanically loaded ex vivo. Bovine trabecular bone cores, with bone marrow removed, were inserted into individual chambers and subjected to daily episodes of dynamic loading. Cores were perfused with either osteogenic media alone or media containing human recombinant sclerostin (rhSCL) (50 ng/ml). Loaded control bone increased in apparent stiffness over time compared with unloaded bone, and this was abrogated in the presence of rhSCL. Loaded bone showed an increase in calcein uptake as a surrogate of mineral accretion, compared with unloaded bone, in which this was substantially inhibited by rhSCL treatment. Sclerostin treatment induced a significant increase in the ionized calcium concentration in the perfusate and the release of β-CTX at several time points, an increased mean osteocyte lacunar size, indicative of osteocytic osteolysis, and the expression of catabolism-related genes. Human primary osteocyte-like cultures treated with rhSCL also released β-CTX from their matrix. These results suggest that osteocytes contribute directly to bone mineral accretion, and to the mechanical properties of bone. Moreover, it appears that sclerostin, acting on osteocytes, can negate this effect by modulating the dimensions of the lacunocanalicular porosity and the composition of the periosteocyte matrix.
RING finger protein 113A regulates C-X-C chemokine receptor type 4 stability and signaling
Authors: Lear Travis , Dunn Sarah R. , McKelvey Alison C. , Mir Aazrin , Evankovich John , Chen Bill B. , Liu Yuan
Published: October 2017

As an α-chemokine receptor specific for stromal-derived-factor-1 (SDF-1, also called CXCL12), C-X-C chemokine receptor type 4 (CXCR4) plays a vital role in chemotactically attracting lymphocytes during inflammation. CXCR4 also regulates HIV infection due to its role as one of the chemokine coreceptors for HIV entry into CD4+ T cells. Chemokine receptors and their signaling pathways have been shown to be regulated by the process of ubiquitination, a posttranslational modification, guided by ubiquitin E3 ligases, which covalently links ubiquitin chains to lysine residues within target substrates. Here we describe a novel mechanism regulating CXCR4 protein levels and subsequent CXCR4/CXCL12 signaling pathway through the ubiquitination and degradation of the receptor in response to ligand stimulation. We identify that an uncharacterized really interesting new gene (RING) finger ubiquitin E3 ligase, RING finger protein 113A (RNF113A), directly ubiquitinates CXCR4 in cells, leading to CXCR4 degradation, and therefore disrupts the signaling cascade. We determined that the K331 residue within CXCR4 is essential for RNF113A-mediated ubiquitin conjugation. Overexpression of RNF113A significantly reduces CXCL12-induced kinase activation in HeLa cells, whereas RNF113A knockdown enhances CXCL12-induced downstream signaling. Further, RNF113A expression and silencing directly affect cell motility in a wound healing assay. These results suggest that RNF113A plays an important role in CXCR4 signaling through the ubiquitination and degradation of CXCR4. This mechanistic study might provide new understanding of HIV immunity and neutrophil activation and motility regulated by CXCR4.
AMPK-KLF2 signaling pathway mediates the proangiogenic effect of erythropoietin in endothelial colony-forming cells
Authors: Wang Dawei , Song Yimeng , Zhang Jianshu , Pang Wei , Wang Xian , Zhu Yi , Li Xiaoxia
Published: October 2017

Endothelial colony-forming cells (ECFCs) were proved to take part in postnatal vasculogenesis and injury repair. The angiogenic properties of ECFCs could be influenced by various cytokines, chemokines, and growth factors. Erythropoietin (EPO) is a promising cytokine participating in angiogenesis. However, the mechanisms for EPO’s proangiogenic effect still remain largely elusive. Here, we investigated the role of the AMP-activated protein kinase (AMPK)-Krüppel-like factor 2 (KLF2) signaling pathway in the proangiogenic effect of EPO in ECFCs. Human ECFCs were isolated from cord blood and cultured. EPO significantly enhanced the migration and tube formation capacities of ECFCs and markedly increased the expression of endothelial markers and vascular endothelial growth factor (VEGF). Further, EPO caused the phosphorylation of AMPK and endothelial nitric oxide synthase, a process in which KLF2 was also upregulated on both mRNA and protein levels. The upregulation of KLF2 was blocked by inhibiting AMPK with Compound C or Ad-AMPK-DN, a recombinant adenovirus that encoded a dominant-negative mutant of AMPK. Furthermore, knockdown of KLF2 showed no effect on AMPK but abolished the EPO-enhanced migration and tube formation capacities of ECFCs. Of note, knockdown of KLF2 also diminished the EPO-induced expression of endothelial markers and VEGF; overexpression of KLF2 promoted the expression of endothelial markers and VEGF and enhanced the migration and tube formation capacities of ECFCs. These data suggest that upregulation of KLF2 by AMPK plays an essential role in EPO-induced angiogenesis.
Loss of inversin decreases transepithelial sodium transport in murine renal cells
Authors: Kulkarni Nalini H. , Smith Rosamund C. , Blazer-Yost Bonnie L.
Published: October 2017

Type II nephronophthisis (NPHP2) is an autosomal recessive renal cystic disorder characterized by mutations in the inversin gene. Humans and mice with mutations in inversin have enlarged cystic kidneys that may be due to fluid accumulation resulting from altered ion transport. To address this, transepithelial ion transport was measured in shRNA-mediated inversin-depleted mouse cortical collecting duct (mCCD) cells. Loss of inversin decreased the basal ion flux in mCCD cells compared with controls. Depletion of inversin decreased vasopressin-induced Na+ absorption but did not alter Cl− secretion by mCCD cells. Addition of amiloride, a specific blocker of the epithelial sodium channel (ENaC), abolished basal ion transport in both inversin knockdown and control cells, indicating ENaC involvement. Transcript levels of ENaC β-subunit were reduced in inversin-knockdown cells consistent with decreased ENaC activity. Furthermore, Nedd4l (neural precursor cell expressed, developmentally downregulated 4 like), an upstream negative regulator of ENaC, was evaluated. The relative amount of the phosphorylated, inactive Nedd4l was decreased in inversin-depleted cells consistent with decreased ENaC activity. The protein levels of Sgk1 (serum and glucocorticoid-inducible kinase), which phosphorylates Nedd4l, remained unchanged although the transcript levels were increased in inversin-depleted cells. Interestingly, mRNA and protein levels of Crtc2 (Creb-regulated transcription coactivator) kinase, a positive regulator of Sgk1, were decreased in inversin-depleted cells. Together these results suggest that loss of inversin decreases Na+ transport via ENaC, mediated in part by transcriptional and posttranslational regulation of Crtc2/Sgk1/Nedd4l axis as a contributory mechanism for enlarged kidneys in NPHP2.
Intramuscular triglyceride synthesis: importance in muscle lipid partitioning in humans
Authors: Bergman Bryan C. , Perreault Leigh , Strauss Allison , Bacon Samantha , Kerege Anna , Harrison Kathleen , Brozinick Joseph T. , Hunerdosse Devon M. , Playdon Mary C. , Holmes William , Bui Hai Hoang , Sanders Phil , Siddall Parker , Wei Tao , Thomas Melissa K. , Kuo Ming Shang , Eckel Robert H.
Published: October 2017

Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the “athlete’s paradox.” We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear. To understand the relationship between IMTG synthesis and insulin sensitivity, we measured IMTG synthesis in obese control subjects, endurance-trained athletes, and individuals with type 2 diabetes during rest, exercise, and recovery. IMTG synthesis rates were positively related to insulin sensitivity, cytosolic accumulation of DAG, and decreased accumulation of C18:0 ceramide and glucosylceramide. Greater rates of IMTG synthesis in athletes were not explained by alterations in FFA concentration, DGAT1 mRNA expression, or protein content. IMTG synthesis during exercise in Ob and T2D indicate utilization as a fuel despite unchanged content, whereas IMTG concentration decreased during exercise in athletes. mRNA expression for genes involved in lipid desaturation and IMTG synthesis were increased after exercise and recovery. Further, in a subset of individuals, exercise decreased cytosolic and membrane di-saturated DAG content, which may help explain insulin sensitization after acute exercise. These data suggest IMTG synthesis rates may influence insulin sensitivity by altering intracellular lipid localization, and decreasing specific ceramide species that promote insulin resistance.
Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis
Authors: Galsgaard Katrine D. , Winther-Sørensen Marie , Ørskov Cathrine , Kissow Hannelouise , Poulsen Steen S. , Vilstrup Hendrik , Prehn Cornelia , Adamski Jerzy , Jepsen Sara L. , Hartmann Bolette , Hunt Jenna , Charron Maureen J. , Pedersen Jens , Wewer Albrechtsen Nicolai J. , Holst Jens J.
Published: October 2017

Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout ( Gcgr−/−) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr−/−and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr−/−mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured α-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (~6-fold) in the media and cell proliferation (~2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25–2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.
Subcutaneous inguinal white adipose tissue is responsive to, but dispensable for, the metabolic health benefits of exercise
Authors: Peppler Willem T. , Townsend Logan K. , Knuth Carly M. , Foster Michelle T. , Wright David C.
Published: October 2017

Exercise training has robust effects on subcutaneous inguinal white adipose tissue (iWAT), characterized by a shift to a brown adipose tissue (BAT)-like phenotype. Consistent with this, transplantation of exercise-trained iWAT into sedentary rodents activates thermogenesis and improves glucose homeostasis, suggesting that iWAT metabolism may contribute to the beneficial effects of exercise. However, it is yet to be determined if adaptations in iWAT are necessary for the beneficial systemic effects of exercise. To test this, male C57BL/6 mice were provided access to voluntary wheel running (VWR) or remained as a cage control (SED) for 11 nights after iWAT removal via lipectomy (LIPX) or SHAM surgery. We found that SHAM and LIPX mice with access to VWR ran similar distances and had comparable reductions in body mass, increased food intake, and increased respiratory exchange ratio (RER). Further, VWR improved indexes of glucose homeostasis and insulin tolerance in both SHAM and LIPX mice. The lack of effect of LIPX in the response to VWR was not explained by compensatory increases in markers of mitochondrial biogenesis and thermogenesis in skeletal muscle, epididymal white adipose tissue, or interscapular brown adipose tissue. Together, these data demonstrate that mice with and without iWAT have comparable adaptations to VWR, suggesting that iWAT may be dispensable for the metabolic health benefits of exercise.
Relationship of Cx43 regulation of vascular permeability to osteopontin-tight junction protein pathway after sepsis in rats
Authors: Zhang Jie , Yang Guangming , Zhu Yu , Peng Xiaoyong , Li Tao , Liu Liangming
Published: October 2017

Our previous study demonstrated that connexin (Cx)43 participated in the regulation of vascular permeability in severe sepsis. Osteopontin (OPN) has been demonstrated to participate in the occurrence of atherosclerosis, inflammation, as well as the adhesion and migration of cells. It is not clear whether OPN is involved in Cx43 regulating vascular permeability after sepsis and if it is related to tight-junction proteins. with the use of cecal ligation and puncture (CLP)-induced septic rats and lipopolysaccharide (LPS)-treated pulmonary vein vascular endothelial cells (VECs), the role of zona occuldens 1 (ZO-1) and claudin-5 in Cx43 regulation of vascular permeability and its relationship to OPN were investigated in the present study. The results showed that the expression of ZO-1 and claudin-5 in pulmonary vein were decreased in CLP rats and LPS-treated pulmonary vein VECs. Cx43-overexpressed lentivirus induced the degradation of ZO-1 and claudin-5, while Cx43 RNAi lentivirus abrogated the degradation of ZO-1 and claudin-5 induced by LPS. The vascular permeability and expression of OPN in pulmonary veins were significantly increased in CLP rats and LPS-treated pulmonary vein VECs. Silencing OPN by OPN RNAi lentivirus inhibited the vascular hyperpermeability induced by LPS. Overexpressed Cx43 lentivirus increased the expression of OPN and vascular permeability and downregulated the expression of ZO-1 and claudin-5 in pulmonary vein VECs. Silencing OPN by OPN RNAi lentivirus inhibited the effects of Cx43-overexpressed lentivirus on downregulation of ZO-1 and claudin-5 and vascular hyperpermeability in pulmonary vein VECs. Transfection of specific double-stranded RNA targeting to β-catenin and T-cell factor-4 (Tcf-4) abolished the upregulation of OPN induced by Cx43 overexpression. These results suggest that OPN participates in the regulation of vascular permeability by Cx43 after sepsis. Cx43 upregulation of OPN is via the Tcf-4/β-catenin transcription pathway; OPN increases vascular permeability by downregulating the expression of the tight junction proteins ZO-1 and claudin-5.
Effects of exercise training on calf muscle oxygen extraction and blood flow in patients with peripheral artery disease
Authors: Baker Wesley B. , Li Zhe , Schenkel Steven S. , Chandra Malavika , Busch David R. , Englund Erin K. , Schmitz Kathryn H. , Yodh Arjun G. , Floyd Thomas F. , Mohler Emile R.
Published: October 2017

We employed near-infrared optical techniques, diffuse correlation spectroscopy (DCS), and frequency-domain near-infrared spectroscopy (FD-NIRS) to test the hypothesis that supervised exercise training increases skeletal muscle microvascular blood flow and oxygen extraction in patients with peripheral artery disease (PAD) who experience claudication. PAD patients ( n = 64) were randomly assigned to exercise and control groups. Patients in the exercise group received 3 mo of supervised exercise training. Calf muscle blood flow and oxygen extraction were optically monitored before, during, and after performance of a graded treadmill protocol at baseline and at 3 mo in both groups. Additionally, measurements of the ankle-brachial index (ABI) and peak walking time (PWT) to maximal claudication were made during each patient visit. Supervised exercise training was found to increase the maximal calf muscle blood flow and oxygen extraction levels during treadmill exercise by 29% (13%, 50%) and 8% (1%, 12%), respectively [ P < 0.001; median (25th percentile, 75th percentile)]. These improvements across the exercise group population were significantly higher than corresponding changes in the control group ( P < 0.004). Exercise training also increased PWT by 49% (18%, 101%) ( P = 0.01). However, within statistical error, the ABI, resting calf muscle blood flow and oxygen extraction, and the recovery half-time for hemoglobin\myoglobin desaturation following cessation of maximal exercise were not altered by exercise training. The concurrent monitoring of both blood flow and oxygen extraction with the hybrid DCS/FD-NIRS instrument revealed enhanced muscle oxidative metabolism during physical activity from exercise training, which could be an underlying mechanism for the observed improvement in PWT.

NEW & NOTEWORTHY We report on noninvasive optical measurements of skeletal muscle blood flow and oxygen extraction dynamics before/during/after treadmill exercise in peripheral artery disease patients who experience claudication. The measurements tracked the effects of a 3-mo supervised exercise training protocol and revealed that supervised exercise training improved patient ability to increase microvascular calf muscle blood flow and oxygen extraction during physical activity.
MyoVision: software for automated high-content analysis of skeletal muscle immunohistochemistry
Authors: Wen Yuan , Murach Kevin A. , Vechetti Ivan J. , Fry Christopher S. , Vickery Chase , Peterson Charlotte A. , McCarthy John J. , Campbell Kenneth S.
Published: October 2017

Analysis of skeletal muscle cross sections is an important experimental technique in muscle biology. Many aspects of immunohistochemistry and fluorescence microscopy can now be automated, but most image quantification techniques still require extensive human input, slowing progress and introducing the possibility of user bias. MyoVision is a new software package that was developed to overcome these limitations. The software improves upon previously reported automatic techniques and analyzes images without requiring significant human input and correction. When compared with data derived by manual quantification, MyoVision achieves an accuracy of ≥94% for basic measurements such as fiber number, fiber type distribution, fiber cross-sectional area, and myonuclear number. Scientists can download the software free from www.MyoVision.org and use it to automate the analysis of their own experimental data. This will improve the efficiency and consistency of the analysis of muscle cross sections and help to reduce the burden of routine image quantification in muscle biology.

NEW & NOTEWORTHY Scientists currently analyze images of immunofluorescently labeled skeletal muscle using time-consuming techniques that require sustained human supervision. As well as being inefficient, these techniques can increase variability in studies that quantify morphological adaptations of skeletal muscle at the cellular level. MyoVision is new software that overcomes these limitations by performing high-content analysis of muscle cross sections with minimal manual input. It is open source and freely available.
TRPC5 is required for the NO-dependent increase in dendritic Ca2+and GABA release from chick retinal amacrine cells
Authors: Maddox J. Wesley , Khorsandi Nikka , Gleason Evanna
Published: October 2017

GABAergic signaling from amacrine cells (ACs) is a fundamental aspect of visual signal processing in the inner retina. We have previously shown that nitric oxide (NO) can elicit release of GABA independently from activation of voltage-gated Ca2+channels in cultured retinal ACs. This voltage-independent quantal GABA release relies on a Ca2+influx mechanism with pharmacological characteristics consistent with the involvement of the transient receptor potential canonical (TRPC) channels TRPC4 and/or TRPC5. To determine the identity of these channels, we evaluated the ability of NO to elevate dendritic Ca2+and to stimulate GABA release from cultured ACs under conditions known to alter the function of TRPC4 and 5. We found that these effects of NO are phospholipase C dependent, have a biphasic dependence on La3+, and are unaffected by moderate concentrations of the TRPC4-selective antagonist ML204. Together, these results suggest that NO promotes GABA release by activating TRPC5 channels in AC dendrites. To confirm a role for TRPC5, we knocked down the expression of TRPC5 using CRISPR/Cas9-mediated gene knockdown and found that both the NO-dependent Ca2+elevations and increase in GABA release are dependent on the expression of TRPC5. These results demonstrate a novel NO-dependent mechanism for regulating neurotransmitter output from retinal ACs.

NEW & NOTEWORTHY Elucidating the mechanisms regulating GABAergic synaptic transmission in the inner retina is key to understanding the flexibility of retinal ganglion cell output. Here, we demonstrate that nitric oxide (NO) can activate a transient receptor potential canonical 5 (TRPC5)-mediated Ca2+influx, which is sufficient to drive vesicular GABA release from retinal amacrine cells. This NO-dependent mechanism can bypass the need for depolarization and may have an important role in processing the visual signal by enhancing retinal amacrine cell GABAergic inhibitory output.
EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming
Authors: Adelaiye-Ogala Remi , Budka Justin , Damayanti Nur P. , Arrington Justine , Ferris Mary , Hsu Chuan-Chih , Chintala Sreenivasulu , Orillion Ashley , Miles Kiersten Marie , Shen Li , Elbanna May , Ciamporcero Eric , Arisa Sreevani , Pettazzoni Piergiorgio , Draetta Giulio F. , Seshadri Mukund , Hancock Bradley , Radovich Milan , Kota Janaiah , Buck Michael , Keilhack Heike , McCarthy Brian P. , Persohn Scott A. , Territo Paul R. , Zang Yong , Irudayaraj Joseph , Tao W. Andy , Hollenhorst Peter , Pili Roberto
Published: October 2017

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle–regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease. Cancer Res; 77(23); 6651–66. ©2017 AACR.
Mobile Screening Units for the Early Detection of Cancer: A Systematic Review
Authors: Greenwald Zoë R. , El-Zein Mariam , Bouten Sheila , Ensha Heydar , Vazquez Fabiana L. , Franco Eduardo L.
Published: October 2017

Mobile screening units (MSUs) provide cancer screening services outside of fixed clinical sites, thereby increasing access to early detection services. We conducted a systematic review of the performance of MSUs for the early detection of cancer. Databases (MEDLINE, EMBASE, Cochrane Library, WHO Global Health Library, Web of Science, PsycINFO) were searched up to July 2015. Studies describing screening for breast, cervical, and colon cancer using MSUs were included. Data were collected for operational aspects including the performance of exams, screening tests used, and outcomes of case detection. Of 268 identified studies, 78 were included. Studies investigated screening for cancers including breast (n = 55), cervical (n = 12), colon (n = 1), and multiphasic screening for multiple cancers (n = 10). The median number of screening exams performed per intervention was 1,767 (interquartile range 5,656–38,233). Programs operated in 20 countries, mostly in North America (36%) and Europe (36%); 52% served mixed rural/urban regions, while 35% and 13% served rural or urban regions, respectfully. We conclude that MSUs have served to expand access to screening in diverse contexts. However, further research on the implementation of MSUs in low-resource settings and health economic research on cost-effectiveness of MSUs compared with fixed clinics to inform policymakers is needed. Cancer Epidemiol Biomarkers Prev; 26(12); 1679–94. ©2017 AACR.
Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β
Authors: Lau Wen Min , Teng Eileen , Huang Kie Kyon , Tan Jin Wei , Das Kakoli , Zang Zhijiang , Chia Tania , Teh Ming , Kono Koji , Yong Wei Peng , Shabbir Asim , Tay Amy , Phua Niam Sin , Tan Patrick , Chan Shing Leng , So Jimmy Bok Yan
Published: October 2017

Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patient-derived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3β as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3β with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3β to gain a survival advantage. Mol Cancer Ther; 17(1); 232–42. ©2017 AACR.
A Murine Model for Quantitative, Real-Time Evaluation of Convection-Enhanced Delivery (RT-CED) Using an 18[F]-Positron Emitting, Fluorescent Derivative of Dasatinib
Authors: Wang Melinda , Kommidi Harikrishna , Tosi Umberto , Guo Hua , Zhou Zhiping , Schweitzer Melanie E. , Wu Linda Y. , Singh Ranjodh , Hou Shengqi , Law Benedict , Ting Richard , Souweidane Mark M.
Published: October 2017

The blood brain barrier can limit the efficacy of systemically delivered drugs in treating neurological malignancies; therefore, alternate routes of drug administration must be considered. The Abl-kinase inhibitor, dasatinib, is modified to give compound 1 ([18F]-1) so that 18F-positron emission tomography (PET) and fluorescent imaging can both be used to observe drug delivery to murine orthotopic glioma. In vitro Western blotting, binding studies (IC50 = 22 ± 5 nmol/L), and cell viability assays (IC50 = 46 ± 30 nmol/L) confirm nanomolar, in vitro effectiveness of [18F]-1, a dasatinib derivative that is visible by 18F-PET and fluorescence. [18F]-1 is used to image dynamic direct drug delivery via two different drug delivery techniques to orthotopic murine brainstem glioma (mBSG) bearing mice. Convection enhanced delivery (CED) delivers higher concentrations of drug to glioma-containing volumes versus systemic, tail-vein delivery. Accurate delivery and clearance data pertaining to dasatinib are observed, providing personalized information that is important in dosimetry and redosing. Cases of missed drug delivery are immediately recognized by PET/CT, allowing for prompt intervention in the case of missed delivery. Mol Cancer Ther; 16(12); 2902–12. ©2017 AACR.
A New Proposal for OFCC-based Instrumentation Amplifier
Authors: Nand Deva , Pandey Neeta
Published: October 2017

This contribution puts forward a new voltage mode instrumentation amplifier (VMIA) based on operational floating current conveyor (OFCC). It presents high impedance at input terminals and provides output at low impedance making the proposal ideal for voltage mode operation. The proposed VMIA architecture has two stages - the first stage comprises of two OFCCs to sense input voltages and coverts the voltage difference to current while the second stage has single OFCC that converts the current to voltage. In addition it employs two resistors to provide gain and imposes no condition on the values of resistors.  The behavior of the proposed structure is also analyzed for OFCC non idealities namely finite transimpedance and tracking error. The proposal is verified through SPICE simulations using CMOS based schematic of OFCC. Experimental results, by bread boarding it using commercially available IC AD844, are also included.
Context Sensitive Search String Composition Algorithm using User Intention to Handle Ambiguous Keywords
Authors: Gajendragadkar Uma , Joshi Sarang
Published: October 2017

Finding the required URL among the first few result pages of a search engine is still a challenging task. This may require number of reformulations of the search string thus adversely affecting user's search time. Query ambiguity and polysemy are major reasons for not obtaining relevant results in the top few result pages. Efficient query composition and data organization are necessary for getting effective results. Context of the information need and the user intent may improve the autocomplete feature of existing search engines. This research proposes a Funnel Mesh-5 algorithm (FM5) to construct a search string taking into account context of information need and user intention with three main steps 1) Predict user intention with user profiles and the past searches via weighted mesh structure 2) Resolve ambiguity and polysemy of search strings with context and user intention 3) Generate a personalized disambiguated search string by query expansion encompassing user intention and predicted query. Experimental results for the proposed approach and a comparison with direct use of search engine are presented. A comparison of FM5 algorithm with K Nearest Neighbor algorithm for user intention identification is also presented. The proposed system provides better precision for search results for ambiguous search strings with improved identification of the user intention. Results are presented for English language dataset as well as Marathi (an Indian language) dataset of ambiguous search strings.

 
5G Coupler Design for Intelligent Transportation System (ITS) Application
Authors: Abang Zaidel Dyg Norkhairunnisa , Seman Norhudah , Mohd Sharip Mohd Ridhuan , Awang Mat Dyg Azra , Athirah Mohtadzar Nur Alia
Published: October 2017

Aiming to achieve 3-dB coupling, operating in fifth generation (5G) technologies, this paper introduces a new design of tight coupling coupler that will be operated in 5G technologies. Two stubs and two slots have been implemented into the 3-dB coupler design in order to achieve impedance matching between the ports and to give better coupling performances, respectively. Moreover, a study on the stubs’ and slots’ effects towards the S31 of the 3-dB coupler has also been presented in this paper. The proposed coupler is designed on Rogers RO4003C substrate. The simulation results and the analytical study on the stubs and slots implementation show that both stubs and slots affect the performance of the coupling coefficient.
SC-FDM-IDMA Scheme Employing BCH Coding
Authors: Agarwal Roopali , Shukla Manoj K.
Published: October 2017

In OFDM-IDMA scheme, intersymbol interference (ISI) is resolved by the OFDM layer and multiple access interference (MAI) is suppressed by the IDMA layer at low cost . However OFDM-IDMA scheme suffers high peak-to-average power ratio (PAPR) problem. For removing high PAPR problem a hybrid multiple access scheme SC-FDM-IDMA has been proposed. In this paper, bit error rate (BER) performance comparison of SC-FDM-IDMA scheme, OFDM-IDMA scheme and IDMA scheme have been duly presented.  Moreover, the BER performance of various subcarrier mapping methods for SC-FDM-IDMA scheme as well as other results with variation of different parameters have also been demonstrated. Finally simulation result for BER performance improvement has been shown employing BCH code. All the simulation results demonstrate the suitability of SC-FDM-IDMA scheme for wireless communication under AWGN channel environment.
Approximation Measures for Conditional Functional Dependencies Using Stripped Conditional Partitions
Authors: Duy Tran Anh , Arch-int Somjit , Arch-int Ngamnij
Published: October 2017

Conditional functional dependencies (CFDs) have been used to improve the quality of data, including detecting and repairing data inconsistencies. Approximation measures have significant importance for data dependencies in data mining. To adapt to exceptions in real data, the measures are used to relax the strictness of CFDs for more generalized dependencies, called approximate conditional functional dependencies (ACFDs). This paper analyzes the weaknesses of dependency degree, confidence and conviction measures for general CFDs (constant and variable CFDs). A new measure for general CFDs based on incomplete knowledge granularity is proposed to measure the approximation of these dependencies as well as the distribution of data tuples into the conditional equivalence classes. Finally, the effectiveness of stripped conditional partitions and this new measure are evaluated on synthetic and real data sets. These results are important to the study of theory of approximation dependencies and improvement of discovery algorithms of CFDs and ACFDs.
Modeling the Vibrational Dynamics of Piezoelectric Actuator by System Identification Technique
Authors: Noor Nurul Bahiah Mohd , Ahmad Mohd Ridzuan
Published: October 2017

Actuators based on smart materials such as piezoelectric actuators (PEAs) are widely used in many applications to transform electrical signal to mechanical signal and vice versa. However, the major drawbacks for these smart actuators are hysteresis nonlinear, creep and residual vibration. In this paper, PEAs are used for active vibration application. Therefore, a model of PEA must be established to control the vibration that occurs in the system. The frequencies of 1 Hz, 20 Hz and 50 Hz were tested on the PEAs. The results obtained from the experimental were used to develop transfer function model by employing system identiﬁcation technique. Meanwhile, the model validation was based on level of models ﬁtness to estimation data, mean squared error (MSE), ﬁnal prediction error (FPE) and correlation test. The experimental result showed that the displacement of the actuator is inversely proportional to the frequency. The following consequences caused the time response criteria at 50 Hz achieved smallest overshoot and fastest response of rise time and settling time.
Parameter Optimisation of Aerobic Granular Sludge at High Temperature Using Response Surface Methodology
Authors: Ibrahim Syahira , Wahab Norhaliza Abdul , Anuar Aznah Nor , Bob Mustafa
Published: October 2017

This paper proposes an improved optimisation of sequencing batch reactors (SBR) for aerobic granular sludge (AGS) at high temperature-low humidity for domestic wastewater treatment using response surface methodology (RSM). The main advantages of RSM are less number of experiment required and suitable for complex process. The sludge from a conventional activated sludge wastewater treatment plant and three sequencing batch reactors (SBRs) were fed with synthetic wastewater. The experiment were carried out at different high temperatures (30, 40 and 50°C) and the formation of AGS for simultaneous organics and nutrients removal were examined in 60 days. RSM is used to model and to optimize the biological parameters for chemical oxygen demand (COD) and total phosphorus removal in SBR system. The simulation results showed that at temperature of 45.33°C give the optimum condition for the total removal of COD and phosphorus, which correspond to performance index R2 of 0.955 and 0.91, respectively.
Comparative Study of Meta-heuristics Optimization Algorithm using Benchmark Function
Authors: Ismail I. , Halim A. Hanif
Published: October 2017

Meta-heuristics optimization is becoming a popular tool for solving numerous problems in real-world application due to the ability to overcome many shortcomings in traditional optimization. Despite of the good performance, there is limitation in some algorithms that deteriorates by certain degree of problem type. Therefore it is necessary to compare the performance of these algorithms with certain problem type. This paper compares 7 meta-heuristics optimization with 11 benchmark functions that exhibits certain difficulties and can be assumed as a simulation relevant to the real-world problems. The tested benchmark function has different type of problem such as modality, separability, discontinuity and surface effects with steep-drop global optimum, bowl- and plateau-typed function. Some of the proposed function has the combination of these problems, which might increase the difficulty level of search towards global optimum. The performance comparison includes computation time and convergence of global optimum.
Shape Based Image Retrieval using Lower Order Zernike Moments
Authors: Sucharitha G. , K. Senapati Ranjan
Published: October 2017

Shape is one of the significant features of Content Based Image Retrieval (CBIR). This paper proposes a strong and successful shape feature, which is based on a set of orthogonal complex moments of images known as Zernike moments. For shape classification Zernike moment (ZM) is the dominant solution. The radial polynomial of Zernike moment produces the number of concentric circles based on the order. As the order increases number of circles will increases, due to this the local information of an image will be ignored. In this paper, we introduced a novel method for radial polynomial where local information of an image given importance. We succeeded to extract the local features and shape features at very a low order of polynomial compared to the state of traditional ZM.The proposed method gives an advantage of a lower order, less complex, and lower dimension feature vector.For more similar images we find that simple  Euclidian distance approximately zero. Proposed method tested on a MPEG-7 CE-1 shape database, Coil-100 databases. Experiments demonstrated that it is outperforming in identifying the shape of an object in the image  and reduced the retrieving time and complexity of calculations.
Economic Efficiency Measure of Induction Motors for Industrial Applications
Authors: Rai Keerti , Seksena S B L , Thakur A N
Published: October 2017

This paper, introduced an expression of Economic Efficiency Measure (EEM) to permit quick evaluation for replacement of faulty induction motor with alternative (new or refurbished motor) for lowest life-cycle cost based on efficiency and rated-load conditions. This approach, simplifies the process for evaluating the energy efficiency to mere proportionate factor called as EEM. During the operating phase, the motor losses correspond to extra energy consumption, based on various parameters like motor operating conditions, operating hours, operating costs, fault factor, depreciation factor and fixed costs.  The approach is effective in addressing the global issue on replacement of the faulty motor that needs a comprehensive analysis and mathematical expression. Compared to other alternatives the EEM provides a simple but effective and reliable means to asses, the feasibility of replacing or refurbishing the faulty motor. A detail analysis here would establish how much the present approach is effective in determining the replacement for a faulty induction motor either by a new one or refurbished one of corresponding rating.
Modulation Index Variation Effect on Harmonic Behavior of Fifteen Multilevel Inverter Neutral-Point-Clamped Topology
Authors: Benioub Rabie , Kadri Laid , Adnane Mohamed , Itaka Kenji
Published: October 2017

The Market for photovoltaic cells (PV) has grown fast due to a higher demand on PV applications. However, there are still the transport and connection problems of the PV systems to the grid because of the difference in the current form. To assure the adequate connection between the PV sources and the network, the conversion of direct current (DC) to an alternative current (AC) is required and provided by an electronic device known as the inverter. In this last years, the conventional inverter structure reached its limits in power level and conversion performance. The multilevel inverter (MLI) structure was introduced and widely used in high power and high voltage applications to solve the conventional inverter limitation problem. In this paper, the Neutral-Point-Clamped (NPC) topology of the MLI was simulated to evaluate the effect of modulation index variation of the control technique on the harmonic behavior of the fifteen-level NPC. The simulation results were useful for the optimization of the MLI control technique toward the decrease of the harmonic (THD) effect on the NPC MLI.
Wind Integrated Thermal Unit Commitment Solution Using Grey Wolf Optimizer
Authors: Sakthi S. Siva , Santhi R.K. , Murali Krishnan N. , Ganesan S. , Subramanian S.
Published: October 2017

The augment of ecological shield and the progressive exhaustion of traditional fossil energy sources have increased the interests in integrating renewable energy sources into existing power system. Wind power is becoming worldwide a significant component of the power generation portfolio. Profuse literature have been reported for the thermal Unit Commitment (UC) solution. In this work, the UC problem has been formulated by integrating wind power generators along with thermal power system. The Wind Generator Integrated UC (WGIUC) problem is more complex in nature, that necessitates a promising optimization tool. Hence, the modern bio-inspired algorithm namely, Grey Wolf Optimization (GWO) algorithm has been chosen as the main optimization tool and real coded scheme has been incorporated to handle the operational constraints. The standard test systems are used to validate the potential of the GWO algorithm. Moreover, the ramp rate limits are also included in the mathematical WGIUC formulation. The simulation results prove that the intended algorithm has the capability of obtaining economical resolutions with good solution quality.
Inertial Navigation for Quadrotor Using Kalman Filter with Drift Compensation
Authors: Lasmadi Lasmadi , Cahyadi Adha Imam , Herdjunanto Samiadji , Hidayat Risanuri
Published: October 2017

The main disadvantage of an Inertial Navigation System is a low accuracy due to noise, bias, and drift error in the inertial sensor. This research aims to develop the accelerometer and gyroscope sensor for quadrotor navigation system, bias compensation, and Zero Velocity Compensation (ZVC). Kalman Filter is designed to reduce the noise on the sensor while bias compensation and ZVC are designed to eliminate the bias and drift error in the sensor data. Test results showed the Kalman Filter design is acceptable to reduce the noise in the sensor data. Moreover, the bias compensation and ZVC can reduce the drift error due to integration process as well as improve the position estimation accuracy of the quadrotor. At the time of testing, the system provided the accuracy above 90 % when it tested indoor.
Link Aggregation Control Protocol on Software Defined Network
Authors: Irawati L. D. , Hariyani Y. Sun , Hadiyoso S.
Published: October 2017

A physical connection of computer network must be made reliably. Breaking connection will cause communication between nodes (for example routers, switches, hosts) can be disconnected. One of the solutions is implemention of link aggregation (LA). LA integrates several of physical ports together to make a single logical communication link. Accordingly, there is load sharing traffic among the member port of the group, high-throughput increasing via a single link, and redundancy providing for broken links. We present the implementation of link aggregation using Ryu controller on Software Defined Network (SDN) topology. The results show that the implementation of SDN with OpenvSwitch and Ryu controller can successfully run link aggregation function to solve the problem of link failure.
A Performance Review of Intra and Inter-Group MANET Routing Protocols under Varying Speed of Nodes
Authors: Sisodia Dilip Singh , Singhal Riya , Khandal Vijay
Published: October 2017

Mobile Ad-hoc Networks (MANETs) are a cluster of self-organizing and self-governing wireless nodes without any backbone infrastructure and centralized administration. The various nodes in MANET move randomly, and this node mobility may pose challenges on the performance of routing protocols.  In this paper, an Intra and intergroup performance review of various MANET routing protocols are performed under varying speed of nodes. The routing protocols included in this study are reactive, proactive, and hybrid protocols. This performance review is done using the NS2 simulator and random waypoint model. The routing protocols performance is assessed through standard performance measure metrics including packet delivery ratio, throughput, routing overhead and end to end delivery with varying speed of nodes. The simulations result shows that there is no significant impact of varying speed of nodes on standard performance evaluation metrics.