bluuebunny/crossref_metadata_2025 huggingface dataset:
Paleontology of Earth's Mantle
Authors: Sleep Norman H. , Bird Dennis K. , Pope Emily
Published: May 2012

Solid, liquid, and gaseous products of life's metabolic processes have a profound effect on the chemistry of Earth and its fluid envelopes. Earth's mantle has been modified by the ubiquitous influence of life on recycled lithosphere, with dramatic changes resulting from subduction of redox-sensitive minerals following the rise of photosynthetic oxygen approximately 2.5 billion years ago. Throughout geological time, production and degradation of organic carbon affected minor-element, trace-element, and isotopic systems in the mantle. Carbon in the mantle decreased as carbonate sediments sequestered CO2, but nitrogen concentrations were augmented by subduction of biologically derived ammonium structurally bound in diagenetic minerals. The biologically modulated mantle vents its biosignatures through island arc and oceanic volcanoes, with fractionated sulfur isotopes providing a durable record. Deeply subducted CO2-rich domains are the source of carbonatite melts, as well as eclogitic diamonds with low 13C/12C ratios and remnant biologically derived nitrogen. The mantle preserves a concentrated biological record throughout Earth history, thus giving expectation of finding a Hadean record of life.
MARCKS actin-binding capacity mediates actin filament assembly during mitosis in human hepatic stellate cells
Authors: Rombouts Krista , Mello Tommaso , Liotta Francesco , Galli Andrea , Caligiuri Alessandra , Annunziato Francesco , Pinzani Massimo
Published: May 2012

Cross-linking between the actin cytoskeleton and plasma membrane actin-binding proteins is a key interaction responsible for the mechanical properties of the mitotic cell. Little is known about the identity, the localization, and the function of actin filament-binding proteins during mitosis in human hepatic stellate cells (hHSC). The aim of the present study was to identify and analyze the cross talk between actin and myristoylated alanine-rich kinase C substrate (MARCKS), an important PKC substrate and actin filament-binding protein, during mitosis in primary hHSC. Confocal analysis and chromosomal fraction analysis of mitotic hHSC demonstrated that phosphorylated (P)-MARCKS displays distinct phase-dependent localizations, accumulates at the perichromosomal layer, and is a centrosomal protein belonging to the chromosomal cytosolic fraction. Aurora B kinase (AUBK), an important mitotic regulator, β-actin, and P-MARCKS concentrate at the cytokinetic midbody during cleavage furrow formation. This localization is critical since MARCKS-depletion in hHSC is characterized by a significant loss in cytosolic actin filaments and cortical β-actin that induces cell cycle inhibition and dislocation of AUBK. A depletion of AUBK in hHSC affects cell cycle, resulting in multinucleation. Quantitative live cell imaging demonstrates that the actin filament-binding capacity of MARCKS is key to regulate mitosis since the cell cycle inhibitory effect in MARCKS-depleted cells caused abnormal cell morphology and an aberrant cytokinesis, resulting in a significant increase in cell cycle time. These findings implicate that MARCKS, an important PKC substrate, is essential for proper cytokinesis and that MARCKS and its partner actin are key mitotic regulators during cell cycle in hHSC.
Indoxyl sulfate promotes vascular smooth muscle cell senescence with upregulation of p53, p21, and prelamin A through oxidative stress
Authors: Muteliefu Gulinuer , Shimizu Hidehisa , Enomoto Atsushi , Nishijima Fuyuhiko , Takahashi Masahide , Niwa Toshimitsu
Published: May 2012

We previously demonstrated that indoxyl sulfate (IS), a uremic toxin, induces aortic calcification in hypertensive rats and induces oxidative stress and the expression of osteoblast-specific proteins in vascular smooth muscle cells. This study aimed to clarify whether IS stimulates senescence of cultured human aortic smooth muscle cells (HASMCs) and aorta in Dahl salt-sensitive hypertensive rats and whether AST-120, an oral sorbent, prevents senescence of aorta in subtotally nephrectomized uremic rats. IS increased the mRNA expression of p53 and p21 in HASMCs, whereas it did not change that of p16 and retinoblastoma protein (pRb). The IS-induced expression of p53 and p21 was suppressed by N-acetylcysteine, an antioxidant. IS promoted protein expression of p53, p21, and senescence-associated β-galactosidase (SA-β-gal) activity in HASMCs, and N-acetylcysteine and pifithrin-α, p-nitro, a p53 inhibitor, blocked these effects. IS upregulated prelamin A, a hallmark of vascular smooth muscle cell senescence, and downregulated FACE1/Zempste24 protein expression in HASMCs, and N-acetylcysteine suppressed these effects. Administration of IS to hypertensive rats increased expression of SA-β-gal, p53, p21, prelamin A, and oxidative stress markers such as 8-hydroxyl-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in the cells embedded in the calcification area of arcuate aorta. Further, the uremic rat model showed positive staining for SA-β-gal, p53, p21, prelamin A, 8-OHdG, and MDA in the cells embedded in the calcification area of arcuate aorta, whereas AST-120 reduced the expression of these biomarkers. Taken together, IS accelerates vascular smooth muscle cell senescence with upregulation of p53, p21, and prelamin A and downregulation of FACE1 through oxidative stress.
Regulation of endothelial BK channels by heme oxygenase-derived carbon monoxide and caveolin-1
Authors: Riddle Melissa A. , Walker Benjimen R.
Published: May 2012

A novel vasodilatory influence of endothelial cell (EC) large-conductance Ca2+-activated K+ (BK) channels is present after in vivo exposure to chronic hypoxia (CH) and may exist in other pathological states. However, the mechanism of channel activation that results in altered vasoreactivity is unknown. Previously, we demonstrated that inhibition of either BK channels or heme oxygenase (HO) restores vasoconstrictor reactivity after CH. Additionally, administration of the scaffolding domain of caveolin (Cav)-1 inhibits EC BK activity and restores vasoconstrictor reactivity in this setting. These results led us to hypothesize that CH exposure results in a loss in Cav-1 inhibition of EC BK channels, resulting in their activation by HO-derived carbon monoxide (CO). Experiments were conducted on freshly dispersed aortic ECs from control and CH-exposed (barometric pressure: 380 mmHg for 48 h) rats. In electrophysiology experiments, outward currents were greater in cells from CH rats as well as from cells from control rats treated with the cholesterol-depleting agent methyl-β-cyclodextrin. These enhanced currents were returned to control by HO inhibition. Channel activity could be restored by the CO donor CO-releasing molecule (CORM)-2 during HO inhibition. Administration of the Cav-1 scaffolding domain eliminated BK currents in cells from CH rats, and current was not restored by the addition of CORM-2. Colocalization experiments in ECs from control and CH rats demonstrated an association between HO-2, Cav-1, and BK. We conclude that EC BK channel activity is HO dependent in the absence of the inhibitory effect of the Cav-1 scaffolding domain.
NAD kinase regulates the size of the NADPH pool and insulin secretion in pancreatic β-cells
Authors: Gray Joshua P. , Alavian Kambiz N. , Jonas Elizabeth A. , Heart Emma A.
Published: May 2012

NADPH is an important component of the antioxidant defense system and a proposed mediator in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. An increase in the NADPH/NADP+ ratio has been reported to occur within minutes following the rise in glucose concentration in β-cells. However, 30 min following the increase in glucose, the total NADPH pool also increases through a mechanism not yet characterized. NAD kinase (NADK) catalyzes the de novo formation of NADP+ by phosphorylation of NAD+. NAD kinases have been shown to be essential for redox regulation, oxidative stress defense, and survival in bacteria and yeast. However, studies on NADK in eukaryotic cells are scarce, and the function of this enzyme has not been described in β-cells. We employed INS-1 832/13 cells, an insulin-secreting rat β-cell line, and isolated rodent islets to investigate the role of NADK in β-cell metabolic pathways. Adenoviral-mediated overexpression of NADK resulted in a two- to threefold increase in the total NADPH pool and NADPH/NADP+ ratio, suggesting that NADP+ formed by the NADK-catalyzed reaction is rapidly reduced to NADPH via cytosolic reductases. This increase in the NADPH pool was accompanied by an increase in GSIS in NADK-overexpressing cells. Furthermore, NADK overexpression protected β-cells against oxidative damage by the redox cycling agent menadione and reversed menadione-mediated inhibition of GSIS. Knockdown of NADK via shRNA exerted the opposite effect on all these parameters. These data suggest that NADK kinase regulates intracellular redox and affects insulin secretion and oxidative defense in the β-cell.
Renal sympathetic nerve activity during asphyxia in fetal sheep
Authors: Booth Lindsea C. , Malpas Simon C. , Barrett Carolyn J. , Guild Sarah-Jane , Gunn Alistair J. , Bennet Laura
Published: May 2012

The sympathetic nervous system (SNS) is an important mediator of fetal adaptation to life-threatening in utero challenges, such as asphyxia. Although the SNS is active well before term, SNS responses mature significantly over the last third of gestation, and its functional contribution to adaptation to asphyxia over this critical period of life remains unclear. Therefore, we examined the hypotheses that increased renal sympathetic nerve activity (RSNA) is the primary mediator of decreased renal vascular conductance (RVC) during complete umbilical cord occlusion in preterm fetal sheep (101 ± 1 days; term 147 days) and that near-term fetuses (119 ± 0 days) would have a more rapid initial vasomotor response, with a greater increase in RSNA. Causality of the relationship of RSNA and RVC was investigated using surgical (preterm) and chemical (near-term) denervation. All fetal sheep showed a significant increase in RSNA with occlusion, which was more sustained but not significantly greater near-term. The initial fall in RVC was more rapid in near-term than preterm fetal sheep and preceded the large increase in RSNA. These data suggest that although RSNA can increase as early as 0.7 gestation, it is not the primary determinant of RVC. This finding was supported by denervation studies. Interestingly, chemical denervation in near-term fetal sheep was associated with an initial fall in blood pressure, suggesting that by 0.8 gestation sympathetic innervation of nonrenal vascular beds is critical to maintain arterial blood pressure during the rapid initial adaptation to asphyxia.
Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency
Authors: Ronden Rianne A. , Houben Alfons J. H. M. , Teerlink Tom , Bakker Jaap A. , Bierau Jörgen , Stehouwer Coen D. A. , De Leeuw Peter W. , Kroon Abraham A.
Published: May 2012

Plasma concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) increase already in the early stages of renal insufficiency. There is no agreement as to whether reduced renal plasma clearance (RPCL) contributes to this increase. Therefore, we investigated the relationship between estimated glomerular filtration rate (eGFR), RPCL, and plasma ADMA and SDMA in essential hypertensive patients with mild to moderate renal insufficiency. In 171 patients who underwent renal angiography, we drew blood samples from the aorta and both renal veins and measured mean renal blood flow (MRBF) using the133Xe washout technique. RPCL was calculated using arteriovenous concentration differences and MRBF. After correction for potential confounders, reduced eGFR was associated with higher plasma ADMA and SDMA [standardized regression coefficient (β) = −0.22 (95% confidence intervals: −0.41, −0.04) and β = −0.66 (95% confidence intervals: −0.83, −0.49), respectively]. However, eGFR was not independently associated with RPCL of ADMA. Moreover, reduced RPCL of ADMA was not associated with higher plasma ADMA. Contrary to ADMA, reduced eGFR was indeed associated with lower RPCL of SDMA [β = 0.21 (95% confidence intervals: 0.02, 0.40)] . In conclusion, our findings indicate that RPCL of ADMA is independent of renal function in hypertensive patients with mild to moderate renal insufficiency. Unlike the case for SDMA, reduced RPCL of ADMA is of minor importance for the increase in plasma ADMA in these patients, which indicates that increased plasma ADMA in this population is not a direct consequence of the kidneys failing as a plasma ADMA-regulating organ.
Nicotine exposure and the progression of chronic kidney disease: role of the α7-nicotinic acetylcholine receptor
Authors: Rezonzew Gabriel , Chumley Phillip , Feng Wenguang , Hua Ping , Siegal Gene P. , Jaimes Edgar A.
Published: May 2012

Clinical studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease (CKD). We have shown that nicotine promotes mesangial cell proliferation and hypertrophy via nonneuronal nicotinic acetylcholine receptors (nAChRs). The α7-nAChR is one of the most important subunits of the nAChRs. These studies were designed to test the hypothesis that nicotine worsens renal injury in rats with 5/6 nephrectomy (5/6Nx) and that the α7-nAChR subunit is required for these effects. We studied five different groups: Sham, 5/6Nx, 5/6Nx + nicotine (Nic; 100 μg/ml dry wt), 5/6Nx + Nic + α7-nAChR blocker methyllicaconitine (MLA; 3 mg·kg−1·day−1 sq), and Sham + Nic. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. After 12 wk, the rats were euthanized and kidneys were collected. We observed expression of the α7-nAChR in the proximal and distal tubules. The administration of nicotine induced a small increase in blood pressure and resulted in cotinine levels similar to those found in the plasma of smokers. In 5/6Nx rats, the administration of nicotine significantly increased urinary protein excretion (onefold), worsened the glomerular injury score and increased fibronectin (∼ 50%), NADPH oxidase 4 (NOX4; ∼100%), and transforming growth factor-β expression (∼200%). The administration of nicotine to sham rats increased total proteinuria but not albuminuria, suggesting direct effects on tubular protein reabsorption. These effects were prevented by MLA, demonstrating a critical role for the α7-nAChR as a mediator of the effects of nicotine in the progression of CKD.
Increasing SK2 channel activity impairs associative learning
Authors: McKay Bridget M. , Oh M. Matthew , Galvez Roberto , Burgdorf Jeffrey , Kroes Roger A. , Weiss Craig , Adelman John P. , Moskal Joseph R. , Disterhoft John F.
Published: May 2012

Enhanced intrinsic neuronal excitability of hippocampal pyramidal neurons via reductions in the postburst afterhyperpolarization (AHP) has been hypothesized to be a biomarker of successful learning. This is supported by considerable evidence that pharmacologic enhancement of neuronal excitability facilitates learning. However, it has yet to be demonstrated that pharmacologic reduction of neuronal excitability restricted to the hippocampus can retard acquisition of a hippocampus-dependent task. Thus, the present study was designed to address this latter point using a small conductance potassium (SK) channel activator NS309 focally applied to the dorsal hippocampus. SK channels are important contributors to intrinsic excitability, as measured by the medium postburst AHP. NS309 increased the medium AHP and reduced excitatory postsynaptic potential width of CA1 neurons in vitro. In vivo, NS309 reduced the spontaneous firing rate of CA1 pyramidal neurons and impaired trace eyeblink conditioning in rats. Conversely, trace eyeblink conditioning reduced levels of SK2 channel mRNA and protein in the hippocampus. Therefore, the present findings indicate that modulation of SK channels is an important cellular mechanism for associative learning and further support postburst AHP reductions in hippocampal pyramidal neurons as a biomarker of successful learning.
Changes in multifinger interaction and coordination in Parkinson's disease
Authors: Park Jaebum , Wu Yen-Hsun , Lewis Mechelle M. , Huang Xuemei , Latash Mark L.
Published: May 2012

In this study, we tested several hypotheses related to changes in finger interaction and multifinger synergies during multifinger force production tasks in Parkinson's disease. Ten patients with Parkinson's disease, mostly early stage, and 11 healthy control subjects participated in the study. Synergies were defined as covaried adjustment of commands to fingers that stabilized the total force produced by the hand. Both Parkinson's disease patients and control subjects performed accurate isometric force production tasks with the fingers of both the dominant and nondominant hands. The Parkinson's disease patients showed significantly lower maximal finger forces and higher unintended force production (enslaving). These observations suggest that changes in supraspinal control have a major effect on finger individuation. The synergy indexes in the patients were weaker in both steady-state and cyclic force production tasks compared with the controls. These indexes also were stronger in the left (nondominant) hand in support of the dynamic-dominance hypothesis. Half of the patients could not perform the cyclic task at the highest frequency (2 Hz). Anticipatory adjustments of synergies prior to a quick force pulse production were delayed and reduced in the patients compared with the controls. Similar differences were observed between the asymptomatic hands of the patients with symptoms limited to one side of the body and matched hands of control subjects. Our study demonstrates that the elusive changes in motor coordination in Parkinson's disease can be quantified objectively, even in patients at a relatively early stage of the disease. The results suggest an important role of the basal ganglia in synergy formation and demonstrate a previously unknown component of impaired feedforward control in Parkinson's disease reflected in the reduced and delayed anticipatory synergy adjustments.
Modulation of thalamic auditory neurons by the primary auditory cortex
Authors: Tang Jie , Yang Weiguo , Suga Nobuo
Published: May 2012

The central auditory system consists of the lemniscal and nonlemniscal pathways or systems, which are anatomically and physiologically different from each other. In the thalamus, the ventral division of the medial geniculate body (MGBv) belongs to the lemniscal system, whereas its medial (MGBm) and dorsal (MGBd) divisions belong to the nonlemniscal system. Lemniscal neurons are sharply frequency-tuned and provide highly frequency-specific information to the primary auditory cortex (AI), whereas nonlemniscal neurons are generally broadly frequency-tuned and project widely to cortical auditory areas including AI. These two systems are presumably different not only in auditory signal processing, but also in eliciting cortical plastic changes. Electric stimulation of narrowly frequency-tuned MGBv neurons evokes the shift of the frequency-tuning curves of AI neurons toward the tuning curves of the stimulated MGBv neurons (tone-specific plasticity). In contrast, electric stimulation of broadly frequency-tuned MGBm neurons augments the auditory responses of AI neurons and broadens their frequency-tuning curves (nonspecific plasticity). In our current studies, we found that electric stimulation of AI evoked tone-specific plastic changes of the MGBv neurons, whereas it degraded the frequency tuning of MGBm neurons by inhibiting their auditory responses. AI apparently modulates the lemniscal and nonlemniscal thalamic neurons in quite different ways. High MGBm activity presumably makes AI neurons less favorable for fine auditory signal processing, whereas high MGBv activity makes AI neurons more suitable for fine processing of specific auditory signals and reduces MGBm activity.
Noise-induced hyperactivity in the inferior colliculus: its relationship with hyperactivity in the dorsal cochlear nucleus
Authors: Manzoor N. F. , Licari F. G. , Klapchar M. , Elkin R. L. , Gao Y. , Chen G. , Kaltenbach J. A.
Published: May 2012

Intense noise exposure causes hyperactivity to develop in the mammalian dorsal cochlear nucleus (DCN) and inferior colliculus (IC). It has not yet been established whether the IC hyperactivity is driven by hyperactivity from extrinsic sources that include the DCN or instead is maintained independently of this input. We have investigated the extent to which IC hyperactivity is dependent on input from the contralateral DCN by comparing recordings of spontaneous activity in the IC of noise-exposed and control hamsters before and after ablation of the contralateral DCN. One group of animals was binaurally exposed to intense sound (10 kHz, 115 dB SPL, 4 h), whereas the control group was not. Both groups were studied electrophysiologically 2–3 wk later by first mapping spontaneous activity along the tonotopic axis of the IC to confirm induction of hyperactivity. Spontaneous activity was then recorded at a hyperactive IC locus over two 30-min periods, one with DCNs intact and the other after ablation of the contralateral DCN. In a subset of animals, activity was again mapped along the tonotopic axis after the time course of the activity was recorded before and after DCN ablation. Following recordings, the brains were fixed, and histological evaluations were performed to assess the extent of DCN ablation. Ablation of the DCN resulted in major reductions of IC hyperactivity. Levels of postablation activity in exposed animals were similar to the levels of activity in the IC of control animals, indicating an almost complete loss of hyperactivity in exposed animals. The results suggest that hyperactivity in the IC is dependent on support from extrinsic sources that include and may even begin with the DCN. This finding does not rule out longer term compensatory or homeostatic adjustments that might restore hyperactivity in the IC over time.
Functionalized Carbon Nanotubes with Gold Nanoparticles to Fabricate a Sensor for Hydrogen Peroxide Determination
Authors: Rajabzade Halimeh , Daneshgar Parandis , Tazikeh Elham , Mehrabian Ramin Zafar
Published: May 2012

A highly sensitive electrode was prepared based on gold nanoparticles/nanotubes/ionic liquid for measurement of Hydrogen peroxide. Gold nanoparticles of 20–25 nm were synthesized on a nanotube carbon paste electrode by cyclic voltammetry technique while the coverage was controlled by applied potential and time. The gold nanoparticles were modified to form a monolayer on CNT, followed by decoration with ionic liquid for determination of hydrogen peroxide. The experimental conditions, applied potential and pH, for hydrogen peroxide monitoring were optimized, and hydrogen peroxide was determined amperometrically at 0.3 V vs. SCE at pH 7.0. Electrocatalytic effects of gold deposited CNT were observed with respect to unmodified one. The sensitivity obtained was 5 times higher for modified one. The presence of Au particles in the matrix of CNTs provides an environment for the enhanced electrocatalytic activities. The sensor has a high sensitivity, quickly response to H2O2 and good stability. The synergistic influence of MWNT, Au particles and IL contributes to the excellent performance for the sensor. The sensor responds to H2O2 in the linear range from 0.02 µM to 0.3 mM. The detection limit was down to 0.4 µM when the signal to noise ratio is 3.
Melamine Trisulfonic Acid as a Highly Efficient and Reusable Catalyst for the Synthesis of β‐Acetamido Ketones
Authors: Zare Abdolkarim
Published: May 2012

A highly efficient protocol for the one‐pot multi‐component condensation of acetophenones with aromatic aldehydes, acetonitrile and acetyl chloride in the presence of melamine trisulfonic acid (MTSA) as a highly efficient and recyclable sulfonic acid‐containing catalyst at room temperature is described. In this method, β‐acetamido ketone derivatives are obtained in high to excellent yields and in relatively short reaction times.
Synthesis and Thermotropic Properties of Some New Schiff Bases, N‐[4‐(4‐n‐Alkanoyloxybenzoyloxy)‐2‐Hydroxybenzylidene]‐4‐Cyano‐, 4‐Hydroxy‐, 4‐Thio‐ and 4‐Nitroanilines
Authors: Ha Sie-Tiong , Yeap Guan-Yeow , Boey Peng-Lim
Published: May 2012

A series of elongated Schiff base esters containing three aromatic rings with hexadecanoyl chain as one of the terminal group and various R substituents (R = CN, OH, SH, and NO2) at the other end of molecule were prepared, and their structures were confirmed via physical measurement. The thermotropic properties of these compounds were investigated via differential scanning calorimetry and polarizing optical microscopy. The thermal data indicate that all of these compounds exhibit mesomorphic properties. Whilst compounds with R = OH, SH and NO2 show nematic phases, compound containing cyano substituent are smectogenic in nature.
Synthesis, Characterization and Antimicrobial Activity of Transition Metal Complexes of Schiff Base Ligand Derived from 3‐Ethoxy Salicylaldehyde and2‐(2‐Aminophenyl) 1‐H‐benzimidazole
Authors: Sunitha Matangi , Jogi Pragathi , Ushaiah Bathini , Kumari C. Gyana
Published: May 2012

Metal complexes of Ni(II), Co(II), Cu(II), Mn(II) and Zn(II) VO(IV) with a Schiff base derived from 3‐Ethoxy Salicylaldehyde and 2‐(2‐amino‐phenyl)1‐H‐Benzimidazol(2‐[(Z)‐{(2‐(1H‐benzimidazole‐2yl)phenyl] imino} methyl]‐6‐ethoxy phenol‐BMEP) were synthesized successfully. The resulting complexes were characterized by elemental analysis, magnetic moment measurements, conductivity measurements, IR, UV‐VIS, 1H NMR, mass spectra and ESR spectral studies. According to these data, we propose an octahedral geometry to all the metal complexes. Antimicrobial activity of the ligand and its metal complexes were studied against two gram negative bacteria: E. coli, Pseudomonas flourescence and two gram positive bacteria: Bacillus subitilis, Staphylococcus aureus. The activity data show that the metal complexes are more potent than the free ligand.
GCMS Determination of Organochlorine Pesticides (OCPs) in Fish from River Cauvery and Veeranam Lake
Authors: Bhuvaneshwari R. , Rajendran R. Babu
Published: May 2012

Organochlorine Pesticides (OCPs) were analyzed using Gas Chromatography‐Mass Spectrometer (Selective Ion Monitoring mode) in the muscle tissues of five fish species such as O. mossambicus, L. parsia, E. suretensis, C. striata and S. wynaadensis from seven locations of River Cauvery and one location in Veeranam Lake. OCPs viz., DDTs, HCHs, CHLs, cyclodienes, heptachlor, HCB and mirex were detected with varying concentrations among species and locations. Mirex which was not reported in the fish tissues elsewhere reported in this study. The study on the risk associated with the consumption of fish species that had higher concentrations of aldrin, dieldrin and mirex showed significant carcinogenic risk to the human beings.
Identification of a Novel Series of Potent TrkA Receptor Tyrosine Kinase Inhibitors
Authors: Raeppel Stéphane L. , Gaudette Frédéric , Nguyen Hannah , Beaulieu Normand , Wang James , Maroun Christiane , Besterman Jeffrey M. , Vaisburg Arkadii
Published: May 2012

A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.
Prevalence of Anaemia and Evaluation of Transferrin Receptor (sTfR) in the Diagnosis of Iron Deficiency in the Hospitalized Elderly Patients: Anaemia Clinical Studies in Chile
Authors: López-Sierra Mauricio , Calderón Susana , Gómez Jorge , Pilleux Lilian
Published: May 2012

Iron constitutes the most prevalent nutritional deficiency worldwide. In Chile, anaemia epidemiological data is scarce, evaluating mainly children and women. Our objective was to determine prevalence of anaemia in an inpatient elderly population (≥60 years) and assess the usefulness of sTfR levels analyzed by other authors as a good predictor in the differential diagnosis of iron deficiency anaemia and anaemia of chronic disease.Method.We studied medical patients admitted at Hospital of Valdivia (HV), Chile, in a 2month period. World Health Organization criteria were used for anaemia.Results.391 patients were hospitalized, average age 62.5 years, 247 elderly and 99 of which had anaemia. Anaemia was normocytic in 88.8%, and we observed: low serum iron in 46.3%, low ferritin 10.1%, high TIBC 2%, low % transferrin saturation (Tsat) 40%, and high sTfR 25%.Conclusions.As a first figure known in Chile, the prevalence of anaemia in the elderly inpatient was 40.1%. Our findings encourage us to promote the implementation of sTfR determination in the clinical setting to analyze the state of erythropoiesis in patients with chronic diseases wich commonly occurs in elderly.
Synthesis, Evaluation and Characterization of Some 1,3,4‐Triazole‐2‐one Derivatives as Antimicrobial Agents
Authors: Neelgundmath Mahabaleshwaraiah , Kotresh Oblennavar
Published: May 2012

A series of novel compounds like 3[(phenyl substituted)‐5‐methyl‐1(Benzosulphonylamine)]‐1,3,4‐triazole‐2‐ones II(a‐f) were synthesized by treating 4‐amino‐1‐phenyl‐3‐methyl‐5‐oxo‐1,2,4‐triazoles with benzene sulphonyl chloride using pyridine as solvent. Similarly by using 4‐amino‐1‐aryl‐3‐methyl‐5‐oxo‐1,2,4‐triazoles and acetic anhydride as starting material 3[(phenyl substituted)‐5‐methyl‐1(acetylamino)]‐1,3,4‐triazole‐2‐ones III(a‐f) were synthesized and also 3[(phenyl substituted)‐5‐methyl‐1(chloroacetyl)]‐1,3,4‐triazole‐2‐ones I(a‐f) were synthesized by treating 4‐amino‐1‐aryl‐3‐methyl‐5‐oxo‐1,2,4‐triazoles with chloroacetyl chloride in presence of a non‐polar solvent like benzene. Elemental analysis, GCMS, IR, and 1H NMR confirmed the structures of the newly synthesised compounds. The newly synthesized compounds are also screened for their antibacterial, antifungal and anti‐inflammatory activities.
Chromatographic Separation of Heavy Metal Cations on a Silica Gel‐G with Amino Acid
Authors: Wanjari S. M. , Deshmukh Lata , Paliwal L. J.
Published: May 2012

Thin layer chromatographic method has been developed for the separation of metal ions such as Cr(VI), Cr(III), As(III), Cd(II), Tl(III) and Hg(II) from their two, three and four component mixtures. The separations were performed on thin layer of silica gel ‘G’ using aqueous l‐Alanine as mobile phase. The effect of concentration and pH of mobile phase on the Rf values of individual metal ions were studied and the optimum conditions for separation of metal ions from their mixture were determined.
Hydrotalcite as an Efficient and Reusable Catalyst for Acylation of Phenols, Amines and Thiols Under Solvent‐free Conditions
Authors: Massah A. R. , Kalbasi R. J. , Toghiani M. , Hojati B. , Adibnejad M.
Published: May 2012

A wide variety of alcohols, phenols, amines and thiols were efficiently acylated with carboxylic acid anhydrides and chlorides in the presence of Hydrotalcite under solvent‐free conditions at room temperature in good to high yields. Eco‐friendly conditions and reusability of the catalyst are the most important advantages of this protocol.
MEK Inhibition Leads to PI3K/AKT Activation by Relieving a Negative Feedback on ERBB Receptors
Authors: Turke Alexa B. , Song Youngchul , Costa Carlotta , Cook Rebecca , Arteaga Carlos L. , Asara John M. , Engelman Jeffrey A.
Published: May 2012

The phosphoinositide 3-kinase (PI3K)/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-agent targeted therapies. In this study, we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers. We found that MEK inhibitor–induced activation of PI3K/AKT resulted from hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2. Mutation of this amino acid led to increased ERBB receptor activation and upregulation of the ERBB3/PI3K/AKT signaling pathway, which was no longer responsive to MEK inhibition. Taken together, these results elucidate an important, dominant feedback network regulating central oncogenic pathways in human cancer. Cancer Res; 72(13); 3228–37. ©2012 AACR.
Abstract A18: Molecular mechanisms of nuclear receptor-dependent chromosomal translocations
Authors: Yang Liuqing
Published: May 2012

Chromosomal translocations are a hallmark of leukemia/lymphoma and also appear widespread in solid tumors, but the underlying molecular basis has remained elusive. By establishing a cellular model to dissect specific and inducible translocations in the absence of proliferative selection, we report an androgen receptor (AR)-dependent pathway for tumor translocation events in prostate cancer cells. This pathway is initiated by binding of liganded AR to specific intronic sites that triggers intra- and inter-chromosomal interactions that place translocation sites in close spatial proximity, and local architectural alterations that permit serial recruitment of an enzymatic machinery, including Activation-Induced Cytidine Deaminase (AID) induced by liganded AR and genotoxic stress. Strikingly, this process is enhanced by the expression of the ORF2 endonuclease from LINE-1 repeats, caused by diminished PIWIL1 and increased AID, generating staggered double-strand breaks (DSBs) at intronic AR binding sites that result in tumor translocation by components of the Non-Homologous Ending Joining (NHEJ) mechanism. Together, these findings reveal specific architectural/enzymatic mechanisms underlying well-defined chromosomal translocations observed in tumors, which may function in many types of tumors and in other biological and pathological processes.

Citation Information: Cancer Res 2009;69(23 Suppl):A18.
Abstract A29: The Notch ligand Jagged2 promotes metastasis through a GATA3/miR-200 regulatory loop
Authors: Yang Yanan , Ahn Young-Ho , Gibbons Don L. , Zang Yi , Lin Wei , Thilaganthan Nishan , Moreira Daniel C. , Creighton Chad J. , Goodall Gregory J. , Kurie Jonathan M.
Published: May 2012

Metastatic disease originates from populations of tumor cells that have the propensity to undergo epithelial-to-mesenchymal transition (EMT), but the signals that initiate EMT in these cells have not been fully defined. Here we addressed this question in mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. We found that metastases arose from a population of tumor cells that had high expression of Notch ligands. Jagged2 promoted EMT by a Notch-dependent suppression of microRNA-200 (miR-200), a family of miRs that negatively regulates ZEB transcriptional repressors. We identified an upstream miR-200 promoter element that is a direct target for GATA3 and, reciprocally, GATA3 mRNA sequences that are direct targets for miR-200, indicating that a double-negative feedback loop tightly controls the levels of GATA3 and miR200. Abrogating miR-200 suppression through knockdown of JAG2 or GATA3 blocked metastasis. In conclusion, Notch promotes metastasis by activating a GATA3/miR-200 regulatory loop.

Citation Information: Cancer Res 2009;69(23 Suppl):A29.
Abstract A35: Tyrosine kinase inhibitors block PDGFR-β signaling and suppress growth in malignant endothelial cells
Authors: Marley Kevin , Helfand Stuart C.
Published: May 2012

Tyrosine kinase inhibitors (TKIs), including imatinib and dasatinib, have shown remarkable efficacy in controlling chronic myelogenous leukemia and gastrointestinal stromal tumors. Their role in treating other solid tumors is less clear. We are investigating the potential to control malignant endothelial cell (EC) growth with TKIs using a spontaneous canine hemangiosarcoma (HSA) model. Canine HSA is a highly malignant EC cancer with cellular features reminiscent of primitive endothelium. Controlling HSA cell growth has implications for improved outcomes of human and canine patients affected with EC cancer as well as for design of antiangiogenic strategies. We evaluated the effects of imatinib and dasatinib on constitutive tyrosine phosphorylation of platelet derived growth factor receptor-beta (PDGFR-β) that we previously determined to be abnormal in HSA cell cultures. Further, we correlated effects of these TKIs on HSA proliferation in vitro to determine if abnormal activation of PDGFR-β contributes to the HSA malignant phenotype. Dasatinib was approximately ten-fold more potent than imatinib in suppressing HSA cell growth. Dasatinib (100 nM) rapidly abrogated signal from full length and a possible truncated form (120 kDa) of phospho-PDGFR-β. Cells with constitutive activation of PDGFR-β also showed tyrosine phosphorylation of extracellular related kinase-1 (ERK-1), ERK-2, and Src suggesting these could be downstream partners of PDGFR-β in aberrant HSA signaling. Dasatinib markedly suppressed phosphorylation of Src in HSA cells. Taken together; these data suggest that tyrosine kinase inhibitors may affect endothelial cell growth in malignancy by blocking PDGFR-β or its downstream signaling partners.

Citation Information: Cancer Res 2009;69(23 Suppl):A35.
Abstract A37: Mechanistic study involving antiproliferative effect of Etoricoxib, a highly selective COX-2 inhibitor on human cancer cell lines
Authors: Tripathi Shweta , Chandna Sudhir , Dwarkanath B.S. , Saluja Daman , Chopra Madhu
Published: May 2012

Introduction: Cyclooxygenase (COX), also known as prostaglandin endoperoxidase or prostaglandin G/H synthase, is a rate limiting enzyme involved in the conversion of arachidonic acid to prostaglandins. Two forms of cyclooxygenase, COX-1 and COX-2, have been identified. COX-1 is constitutively expressed in many tissues, while COX-2 is an inducible enzyme involved in inhibition of apoptosis, potentiation of cell growth and angiogenesis and as such is a target for drug development. Recently clinical, cellular and animal experimental studies have indicated its relevance to tumor invasion and metastasis. Etoricoxib is a novel non-steroidal anti-inflammatory drug (NSAIDs) that stops the production of inflammatory prostaglandins, without stopping the production of prostaglandins that protect the stomach and intestine. There is persuasive evidence that COX-2 inhibitors suppress tumor growth due to their ability to inhibit cell proliferation and induce apoptosis. The purpose of this study was to elucidate the mechanism of action by which Etoricoxib induces the arrest of Human cervical tumor cells growth.

Methods: Cell viability was measured by MTT assay and trypan blue exclusion method. Apoptosis was examined by DNA fragmentation and Comet Assay and the distribution of cells in the cell cycle was estimated by flow cytometry. Western blotting was used to explore various mechanisms of Etoricoxib induced apoptosis.

Results: Etoricoxib in the concentration range of 100–200 µM was 2–3 fold more cytotoxic (MTT assay) in the tumorigenic cell lines HeLa (cervical COX-2 positive), C-33A (cervical COX-2 negative), U-87, MCF-7, Hep3B, MiaPaCa-2 as compared to the non-tumorigenic cell lines (Cos-7, NIH3T3, HEK). These results correlated well with the observations on inhibition of cell growth and were comparable to the results reported for Celecoxib, another COX-2 selective inhibitor. Interestingly, Methotrexate widely used anticancer agent, showed 70–80% cytotoxicity in the non tumorigenic cell lines as compared to only 20% cytotoxicity with etoricoxib, suggesting thereby that it is selectively toxic to tumor cells unlike many other anticancer drugs. Comet assay results in HeLa cells showed a dose and time dependent increase in DNA damage suggestive of drug induced DNA damage at early times, followed by apoptotic DNA fragmentation and necrotic DNA degradation at later times. Western blotting results confirms the downregulation of the NF-κB pathway. In conclusion this study shows that in the human cervical cancer cell lines, HeLa & C33A, Etoricoxib suppresses proliferation, induces apoptosis and causes cell death by DNA damage in both Cox-2 dependent as well as independent pathway.

Citation Information: Cancer Res 2009;69(23 Suppl):A37.
Abstract A39: An oncogenomics-based in vivo cDNA screen pinpoints coamplified Ccnd1 and Fgf19 as therapeutic targets for liver cancer
Authors: Sawey Eric T. , Cai Chunlin , Bakleh Amy , Liu Qing , Lowe Scott W. , Powers Scott
Published: May 2012

Human cancer genome profiling is becoming increasingly effective at revealing novel recurrent genomic aberrations, but it remains challenging to identify the underlying driver genes. Here we describe an oncogenomic cDNA screen used to identify genes involved in liver tumorigenesis. Using array CGH analysis, we first identified recurrent focal amplicons present in hepatocellular carcinoma (HCC). Next, we assayed their tumorigenic potential by introducing pools of cDNAs corresponding to genes found in focal amplicons into sensitized liver progenitor cells. We identified 18 genes that promote tumor formation, including known oncogene Ccnd1 and co-amplified Fgf19, which we show cooperate during tumorigenesis. These two closely linked genes are co-amplified and co-overexpressed in 15% of human HCC. Knockdown of either Ccnd1 or Fgf19 inhibited colony formation of amplified human HCC cell lines and inhibited tumorigenicity. Knockdown in non-amplified human cell lines was without phenotypic effect. Downstream analysis revealed that FGF-19 leads to the activation of β-catenin and increased levels of CyclinD1. These results show that gene amplification predicts response to both Ccnd1 and Fgf19 inhibition, and that oncogenomic cDNA screens are an effective new tool to identify therapeutic strategies that are directly linked to cancer genotypes.

Citation Information: Cancer Res 2009;69(23 Suppl):A39.
Abstract A40: Six1 is dependent on its coactivator Eya2 to mediate tumor progression in the MCF7 mammary carcinoma cell line
Authors: Farabaugh Susan M. , Welm Alana L. , Ford Heide L.
Published: May 2012

The homeobox transcription factor Six1 is a critical mediator of embryonic development. In adults, upregulation of Six1 has been associated with a number of cancers where it not only promotes proliferation and survival, contributing to tumorigenesis, but also upregulates the TGFβ pathway, brings about an EMT-like transformation, and promotes metastasis. The Eya coactivator family is critical for Six1-mediated transcriptional activation in development. Our research is aimed at identifying what role the Eya family plays in Six1-mediated breast cancer progression. Examination of publicly available microarray data sets revealed that although high levels of Six1 significantly correlates with a shortened time to metastasis in breast cancer patients, presence of the Eya1-Six1 or Eya2-Six1 transcriptional complex correlates with a further reduced time to metastasis as well as with a significant decrease in survival time in breast cancer patients. Utilizing Six1 overexpressing MCF7 breast carcinoma cells with stable knock down of Eya2, we have found that lack of Eya2 reverses Six1-induced upregulation of the TGFβ pathway. Additionally, most Six1-induced EMT properties, including increased β-catenin responsive transcription and increased levels of the mesenchymal marker Fibronectin, were reversed with loss of Eya2. Overall, these data implicate Eya2 as a critical coactivator that is necessary for most of the metastasis-associated properties induced by Six1. Thus, as Six1 and Eya are not normally expressed in most adult tissues, the Six1-Eya interaction may be a valuable future drug target whose inhibition should result in limited side effects while potently targeting the tumor and its associated metastases.

Citation Information: Cancer Res 2009;69(23 Suppl):A40.
Abstract A41: Impact of vitamin D receptor and the vitamin D hydroxylase CYP27B1 on morphology and gene expression in the mouse mammary gland
Authors: Matthews Donald G. , Lloyd-Coronado Teresa M. , Welsh JoEllen
Published: May 2012

Multiple epidemiological studies have demonstrated correlations between vitamin D status and incidence of many types of cancer, including colon and breast. Our long term goal is to understand the mechanisms by which the vitamin D signaling pathway impacts on breast cancer. Upon absorption or endogenous synthesis, vitamin D is metabolized into 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in multiple tissues. 1,25D is a high-affinity ligand for the nuclear vitamin D receptor (VDR) that alters gene expression and inhibits growth of normal and transformed mammary cells. However, 25D and other steroid-like compounds such as bile acids, can also activate VDR in vitro. Although studies with VDR knockout (KO) mice have demonstrated that VDR affects proliferation, differentiation and apoptosis in the mammary gland, the specific ligands that trigger VDR signaling in mammary tissue have yet to be identified. Generation of 1,25D from 25D is mediated by the mitochondrial enzyme CYP27B1 (also known as 25-hydroxyvitamin D 1α-hydroxylase) which is present and developmentally regulated in mammary gland. Studies with the VDRKO mouse have formally established that its phenotype is different from mice lacking CYP27B1, supporting the concept that other VDR ligands exist, and/or that the VDR may act in the absence of ligand. In our studies, we are using animal models to determine whether VDR exerts 1,25D-independent effects on growth, apoptosis or differentiation of mammary epithelial cells in vivo. Glands from VDRKO and CYP27B1KO mice during puberty, pregnancy, lactation, involution and aging have been collected for analysis of gross morphology, histology, and genomic profiling in comparison to age-matched control mice. Our data indicate that mammary glands from VDRKO mice display accelerated branching, enhanced sensitivity to estrogen and progesterone and altered gene expression during puberty and early pregnancy. Surprisingly, initial studies indicate that similar changes are not observed in glands from CYP27B1KO mice, suggesting that 25D or other VDR ligands may substitute for 1,25D in control of mammary cell turnover in vivo. Alternatively, our results are consistent with the concept that unoccupied VDR may function in the mammary gland. To further explore the role of VDR and CYP27B1 in the glandular epithelial compartment, mice with mammary epithelial-specific deletion of VDR or CYP27B1 were generated by crossing MMTV-cre mice with mice carrying floxed alleles of VDR or CYP27B1. Quantitation of VDR and CYP27B1 expression in mammary gland, and characterization of the phenotype of these cre-flox mouse strains is in progress. Collectively, these studies have identified novel roles for the VDR and its ligands in mammary gland development that provide insight into the relationship between vitamin D status and breast cancer. Supported by NIH CA69700.

Citation Information: Cancer Res 2009;69(23 Suppl):A41.