bluuebunny/crossref_metadata_2025 huggingface dataset:
The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea
Authors: Pulkkinen Ville , Manson Martijn L. , Säfholm Jesper , Adner Mikael , Dahlén Sven-Erik
Published: September 2012

Activation of taste receptors (TAS2Rs) by bitter taste agonists has been reported to cause bronchodilation. The aim of this study was to extend the information on the effects of bitter taste agonists on responses induced by different contractile mediators in a standard airway physiology preparation. Isometric responses were assessed in guinea pig trachea (GPT). TAS2R agonists were administered either to segments precontracted with different agonists for contraction or given before challenge with the different contractile stimuli, including antigen in tissues from ovalbumin-sensitized animals. TAS2R mRNA expression on GPT epithelium and smooth muscle was measured with real-time PCR. Denatonium, chloroquine, thiamine, and noscapine induced concentration-dependent relaxations (Rmax: 98.3 ± 1.6, 100.0 ± 0.0, 100.0 ± 0.0, and 52.3 ± 1.1% of maximum, respectively, in the presence of indomethacin) in segments precontracted with carbachol. The receptors for denatonium (TAS2R4, TAS2R10) and chloroquine (TAS2R3, TAS2R10) were expressed in GPT. Whereas denatonium selectively inhibited contractions induced by carbachol, chloroquine uniformly inhibited contractions evoked by prostaglandin E2, the thromboxane receptor agonist U-46619, leukotriene D4, histamine, and antigen. The effects of denatonium, but not those of chloroquine, were partly inhibited by blockers of the large Ca2+-activated K+ channels and decreased by an increase of the level of precontraction. In conclusion, TAS2R agonists mediated strong relaxations and substantial inhibition of contractions in GPT. Chloroquine and denatonium had distinct patterns of activity, indicating different signaling mechanisms. The findings reinforce the hypothesis that TAS2Rs are potential targets for the development of a new class of more efficacious agonists for bronchodilation.
Implication of the ryanodine receptor in TRPV4-induced calcium response in pulmonary arterial smooth muscle cells from normoxic and chronically hypoxic rats
Authors: Dahan Diana , Ducret Thomas , Quignard Jean-François , Marthan Roger , Savineau Jean-Pierre , Estève Eric
Published: September 2012

There is a growing body of evidence indicating that transient receptor potential (TRP) channels are implicated in calcium signaling and various cellular functions in the pulmonary vasculature. The aim of this study was to investigate the expression, functional role, and coupling to reticulum calcium channels of the type 4 vanilloid TRP subfamily (TRPV4) in the pulmonary artery from both normoxic (Nx) and chronically hypoxic (CH) rats. Activation of TRPV4 with the specific agonist 4α-phorbol-12,13-didecanoate (4α-PDD, 5 μM) increased the intracellular calcium concentration ([Ca2+]i). This effect was significantly reduced by a high concentration of ryanodine (100 μM) or chronic caffeine (5 mM) that blocked ryanodine receptor (RyR) but was insensitive to xestospongin C (10 μM), an inositol trisphosphate receptor antagonist. Inhibition of RyR1 and RyR3 only with 10 μM of dantrolene did not attenuate the 4α-PDD-induced [Ca2+]iincrease. Western blotting experiments revealed the expression of TRPV4 and RyR2 with an increase in both receptors in pulmonary arteries from CH rats vs. Nx rats. Accordingly, the 4α-PDD-activated current, measured with patch-clamp technique, was increased in pulmonary artery smooth muscle cells (PASMC) from CH rats vs. Nx rats. 4α-PDD increased isometric tension in artery rings, and this response was also potentiated under chronic hypoxia conditions. 4α-PDD-induced calcium response, current, and contraction were all inhibited by the selective TRPV4 blocker HC-067047. Collectively, our findings provide evidence of the interplay between TRPV4 and RyR2 in the Ca2+release mechanism and contraction in PASMC. This study provides new insights onto the complex calcium signaling in PASMC and point out the importance of the TRPV4-RyR2 signaling pathway under hypoxic conditions that may lead to pulmonary hypertension.
Phrenic long-term facilitation after acute intermittent hypoxia requires spinal ERK activation but not TrkB synthesis
Authors: Hoffman M. S. , Nichols N. L. , Macfarlane P. M. , Mitchell G. S.
Published: September 2012

Acute intermittent hypoxia (AIH) elicits a form of spinal respiratory plasticity known as phrenic long-term facilitation (pLTF). pLTF requires spinal serotonin receptor-2 activation, the synthesis of new brain-derived neurotrophic factor (BDNF), and the activation of its high-affinity receptor tyrosine kinase, TrkB. Spinal adenosine 2A receptor activation elicits a distinct pathway to phrenic motor facilitation (pMF); this BDNF synthesis-independent pathway instead requires new synthesis of an immature TrkB isoform. Since hypoxia increases extracellular adenosine levels, we tested the hypothesis that new synthesis of TrkB and BDNF contribute to AIH-induced pLTF. Furthermore, given that signaling mechanisms “downstream” from TrkB are unknown in either mechanism, we tested the hypothesis that pLTF requires MEK/ERK and/or phosphatidylinositol 3-kinase (PI3K)/Akt activation. In anesthetized Sprague-Dawley rats, an intrathecal catheter at cervical level 4 was used to deliver drugs near the phrenic motor nucleus. Since pLTF was blocked by spinal injections of small interfering RNAs targeting BDNF mRNA but not TrkB mRNA, only new BDNF synthesis is required for AIH-induced pLTF. Pretreatment with a MEK inhibitor (U0126) blocked pLTF, whereas a PI3K inhibitor (PI-828) had no effect. Thus, AIH-induced pLTF requires MEK/ERK (not PI3K/AKT) signaling pathways. When U0126 was injected post-AIH, pLTF development was halted but not reversed, suggesting that ERK is critical for the development but not maintenance of pLTF. Thus, there are clear mechanistic distinctions between AIH-induced pLTF (i.e., BDNF synthesis and MEK/ERK dependent) versus adenosine 2A receptor-induced pMF (i.e., TrkB synthesis and PI3K/Akt dependent).
Nitric oxide regulates cytokine induction in the diaphragm in response to inspiratory resistive breathing
Authors: Sigala Ioanna , Zacharatos Panayiotis , Boulia Stavroula , Toumpanakis Dimitris , Michailidou Tatiana , Parthenis Dimitris , Roussos Charis , Papapetropoulos Andreas , Hussain Sabah N. , Vassilakopoulos Theodoros
Published: September 2012

Resistive breathing (encountered in chronic obstructive pulmonary disease and asthma) results in cytokine upregulation and decreased nitric oxide (NO) levels in the strenuously contracting diaphragm. NO can regulate gene expression. We hypothesized that endogenously produced NO downregulates cytokine production triggered by strenuous diaphragmatic contraction. Wistar rats treated with vehicle, the nonselective NO synthase inhibitor NG-nitro-l-arginine-methylester (l-NAME), or the NO donor diethylenetriamine-NONOate (DETA) were subjected to inspiratory resistive breathing (IRB; 50% of maximal inspiratory pressure) for 6 h or sham operation. Additional groups of rats were subjected to IRB for 6 h with concurrent administration of l-NAME and inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), or P38 (SB203580). Inhibition of NO production (with l-NAME) resulted in upregulation of IRB-induced diaphragmatic IL-6, IL-10, IL-2, TNF-α, and IL-1β levels by 50%, 53%, 60%, 47%, and 45%, respectively. In contrast, the NO donor (DETA) attenuated the IRB-induced cytokine upregulation to levels characteristic of quietly breathing animals. l-NAME augmented IRB-induced activation of MAPKs (P38 and ERK1/2) and NF-κB, whereas DETA triggered the opposite effect. NF-κB and ERK1/2 inhibition in l-NAME-treated animals blunted the l-NAME-induced cytokine upregulation except IL-6, whereas P38 inhibition blunted all (including IL-6) cytokine upregulation. NO downregulates IRB-induced cytokine production in the strenuously contracting diaphragm through its action on MAPKs and NF-κB.
Motor cortex and corticospinal excitability in humans with a history of illicit stimulant use
Authors: Flavel Stanley C. , White Jason M. , Todd Gabrielle
Published: September 2012

Illicit use of stimulant drugs such as methamphetamine, ecstasy, and cocaine is a current and growing problem throughout the world. The aim of the current study was to investigate the long-term effect of illicit stimulant use on human motor cortical and corticospinal circuitry. We hypothesized that individuals with a history of primarily methamphetamine and ecstasy use would exhibit altered corticospinal excitability and intracortical inhibition within motor cortex. The study involved 52 healthy adults (aged 26 ± 7 yr) comprising 26 abstinent stimulant users, 9 cannabis users, and 17 nondrug users. The experiment involved a routine urine drug screen, drug history questionnaire, neuropsychological assessment, and single- and paired-pulse transcranial magnetic stimulation (TMS) over motor cortex. EMG responses to stimulation [motor evoked potentials (MEPs)] were recorded from the contralateral first dorsal interosseus. At a given stimulus intensity, MEP area was significantly larger in abstinent stimulant users than in nondrug users during both relaxation ( P = 0.045) and muscle contraction ( P < 0.001). MEP latency was also significantly longer in abstinent stimulant users ( P < 0.009), and they exhibited significantly greater muscle activity during performance of a given task ( P = 0.004). However, resting motor threshold and the response to paired-pulse TMS were unaffected. The results suggest that abstinent stimulant users exhibit long-term changes in the excitability of motor cortical and corticospinal circuitry and muscle activity during movement. These changes may partly underlie anecdotal and objective reports of movement dysfunction in chronic stimulant users.
Nitric oxide and receptors for VIP and PACAP in cutaneous active vasodilation during heat stress in humans
Authors: Kellogg Dean L. , Zhao Joan L. , Wu Yubo , Johnson John M.
Published: September 2012

VPAC2 receptors sensitive to vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase activating polypeptide (PACAP), PAC1 receptors sensitive to PACAP, and nitric oxide (NO) generation by NO synthase (NOS) are all implicated in cutaneous active vasodilation (AVD) through incompletely defined mechanisms. We hypothesized that VPAC2/PAC1 receptor activation and NO are synergistic and interdependent in AVD and tested our hypothesis by examining the effects of VPAC2/PAC1 receptor blockade with and without NOS inhibition during heat stress. The VPAC2/PAC1 antagonist, pituitary adenylate cyclase activating peptide 6–38 (PACAP6–38) and the NOS inhibitor, NG-nitro-l-arginine methyl ester (l-NAME) were administered by intradermal microdialysis. PACAP6–38, l-NAME, a combination of PACAP6–38 and l-NAME, or Ringer's solution alone were perfused at four separate sites. Skin blood flow was monitored by laser-Doppler flowmetry at each site. Body temperature was controlled with water-perfused suits. Blood pressure was monitored by Finapres, and cutaneous vascular conductance (CVC) calculated (CVC = laser-Doppler flowmetry/mean arterial pressure). The protocol began with a 5- to 10-min baseline period without antagonist perfusion, followed by perfusion of PACAP6–38, l-NAME, or combined PACAP6–38 and l-NAME at the different sites in normothermia (45 min), followed by 3 min of whole body cooling. Whole body heating was then performed to induce heat stress and activate AVD. Finally, 58 mM sodium nitroprusside were perfused at all sites to effect maximal vasodilation for normalization of blood flow data. No significant differences in CVC (normalized to maximum) were found among Ringer's PACAP6–38, l-NAME, or combined antagonist sites during normothermia ( P > 0.05 among sites) or cold stress ( P > 0.05 among sites). CVC responses at all treated sites were attenuated during AVD ( P < 0.05 vs. Ringer's). Attenuation was greater at l-NAME and combined PACAP6–38- and l-NAME-treated sites than at PACAP6–38 sites ( P > 0.05). Because responses did not differ between l-NAME and combined treatment sites ( P > 0.05), we conclude that VPAC2/PAC1 receptors require NO in series to effect AVD.
Atherosclerosis and Rheumatoid Arthritis: More Than a Simple Association
Authors: Cavagna Lorenzo , Boffini Nicola , Cagnotto Giovanni , Inverardi Flora , Grosso Vittorio , Caporali Roberto
Published: September 2012

In the last decades a large amount of evidence linked rheumatoid arthritis (RA) to atherosclerosis. In fact, RA patients have an increased risk of cardiovascular events that is not fully explained by other classic cardiovascular risk factors. RA and atherosclerosis may share several common pathomechanisms and inflammation undoubtedly plays a primary role. The proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-6, involved in the pathogenesis of RA, are also independently predictive of subsequent cardiovascular disease (CVD). In RA, inflammation alters HDL constituents and the concentration of LDL and HDL, thus facilitating atherosclerosis and CVD events. On the other hand, also the increase of oxidative processes, frequently observed in RA, induces atherosclerosis. Interestingly, some genetic polymorphisms associated with RA occurrence enhance atherosclerosis, however, other polymorphisms associated with RA susceptibility do not increase CVD risk. Several other mechanisms may influence atherosclerotic processes in RA. Moreover, atherosclerosis may be directly mediated also by underlying autoimmune processes, and indirectly by the occurrence of metabolic syndrome and impaired physical activity. Finally, the effects of RA therapies on cardiovascular system in general and on atherosclerosis in particular are really wide and different. However, the starting point of every RA treatment is that disease control, or better remission, is the best way we have for the reduction of CVD occurrence.
Metastatic Parotid Myoepithelial Carcinoma in a 7-Year-Old Boy
Authors: Saliba Issam , El Khatib Nazir , Nehme Antoine , Nasser Selim , Moukarzel Nabil
Published: September 2012

Myoepithelial carcinoma is a rare malignancy of the parotid gland that is usually seen in adults. We report the first case in children of myoepithelial carcinoma of the parotid gland with massive invasion of the facial nerve and metastasis to cervical lymph nodes. Due to its rarity, the treatment and the clinical course of this tumor are not well defined yet. We performed a total parotidectomy, a modified neck dissection, and a postoperative radiotherapy in 7-year-old boy. Sparing of the facial nerve was impossible; it was sacrificed and grafted with a sural nerve. Histopathology confirmed the diagnosis of a parotid gland carcinoma and immunohistochemical markers showed that the tumor cells express cytokeratin, epithelial membrane antigen, cytokeratin 7, smooth muscle actin, P63, CEA, and S100. This pattern of immunostaining is consistent with the diagnosis of myoepithelial carcinoma. On the postoperative tenth month he presented with a pulmonary and lumbar vertebra metastasis.
Folate Intake and Markers of Folate Status in Women of Reproductive Age, Pregnant and Lactating Women: A Meta-Analysis
Authors: Berti Cristiana , Fekete Katalin , Dullemeijer Carla , Trovato Monica , Souverein Olga W. , Cavelaars Adriënne , Dhonukshe-Rutten Rosalie , Massari Maddalena , Decsi Tamás , van't Veer Pieter , Cetin Irene
Published: September 2012

Background. Pregnant and breastfeeding women are at risk for folate deficiency. Folate supplementation has been shown to be associated with enhanced markers of folate status. However, dose-response analyses for adult women are still lacking.Objective. To assess the dose-response relationship between total folate intake (folic acidplusdietary folate) and markers of folate status (plasma/serum folate, red blood cell folate, and plasma homocysteine); to evaluate potential differences between women in childbearing age, pregnant and lactating women.Methods. Electronic literature searches were carried out on three databases until February 2010. The overall pooled regression coefficient (β) and SE(β) were calculated using meta-analysis on a double-log scale.Results. The majority of data was based on nonpregnant, nonlactating women in childbearingage. The pooled estimate of the relationship between folate intake and serum/plasma folate was 0.56 (95% CI = 0.40–0.72,P<0.00001); that is, the doubling of folate intake increases the folate level in serum/plasma by 47%. For red blood cell folate, the pooled-effect estimate was 0.30 (95% CI = 0.22–0.38,P<0.00001), that is, +23% for doubling intake. For plasma-homocysteine it was –0.10 (95% = –0.17 to –0.04,P=0.001), that is, –7% for doubling the intake. Associations tended to be weaker in pregnant and lactating women.Conclusion. Significant relationships between folate intake and serum/plasma folate, red blood cell folate, and plasma homocysteine were quantified. This dose-response methodology may be applied for setting requirements for women in childbearing age, as well as for pregnant and lactating women.
Polygonum cuspidatumExtract Induces Anoikis in Hepatocarcinoma Cells Associated with Generation of Reactive Oxygen Species and Downregulation of Focal Adhesion Kinase
Authors: Hu Bing , An Hong-Mei , Shen Ke-Ping , Song Hai-Yan , Deng Shan
Published: September 2012

Anoikis has been recognized as a potential target for anticancer therapy.Polygonum cuspidatum(Huzhang) is a frequently used Chinese herb in hepatocarcinoma. In present study, we evaluated the effects ofPolygonum cuspidatumextract (PCE) in hepatocarcinoma cells in suspension. The results showed that PCE inhibited the proliferation of hepatocarcinoma cells in suspension in a dose- and time-dependent manner. PCE also inhibited anchorage-independent growth of hepatocarcinoma cells in soft agar. PCE induced anoikis in human hepatocarcinoma Bel-7402 cells accompanied by caspase-3 and caspase-9 activation and poly(ADP-ribose) polymerase cleavage, which was completely abrogated by a pan caspase inhibitor, Z-VAD-FMK. In addition, PCE treatment induced intracellular reactive oxygen species (ROS) production in Bel-7402 cells. NAC, an ROS scavenger, partially attenuated PCE-induced anoikis and activation of caspase-3 and caspase-9. Furthermore, PCE inhibited expression of focal adhesion kinase (FAK) in Bel-7402 cells. Overexpression of FAK partially abrogated PCE-induced anoikis. These data suggest that PCE may inhibit suspension growth and induce caspase-mediated anoikis in hepatocarcinoma cells and may relate to ROS generation and FAK downregulation. The present study provides new insight into the application of Chinese herb for hepatocarcinoma treatment.
Coderivations of Ranked Bigroupoids
Authors: Jun Young Bae , Lee Kyoung Ja , Park Chul Hwan
Published: September 2012

The notion of (co)derivations of ranked bigroupoids is discussed by Alshehri et al. (in press), and their generalized version is studied by Jun et al. (under review press). In particular, Jun et al. (under review press) studied coderivations of ranked bigroupoids. In this paper, the generalization of coderivations of ranked bigroupoids is discussed. The notion of generalized coderivations in ranked bigroupoids is introduced, and new generalized coderivations of ranked bigroupoids are obtained by combining a generalized self‐coderivation with a rankomorphism. From the notion of (X, ∗, &)‐derivation, the existence of a rankomorphism of ranked bigroupoids is established.
Selecting the Best Project Using the Fuzzy ELECTRE Method
Authors: Daneshvar Rouyendegh Babak , Erol Serpil
Published: September 2012

Selecting projects is often a difficult task. It is complicated because there is usually more than one dimension for measuring the impact of each project, especially when there is more than one decision maker. This paper is aimed to present the fuzzy ELECTRE approach for prioritizing the most effective projects to improve decision making. To begin with, the ELECTRE is one of most extensively used methods to solve multicriteria decision making (MCDM) problems. The ELECTRE evaluation method is widely recognized for high‐performance policy analysis involving both qualitative and quantitative criteria. In this paper, we consider a real application of project selection using the opinion of experts to be applied into a model by one of the group decision makers, called the fuzzy ELECTRE method. A numerical example for project selection is given to clarify the main developed result in this paper.
Meeting the Contraceptive Needs of Key Populations Affected by HIV in Asia: An Unfinished Agenda
Authors: Petruney Tricia , Minichiello Shanthi Noriega , McDowell Misti , Wilcher Rose
Published: September 2012

Like all women, women living with and at risk of acquiring HIV have the right to determine the number and timing of their pregnancies and to safely achieve their reproductive intentions. Yet, many women in Asia affected by HIV lack access to family planning services and experience disproportionately high rates of unintended pregnancy and abortion. Programs that have succeeded in promoting condom use and providing HIV prevention and treatment services in this region have largely missed the opportunity to address the contraceptive needs of the key populations they serve. The importance of better linkages between family planning and HIV policies and programs is now widely recognized by global health policymakers and donors. However, to date, most of the efforts to improve these linkages have been conducted in Africa. Greater attention is needed to the developing, implementing, and evaluating of integrated family planning/HIV approaches that are tailored to the political, cultural, and public health context in Asia. In this paper, we describe the use of and need for family planning among key populations affected by HIV in Asia, discuss the challenges to effectively addressing of these needs, and offer recommendations for strengthening the linkages between family planning and HIV policies and programs in the region.
Two Weighted Fuzzy Goal Programming Methods to Solve Multiobjective Goal Programming Problem
Authors: Gupta Mousumi , Bhattacharjee Debasish
Published: September 2012

We propose two new methods to find the solution of fuzzy goal programming (FGP) problem by weighting method. Here, the relative weights represent the relative importance of the objective functions. The proposed methods involve one additional goal constraint by introducing only underdeviation variables to the fuzzy operator λ (resp., 1‐λ), which is more efficient than some well‐known existing methods such as those proposed by Zimmermann, Hannan, Tiwari, and Mohamed. Mohamed proposed that every fuzzy linear program has an equivalent weighted linear goal program where the weights are restricted as the reciprocals of the admissible violation constants. But the above proposition of Mohamed is not always true. Furthermore, the proposed methods are easy to apply in real‐life situations which give better solution in the sense that the objective values are sufficiently closer to their aspiration levels. Finally, for illustration, two real examples are used to demonstrate the correctness and usefulness of the proposed methods.
Bernstein‐Polynomials‐Based Highly Accurate Methods for One‐Dimensional Interface Problems
Authors: Liu Jiankang , Zheng Zhoushun , Xu Qinwu
Published: September 2012

A new numerical method based on Bernstein polynomials expansion is proposed for solving one‐dimensional elliptic interface problems. Both Galerkin formulation and collocation formulation are constructed to determine the expansion coefficients. In Galerkin formulation, the flux jump condition can be imposed by the weak formulation naturally. In collocation formulation, the results obtained by B‐polynomials expansion are compared with that obtained by Lagrange basis expansion. Numerical experiments show that B‐polynomials expansion is superior to Lagrange expansion in both condition number and accuracy. Both methods can yield high accuracy even with small value of N.
Partial PIC-MRC Receiver Design for Single Carrier Block Transmission System over Multipath Fading Channels
Authors: Deng Juinn-Horng , Huang Sheng-Yang
Published: September 2012

Single carrier block transmission (SCBT) system has become one of the most popular modulation systems due to its low peak-to-average power ratio (PAPR), and it is gradually considered to be used for uplink wireless communication systems. In this paper, a low complexity partial parallel interference cancellation (PIC) with maximum ratio combining (MRC) technology is proposed to use for receiver to combat the intersymbol interference (ISI) problem over multipath fading channel. With the aid of MRC scheme, the proposed partial PIC technique can effectively perform the interference cancellation and acquire the benefit of time diversity gain. Finally, the proposed system can be extended to use for multiple antenna systems to provide excellent performance. Simulation results reveal that the proposed low complexity partial PIC-MRC SIMO system can provide robust performance and outperform the conventional PIC and the iterative frequency domain decision feedback equalizer (FD-DFE) systems over multipath fading channel environment.
A Characteristic Investigation of Aminocyclohexane‐N′‐methylurea as a Corrosion Inhibitor for Mild Steel in 1 N H2SO4
Authors: Thiraviyam P. , Kannan K. , Premkumar P.
Published: September 2012

The newly synthesized aminocyclohexane‐N′‐methylurea Mannich base was characterised using FT‐IR, H1NMR, and C13NMR spectra and also it was tested as corrosion inhibitor for the mild steel in 1 N sulphuric acid. Inhibitive study of this compound was carried out by weight loss method over the temperature range of 303–333 K, potentiodynamic polarisation, and AC impedance methods. The inhibition efficiency was increased with increasing concentration of inhibitor whereas it was decreased with increasing temperature. Potentiodynamic polarisation study showed that ACMU is a mixed type inhibitor. AC Impedance study reveals that the corrosion of steel was mainly controlled by a charge transfer process. Surface analysis was carried out using SEM technique. The adsorption of inhibitor follows the Tempkin and Langmuir adsorption isotherms. The activation energy (Ea), free energy change (ΔGads), enthalpy change (ΔHads) and entropy change (ΔSads) were calculated to understand the corrosion inhibition mechanism.
Classification of Green Bristle Grass, Yellow Foxtail and Chinese Pennisetum Seeds via HATR-FT-IR Combined with Chemometrics
Authors: Yu Peng , Wan Cha-Yan , Wu Chang-Shun , Shou Jia-Ni , Cheng Cun-Gui
Published: September 2012

Fourier transform infrared (FT-IR) and horizontal attenuated total reflectance (HATR) technique are used to obtain the FT-IR spectra of the seed of green bristle grass (the seed fromSetaria viridis(L.) Beauv), yellow foxtail seed (the seed fromSetaria glauca(L.) Beauv), and the Chinese pennisetum seed (the seed fromSetaria faberiiHerrum). In order to extrude the difference among them, cluster analysis is considered to identify the three kinds of plant seeds. Because they belong to the sibling plant seeds, and have similar chemical components and close FT-IR spectra. The result of Cluster analysis is not satisfactory. The discrete wavelet transformation (DWT) and a support vector machine (SVM) were used for further study. The compression detail 3 and 4 in DWT are used to extract the feature vectors, which are used to train SVM. The trained SVM is used to classify seed of green bristle grass, yellow foxtail seed and Chinese pennisetum seed. The seed samples are collected from different places around the country. With 40 testing samples we could effectively identify the sibling plants, seed of green bristle grass, yellow foxtail seed and Chinese pennisetum seed by FT-IR with discrete wavelet feature extraction and SVM classification.
Iodide Transporter NIS Regulates Cancer Cell Motility and Invasiveness by Interacting with the Rho Guanine Nucleotide Exchange Factor LARG
Authors: Lacoste Claire , Hervé Julie , Bou Nader Myriam , Dos Santos Alexandre , Moniaux Nicolas , Valogne Yannick , Montjean Rodrick , Dorseuil Olivier , Samuel Didier , Cassio Doris , Portulano Carla , Carrasco Nancy , Bréchot Christian , Faivre Jamila
Published: September 2012

A number of solute carrier (SLC) proteins are subject to changes in expression and activity during carcinogenesis. Whether these changes play a role in carcinogenesis is unclear, except for some nutrients and ion carriers whose deregulation ensures the necessary reprogramming of energy metabolism in cancer cells. In this study, we investigated the functional role in tumor progression of the sodium/iodide symporter (NIS; aka SLC5A5), which is upregulated and mislocalized in many human carcinomas. Notably, we found that NIS enhanced cell migration and invasion without ion transport being involved. These functions were mediated by NIS binding to leukemia-associated RhoA guanine exchange factor, a Rho guanine exchange factor that activates the small GTPase RhoA. Sequestering NIS in intracellular organelles or impairing its targeting to the cell surface (as observed in many cancers) led to a further increase in cell motility and invasiveness. In sum, our results established NIS as a carrier protein that interacts with a major cell signaling hub to facilitate tumor cell locomotion and invasion. Cancer Res; 72(21); 5505–15. ©2012 AACR.
Role of the Human High-Affinity Copper Transporter in Copper Homeostasis Regulation and Cisplatin Sensitivity in Cancer Chemotherapy
Authors: Kuo Macus Tien , Fu Siqing , Savaraj Niramol , Chen Helen H.W.
Published: September 2012

The high-affinity copper transporter (Ctr1; SCLC31A1) plays an important role in regulating copper homeostasis because copper is an essential micronutrient and copper deficiency is detrimental to many important cellular functions, but excess copper is toxic. Recent research has revealed that human copper homeostasis is tightly controlled by interregulatory circuitry involving copper, Sp1, and human (hCtr1). This circuitry uses Sp1 transcription factor as a copper sensor in modulating hCtr1 expression, which in turn controls cellular copper and Sp1 levels in a 3-way mutual regulatory loop. Posttranslational regulation of hCtr1 expression by copper stresses has also been described in the literature. Because hCtr1 can also transport platinum drugs, this finding underscores the important role of hCtr1 in platinum-drug sensitivity in cancer chemotherapy. Consistent with this notion is the finding that elevated hCtr1 expression was associated with favorable treatment outcomes in cisplatin-based cancer chemotherapy. Moreover, cultured cell studies showed that elevated hCtr1 expression can be induced by depleting cellular copper levels, resulting in enhanced cisplatin uptake and its cell-killing activity. A phase I clinical trial using a combination of trientine (a copper chelator) and carboplatin has been carried out with encouraging results. This review discusses new insights into the role of hCtr1 in regulating copper homeostasis and explains how modulating cellular copper availability could influence treatment efficacy in platinum-based cancer chemotherapy through hCtr1 regulation. Cancer Res; 72(18); 4616–21. ©2012 AACR.
Targeting BRCA1 Localization to Augment Breast Tumor Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition
Authors: Yang Eddy S. , Nowsheen Somaira , Rahman Mohammad A. , Cook Rebecca S. , Xia Fen
Published: September 2012

PARP inhibitors have gained recent attention due to their highly selective killing of BRCA1/2-mutated and DNA double-strand break (DSB) repair–deficient tumors. Unfortunately, the majority of sporadic breast cancers carry wild-type BRCA1/2 and are proficient in DSB repair. We and others have shown that BRCA1 is a nuclear/cytoplasm shuttling protein that is transiently exported from the nucleus to the cytosol upon various stimuli. Thus, we hypothesized that depletion of nuclear BRCA1 would compromise DSB repair and subsequently render sporadic tumors susceptible to PARP inhibition. Indeed, in human sporadic breast cancer cells with functional BRCA1 and proficient DSB repair, a transient nuclear depletion of BRCA1 and subsequent homologous recombination repair deficit was induced with either truncated BRCA1 or irradiation. This rendered these human sporadic breast cancer cells susceptible to PARP inhibition. These observations were confirmed genetically using mislocated BRCA1 mutants as well as in vivo in mice bearing breast tumor xenografts. These data support the potential strategy of targeting BRCA1 location to convert BRCA1-proficient sporadic tumors to be susceptible to the synthetic lethal combination with PARP inhibitors. Cancer Res; 72(21); 5547–55. ©2012 AACR.
Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers
Authors: Mereniuk Todd R. , Maranchuk Robert A. , Schindler Anja , Penner-Chea Jonathan , Freschauf Gary K. , Hegazy Samar , Lai Raymond , Foley Edan , Weinfeld Michael
Published: September 2012

A genetic screen using a library of 6,961 siRNAs led to the identification of SHP-1 (PTPN6), a tumor suppressor frequently mutated in malignant lymphomas, leukemias, and prostate cancer, as a potential synthetic lethal partner of the DNA repair protein polynucleotide kinase/phosphatase (PNKP). After confirming the partnership with SHP-1, we observed that codepletion of PNKP and SHP-1 induced apoptosis. A T-cell lymphoma cell line that is SHP-1 deficient (Karpas 299) was shown to be sensitive to a chemical inhibitor of PNKP, but resistance was restored by expression of wild-type SHP-1 in these cells. We determined that while SHP-1 depletion does not significantly impact DNA strand-break repair, it does amplify the level of reactive oxygen species (ROS) and elevate endogenous DNA damage. The ROS scavenger WR1065 afforded protection to SHP-1–depleted cells treated with the PNKP inhibitor. We propose that codisruption of SHP-1 and PNKP leads to an increase in DNA damage that escapes repair, resulting in the accumulation of cytotoxic double-strand breaks and induction of apoptosis. This supports an alternative paradigm for synthetic lethal partnerships that could be exploited therapeutically. Cancer Res; 72(22); 5934–44. ©2012 AACR.
Cross-Species Functional Analysis of Cancer-Associated Fibroblasts Identifies a Critical Role for CLCF1 and IL-6 in Non–Small Cell Lung Cancer In Vivo
Authors: Vicent Silvestre , Sayles Leanne C. , Vaka Dedeepya , Khatri Purvesh , Gevaert Olivier , Chen Ron , Zheng Yanyan , Gillespie Anna K. , Clarke Nicole , Xu Yue , Shrager Joseph , Hoang Chuong D. , Plevritis Sylvia , Butte Atul J. , Sweet-Cordero E. Alejandro
Published: September 2012

Cancer-associated fibroblasts (CAF) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non–small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLCs, a cross-species functional characterization of mouse and human lung CAFs was conducted. CAFs supported the growth of lung cancer cells in vivo by secretion of soluble factors that directly stimulate the growth of tumor cells. Gene expression analysis comparing normal mouse lung fibroblasts and mouse lung CAFs identified multiple genes that correlate with the CAF phenotype. A gene signature of secreted genes upregulated in CAFs was an independent marker of poor survival in patients with NSCLC. This secreted gene signature was upregulated in normal lung fibroblasts after long-term exposure to tumor cells, showing that lung fibroblasts are “educated” by tumor cells to acquire a CAF-like phenotype. Functional studies identified important roles for CLCF1–CNTFR and interleukin (IL)-6–IL-6R signaling in promoting growth of NSCLCs. This study identifies novel soluble factors contributing to the CAF protumorigenic phenotype in NSCLCs and suggests new avenues for the development of therapeutic strategies. Cancer Res; 72(22); 5744–56. ©2012 AACR.
Hypoxia-Inducible miR-210 Regulates the Susceptibility of Tumor Cells to Lysis by Cytotoxic T Cells
Authors: Noman Muhammad Zaeem , Buart Stéphanie , Romero Pedro , Ketari Sami , Janji Bassam , Mari Bernard , Mami-Chouaib Fathia , Chouaib Salem
Published: September 2012

Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes (CTL). miR-210 was induced in hypoxic zones of human tumor tissues. Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis. Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis, by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve. Cancer Res; 72(18); 4629–41. ©2012 AACR.
T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control after Regulatory T-Cell Depletion
Authors: Hindley James P. , Jones Emma , Smart Kathryn , Bridgeman Hayley , Lauder Sarah N. , Ondondo Beatrice , Cutting Scott , Ladell Kristin , Wynn Katherine K. , Withers David , Price David A. , Ager Ann , Godkin Andrew J. , Gallimore Awen M.
Published: September 2012

The evolution of immune blockades in tumors limits successful antitumor immunity, but the mechanisms underlying this process are not fully understood. Depletion of regulatory T cells (Treg), a T-cell subset that dampens excessive inflammatory and autoreactive responses, can allow activation of tumor-specific T cells. However, cancer immunotherapy studies have shown that a persistent failure of activated lymphocytes to infiltrate tumors remains a fundamental problem. In evaluating this issue, we found that despite an increase in T-cell activation and proliferation following Treg depletion, there was no significant association with tumor growth rate. In contrast, there was a highly significant association between low tumor growth rate and the extent of T-cell infiltration. Further analyses revealed a total concordance between low tumor growth rate, high T-cell infiltration, and the presence of high endothelial venules (HEV). HEV are blood vessels normally found in secondary lymphoid tissue where they are specialized for lymphocyte recruitment. Thus, our findings suggest that Treg depletion may promote HEV neogenesis, facilitating increased lymphocyte infiltration and destruction of the tumor tissue. These findings are important as they point to a hitherto unidentified role of Tregs, the manipulation of which may refine strategies for more effective cancer immunotherapy. Cancer Res; 72(21); 5473–82. ©2012 AACR.
DNA Methylation Biomarkers Offer Improved Diagnostic Efficiency in Lung Cancer
Authors: Nikolaidis Georgios , Raji Olaide Y. , Markopoulou Soultana , Gosney John R. , Bryan Julie , Warburton Chris , Walshaw Martin , Sheard John , Field John K. , Liloglou Triantafillos
Published: September 2012

The exceptional high mortality of lung cancer can be instigated to a high degree by late diagnosis. Despite the plethora of studies on potential molecular biomarkers for lung cancer diagnosis, very few have reached clinical implementation. In this study, we developed a panel of DNA methylation biomarkers and validated their diagnostic efficiency in bronchial washings from a large retrospective cohort. Candidate targets from previous high-throughput approaches were examined by pyrosequencing in an independent set of 48 lung tumor/normal paired. Ten promoters were selected and quantitative methylation-specific PCR (qMSP) assays were developed and used to screen 655 bronchial washings from the Liverpool Lung Project (LLP) subjects divided into training (194 cases and 214 controls) and validation (139 cases and 109 controls) sets. Three statistical models were used to select the optimal panel of markers and to evaluate the performance of the discriminatory algorithms. The final logit regression model incorporated hypermethylation at p16, TERT, WT1, and RASSF1. The performance of this 4-gene methylation signature in the validation set showed 82% sensitivity and 91% specificity. In comparison, cytology alone in this set provided 43% sensitivity at 100% specificity. The diagnostic efficiency of the panel did not show any biases with age, gender, smoking, and the presence of a nonlung neoplasm. However, sensitivity was predictably higher in central (squamous and small cell) than peripheral (adenocarcinomas) tumors, as well as in stage 2 or greater tumors. These findings clearly show the impact of DNA methylation-based assays in the diagnosis of cytologically occult lung neoplasms. A prospective trial is currently imminent in the LLP study to provide data on the enhancement of diagnostic accuracy in a clinical setting, including by additional markers. Cancer Res; 72(22); 5692–701. ©2012 AACR.
A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report
Authors: Widemann Brigitte C. , Kim AeRang , Fox Elizabeth , Baruchel Sylvain , Adamson Peter C. , Ingle Ashish M. , Bender Julia Glade , Burke Michael , Weigel Brenda , Stempak Diana , Balis Frank M. , Blaney Susan M.
Published: September 2012

Purpose: To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias.

Experimental Design: Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1.

Results: Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/aspartate aminotransferase (AST)] at the starting dose (150 mg/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/dose for solid tumors and 150 mg/m2/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%.

Conclusions: The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m2/dose and 150 mg/m2/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing. Clin Cancer Res; 18(21); 6011–22. ©2012 AACR.
Pharmacokinetic and Pharmacodynamic Analysis of Circulating Biomarkers of Anti-NRP1, a Novel Antiangiogenesis Agent, in Two Phase I Trials in Patients with Advanced Solid Tumors
Authors: Xin Yan , Li Jessica , Wu Jenny , Kinard Rashell , Weekes Colin D. , Patnaik Amita , LoRusso Patricia , Brachmann Rainer , Tong Raymond K. , Yan Yibing , Watts Ryan , Bai Shuang , Hegde Priti S.
Published: September 2012

Purpose: MNRP1685A is a monoclonal antibody to neuropilin-1 (NRP1). We evaluated blood-based pharmacodynamic biomarkers of MNRP1685A in two phase I studies to assess exposure/response relationships to inform target dose and regimen selection.

Experimental Design: The phase I studies evaluated escalating doses of MNRP1685A as a single agent or in combination with bevacizumab. Plasma placental growth factor (PlGF), VEGF, and circulating NRP1 (cNRP1) were evaluated at multiple time points using meso-scale discovery (MSD) assays and ELISA, respectively. Plasma PlGF was also measured in a phase I/II trial of bevacizumab in metastatic breast cancer (AVF0776). The association between PlGF and MNRP1685A dose was described by a sigmoid Emax model. cNRP1 and MNRP1685A PK profiles were described using a two-target quasi-steady state (QSS) model.

Results: A dose- and time-dependent increase in plasma PlGF and cNRP1 was observed in all patients treated with MNRP1685A. PK/PD analysis showed that bevacizumab and MNRP1685A had an additive effect in elevating PlGF. Predictions based on the two-target QSS model showed that the free drug concentration to maintain greater than 90% saturation of membrane NRP1 (mNRP1) and cNRP1 is about 8 μg/mL.

Conclusion: These data show that MNRP1685A inhibits the VEGF pathway in humans as assessed by an increase in plasma PlGF. MNRP1685A seems to enhance bevacizumab-mediated VEGF pathway blockade, as showed by an increase in the magnitude of PlGF elevation when combined with bevacizumab. PK/PD analysis of biomarkers in the phase I population allowed identification of doses at which apparent maximal pathway modulation was observed. Clin Cancer Res; 18(21); 6040–8. ©2012 AACR.