bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Herbal Medicinal Formulas on Suppressing Viral Replication and Modulating Immune Responses
Authors: Liao Hui-Fen , Lu Min-Chi , Chang Hon-Chou , Wei Cheng-Chung , Kao Chih-Hsiung , Chen Zong-Huei , Huang Chin-Chin , Li Ching
Published: February 2010

The Chinese medicinal herbs Radix Isatidis and Viola yedoensis Makino have been suggested to possess antiviral activity. This study tests whether these and other Chinese and Western herbal medicinal formulas can modulate the immune functions involving virus-suppression in BALB/c mouse. We first confirmed the extract from Viola yedoensis Makino, but not from Radix Isatidis, the traditional Chinese medicine (TCM) formula Chui-Uren-Chien (CUC), or a Western homeopathic medicinal drink Método Canova, could inhibit the replications of herpes simplex virus-1 and enterovirus 71 in the human neuroblastoma SK-N-SH cell line. Subsequently, the same herbal extracts and drink underwent toxicity and immunomodulatory tests on mice of 5–7 weeks old. After 8 weeks of feeding different herbal medicinal formulas, no hepatic or renal toxicity was noted in any tested animal; whereas among the immune function evaluations, only the mice treated with CUC extract were found to be associated with significant increases (p < 0.05) in both the level of plasma IgG and the percentage of monocyte in blood mononuclear cells as well as the activation of macrophage Raw264.7 cells for nitric oxide production, suggesting its role in modulating the non-specific immune response. Analyses using protein arrays showed CUC was the most potent herbal medicinal formula eliciting fluctuations in plasma cytokine and chemokine concentrations. Taking all experimental data together, we conclude Chui-Uren-Chien possesses immunomodulatory capability in mouse, but none of the herbal medicinal formulas tested here are involved in strengthening antiviral immunity.
EFFECT OF COPPER OXIDE ON THE GRAIN GROWTH AND INITIAL PERMEABILITY OF Mg–Cu–Zn FERRITES
Authors: HAQUE M. MANJURUL , HUQ M. , FARHAD SYED FARID UDDIN , KHAN JASIM UDDIN , HAKIM M. A.
Published: February 2010

The microstructure and magnetic properties of Mg – Cu – Zn ferrites prepared by using solid-state reaction method have been investigated. X-ray diffraction (XRD), a scanning electron microscope (SEM), impedance analyzer and a vibrating sample magnetometer (VSM) were utilized in order to study the effect of copper substitution and its impact on the crystal structure, grain size, microstructure and magnetic properties of the Mg – Cu – Zn ferrite. The formation of cubic spinel phase was identified using XRD technique. The microstructures of the samples show that the grain growth is greatly enhanced by the addition of CuO which is attributed to the liquid phase during sintering. The average grain size (Dm) increases significantly with increasing Cu content. The initial permeability (μ') of the samples increases appreciably with increasing Cu content which is attributed to the increase of grain size and density of the samples. The resonance frequency (fr) of the samples shifts toward the lower frequency as the Cu content increases. The sharp fall of μ' in μ'-T curves is observed for all the samples which indicate the homogeneity of the samples. The saturation magnetization (Ms) of the Mg – Cu – Zn ferrites increases slightly with increasing Cu concentration.
A HIERARCHY OF HAMILTONIAN EQUATIONS ASSOCIATED WITH THE MODIFIED JAULENT–MIODEK HIERARCHY
Authors: DING HAI-YONG , YANG HONG-XIANG , SUN YE-PENG , ZHU LI-LI
Published: February 2010

By considering a new four-by-four matrix eigenvalue problem, a hierarchy of Lax integrable evolution equations with four potentials is derived. The Hamiltonian structures of the resulting hierarchy are established by means of the generalized trace identity. The Liouville integrability for the hierarchy of the resulting Hamiltonian equations is presented.
BOSE–EINSTEIN CONDENSATION OF A q-DEFORMED BOSE GAS IN A RANDOM BOX
Authors: WANG YING , KONG XIANG-MU
Published: February 2010

The q-deformed Bose–Einstein distribution is used to study the Bose–Einstein condensation (BEC) of a q-deformed Bose gas in random box. It is shown that the BEC transition temperature is lowered due to random boundary conditions. The effects of q-deformation on the properties of the system are also discussed. We find some properties of a q-deformed Bose gas, which are different from those of an ordinary Bose gas. Similar results are also shown for q-bosons confined in a harmonic oscillator potential well.
CODIMENSION-THREE BIFURCATIONS OF NONLINEAR VIBRATION-CONTROLLED SYSTEMS
Authors: TSAI HSUN-HENG , TSENG CHYUAN-YOW
Published: February 2010

The nonlinear dynamics of a vibration-controlled magnetic system are studied via a three-mode discretization of the governing partial differential equations. The analysis focuses specifically on the effects of modal coupling through the nonlinear terms of the system equation. A bifurcation analysis of the system is performed using sophisticated nonlinear theories, including the center manifold theory and the normal form theorem. The results show that when the first mode and the higher modes are excited simultaneously by the control forces, the three-mode approximation method predicts the existence of a triple zero degeneracy accompanied by complicated bifurcation phenomena. Comparing the dynamics structure predicted by the three-mode approximation model with that obtained from a single-mode approach, it is found that if the higher modes are excited by the control forces, the effects of modal coupling should be taken into consideration since a complicated dynamics structure may exist as a result.
NON-CONJUGATE BRAIDS WHOSE CLOSURES RESULT IN THE SAME KNOT
Authors: SHINJO REIKO
Published: February 2010

For any knot K represented as an n-braid (n ≥ 3), we construct an infinite sequence of pairwise non-conjugate (n + 1)-braids {bm, m ∈ ℕ} representing K.
ORIENTED STATE MODEL OF THE JONES POLYNOMIAL AND ITS CONNECTION TO THE DICHROMATIC POLYNOMIAL
Authors: JIN XIAN'AN , ZHANG FUJI
Published: February 2010

It is well known that Kauffman constructed a state model of the Jones polynomial based on unoriented link diagrams. In his approach, in order to obtain Jones polynomial one needs to calculate both the writhe and the Kauffman bracket. Stimulated by a paper of Altintas (An oriented state model for the Jones polynomial and its applications to alternating links, Appl. Math. Comput.194 (2007) 168–178), in this paper we present a state sum model based on oriented link diagrams. In our approach, we succeed in adding the writhe to the state sum model and need not to compute the writher any more. We further show that, via our state sum model, Jones polynomial of any link (alternating or not) is a special parametrization of the dichromatic polynomial of a weighted graph with two different edge weights.
MULTIVARIABLE LINK INVARIANTS ARISING FROM LIE SUPERALGEBRAS OF TYPE I
Authors: GEER NATHAN , PATUREAU-MIRAND BERTRAND
Published: February 2010

In this paper, we construct new links invariants from a type I basic Lie superalgebra 𝔤. The construction uses the existence of an unexpected replacement of the vanishing quantum dimension of typical module, by non-trivial "fake quantum dimensions". Using this, we get a multivariable link invariant associated to any one parameter family of irreducible 𝔤-modules.
MEDIUM-TERM OUTCOME FOLLOWING INTRA-ARTICULAR CORTICOSTEROID INJECTION IN FIRST CMC JOINT ARTHRITIS USING FLUOROSCOPY
Authors: Maarse Wies , Watts Adam C. , Bain Gregory I.
Published: February 2010

First carpometacarpal joint osteoarthritis (1stCMCJ OA) is a common condition with variable results reported from local corticosteroid injection. This study aims to explore the medium-term outcome with respect to pain relief, patient satisfaction and the need for subsequent surgical intervention. A prospective review was performed of patients undergoing fluoroscopically guided corticosteroid injection by one surgeon, with postal questionnaires for medium-term follow-up. Forty-one patients were included. Thirty-one were female and ten male, with a mean age of 60 years. In the short term 76% of patients reported pain relief with an average duration of four weeks and 69% of the patients reported benefit from injection. After a median follow-up of 36 months 76% of patients reported continuing pain but 59% reported satisfaction with the outcome. Twenty-eight per cent of the patients had undergone surgery. Local corticosteroid injection of the CMCJ provides only short-term pain relief, but few patients go on to surgical intervention.
MULTIPLE SIMULTANEOUS MALLET FINGERS IN GOALKEEPER
Authors: Degreef Ilse , Smet Luc De
Published: February 2010

The mallet finger is a common hand injury in sports with ball use. Here, we present the case of a goalkeeper with simultaneous bilateral mallet fingers in the third and fourth ray, successfully treated with splinting. Origin and treatment options are discussed.
NEW METHOD FOR THE PREPARATION OF ZINC OXIDE AS SINGLE-PHASE IN THE NANOMETER RANGE
Authors: DIMESSO L.
Published: February 2010

A novel and uncomplicated method for preparing nanocrystalline zinc oxide by precipitation in a basic aqueous solution with the addition of an oxidation agent and in the presence of flowing gas is presented. Firstly, the value of pH of the starting solution containing the zinc salts is adjusted to a value of 5–5.5. Then, zinc oxide is precipitated by adding NH4OH and bubbling flowing air. Finally, the precipitated materials are washed with a basic solution (0.01 M NaOH ). The X-ray diffraction patterns show nanocrystalline single-phase ZnO with a grain size of 12–14 nm (Scherrer method). No further thermal treatment of the prepared material is required. The surface of the prepared material can be successfully modified. This new route is reproducible and can be used on industrial level.
COATING THICKNESS STUDY OF BIOPOLYMER-MAGNETITE CORE–SHELL NANOPARTICLES
Authors: SATHYANARAYANAN P. , RAINA G.
Published: February 2010

Magnetite and biopolymer-magnetite nanoparticles coated with polyethylene glycol (PEG) and chitosan have been synthesized. The adsorption of the biopolymers on the magnetite nanoparticles is confirmed using Fourier Transform Infrared (FTIR) Spectroscopy. Atomic Force Microscopy (AFM) imaging revealed magnetite-biopolymer core–shell nanoparticles of typical size range 25–80 nm. We report a novel way of determining the thickness of the biopolymer coating using noncontact AFM imaging. AFM has been used to study the variation of the biopolymer coating thickness as a function of the magnetite core diameter, biopolymer type, and its concentration. The thickness of the chitosan coating varies in the range of 4–11 nm and increases linearly with increase in magnetite core size. PEG coating thickness has similar values as for the chitosan coating.
INVESTIGATION OF HYDROGEN ADSORPTION ON PLATINUM-DECORATED SINGLE-WALLED CARBON NANOTUBE USING MOLECULAR DYNAMICS SIMULATIONS
Authors: JALILI SEIFOLLAH , JABERI AREZOU , MAHJANI MOHAMMAD GHASEM , JAFARIAN MAJID
Published: February 2010

Hydrogen adsorption isotherms for (8, 0) platinum-decorated single-walled carbon nanotube were studied using molecular dynamics simulation. Adsorption isotherms were obtained for both internal and external surfaces of nanotube at several temperatures from 77 K up to 400 K. The results were compared with the bare nanotube at the same conditions. Adsorption coverage, isosteric heat, binding energy, hydrogen desorption, and readsorption were calculated for both internal and external surfaces of nanotube. At low temperatures, hydrogen molecules were adsorbed significantly, but at higher temperatures, thermal energies reduced this capacity. Under the same conditions, the platinum-decorated single-walled carbon nanotube hydrogen adsorption is significantly higher than the bare one.
A SHORT REVIEW ON DEEP-SUB-VOLTAGE NANOELECTRONICS AND RELATED TECHNOLOGIES
Authors: DESPOTULI ALEXANDER , ANDREEVA ALEXANDRA
Published: February 2010

The decrease of energy consumption per 1 bit processing (ε) and power supply voltage (V dd ) of integrated circuits (ICs) are long-term tendencies in micro- and nanoelectronics. In this framework, deep-sub-voltage nanoelectronics (DSVN), i.e., ICs of ~1011–1012 cm-2 component densities operating near the theoretical limit of ε, is sure to find application in the next 10 years. In nanoelectronics, the demand on high-capacity capacitors of micron sizes sharply increases with a decrease of technological norms, ε and V dd . Creation of high-capacity capacitors of micron size to meet the challenge of DSVN and related technologies is considered. The necessity of developing all-solid-state impulse micron-sized supercapacitors on the basis of advanced superionic conductors (nanoionic supercapacitors) is discussed. Theoretical estimates and experimental data on prototype nanoionic supercapacitors with capacity density δC ≈ 100 μF/cm2 are presented. Future perspectives of nanoionic devices are briefly discussed.
Cerebellar Cortex Contributions to the Expression and Timing of Conditioned Eyelid Responses
Authors: Kalmbach Brian E. , Davis Tobin , Ohyama Tatsuya , Riusech Frank , Nores William L. , Mauk Michael D.
Published: February 2010

We used micro-infusions during eyelid conditioning in rabbits to investigate the relative contributions of cerebellar cortex and the underlying deep nuclei (DCN) to the expression of cerebellar learning. These tests were conducted using two forms of cerebellum-dependent eyelid conditioning for which the relative roles of cerebellar cortex and DCN are controversial: delay conditioning, which is largely unaffected by forebrain lesions, and trace conditioning, which involves interactions between forebrain and cerebellum. For rabbits trained with delay conditioning, silencing cerebellar cortex by micro-infusions of the local anesthetic lidocaine unmasked stereotyped short-latency responses. This was also the case after extinction as observed previously with reversible blockade of cerebellar cortex output. Conversely, increasing cerebellar cortex activity by micro-infusions of the GABAA antagonist picrotoxin reversibly abolished conditioned responses. Effective cannula placements were clustered around the primary fissure and deeper in lobules hemispheric lobule IV (HIV) and hemispheric lobule V (HV) of anterior lobe. In well-trained trace conditioned rabbits, silencing this same area of cerebellar cortex or reversibly blocking cerebellar cortex output also unmasked short-latency responses. Because Purkinje cells are the sole output of cerebellar cortex, these results provide evidence that the expression of well-timed conditioned responses requires a well-timed decrease in the activity of Purkinje cells in anterior lobe. The parallels between results from delay and trace conditioning suggest similar contributions of plasticity in cerebellar cortex and DCN in both instances.
Optimal Control of a Hybrid Rhythmic-Discrete Task: The Bouncing Ball Revisited
Authors: Ronsse Renaud , Wei Kunlin , Sternad Dagmar
Published: February 2010

Rhythmically bouncing a ball with a racket is a hybrid task that combines continuous rhythmic actuation of the racket with the control of discrete impact events between racket and ball. This study presents experimental data and a two-layered modeling framework that explicitly addresses the hybrid nature of control: a first discrete layer calculates the state to reach at impact and the second continuous layer smoothly drives the racket to this desired state, based on optimality principles. The testbed for this hybrid model is task performance at a range of increasingly slower tempos. When slowing the rhythm of the bouncing actions, the continuous cycles become separated into a sequence of discrete movements interspersed by dwell times and directed to achieve the desired impact. Analyses of human performance show increasing variability of performance measures with slower tempi, associated with a change in racket trajectories from approximately sinusoidal to less symmetrical velocity profiles. Matching results of model simulations give support to a hybrid control model based on optimality, and therefore suggest that optimality principles are applicable to the sensorimotor control of complex movements such as ball bouncing.
High Precision and Fast Functional Mapping of Cortical Circuitry Through a Novel Combination of Voltage Sensitive Dye Imaging and Laser Scanning Photostimulation
Authors: Xu Xiangmin , Olivas Nicholas D. , Levi Rafael , Ikrar Taruna , Nenadic Zoran
Published: February 2010

The development of modern neuroscience tools is critical for deciphering brain circuit organization and function. An important aspect for technical development is to enhance each technique's advantages and compensate for limitations. We developed a high-precision and fast functional mapping technique in brain slices that incorporates the spatial precision of activation that can be achieved by laser-scanning photostimulation with rapid and high-temporal resolution assessment of evoked network activity that can be achieved by voltage-sensitive dye imaging. Unlike combination of whole cell recordings with photostimulation for mapping local circuit inputs to individually recorded neurons, this innovation is a new photostimulation-based technique to map cortical circuit output and functional connections at the level of neuronal populations. Here we report on this novel technique in detail and show its effective applications in mapping functional connections and circuit dynamics in mouse primary visual cortex and hippocampus. Given that this innovation enables rapid mapping and precise evaluation of cortical organization and function, it can have broad impacts in the field of cortical circuitry.
Extended Stokes′ Problems for Relatively Moving Porous Half‐Planes
Authors: Liu Chi-Min
Published: February 2010

A shear flow motivated by relatively moving half‐planes is theoretically studied in
this paper. Either the mass influx or the mass efflux is allowed on the boundary. This
flow is called the extended Stokes′ problems. Traditionally, exact solutions to the
Stokes′ problems can be readily obtained by directly applying the integral transforms
to the momentum equation and the associated boundary and initial conditions.
However, it fails to solve the extended Stokes′ problems by using the
integral‐transform method only. The reason for this difficulty is that the inverse
transform cannot be reduced to a simpler form. To this end, several crucial
mathematical techniques have to be involved together with the integral transforms to
acquire the exact solutions. Moreover, new dimensionless parameters are defined to
describe the flow phenomena more clearly. On the basis of the exact solutions derived
in this paper, it is found that the mass influx on the boundary hastens the development
of the flow, and the mass efflux retards the energy transferred from the plate to the
far‐field fluid.
Commutators and Squares in Free Nilpotent Groups
Authors: Akhavan-Malayeri Mehri
Published: February 2010

In a free group no nontrivial commutator is a square. And in the
free group F2 = F(x1, x2) freely generated by x1, x2 the commutator [x1, x2] is never the product of two squares in F2, although it is always the product of three squares. Let F2,3 = 〈x1, x2〉 be a free nilpotent group of rank 2 and class
3 freely generated by x1, x2. We prove that in F2,3 = 〈x1, x2〉, it is possible
to write certain commutators as a square. We denote by Sq(γ) the minimal
number of squares which is required to write γ as a product of squares in group G. And we define Sq(G) = sup{Sq(γ); γ ∈ G′}.
We discuss the question of when the square length of a given commutator of
F2,3 is equal to 1 or 2 or 3. The precise formulas for expressing any commutator of F2,3 as the minimal number of squares are given. Finally as an application of these results we prove that .
Recombinant Activated Factor VII (rFVIIa) in the Management of Major Obstetric Haemorrhage: A Case Series and a Proposed Guideline for Use
Authors: Bomken Charlotte , Mathai Sue , Biss Tina , Loughney Andrew , Hanley John
Published: February 2010

Major obstetric haemorrhage remains a significant cause of maternal morbidity and mortality. Previous case reports suggest the potential benefit of recombinant activated factor VII (rFVIIa: ) as a haemostatic agent. We performed a retrospective review of the use of rVIIa in major obstetric haemorrhage in the Northern Region between July 2004 and February 2007. Fifteen women received rFVIIa. The median patient age was 34 years. Major haemorrhage occurred antepartum (5 patients), intrapartum (1), and postpartum (9). All women received an initial dose of 90 mcg/kg rFVIIa and one received 2 further doses. Bleeding stopped or decreased in 12 patients (80%). Additional measures included antifibrinolytic and uterotonic agents, Rusch balloon insertion, uterine curettage/packing, and vessel embolisation. Eight patients required hysterectomy. All women survived to discharge from hospital. No adverse events, including thrombosis, were recorded. This study provides further support for the safety and efficacy of rFVIIa as adjunct therapy in major obstetric haemorrhage.
Some New Weakly Contractive Type Multimaps and Fixed Point Results in Metric Spaces
Authors: Latif Abdul , Abdou Afrah A. N.
Published: February 2010

Some new weakly contractive type multimaps in the setting of metric spaces are introduced, and we prove some results on the existence of fixed points for such maps under certain conditions. Our results extend and improve several known results including the corresponding recent fixed point results of Pathak and Shahzad (2009), Latif and Abdou (2009), Latif and Albar (2008), Cirić (2008), Feng and Liu (2006), and Klim and Wardowski (2007).
The Roles of Streptozotocin Neurotoxicity and Neutral Endopeptidase in Murine Experimental Diabetic Neuropathy
Authors: Davidson Eric , Coppey Lawrence , Lu Bao , Arballo Victor , Calcutt Nigel A. , Gerard Craig , Yorek Mark
Published: February 2010

We demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuroactive peptides, improves vascular and neural function in diabetic animal models. In this study we explored the role of NEP in neuropathy related to either insulin-deficient diabetes or diet-induced obesity using NEP deficient (−/−) mice. Initial studies showed that streptozotocin, in the absence of subsequent hyperglycemia, did not induce nerve conduction slowing or paw thermal hypoalgesia. Glucose disposal was impaired in both C57Bl/6 and NEP −/− mice fed a high fat diet. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and high fat fed C57Bl/6 mice but not in NEP −/− mice exposed to either streptozotocin-induced diabetes or a high fat diet. These studies suggest that streptozotocin does not induce neurotoxicity in mice and that NEP plays a role in regulating nerve function in insulin-deficient diabetes and diet-induced obesity.
Computational Study of 3,4‐Diphenyl‐1,2,5‐Thiadiazole 1‐Oxide for Organic Photovoltaics
Authors: Glossman-Mitnik Daniel
Published: February 2010

We make use of a model chemistry within Density Functional
Theory (DFT) recently presented, which is called CHIH‐DFT, to calculate
the molecular structure of 3,4‐diphenyl‐1,2,5‐thiadiazole 1‐oxide (TSO), as
well to predict its infrared (IR), ultraviolet (UV‐Vis) and fluorescence (Fluo)
spectra, the dipole moment and polarizability, the free energy of solvation in
different solvents as an indication of solubility, and the chemical reactivity
parameters that arise from Conceptual DFT. The calculated values are compared with the available experimental data for this molecule as a means of
validation of our proposed model chemistry.
Simple‐Zero and Double‐Zero Singularities of a Kaldor‐Kalecki Model of Business Cycles with Delay
Authors: Wu Xiaoqin P.
Published: February 2010

We study the Kaldor‐Kalecki model of business cycles
with delay in both the gross product and the capital stock. Simple‐zero
and double‐zero singularities are investigated when bifurcation parameters
change near certain critical values. By performing center manifold
reduction, the normal forms on the center manifold are derived to obtain
the bifurcation diagrams of the model such as Hopf, homoclinic and
double limit cycle bifurcations. Some examples are given to confirm the
theoretical results.
Decoupling Action Potential Bias from Cortical Local Field Potentials
Authors: David Stephen V. , Malaval Nicolas , Shamma Shihab A.
Published: February 2010

Neurophysiologists have recently become interested in studying neuronal population activity through local field potential (LFP) recordings during experiments that also record the activity of single neurons. This experimental approach differs from early LFP studies because it uses high impendence electrodes that can also isolate single neuron activity. A possible complication for such studies is that the synaptic potentials and action potentials of the small subset of isolated neurons may contribute disproportionately to the LFP signal, biasing activity in the larger nearby neuronal population to appear synchronous and cotuned with these neurons. To address this problem, we used linear filtering techniques to remove features correlated with spike events from LFP recordings. This filtering procedure can be applied for well-isolated single units or multiunit activity. We illustrate the effects of this correction in simulation and on spike data recorded from primary auditory cortex. We find that local spiking activity can explain a significant portion of LFP power at most recording sites and demonstrate that removing the spike-correlated component can affect measurements of auditory tuning of the LFP.
Application of Periodized Harmonic Wavelets towards Solution of Eigenvalue Problems for Integral Equations
Authors: Cattani Carlo , Kudreyko Aleksey
Published: February 2010

This article deals with the application of the periodized harmonic wavelets for solution of integral equations and eigenvalue problems. The solution is searched as a series of products of wavelet coefficients and wavelets. The absolute error for a general case of the wavelet approximation was analytically estimated.
Transcription Factor KLF11 Integrates Progesterone Receptor Signaling and Proliferation in Uterine Leiomyoma Cells
Authors: Yin Ping , Lin Zhihong , Reierstad Scott , Wu Ju , Ishikawa Hiroshi , Marsh Erica E. , Innes Joy , Cheng Youhong , Pearson Kerry , Coon John Sayler , Kim J. Julie , Chakravarti Debabrata , Bulun Serdar E.
Published: February 2010

Uterine leiomyoma is the most common tumor of the female genital tract and the leading cause of hysterectomy. Although progesterone stimulates the proliferation of uterine leiomyoma cells, the mechanism of progesterone action is not well understood. We used chromatin immunoprecipitation (ChIP)–cloning approach to identify progesterone receptor (PR) target genes in primary uterine leiomyoma smooth muscle cells. We identified 18 novel PR-binding sites, one of which was located 20.5 kb upstream of the transcriptional start site of the Krüppel-like transcription factor 11 (KLF11) gene. KLF11 mRNA levels were minimally downregulated by progesterone but robustly upregulated by the progesterone antagonist RU486. Luciferase reporter assays showed significant baseline and RU486-inducible promoter activity in the KLF11 basal promoter or distal PR-binding region, both of which contained multiple Sp1-binding sequences but lacked classic progesterone response elements. RU486 stimulated recruitment of Sp1, RNA polymerase II, PR, and the coactivators SRC-1 and SRC-2 to the distal region and basal promoter. siRNA knockdown of PR increased KLF11 expression, whereas knockdown of KLF11 increased leiomyoma cell proliferation and abolished the antiproliferative effect of RU486. In vivo, KLF11 expression was significantly lower in leiomyoma tissues compared with adjacent myometrial tissues. Taken together, using a ChIP-cloning approach, we uncovered KLF11 as an integrator of PR signaling and proliferation in uterine leiomyoma cells. Cancer Res; 70(4); 1722–30
miR-146a Suppresses Invasion of Pancreatic Cancer Cells
Authors: Li Yiwei , VandenBoom Timothy G. , Wang Zhiwei , Kong Dejuan , Ali Shadan , Philip Philip A. , Sarkar Fazlul H.
Published: February 2010

The aggressive course of pancreatic cancer is believed to reflect its unusually invasive and metastatic nature, which is associated with epidermal growth factor receptor (EGFR) overexpression and NF-κB activation. MicroRNAs (miRNA) have been implicated in the regulation of various pathobiological processes in cancer, including metastasis in pancreatic cancer and in other human malignancies. In this study, we report lower expression of miR-146a in pancreatic cancer cells compared with normal human pancreatic duct epithelial cells. Reexpression of miR-146a inhibited the invasive capacity of pancreatic cancer cells with concomitant downregulation of EGFR and the NF-κB regulatory kinase interleukin 1 receptor–associated kinase 1 (IRAK-1). Cellular mechanism studies revealed crosstalk between EGFR, IRAK-1, IκBα, NF-κB, and MTA-2, a transcription factor that regulates metastasis. Treatment of pancreatic cancer cells with the natural products 3,3′-diinodolylmethane (DIM) or isoflavone, which increased miR-146a expression, caused a downregulation of EGFR, MTA-2, IRAK-1, and NF-κB, resulting in an inhibition of pancreatic cancer cell invasion. Our findings reveal DIM and isoflavone as nontoxic activators of a miRNA that can block pancreatic cancer cell invasion and metastasis, offering starting points to design novel anticancer agents. Cancer Res; 70(4); 1486–95
Serologic Markers of Effective Tumor Immunity against Chronic Lymphocytic Leukemia Include Nonmutated B-Cell Antigens
Authors: Marina Ovidiu , Hainz Ursula , Biernacki Melinda A. , Zhang Wandi , Cai Ann , Duke-Cohan Jonathan S. , Liu Fenglong , Brusic Vladimir , Neuberg Donna , Kutok Jeffery L. , Alyea Edwin P. , Canning Christine M. , Soiffer Robert J. , Ritz Jerome , Wu Catherine J.
Published: February 2010

Patients with chronic lymphocytic leukemia (CLL) who relapse after allogeneic transplant may achieve durable remission following donor lymphocyte infusion (DLI), showing the potency of donor-derived immunity in eradicating tumors. We sought to elucidate the antigenic basis of the effective graft-versus-leukemia (GvL) responses associated with DLI for the treatment of CLL by analyzing the specificity of plasma antibody responses developing in two DLI-treated patients who achieved long-term remission without graft-versus-host disease. By probing high-density protein microarrays with patient plasma, we discovered 35 predominantly intracellular antigens that elicited high-titer antibody reactivity greater in post-DLI than in pre-DLI plasma. Three antigens—C6orf130, MDS032, and ZFYVE19—were identified by both patients. Along with additional candidate antigens DAPK3, SERBP1, and OGFOD1, these proteins showed higher transcript and protein expression in B cells and CLL cells compared with normal peripheral blood mononuclear cells. DAPK3 and the shared antigens do not represent minor histocompatibility antigens, as their sequences are identical in both donor and tumor. Although ZFYVE19, DAPK3, and OGFOD1 elicited minimal antibody reactivity in 12 normal subjects and 12 chemotherapy-treated CLL patients, 5 of 12 CLL patients with clinical GvL responses were serologically reactive to these antigens. Moreover, antibody reactivity against these antigens was temporally correlated with clinical disease regression. These B-cell antigens represent promising biomarkers of effective anti-CLL immunity. Cancer Res; 70(4); 1344–55
Genomic and Gene Expression Profiling Defines Indolent Forms of Mantle Cell Lymphoma
Authors: Fernàndez Verònica , Salamero Olga , Espinet Blanca , Solé Francesc , Royo Cristina , Navarro Alba , Camacho Francisca , Beà Sílvia , Hartmann Elena , Amador Virginia , Hernández Luis , Agostinelli Claudio , Sargent Rachel L. , Rozman Maria , Aymerich Marta , Colomer Dolors , Villamor Neus , Swerdlow Steven H. , Pileri Stefano A. , Bosch Francesc , Piris Miguel A. , Montserrat Emili , Ott German , Rosenwald Andreas , López-Guillermo Armando , Jares Pedro , Serrano Sergi , Campo Elías
Published: February 2010

Mantle cell lymphoma (MCL) is typically a very aggressive disease with poor outcomes, but some cases display an indolent behavior that might not necessitate treatment at diagnosis. To define molecular criteria that might permit recognition of such cases, we compared the clinicopathologic features, gene expression, and genomic profile of patients who had indolent or conventional disease (iMCL or cMCL). Patients with iMCL displayed nonnodal leukemic disease with predominantly hypermutated IGVH and noncomplex karyotypes. iMCL and cMCL shared a common gene expression profile that differed from other leukemic lymphoid neoplasms. However, we identified a signature of 13 genes that was highly expressed in cMCL but underexpressed in iMCL. SOX11 was notable in this signature and we confirmed a restriction of SOX11 protein expression to cMCL. To validate the potential use of SOX11 as a biomarker for cMCL, we evaluated SOX11 protein expression in an independent series of 112 cases of MCL. Fifteen patients with SOX11-negative tumors exhibited more frequent nonnodal presentation and better survival compared with 97 patients with SOX11-positive MCL (5-year overall survival of 78% versus 36%, respectively; P = 0.001). In conclusion, we defined nonnodal presentation, predominantly hypermutated IGVH, lack of genomic complexity, and absence of SOX11 expression as qualities of a specific subtype of iMCL with excellent outcomes that might be managed more conservatively than cMCL. Cancer Res; 70(4); 1408–18
CLOCKin Breast Tumorigenesis: Genetic, Epigenetic, and Transcriptional Profiling Analyses
Authors: Hoffman Aaron E. , Yi Chun-Hui , Zheng Tongzhang , Stevens Richard G. , Leaderer Derek , Zhang Yawei , Holford Theodore R. , Hansen Johnni , Paulson Jennifer , Zhu Yong
Published: February 2010

The transcription factors responsible for maintaining circadian rhythm influence a variety of biological processes. Recently, it has been suggested that the core circadian genes may play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. To evaluate this hypothesis, we conducted a genetic and epigenetic association study, as well as a transcriptional profiling array and a pathway-based network analysis. We report significant correlations between single nucleotide polymorphisms associated with the central circadian regulator CLOCK and breast cancer risk, with apparent effect modification by estrogen receptor/progesterone receptor status. We also found that hypermethylation in the CLOCK promoter reduced the risk of breast cancer, and lower levels of CLOCK expression were documented in healthy controls relative to normal or tumor tissue from patients with breast cancer. Finally, we silenced CLOCK in vitro and performed a whole-genome expression microarray and pathway analysis, which identified a cancer-relevant network of transcripts with altered expression following CLOCK gene knockdown. Our findings support the hypothesis that circadian genes influence tumorigenesis, and identify a set of circadian gene variants as candidate breast cancer susceptibility biomarkers. Cancer Res; 70(4); 1459–68
Loss of Kelch-Like ECH-Associated Protein 1 Function in Prostate Cancer Cells Causes Chemoresistance and Radioresistance and Promotes Tumor Growth
Authors: Zhang Ping , Singh Anju , Yegnasubramanian Srinivasan , Esopi David , Kombairaju Ponvijay , Bodas Manish , Wu Hailong , Bova Steven G. , Biswal Shyam
Published: February 2010

Loss-of-function mutations in the nuclear factor erythroid-2–related factor 2 (Nrf2) inhibitor Kelch-like ECH-associated protein 1 (Keap1) result in increased Nrf2 activity in non–small cell lung cancer and confer therapeutic resistance. We detected point mutations in Keap1 gene, leading to nonconservative amino acid substitutions in prostate cancer cells. We found novel transcriptional and posttranscriptional mechanisms of Keap1 inactivation, such as promoter CpG island hypermethylation and aberrant splicing of Keap1, in DU-145 cells. Very low levels of Keap1 mRNA were detected in DU-145 cells, which significantly increased by treatment with DNA methyltransferase inhibitor 5-aza-deoxycytidine. The loss of Keap1 function led to an enhanced activity of Nrf2 and its downstream electrophile/drug detoxification pathway. Inhibition of Nrf2 expression in DU-145 cells by RNA interference attenuated the expression of glutathione, thioredoxin, and the drug efflux pathways involved in counteracting electrophiles, oxidative stress, and detoxification of a broad spectrum of drugs. DU-145 cells constitutively expressing Nrf2 short hairpin RNA had lower levels of total glutathione and higher levels of intracellular reactive oxygen species. Attenuation of Nrf2 function in DU-145 cells enhanced sensitivity to chemotherapeutic drugs and radiation-induced cell death. In addition, inhibition of Nrf2 greatly suppressed in vitro and in vivo tumor growth of DU-145 prostate cancer cells. Thus, targeting the Nrf2 pathway in prostate cancer cells may provide a novel strategy to enhance chemotherapy and radiotherapy responsiveness and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes. Mol Cancer Ther; 9(2); 336–46
Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors
Authors: Koblish Holly K. , Hansbury Michael J. , Bowman Kevin J. , Yang Gengjie , Neilan Claire L. , Haley Patrick J. , Burn Timothy C. , Waeltz Paul , Sparks Richard B. , Yue Eddy W. , Combs Andrew P. , Scherle Peggy A. , Vaddi Kris , Fridman Jordan S.
Published: February 2010

Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose- and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell–derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients. Mol Cancer Ther; 9(2); 489–98
ALK1-Fc Inhibits Multiple Mediators of Angiogenesis and Suppresses Tumor Growth
Authors: Mitchell Dianne , Pobre Eileen G. , Mulivor Aaron W. , Grinberg Asya V. , Castonguay Roselyne , Monnell Travis E. , Solban Nicolas , Ucran Jeffrey A. , Pearsall R. Scott , Underwood Kathryn W. , Seehra Jasbir , Kumar Ravindra
Published: February 2010

Activin receptor–like kinase-1 (ALK1) is a type I, endothelial cell–specific member of the transforming growth factor-β superfamily of receptors known to play an essential role in modulating angiogenesis and vessel maintenance. In the present study, we sought to examine the angiogenic and tumorigenic effects mediated upon the inhibition of ALK1 signaling using a soluble chimeric protein (ALK1-Fc). Of 29 transforming growth factor-β–related ligands screened by surface plasmon resonance, only bone morphogenetic protein (BMP9) and BMP10 displayed high-affinity binding to ALK1-Fc. In cell-based assays, ALK1-Fc inhibited BMP9-mediated Id-1 expression in human umbilical vein endothelial cells and inhibited cord formation by these cells on a Matrigel substrate. In a chick chorioallantoic membrane assay, ALK1-Fc reduced vascular endothelial growth factor–, fibroblast growth factor–, and BMP10-mediated vessel formation. The growth of B16 melanoma explants was also inhibited significantly by ALK1-Fc in this assay. Finally, ALK1-Fc treatment reduced tumor burden in mice receiving orthotopic grafts of MCF7 mammary adenocarcinoma cells. These data show the efficacy of chimeric ALK1-Fc proteins in mitigating vessel formation and support the view that ALK1-Fc is a powerful antiangiogenic agent capable of blocking vascularization. Mol Cancer Ther; 9(2); 379–
Restoration of p53 Functions Protects Cells from Concanavalin A–Induced Apoptosis
Authors: Amin A.R.M. Ruhul , Thakur Vijay S. , Gupta Kalpana , Jackson Mark W. , Harada Hisashi , Agarwal Mukesh K. , Shin Dong M. , Wald David N. , Agarwal Munna L.
Published: February 2010

A great majority of human cancers encounter disruption of the p53 network. Identification and characterization of molecular components important in both p53-dependent and p53-independent apoptosis might be useful in developing novel therapies. Previously, we reported that concanavalin A (Con A) induced p73-dependent apoptosis of cells lacking functional p53. In the present study, we investigated the mechanism and role of p53 in protection from apoptosis induced by Con A. Treatment with Con A resulted in apoptosis of p53-null ovarian cancer, SKOV3, or Li-Fraumeni syndrome, MDAH041 (041), cells. However, their isogenic pairs, SKP53 and TR9-7, expressing wild-type p53 were much less sensitive and were protected by G1 arrest. Inhibition of p53 function rendered these cells sensitive to Con A. Con A–induced apoptosis was accompanied by upregulation of forkhead box O1a (FOXO1a) and Bcl-2–interacting mediator (Bim), which were strongly inhibited after p53 expression and rescued after p53 ablation. Moreover, ablation of Bim by short hairpin RNA protected cells from apoptosis. Taken together, our study suggests that Con A induces apoptosis of cells lacking p53 by activating FOXO1a-Bim signaling and that expression of p53 protects these cells by inducing G1 arrest and by downregulating the expression of both FOXO1a and Bim, identifying a novel cross-talk between FOXO1a and p53 transcription factors. Mol Cancer Ther; 9(2); 471–9
ATM Deficiency Sensitizes Mantle Cell Lymphoma Cells to Poly(ADP-Ribose) Polymerase-1 Inhibitors
Authors: Williamson Chris T. , Muzik Huong , Turhan Ali G. , Zamò Alberto , O'Connor Mark J. , Bebb D. Gwyn , Lees-Miller Susan P.
Published: February 2010

Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The ataxia telangiectasia mutated (ATM) gene is altered in several human cancers including mantle cell lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small-molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive, and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (known previously as AZD2281/KU-0059436) significantly decreased tumor growth and increased overall survival in mice bearing s.c. xenografts of ATM-deficient Granta-519 cells while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL, and the concept of synthetic lethality extends to human cancers with ATM alterations. Mol Cancer Ther; 9(2); 347–57
Deregulated E2F and the AAA+ Coregulator ANCCA Drive Proto-Oncogene ACTR/AIB1 Overexpression in Breast Cancer
Authors: Hsia Elaine Y.C. , Kalashnikova Ekaterina V. , Revenko Alexey S. , Zou June X. , Borowsky Alexander D. , Chen Hong-Wu
Published: February 2010

The proto-oncogene ACTR/AIB1, a coactivator for transcription factors such as the nuclear receptors and E2Fs, is frequently overexpressed in various cancers including breast cancers. However, the underlying mechanism is poorly understood. Here, we identified several functional, noncanonical E2F binding sites in the ACTR first exon and intron that are critical for ACTR gene activation. We also found that the newly identified AAA+ coregulator AAA+ nuclear coregulator cancer associated (ANCCA) is recruited to the ACTR promoter and directly controls ACTR expression in breast cancer cells. Importantly, immunohistochemistry analysis indicated that ACTR overexpression is highly correlated with the expression of E2F1 and ANCCA in a cohort of human primary and lymph node–metastasized breast cancer specimens. Along with previous findings from us and others that ACTR is involved in its own gene regulation, these results suggest that one major mechanism of ACTR overexpression in cancer is the concerted, aberrant function of the nuclear coregulators such as ANCCA and ACTR, and they point to therapeutic strategies that target the Rb-E2F axis and/or the coregulator ANCCA for ACTR-overexpressing cancers. Mol Cancer Res; 8(2); 183–93
Neuropsychiatric Symptoms in Korean Patients with Alzheimer’s Disease: Exploratory Factor Analysis and Confirmatory Factor Analysis of the Neuropsychiatric Inventory
Authors: Kang Hyo Shin , Ahn Inn Sook , Kim Ji Hae , Kim Doh Kwan
Published: February 2010

Background/Aims: We designed this study to examine subsyndromes in Korean patients with Alzheimer’s disease (AD) using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Methods: Initial participants were 778 AD patients recruited from the Clinical Research Center for Dementia of South Korea and assessed via the Korean Neuropsychiatric Inventory. Those with ≧1 neuropsychiatric symptom were randomly divided into groups. Principal axis factoring with oblimin rotation was used to analyze group 1 inventory results, and maximum likelihood estimation extraction with Bollen-Stine bootstrapping was used for group 2. Results: The results of the EFA showed the presence of 4 subsyndromes: hyperactivity, affect, psychosis and apathy/vegetative symptom. The CFA results indicated this model was the best-fitting model for explaining these subsyndromes. Conclusion: Our model showed the best fit and identified 4 subsyndromes. This study might contribute to a clearer understanding of the neuropsychiatric symptoms in AD.