bluuebunny/crossref_metadata_2025 huggingface dataset:
FULLY INTEGRATED FREQUENCY SYNTHESIZERS: A TUTORIAL
Authors: Moon Sung Tae , Valero-López Ari Yakov , Sánchez-Sinencio Edgar
Published: February 2006

Frequency synthesizer is a key building block of fully-integrated wireless communications systems. Design of a frequency synthesizer (FS) requires the understanding of not only the circuit-level but also of the transceiver system-level considerations. The FS design challenge involves strong trade-offs, and often conflicting requirements. In this tutorial, the general implementation issues and recent developments of frequency synthesizer design are discussed. Simplified design approach should provide readers with sufficient intuition for fast design and troubleshooting capability. Open problems in this FS field are briefly discussed.
FOUR-DIMENSIONAL SUPERGRAVITY FROM STRING THEORY
Authors: DEO B. B.
Published: February 2006

A derivation of N = 1 supergravity action from string theory is presented. Starting from a Nambu–Goto bosonic string, matter field is introduced to obtain a superstring in four dimensions. The excitation quanta of this string contain graviton and the gravitino. Using the principle of equivalence, the action in curved space–time are found and the sum of them is the Deser–Zumino N = 1 supergravity action. The energy tensor is Lorentz invariant due to supersymmetry.
LÉVY STATISTICAL FLUCTUATIONS FROM A RANDOM AMPLIFYING MEDIUM
Authors: SHARMA DIVYA , RAMACHANDRAN HEMA , KUMAR N.
Published: February 2006

We report our studies of emission from a dye-scatterer system, commonly known as random amplifying medium (RAM). It is found to exhibit non-Gaussian statistics of emission intensity over the ensemble of random realizations. The amplification is dominated by certain improbable events that are "larger than rare", which give the intensity statistics a Lévy-like fat tail. This, to the best of our knowledge, provides the first experimental realization of the Lévy statistics in the optics of a random amplifying medium, and the analysis thereof. Notably, the Lévy exponent is continuously tunable parametrically.
ON THE ALGEBRAIC PARAMETERS OF CONVOLUTIONAL CODES WITH CYCLIC STRUCTURE
Authors: GLUESING-LUERSSEN HEIDE , LANGFELD BARBARA
Published: February 2006

In this paper convolutional codes with cyclic structure will be investigated. These codes can be understood as left principal ideals in a suitable skew-polynomial ring. It has been shown in [4] that only certain combinations of the algebraic parameters (field size, length, dimension, and Forney indices) can occur for such cyclic codes. We will investigate whether all these combinations can indeed be realized by a suitable cyclic code and, if so, how to construct such a code. A complete characterization and construction will be given for minimal cyclic codes. It is derived from a detailed investigation of the units in the skew-polynomial ring.
IDENTITIES RELATING THE JORDAN PRODUCT AND THE ASSOCIATOR IN THE FREE NONASSOCIATIVE ALGEBRA
Authors: BREMNER MURRAY R. , HENTZEL IRVIN R.
Published: February 2006

We determine the identities of degree ≤ 6 satisfied by the symmetric (Jordan) product a○b = ab + ba and the associator [a,b,c] = (ab)c - a(bc) in every nonassociative algebra. In addition to the commutative identity a○b = b○a we obtain one new identity in degree 4 and another new identity in degree 5. We demonstrate the existence of further new identities in degree 6. These identities define a variety of binary-ternary algebras which generalizes the variety of Jordan algebras in the same way that Akivis algebras generalize Lie algebras.
DIEUDONNÉ DETERMINANTS FOR SKEW POLYNOMIAL RINGS
Authors: TAELMAN LENNY
Published: February 2006

We observe that the Dieudonné determinant induces a non-negative degree function on the ring of matrices over a skew polynomial ring. We then apply this degree function to two examples. In the first one, we find an expression for the rank of the kernel of an algebraic endomorphism of [Formula: see text] over a field of characteristic p > 0. In the second, we calculate the dimension of the solution space of linear matrix differential equations.
THE SCHEME OF FORMAL CURVES ON AN ABELIAN VARIETY
Authors: PABLOS ROMO FERNANDO
Published: February 2006

Let X be an abelian variety defined over an algebraically closed field k of arbitrary characteristic. The aim of this note is to show that the scheme [Formula: see text], which parametrizes germs of formal curves on X, is the Picard scheme of a formal scheme.
ON SOME LATTICES OF MODULE CLASSES
Authors: GARCÍA ALEJANDRO ALVARADO , RINCÓN-MEJÍA HUGO ALBERTO , MONTES JOSÉ RÍOS
Published: February 2006

In this work we continue the discussion of the conatural classes introduced in [1]. We prove that the collection R-conat of all conatural classes of left modules over a ring R is a set, and it is a boolean lattice. Afterwards we study relationships between some lattices of module classes: R-conat and R-tors, R-her and R-quot. As a consequence of the developed theory we obtain characterizations of left MAX rings and artinian principal ideal rings.
THE DISCRIMINANT OF ABELIAN NUMBER FIELDS
Authors: INTERLANDO J. CARMELO , LOPES JOSÉ OTHON DANTAS , NETO TRAJANO PIRES DA NÓBREGA
Published: February 2006

A formula for computing the discriminant of any Abelian number field K is given. It is presented as a function of the conductor m of K and of the degrees of the fields K ∩ ℚ(ζpα) over ℚ, where p runs through the set of primes that divide m, and pαis the greatest power of p that divides m.
The Long Twentieth Century in American Sociology: A Semiautobiographical Survey
Authors: Williams Robin M.
Published: February 2006

In this essay, I draw on a professional life history to suggest how sociological knowledge is generated by encounters with changing research opportunities, here called targets of opportunity. In my case, a study of rural communities led to unanticipated conclusions concerning buffering mechanisms that protected authorities by absorbing dissatisfactions and rebellions. Wartime research in a military setting identified sources of group solidarity and effective performance under stress. Major societal changes in racial/ethnic relations provided opportunities to develop new concepts and empirical findings. Synoptic studies of post–World War II American society led to extensive research on values and institutions. These macrosociological analyses of ethnicity and social systems, in turn, led me to a new sociology of war and interstate relations. I also offer here some critical reflections on recurrent issues and chronic controversies in American sociology. Final sections of the review deal with the continuing search for conceptual clarity and cumulative knowledge. I note the obstacles of disciplinary fragmentation, but my closing judgment is that sociology now has the base of substantial scientific knowledge and methodological expertise necessary for investigating crucial twenty-first century problems.
Serotonin type-3 receptors mediate cholecystokinin-induced satiation through gastric distension
Authors: Hayes Matthew R. , Chory Fiona M. , Gallagher Claire A. , Covasa Mihai
Published: February 2006

We have previously shown that serotonin type-3 (5-HT3) receptors mediate cholecystokinin (CCK)-induced satiation and that this effect is dependent on postoropharyngeal feedback. However, the independent contributions of gastric and intestinal feedback in 5-HT3 receptor mediation of suppression of food intake by CCK have not been determined. Using a sham-feeding preparation combined with intraduodenal sucrose infusion, we show that blockade of 5-HT3 receptors by ondansetron (1 mg/kg ip) had no effect on suppression of sham feeding by intraduodenal 15% sucrose infusion (4 ml/10 min), CCK (2 μg/kg ip) administration, or the combination of the two treatments. In separate experiments consisting of either sham-feeding rats that received gastric distension with the use of a balloon or real-feeding rats whose stomachs were distended using gastric loads of saline after the occlusion of the pylorus, we tested the hypothesis that gastric feedback signals are necessary for activation of 5-HT3 receptors. Ondansetron significantly attenuated suppression of sham sucrose intake after a 10-ml gastric balloon distension (30.5 ± 2.2 vs. 20.2 ± 2.2 ml, respectively) and gastric distension combined with CCK (21.9 ± 1.4 vs. 12.0 ± 1.7 ml, respectively). When intestinal feedback was eliminated in a real-feeding paradigm by closing the pylorus using a cuff preparation, ondansetron attenuated suppression of sucrose intake produced by a 10-ml saline gastric load (6.8 ± 0.7 vs. 4.2 ± 0.4 ml, respectively). Finally, when CCK (1 μg/kg) was administered in combination with a 5-ml saline gastric load in a real-feeding preparation, ondansetron significantly attenuated suppression of sucrose intake by CCK (9.0 ± 0.9 vs. 6.3 ± 0.5 ml, respectively), as well as the enhanced suppression of intake by CCK plus gastric load (6.9 ± 0.6 vs. 4.6 ± 0.5 ml, respectively). These findings demonstrate that CCK-induced activation of 5-HT3 receptors requires gastric, but not intestinal feedback.
Effects of ATP-induced leg vasodilation on V̇o2 peakand leg O2extraction during maximal exercise in humans
Authors: Calbet J. A. L. , Lundby C. , Sander M. , Robach P. , Saltin B. , Boushel R.
Published: February 2006

During maximal whole body exercise V̇o2 peakis limited by O2delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2delivery and leg V̇o2during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 μg·kg body mass−1·min−1. During near-maximal exercise (92% of V̇o2 peak), the infusion of ATP increased leg vascular conductance (+43%, P < 0.05), leg blood flow (+20%, 1.7 l/min, P < 0.05), and leg O2delivery (+20%, 0.3 l/min, P < 0.05). No effects were observed on leg or systemic V̇o2. Leg O2fractional extraction was decreased from 85 ± 3 (control) to 78 ± 4% (ATP) in the infused leg ( P < 0.05), while it remained unchanged in the left leg (84 ± 2 and 83 ± 2%; control and ATP; n = 3). ATP infusion at maximal exercise increased leg vascular conductance by 17% ( P < 0.05), while leg blood flow tended to be elevated by 0.8 l/min ( P = 0.08). However, neither systemic nor leg peak V̇o2values where enhanced due to a reduction of O2extraction from 84 ± 4 to 76 ± 4%, in the control and ATP conditions, respectively ( P < 0.05). In summary, the V̇o2of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb.
Plasticity in the nucleus tractus solitarius and its influence on lung and airway reflexes
Authors: Bonham Ann C. , Chen Chao-Yin , Sekizawa Shin-ichi , Joad Jesse P.
Published: February 2006

The nucleus tractus solitarius (NTS) is the first central nervous system (CNS) site for synaptic contact of the primary afferent fibers from the lungs and airways. The signal processing at these synapses will determine the output of the sensory information from the lungs and airways to all downstream synapses in the reflex pathways. The second-order NTS neurons bring to bear their own intrinsic and synaptic properties to temporally and spatially integrate the sensory information with inputs from local networks, higher brain regions, and circulating mediators, to orchestrate a coherent reflex output. There is growing evidence that NTS neurons share the rich repertoire of forms of plasticity demonstrated throughout the CNS. This review focuses on existing evidence for plasticity in the NTS, potential targets for plasticity in the NTS, and the impact of this plasticity on lung and airway reflexes.
Compression-induced deep tissue injury examined with magnetic resonance imaging and histology
Authors: Stekelenburg A. , Oomens C. W. J. , Strijkers G. J. , Nicolay K. , Bader D. L.
Published: February 2006

The underlying mechanisms leading to deep tissue injury after sustained compressive loading are not well understood. It is hypothesized that initial damage to muscle fibers is induced mechanically by local excessive deformation. Therefore, in this study, an animal model was used to study early damage after compressive loading to elucidate on the damage mechanisms leading to deep pressure ulcers. The tibialis anterior of Brown-Norway rats was loaded for 2 h by means of an indenter. Experiments were performed in a magnetic resonance (MR)-compatible loading device. Muscle tissue was evaluated with transverse relaxation time (T2)-weighted MRI both during loading and up to 20 h after load removal. In addition, a detailed examination of the histopathology was performed at several time points (1, 4, and 20 h) after unloading. Results demonstrated that, immediately after unloading, T2-weighted MR images showed localized areas with increased signal intensity. Histological examination at 1 and 4 h after unloading showed large necrotic regions with complete disorganization of the internal structure of the muscle fibers. Hypercontraction zones were found bilateral to the necrotic zone. Twenty hours after unloading, an extensive inflammatory response was observed. The proposed relevance of large deformation was demonstrated by the location of damage indicated by T2-weighted MRI and the histological appearance of the compressed tissues. Differences in damage development distal and proximal to the indenter position suggested a contribution of perfusion status in the measured tissue changes that, however, appeared be to reversible.
Effect of severe short-term malnutrition on diaphragm muscle signal transduction pathways influencing protein turnover
Authors: Lewis Michael I. , Bodine Sue C. , Kamangar Nader , Xu Xuan , Da Xiaoyu , Fournier Mario
Published: February 2006

The aim of this study was to evaluate the effect of nutritional deprivation (ND) on signal transduction pathways influencing the translational apparatus in the diaphragm muscle. Male rats were divided into two groups: 1) 20% of usual food intake for 4 days (ND) with water provided at libitum and 2) free-eating control (Ctl). Total protein and RNA were extracted from the diaphragm. Insulin-like growth factor I mRNA was analyzed by RT-PCR. Protein analyses of key cytoplasmic proteins for three signaling pathways deemed important in influencing protein turnover [phosphatidylinositol 3-kinase- Akt-mammalian target of rapamycin, P13K/Akt/glycogen synthase kinase (GSK)-3, and MAPK-ERK] were performed by Western blot. Body weight decreased 30% in ND and increased 17% in Ctl animals. Diaphragm mass decreased 29% in ND animals. Muscle insulin-like growth factor I mRNA abundance was reduced 63% in ND animals. ND resulted in a 55% reduction in phosphorylated (Ser473) Akt. Phosphorylation of mammalian target of rapamycin at Ser2448was reduced by 85% in ND animals. Downstream effectors important in translation initiation were also affected by ND. Phosphorylated (Thr389) 70-kDa ribosomal protein S6 kinase was significantly reduced (35%) by ND. ND also resulted in significant dephosphorylation of the translational repressor initiation factor 4E-binding protein 1. Phosphorylation of GSK-3α (Ser21) and GSK-3β (Ser9) was increased 55 and 45%, respectively, with ND. Phosphorylation of ERK1 (Thr202) and ERK2 (Tyr204), p44 and p42, respectively, was reduced 64 and 55%, respectively, with ND. Total protein concentration for all signaling intermediates of the three pathways was preserved. We conclude that short-term ND altered the phosphorylation states of key proteins of several pathways involved in protein turnover. This forms the framework for future studies aimed at identifying therapeutic targets in the management of short-term nutritionally induced cachectic states.
Differential Role of Transient Receptor Potential Channels in Ca2+ Entry and Proliferation of Prostate Cancer Epithelial Cells
Authors: Thebault Stephanie , Flourakis Matthieu , Vanoverberghe Karine , Vandermoere Franck , Roudbaraki Morad , Lehen'kyi V'yacheslav , Slomianny Christian , Beck Benjamin , Mariot Pascal , Bonnal Jean-Louis , Mauroy Brigitte , Shuba Yaroslav , Capiod Thierry , Skryma Roman , Prevarskaya Natalia
Published: February 2006

One major clinical problem with prostate cancer is the cells' ability to survive and proliferate upon androgen withdrawal. Because Ca2+ is central to growth control, understanding the mechanisms of Ca2+ homeostasis involved in prostate cancer cell proliferation is imperative for new therapeutic strategies. Here, we show that agonist-mediated stimulation of α1-adrenergic receptors (α1-AR) promotes proliferation of the primary human prostate cancer epithelial (hPCE) cells by inducing store-independent Ca2+ entry and subsequent activation of nuclear factor of activated T cells (NFAT) transcription factor. Such an agonist-induced Ca2+ entry (ACE) relied mostly on transient receptor potential canonical 6 (TRPC6) channels, whose silencing by antisense hybrid depletion decreased both hPCE cell proliferation and ACE. In contrast, ACE and related growth arrest associated with purinergic receptors (P2Y-R) stimulation involved neither TRPC6 nor NFAT. Our findings show that α1-AR signaling requires the coupled activation of TRPC6 channels and NFAT to promote proliferation of hPCE cells and thereby suggest TRPC6 as a novel potential therapeutic target. (Cancer Res 2006; 66(4): 2038-47)
α-Sulfoquinovosylmonoacylglycerol Is a Novel Potent Radiosensitizer Targeting Tumor Angiogenesis
Authors: Sakimoto Ippei , Ohta Keisuke , Yamazaki Takayuki , Ohtani Seiji , Sahara Hiroeki , Sugawara Fumio , Sakaguchi Kengo , Miura Masahiko
Published: February 2006

Angiogenesis is a promising target for the treatment of cancer, and varying types of antiangiogenic agents have been developed. However, limitations and problems associated with antiangiogenic therapy have recently arisen. Although radiotherapy can be combined with antiangiogenic compounds to overcome these difficulties, almost all previously described angiogenesis inhibitors could still cause side effects at effective doses, and only additive effects are seen in current combination therapy. In this study, we identified a member of the sulfoquinovosylacylglycerols, α-sulfoquinovosylmonoacylglycerol (α-SQMG), originally derived from sea urchins, as a potent radiosensitizer. The agent synergistically inhibits angiogenesis at low doses when combined with ionizing radiation. Combined treatment with α-SQMG and radiation seems to promote the adoption of a senescence-like phenotype by vascular endothelial cells. Finally, the agent remarkably enhances the radioresponse of human tumors transplanted into nude mice, accompanied by a significant reduction in the vascularity of the tumors. Collectively, α-SQMG may be a novel potent radiosensitizer targeting angiogenesis. (Cancer Res 2006; 66(4): 2287-95)
Minimal Active Domain and Mechanism of Action of the Angiogenesis Inhibitor Histidine-Rich Glycoprotein
Authors: Dixelius Johan , Olsson Anna-Karin , Thulin Åsa , Lee Chunsik , Johansson Irja , Claesson-Welsh Lena
Published: February 2006

Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein that efficiently arrests growth and vascularization of mouse tumor models. We have shown that the antiangiogenic effect of HRGP is dependent on its histidine/proline–rich domain, which needs to be released from the mother protein to exert its effects. Here we identify a 35-amino-acid peptide, HRGP330, derived from the histidine/proline–rich domain as endowed with antiangiogenic properties in vitro and in vivo. The mechanism of action of HRGP330 involves subversion of focal adhesion function by disruption of integrin-linked kinase (ILK) and focal adhesion kinase (FAK) functions, inhibition of vascular endothelial growth factor (VEGF)–induced tyrosine phosphorylation of the FAK substrate α-actinin, and, as a consequence, an arrest in endothelial cell motility. The disturbed focal adhesion function is reflected in the ability of HRGP as well as of HRGP330 to prevent endothelial cell adhesion to vitronectin in a manner involving αvβ3 integrin. In conclusion, HRGP330, which we define as the minimal antiangiogenic domain of HRGP, exerts its effects through signal transduction targeting focal adhesions, thereby interrupting VEGF-induced endothelial cell motility. (Cancer Res 2006; 66(4): 2089-97)
Genistein Represses Telomerase Activity via Both Transcriptional and Posttranslational Mechanisms in Human Prostate Cancer Cells
Authors: Jagadeesh Shankar , Kyo Satoru , Banerjee Partha P.
Published: February 2006

Genistein, the most abundant isoflavone present in soybean has antiproliferative effects on a variety of cancer cells, including prostate cancer. However, the molecular mechanism of antiproliferative effects of genistein is not entirely understood. Because the activation of telomerase is crucial for cells to gain immortality and proliferation ability, we examined the role of genistein in the regulation of telomerase activity in prostate cancer cells. Here, we show that genistein-induced inhibition in cell proliferation is associated with a reduction in telomerase activity. Using reverse transcriptase-PCR and hTERT promoter activity assays, we showed that genistein decreased hTERT expression and transcriptional activity dose-dependently. Using various deleted hTERT promoter constructs, we defined that the hTERT core promoter is enough to observe the genistein-induced repression of hTERT transcriptional activity. Because c-Myc is involved in transcriptional regulation of hTERT, c-Myc expression was examined. A dose-dependent decrease in c-Myc message and proteins was observed with genistein treatment. These results indicate that genistein represses hTERT transcriptional activity via the down-regulation of c-Myc expression. However, genistein-induced repression of hTERT transcriptional activity was not blocked by the mutation of c-Myc at the hTERT promoter, suggesting that additional factors are involved in genistein-dependent repression of telomerase activity. Interestingly, we observed that genistein down-regulates the activation of Akt thereby phosphorylation of hTERT and inhibits its translocation to the nucleus. These results show for the first time that genistein represses telomerase activity in prostate cancer cells not only by repressing hTERT transcriptional activity via c-Myc but also by posttranslational modification of hTERT via Akt. (Cancer Res 2006; 66(4): 2107-15)
Relationship of Gene Expression and Chromosomal Abnormalities in Colorectal Cancer
Authors: Tsafrir Dafna , Bacolod Manny , Selvanayagam Zachariah , Tsafrir Ilan , Shia Jinru , Zeng Zhaoshi , Liu Hao , Krier Curtis , Stengel Robert F. , Barany Francis , Gerald William L. , Paty Philip B. , Domany Eytan , Notterman Daniel A.
Published: February 2006

Several studies have verified the existence of multiple chromosomal abnormalities in colon cancer. However, the relationships between DNA copy number and gene expression have not been adequately explored nor globally monitored during the progression of the disease. In this work, three types of array-generated data (expression, single nucleotide polymorphism, and comparative genomic hybridization) were collected from a large set of colon cancer patients at various stages of the disease. Probes were annotated to specific chromosomal locations and coordinated alterations in DNA copy number and transcription levels were revealed at specific positions. We show that across many large regions of the genome, changes in expression level are correlated with alterations in DNA content. Often, large chromosomal segments, containing multiple genes, are transcriptionally affected in a coordinated way, and we show that the underlying mechanism is a corresponding change in DNA content. This implies that whereas specific chromosomal abnormalities may arise stochastically, the associated changes in expression of some or all of the affected genes are responsible for selecting cells bearing these abnormalities for clonal expansion. Indeed, particular chromosomal regions are frequently gained and overexpressed (e.g., 7p, 8q, 13q, and 20q) or lost and underexpressed (e.g., 1p, 4, 5q, 8p, 14q, 15q, and 18) in primary colon tumors, making it likely that these changes favor tumorigenicity. Furthermore, we show that these aberrations are absent in normal colon mucosa, appear in benign adenomas (albeit only in a small fraction of the samples), become more frequent as disease advances, and are found in the majority of metastatic samples. (Cancer Res 2006; 66(4): 2129-37)
Increased Frequency of Aberrations in the p53/MDM2/p14ARF Pathway in Neuroblastoma Cell Lines Established at Relapse
Authors: Carr Jane , Bell Emma , Pearson Andrew D.J. , Kees Ursula R. , Beris Helen , Lunec John , Tweddle Deborah A.
Published: February 2006

p53 mutations have been reported in cell lines derived from relapsed neuroblastoma tumors. We hypothesize that functional inactivation of p53 by mutation or other mechanisms is common in relapsed neuroblastoma and can contribute to chemoresistance. Our aim was to determine the frequency of p53 mutations, p14ARF methylation, or deletion and MDM2 amplification in 23 neuroblastoma cell lines (6 derived at diagnosis and 17 derived at relapse). One cell line was p53 mutant (BE2c) and two cell lines were deleted for p14ARF (LAN-6 and SHEP). Two cell lines were methylated for p14ARF (GIMEN and PER-108), one of which had low levels of p14ARF mRNA expression which increased following demethylation with 5-aza-2/deoxycytidine treatment (GIMEN), and four cell lines were confirmed to be MDM2-amplified. All these cell lines were derived from neuroblastomas at relapse. Inactivation of the p53 pathway was observed in 9 out of 17 neuroblastoma cell lines (53%) established at relapse and in none of the cell lines established from pretreatment tumors. If these data are confirmed in neuroblastoma tumors, this suggests that p53-independent therapy and reactivation of inactive p53 approaches would be useful in the management of relapsed neuroblastoma. (Cancer Res 2006; 66(4): 2138-45)
Glioma Virotherapy: Effects of Innate Immune Suppression and Increased Viral Replication Capacity
Authors: Friedman Avner , Tian Jianjun Paul , Fulci Giulia , Chiocca E. Antonio , Wang Jin
Published: February 2006

Oncolytic viruses are genetically altered replication-competent viruses that infect, and reproduce in, cancer cells but do not harm normal cells. On lysis of the infected cells, the newly formed viruses burst out and infect other tumor cells. Experiments with injecting mutant herpes simplex virus 1 (hrR3) into glioma implanted in brains of rats show lack of efficacy in eradicating the cancer. This failure is attributed to interference by the immune system. Initial pretreatment with immunosuppressive agent cyclophosphamide reduces the percentage of immune cells. We introduce a mathematical model and use it to determine how different protocols of cyclophosphamide treatment and how increased burst size of the mutated virus will affect the growth of the cancer. One of our conclusions is that the diameter of the cancer will decrease from 4 mm to eventually 1 mm if the burst size of the virus is triple that which is currently available. The effect of repeated cyclophosphamide treatment is to maintain a low density of uninfected cells in the tumor, thus reducing the probability of migration of tumor cells to other locations in the brain. (Cancer Res 2006; 66(4): 2314-9)
Lymphocyte Activation Antigen CD70 Expressed by Renal Cell Carcinoma Is a Potential Therapeutic Target for Anti-CD70 Antibody-Drug Conjugates
Authors: Law Che-Leung , Gordon Kristine A. , Toki Brian E. , Yamane Andrew K. , Hering Michelle A. , Cerveny Charles G. , Petroziello Joseph M. , Ryan Maureen C. , Smith Leia , Simon Ronald , Sauter Guido , Oflazoglu Ezogelin , Doronina Svetlana O. , Meyer Damon L. , Francisco Joseph A. , Carter Paul , Senter Peter D. , Copland John A. , Wood Christopher G. , Wahl Alan F.
Published: February 2006

Metastatic renal cell carcinoma (RCC) is an aggressive disease refractory to most existing therapeutic modalities. Identifying new markers for disease progression and drug targets for RCC will benefit this unmet medical need. We report a subset of clear cell and papillary cell RCC aberrantly expressing the lymphocyte activation marker CD70, a member of the tumor necrosis factor superfamily. Importantly, CD70 expression was found to be maintained at the metastatic sites of RCC. Anti-CD70 antibody-drug conjugates (ADC) consisting of auristatin phenylalanine phenylenediamine (AFP) or monomethyl auristatin phenylalanine (MMAF), two novel derivatives of the anti-tubulin agent auristatin, mediated potent antigen-dependent cytotoxicity in CD70-expressing RCC cells. Cytotoxic activity of these anti-CD70 ADCs was associated with their internalization and subcellular trafficking through the endosomal-lysosomal pathway, disruption of cellular microtubule network, and G2-M phase cell cycle arrest. The efficiency of drug delivery using anti-CD70 as vehicle was illustrated by the much enhanced cytotoxicity of antibody-conjugated MMAF compared with free MMAF. Hence, ADCs targeted to CD70 can selectively recognize RCC, internalize, and reach the appropriate subcellular compartment(s) for drug release and tumor cell killing. In vitro cytotoxicity of these ADCs was confirmed in xenograft models using RCC cell lines. Our findings provide evidence that CD70 is an attractive target for antibody-based therapeutics against metastatic RCC and suggest that anti-CD70 ADCs can provide a new treatment approach for advanced RCC patients who currently have no chemotherapeutic options. (Cancer Res 2006; 66(4): 2328-37)
The Forkhead Box m1 Transcription Factor Stimulates the Proliferation of Tumor Cells during Development of Lung Cancer
Authors: Kim Il-Man , Ackerson Timothy , Ramakrishna Sneha , Tretiakova Maria , Wang I-Ching , Kalin Tanya V. , Major Michael L. , Gusarova Galina A. , Yoder Helena M. , Costa Robert H. , Kalinichenko Vladimir V.
Published: February 2006

The proliferation-specific Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) regulates expression of cell cycle genes essential for progression into DNA replication and mitosis. Expression of Foxm1 is found in a variety of distinct human cancers including hepatocellular carcinomas, intrahepatic cholangiocarcinomas, basal cell carcinomas, ductal breast carcinomas, and anaplastic astrocytomas and glioblastomas. In this study, we show that human Foxm1 protein is abundantly expressed in highly proliferative human non–small cell lung cancers (NSCLC) as well as in mouse lung tumors induced by urethane. To determine the role of Foxm1 during the development of mouse lung tumors, we used IFN-inducible Mx-Cre recombinase transgene to delete mouse Foxm1 fl/fl–targeted allele before inducing lung tumors with urethane. We show that Mx-Cre Foxm1−/− mice exhibit diminished proliferation of lung tumor cells causing a significant reduction in number and size of lung adenomas. Transient transfection experiments with A549 lung adenocarcinoma cells show that depletion of Foxm1 levels by short interfering RNA caused diminished DNA replication and mitosis and reduced anchorage-independent growth of cell colonies on soft agar. Foxm1-depleted A549 cells exhibit reduced expression of cell cycle–promoting cyclin A2 and cyclin B1 genes. These data show that Foxm1 stimulates the proliferation of tumor cells during progression of NSCLC. (Cancer Res 2006; 66(4): 2153-61)
Down-regulation of Insulin Receptor by Antibodies against the Type I Insulin-Like Growth Factor Receptor: Implications for Anti–Insulin-Like Growth Factor Therapy in Breast Cancer
Authors: Sachdev Deepali , Singh Rajeeva , Fujita-Yamaguchi Yoko , Yee Douglas
Published: February 2006

Insulin-like growth factor-I (IGF-I), IGF-II, and insulin have all been implicated in regulating several aspects of the malignant phenotype via the type I IGF receptor (IGF1R) and insulin receptor (IR). We have previously shown that a chimeric single-chain antibody against IGF1R (scFv-Fc) and a murine antibody EM164 down-regulate IGF1R, making breast cancer cells unresponsive to IGF-I. To determine if IR signaling is affected, we examined regulation of IR in MCF-7 cells after exposure to these antibodies. Surprisingly, both scFv-Fc and EM164 resulted in decreased levels of IR in vitro and in vivo despite their lack of reactivity against IR. Twenty-four-hour pretreatment with EM164 also inhibited insulin-mediated phosphorylation of IR and insulin-stimulated proliferation of MCF-7 cells. Neither scFv-Fc nor EM164 caused down-regulation of IR in cells that express very low levels of IGF1R or no IGF1R. Expression of IGF1R was required for IR down-regulation, which was specific as neither antibody caused down-regulation of β1 integrin or epidermal growth factor receptor. Reagents that disrupt lipid rafts inhibited IR down-regulation by the antibodies, suggesting that IR in close physical proximity to IGF1R in lipid rafts was being endocytosed. Our data show that down-regulation of IR by monoclonal antibodies against IGF1R requires the coexpression of IGF1R and may be due to endocytosis of hybrid IR/IGF1R or holo-IR. Thus, antibodies against IGF1R provide inhibition of both IGF and insulin signaling in cancer cells. (Cancer Res 2006; 66(4): 2391-402)
A Gene Expression Signature that Can Predict Green Tea Exposure and Chemopreventive Efficacy of Lung Cancer in Mice
Authors: Lu Yan , Yao Ruisheng , Yan Ying , Wang Yian , Hara Yukihiko , Lubet Ronald A. , You Ming
Published: February 2006

Green tea has been shown to be a potent chemopreventive agent against lung tumorigenesis in animal models. Previously, we found that treatment of A/J mice with either green tea (0.6% in water) or a defined green tea catechin extract (polyphenon E; 2.0 g/kg in diet) inhibited lung tumor tumorigenesis. Here, we described expression profiling of lung tissues derived from these studies to determine the gene expression signature that can predict the exposure and efficacy of green tea in mice. We first profiled global gene expressions in normal lungs versus lung tumors to determine genes which might be associated with the tumorigenic process (TUM genes). Gene expression in control tumors and green tea–treated tumors (either green tea or polyphenon E) were compared to determine those TUM genes whose expression levels in green tea–treated tumors returned to levels seen in normal lungs. We established a 17-gene expression profile specific for exposure to effective doses of either green tea or polyphenon E. This gene expression signature was altered both in normal lungs and lung adenomas when mice were exposed to green tea or polyphenon E. These experiments identified patterns of gene expressions that both offer clues for green tea's potential mechanisms of action and provide a molecular signature specific for green tea exposure. (Cancer Res 2006; 66(4): 1956-63)
Xanthine Oxidase–Dependent Regulation of Hypoxia-Inducible Factor in Cancer Cells
Authors: Griguer Corinne E. , Oliva Claudia R. , Kelley Eric E. , Giles Gregory I. , Lancaster Jack R. , Gillespie G. Yancey
Published: February 2006

During chemical hypoxia induced by cobalt chloride (CoCl2), hypoxia-inducible factor 1α (HIF1-α) mediates the induction of a variety of genes including erythropoietin and vascular endothelial growth factor. We used glioma cells with oxidative phosphorylation–dependent (D54-MG) and glycolytic-dependent (U251-MG) phenotypes to monitor HIF1-α regulation in association with redox responsiveness to CoCl2 treatment. We showed that CoCl2 increased xanthine oxidase (XO)–derived reactive oxygen species (ROS), which causes accumulation of HIF1-α protein in U251-MG cells. Under these conditions, blockade of XO activity by pharmacologic (N-acetyl-l-cysteine or allopurinol) or molecular (by small interfering RNA) approaches significantly attenuated HIF1-α expression. Exogenous H2O2 stabilizes HIF1-α protein. XO was present in these cells and was the primary source of free radicals. We also showed higher XO activity in cells exposed to CoCl2 compared with cells grown in normoxia. From the experiments shown here, we concluded that ROS were indeed generated in D54-MG cells exposed to CoCl2 but it was unlikely that ROS participated in the hypoxic signal transduction pathways in this cell type. Possibly, cell type–dependent and stimulus-dependent factors may control ROS dependency or redox sensitivity of HIF1-α and thus HIF1-α activation either directly or by induction of specific signaling cascades. Our findings reveal that XO-derived ROS is a novel and critical component of HIF1-α regulation in U251-MG cells, pointing toward a more general role of this transcription factor in tumor progression. (Cancer Res 2006; 66(4): 2257-63)
Tumor Endothelial Cells Express Epidermal Growth Factor Receptor (EGFR) but not ErbB3 and Are Responsive to EGF and to EGFR Kinase Inhibitors
Authors: Amin Dhara N. , Hida Kyoko , Bielenberg Diane R. , Klagsbrun Michael
Published: February 2006

Epidermal growth factor (EGF) receptor family members are expressed by tumor cells and contribute to tumor progression. The expression and activity of EGF receptors in endothelial cells are less well characterized. Analysis of tumor-derived endothelial cells showed that they express EGFR, ErbB2, and ErbB4, whereas their normal counterparts express ErbB2, ErbB3, and ErbB4. The gain in expression of EGFR and the loss of ErbB3 expression in tumor vasculature was also observed in vivo. As a consequence of their expressing EGFR, tumor endothelial cells responded to EGF and other EGF family members by activating both EGFR and ErbB2, by activating the downstream mitogen-activated protein kinase pathway, and by enhanced proliferation. On the other hand, normal endothelial cells did not respond to EGF but instead were responsive to neuregulin (NRG), a ligand for ErbB3 and ErbB4. NRG activated ErbB3 in normal endothelial cells and inhibited growth of these cells. In contrast, tumor endothelial cells, which do not express ErbB3, were not growth inhibited by NRG. Furthermore, due to their expression of EGFR, tumor endothelial cells, unlike normal endothelial cells, are direct targets for EGFR kinase inhibitors. These low-molecular-weight compounds block EGF-induced EGFR activation and proliferation of tumor endothelial cells. These results suggest that a gain of EGF-induced endothelial cell proliferation, and loss of NRG-induced growth inhibition in tumor endothelial cells constitutes a switch that promotes tumor angiogenesis. In addition, these results suggest that EGFR kinase inhibitors may be effective for antiangiogenesis therapy by specifically targeting the tumor, but not the normal, vasculature. (Cancer Res 2006; 66(4): 2173-80)
Endocytic Recycling Compartments Altered in Cisplatin-Resistant Cancer Cells
Authors: Liang Xing-Jie , Mukherjee Sushmita , Shen Ding-Wu , Maxfield Frederick R. , Gottesman Michael M.
Published: February 2006

The clinical utility of cisplatin to treat human malignancies is often limited by the development of drug resistance. We have previously shown that cisplatin-resistant human KB adenocarcinoma cells that are cross-resistant to methotrexate and heavy metals have altered endocytic recycling. In this work, we tracked lipids in the endocytic recycling compartment (ERC) and found that the distribution of the ERC is altered in KB-CP.5 cells compared with parental KB-3-1 cells. A tightly clustered ERC is located near the nucleus in parental KB-3-1 cells but it appears loosely arranged and widely dispersed throughout the cytoplasm in KB-CP.5 cells. The altered distribution of the ERC in KB-CP.5 cells is related to the amount and distribution of stable detyrosinated microtubules (Glu-α-tubulin), as previously shown in Chinese hamster ovary B104-5 cells that carry a temperature-sensitive Glu-α-tubulin allele. In addition, B104-5 cells with a dispersed ERC under nonpermissive conditions were more resistant to cisplatin compared with B104-5 cells with a clustered ERC under permissive conditions. We conclude that resistance to cisplatin might be due, in part, to reduced uptake of cisplatin resulting from an endocytic defect reflecting defective formation of the ERC, possibly related to a shift in the relative amounts and distributions of stable microtubules. (Cancer Res 2006; 66(4): 2346-53)
Molecular Target-Based Therapy of Pancreatic Cancer
Authors: Lebedeva Irina V. , Sarkar Devanand , Su Zao-Zhong , Gopalkrishnan Rahul V. , Athar Mohammad , Randolph Aaron , Valerie Kristoffer , Dent Paul , Fisher Paul B.
Published: February 2006

Pancreatic cancer is genetically complex, and without effective therapy. Mutations in the Kirsten-ras (K-ras) oncogene occur early and frequently (∼90%) during pancreatic cancer development and progression. In this context, K-ras represents a potential molecular target for the therapy of this highly aggressive cancer. We now show that a bipartite adenovirus expressing a novel cancer-specific apoptosis-inducing cytokine gene, mda-7/interleukin-24 (IL-24), and a K-ras AS gene, but not either gene alone, promotes growth suppression, induction of apoptosis, and suppression of tumor development mediated by K-ras mutant pancreatic cancer cells. Equally, the combination of an adenovirus expressing mda-7/IL-24 and pharmacologic and genetic agents simultaneously blocking K-ras or downstream extracellular regulated kinase 1/2 signaling also promotes similar inhibitory effects on the growth and survival of K-ras mutant pancreatic carcinoma cells. This activity correlates with the reversal of a translational block in mda-7/IL-24 mRNA in pancreatic cancer cells that limits message association with polysomes, thereby impeding translation into protein. Our study provides support for a “dual molecular targeted therapy” involving oncogene inhibition and selective cancer apoptosis-inducing gene expression with potential for effectively treating an invariably fatal cancer. (Cancer Res 2006; 66(4): 2403-13)
Regression of Melanoma in a Murine Model by RLIP76 Depletion
Authors: Singhal Sharad S. , Awasthi Yogesh C. , Awasthi Sanjay
Published: February 2006

RLIP76/RALBP1 is a stress-responsive membrane protein implicated in the regulation of multiple cellular signaling pathways. It represents the predominant glutathione-conjugate transporter in cells, and our previous studies have shown that its inhibition by antibodies or depletion by short interfering RNA (siRNA) causes apoptosis in a number of cancer cell types. The present studies were done to explore the potential clinical applicability of our previous observations by comparing the relative expression of RLIP76 in cancer versus normal cell lines and to determine whether depletion of RLIP76 activity can exert cancer-specific apoptosis. RLIP76 expression was found to be significantly greater in malignant cells compared to nonmalignant cells. Inhibition of RLIP76, using antibodies towards a cell surface epitope, or depletion of RLIP76 using either siRNA or antisense phosphorothioate oligonucleotides preferentially caused apoptosis in malignant cells. More importantly, in vivo studies showed that administration of RLIP76 antibodies, siRNA, or antisense oligonucleotides to mice bearing syngeneic B16 mouse melanoma cells caused complete tumor regression within 10 days. These findings strongly suggest that RLIP76 depletion by genetic approaches or inhibition by antibodies may be a clinically viable antineoplastic therapy, particularly for melanoma. (Cancer Res 2006; 66(4): 2354-60)
Runx2 and MYC Collaborate in Lymphoma Development by Suppressing Apoptotic and Growth Arrest Pathways In vivo
Authors: Blyth Karen , Vaillant François , Hanlon Linda , Mackay Nancy , Bell Margaret , Jenkins Alma , Neil James C. , Cameron Ewan R.
Published: February 2006

Members of the Runx and MYC families have been implicated as collaborating oncogenes. The mechanism of this potent collaboration is elucidated in this study of Runx2/MYC mice. As shown previously, ectopic expression of Runx2 in the thymus leads to a preneoplastic state defined by an accumulation of cells with an immature phenotype and a low proliferative rate. We now show that c-MYC overexpression is sufficient to rescue proliferation and to release the differentiation block imposed by Runx2. Analysis of Runx2-expressing lymphomas reveals a consistently low rate of apoptosis, in contrast to lymphomas of MYC mice which are often highly apoptotic. The low apoptosis phenotype is dominant in Runx2/MYC tumors, indicating that Runx2 confers a potent survival advantage to MYC-expressing tumor cells. The role of the p53 pathway in Runx2/MYC tumors was explored on a p53 heterozygote background. Surprisingly, functional p53 was retained in vivo, even after transplantation, whereas explanted tumor cells displayed rapid allele loss in vitro. Our results show that Runx2 and MYC overcome distinct “fail-safe” responses and that their selection as collaborating genes is due to their ability to neutralize each other's negative growth effect. Furthermore, the Runx2/MYC combination overcomes the requirement for genetic inactivation of the p53 pathway in vivo. (Cancer Res 2006; 66(4): 2195-201)
The p38 Kinases MKK4 and MKK6 Suppress Metastatic Colonization in Human Ovarian Carcinoma
Authors: Hickson Jonathan A. , Huo Dezheng , Vander Griend Donald J. , Lin Anning , Rinker-Schaeffer Carrie W. , Yamada S. Diane
Published: February 2006

Despite considerable efforts to improve early detection of ovarian cancer, the majority of women at time of diagnosis will have metastatic disease. Understanding and targeting the molecular underpinnings of metastasis continues to be the principal challenge in the clinical management of ovarian cancer. Whereas the multistep process of metastasis development has been well established in both clinical and experimental models, the molecular factors and signaling pathways involved in successful colonization of a secondary site by disseminated cancer cells are not well defined. We have previously identified mitogen-activated protein kinase (MAPK) kinase 4/c-Jun NH2-terminal kinase (JNK)-activating kinase (MKK4/JNKK1/SEK1, hereafter referred to as MKK4) as a metastasis suppressor protein in ovarian carcinoma. In this study, we elucidate key mechanisms of MKK4-mediated metastasis suppression. Through the use of a kinase-inactive mutant, we show that MKK4 kinase activity is essential for metastasis suppression and prolongation of animal survival. Because MKK4 can activate either of two MAPKs, p38 or JNK, we expressed MKK6 or MKK7, specific activators of these MAPKs, respectively, to delineate which MAPK signaling module was involved in MKK4-mediated metastasis suppression. We observed that MKK6 expression suppressed metastatic colonization whereas MKK7 had no effect. Our finding that MKK4 and MKK6 both suppress metastasis points to the p38 pathway as an important regulatory pathway for metastatic colonization in ovarian cancer. (Cancer Res 2006; 66(4): 2264-70)