bluuebunny/crossref_metadata_2025 huggingface dataset:
Changing inclination of earth satellites using the gravity of the moon
Authors: Torres Karla de Souza , Prado A. F. B. A.
Published: August 2006

We analyze the problem of the orbital control of an Earth′s satellite using the gravity of the Moon. The main objective is to study a technique to decrease the fuel consumption of a plane change maneuver to be performed in a satellite that is in orbit around the Earth. The main idea of this approach is to send the satellite to the Moon using a single‐impulsive maneuver, use the gravity field of the Moon to make the desired plane change of the trajectory, and then return the satellite to its nominal semimajor axis and eccentricity using a bi‐impulsive Hohmann‐type maneuver. The satellite is assumed to start in a Keplerian orbit in the plane of the lunar orbit around the Earth and the goal is to put it in a similar orbit that differs from the initial orbit only by the inclination. A description of the close‐approach maneuver is made in the three‐dimensional space. Analytical equations based on the patched conics approach are used to calculate the variation in velocity, angular momentum, energy, and inclination of the satellite. Then, several simulations are made to evaluate the savings involved. The time required by those transfers is also calculated and shown.
Stabilization of fuzzy systems with constrained controls by using positively invariant sets
Authors: El Hajjaji A. , Benzaouia A. , Naib M.
Published: August 2006

We deal with the extension of the positive invariance approach to nonlinear systems modeled by Takagi‐Sugeno fuzzy systems. The saturations on the control are taken into account during the design phase. Sufficient conditions of asymptotic stability are given ensuring at the same time that the control is always admissible inside the corresponding polyhedral set. Both a common Lyapunov function and piecewise Lyapunov function are used.
Lean buffering in serial production lines with Bernoulli machines
Authors: Hu A. B. , Meerkov S. M.
Published: August 2006

Lean buffering is the smallest buffer capacity necessary to ensure the desired production rate of a manufacturing system. In this paper, analytical methods for selecting lean buffering in serial production lines are developed under the assumption that the machines obey the Bernoulli reliability model. Both closed‐form expressions and recursive approaches are investigated. The cases of identical and nonidentical machines are analyzed. Results obtained can be useful for production line designers and production managers to maintain the required production rate with the smallest possible inventories.
Model for determining flow diameter and economic velocity in water elevating systems
Authors: Zocoler João L. , Filho Francisco C. Baggio , Oliveira Luís A. F. , Hernandez Fernando B. T.
Published: August 2006

The purpose of this paper was to develop a model for calculating the economical flow diameter and velocity, by obtaining the economical diameter, using Swamee′s friction factor equation, by minimizing the total annual cost. The application of the model to a regular supply condition showed that the diameter of the actual condition, 250 mm, compared with the diameter calculated by the mode, at the same tariff as that applied to the property (ground), 284.1 mm, involved the necessity to generate, transmit, and distribute extra electrical energy, due to the higher load loss caused by the original diameter, approximately 30800 kWh/year. This means that in one year, the consumer would spend R$2,804.00 more on pumping cost alone.
On improving the convergence rate of linear continuous‐time systems subject to asymmetrically constrained control
Authors: Baddou A. , Naib M. , Tadeo F. , Benzaouia A.
Published: August 2006

This paper solves the problem of controlling linear continuous‐time systems subject to control signals constrained in magnitude (maybe asymmetrically). A controller design methodology is proposed, based on using an asymmetric Lyapunov function, that avoids the discontinuities in the control vector components resulting from the application of a piecewise linear control law previously proposed. The proposed method gives improved speed of convergence without discontinuities of the control vector components, respecting always the imposed asymmetric constraints. An example illustrates the approach.
Inhibition of Carrageenan-Induced Cutaneous Inflammation by PPAR Agonists Is Dependent on Hepatocyte-Specific Retinoid X ReceptorAlpha
Authors: Wan Yu-Jui Yvonne , Badr Mostafa Z.
Published: August 2006

It has been proposed that PPAR-dependent, accelerated catabolism of proinflammatory mediators may contribute to the fast resolution of inflammation. Because retinoid X receptors are obligate heterodimer partners of PPARs, we investigated the impact of deleting hepatocyte-specific RXRαon the antiedema effect of PPAR agonists. In wild-type mice (WT), pretreatment with the PPARαagonist perfluorooctanoic acid diminished carrageenan-induced paw edema by66±10%. This effect was essentially absent (13±8%) in hepatocyte-specific RXRα-deficient mice. Similarly, pretreatment of WT mice with the PPARδagonist L-783483 or the PPARγagonist L-805645 caused54±1%and38±8%reduction in carrageenan-induced paw edema, respectively. These effects were also significantly diminished or absent in hepatocyte-specific RXRα-deficient mice. In contrast, aspirin reduced carrageenan-induced paw edema equally in WT and hepatocyte-specific RXRα-deficient mice. The identification of RXRαas an important factor involved in the antiedema effect produced by agonists of the three PPAR subtypes is a significant achievement towards the goal of designing novel, effective anti-inflammatory drugs.
Metabolic Consequences of p300 Gene Deletion in Human Colon Cancer Cells
Authors: Bundy Jacob G. , Iyer N. Gopalakrishna , Gentile Michelle S. , Hu De-En , Kettunen Mikko , Maia Ana-Teresa , Thorne Natalie P. , Brenton James D. , Caldas Carlos , Brindle Kevin M.
Published: August 2006

Metabolite profiling using 1H nuclear magnetic resonance (NMR) spectroscopy was used to investigate the metabolic changes associated with deletion of the gene for the transcriptional coactivator p300 in the human colon carcinoma cell line HCT116. Multivariate statistical methods were used to distinguish between metabolite patterns that were dependent on cell growth conditions and those that were specifically associated with loss of p300 function. In the absence of serum, wild-type cells showed slower growth, which was accompanied by a marked decrease in phosphocholine concentration, which was not observed in otherwise isogenic cell lines lacking p300. In the presence of serum, several metabolites were identified as being significantly different between the two cell types, including glutamate and glutamine, a nicotinamide-related compound and glycerophosphocholine (GPC). However, in the absence of serum, these metabolites, with the exception of GPC, were not significantly different, leading us to conclude that most of these changes were context dependent. Transcript profiling, using DNA microarrays, showed changes in the levels of transcripts for several enzymes involved in choline metabolism, which might explain the change in GPC concentration. Localized in vivo 1H NMR measurements on the tumors formed following s.c. implantation of these cells into mice showed an increase in the intensity of the peak from choline-containing compounds in the p300− tumors. These data show that NMR-based metabolite profiling has sufficient sensitivity to identify the metabolic consequences of p300 gene deletion in tumor cells in vitro and in vivo. (Cancer Res 2006; 66(15): 7606-14)
Cyclin-Dependent Kinase 5 Activity Controls Cell Motility and Metastatic Potential of Prostate Cancer Cells
Authors: Strock Christopher J. , Park Jong-In , Nakakura Eric K. , Bova G. Steven , Isaacs John T. , Ball Douglas W. , Nelkin Barry D.
Published: August 2006

We show here that cyclin-dependent kinase 5 (CDK5), a known regulator of migration in neuronal development, plays an important role in prostate cancer motility and metastasis. P35, an activator of CDK5 that is indicative of its activity, is expressed in a panel of human and rat prostate cancer cell lines, and is also expressed in 87.5% of the human metastatic prostate cancers we examined. Blocking of CDK5 activity with a dominant-negative CDK5 construct, small interfering RNA, or roscovitine resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Expression of a dominant-negative CDK5 in the highly metastatic Dunning AT6.3 prostate cancer cell line also greatly impaired invasive capacity. CDK5 activity was important for spontaneous metastasis in vivo; xenografts of AT6.3 cells expressing dominant-negative CDK5 had less than one-fourth the number of lung metastases exhibited by AT6.3 cells expressing the empty vector. These results show that CDK5 activity controls cell motility and metastatic potential in prostate cancer. (Cancer Res 2006; 66(15): 7509-15) (Cancer Res 2006; 66(15): 7509-15)
Role of Androgens on MCF-7 Breast Cancer Cell Growth and on the Inhibitory Effect of Letrozole
Authors: Macedo Luciana F. , Guo Zhiyong , Tilghman Syreeta L. , Sabnis Gauri J. , Qiu Yun , Brodie Angela
Published: August 2006

Previous work has shown that androgens inhibit breast cancer cells and tumor growth. On the other hand, androgens can be converted to mitogenic estrogens by aromatase in breast cancer cells. Here, we report that androgens, such as the aromatizable androstenedione and the non-aromatizable 5α-dihydrotestosterone, inhibit MCF-7 cell proliferation. This effect is observed only in the absence or at a low concentration of estrogens and is evident in cells with low aromatase activity. Growth of a new aromatase stably transfected MCF-7 cell line (Ac1) was stimulated by conversion of androstenedione into estrogens and was sensitive to aromatase inhibitors. We show that blockade of the androgen receptor (AR) in these cells by the antiandrogen casodex or by the anti-AR small interfering RNA inhibited the antiproliferative effect of dihydrotestosterone and letrozole (aromatase inhibitor). We also show that suppression of the estrogen-induced antiapoptotic protein Bcl-2 may be involved in the antiproliferative effects of androgens and letrozole. These effects can be reversed by casodex. In conclusion, the results suggest that aromatase inhibitors may exert their antiproliferative effect not only by reducing the intracellular production of estrogens but also by unmasking the inhibitory effect of androgens acting via the AR. (Cancer Res 2006; 66(15): 7775-82)
Genetic Bases of Estrogen-Induced Tumorigenesis in the Rat: Mapping of Loci Controlling Susceptibility to Mammary Cancer in a Brown Norway × ACI Intercross
Authors: Schaffer Beverly S. , Lachel Cynthia M. , Pennington Karen L. , Murrin Clare R. , Strecker Tracy E. , Tochacek Martin , Gould Karen A. , Meza Jane L. , McComb Rodney D. , Shull James D.
Published: August 2006

Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17β-estradiol (E2)–induced mammary cancer. We previously mapped two loci, Emca1 and Emca2 (estrogen-induced mammary cancer), that act independently to determine susceptibility to E2-induced mammary cancer in crosses between the susceptible ACI rat strain and the genetically related, but resistant, Copenhagen (COP) rat strain. In this study, we evaluate susceptibility to E2-induced mammary cancer in a cross between the ACI strain and the unrelated Brown Norway (BN) rat strain. Whereas nearly 100% of the ACI rats developed mammary cancer when treated continuously with E2, BN rats did not develop palpable mammary cancer during the 196-day course of E2 treatment. Susceptibility to E2-induced mammary cancer segregated as a dominant or incompletely dominant trait in a cross between BN females and ACI males. In a population of 251 female (BN × ACI)F2 rats, we observed evidence for a total of five genetic determinants of susceptibility. Two loci, Emca4 and Emca5, were identified when mammary cancer status at sacrifice was evaluated as the phenotype, and three additional loci, Emca6, Emca7, and Emca8, were identified when mammary cancer number was evaluated as the phenotype. A total of three genetic interactions were identified. These data indicate that susceptibility to E2-induced mammary cancer in the BN × ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions. (Cancer Res 2006; 66(15): 7793-800)
MLH3 Mutation in Endometrial Cancer
Authors: Taylor Nicholas P. , Powell Matthew A. , Gibb Randall K. , Rader Janet S. , Huettner Phyllis C. , Thibodeau Stephen N. , Mutch David G. , Goodfellow Paul J.
Published: August 2006

MLH3 is a recently described member of the DNA mismatch repair gene family. Based on its interaction with the MutL homologue MLH1, it was postulated that MLH3 might play a role in tumorigenesis. Germ line and somatic mutations in MLH3 have been identified in a small fraction of colorectal cancers, but the role of MLH3 in colorectal cancer tumorigenesis remains controversial. We investigated MLH3's role in endometrial tumorigenesis through analysis of tumor and germ line DNA from 57 endometrial cancer patients who were at increased risk for having inherited cancer susceptibility. Patients with known MSH2 or MSH6 mutations were excluded as well as those who had MLH1-methylated tumors. Sixteen different variants were identified by single-strand conformational variant analysis. Of the 12 missense changes identified, three were somatic mutations. One patient had a germ line missense variant and loss of heterozygosity (LOH) in her tumor specimen. There was no evidence of MLH3 promoter methylation based on combined bisulfite restriction analysis. The identification of inherited missense variants, somatic missense mutations (present in 3 of 57 tumors), and LOH in the tumor from a patient with a germ line missense change suggest a role for MLH3 in endometrial tumorigenesis. (Cancer Res 2006; 66(15): 7502-8)
The Hedgehog Signaling Molecule Gli2 Induces Parathyroid Hormone-Related Peptide Expression and Osteolysis in Metastatic Human Breast Cancer Cells
Authors: Sterling Julie A. , Oyajobi Babatunde O. , Grubbs Barry , Padalecki Susan S. , Munoz Steve A. , Gupta Anjana , Story Beryl , Zhao Ming , Mundy Gregory R.
Published: August 2006

Parathyroid hormone-related peptide (PTHrP) is a major factor involved in tumor-induced osteolysis caused by breast cancers that have metastasized to bone. However, the molecular mechanisms that mediate PTHrP production by breast cancer cells are not entirely clear. We hypothesized that Gli2, a downstream transcriptional effector of the Hedgehog (Hh) signaling pathway, regulates PTHrP expression in metastatic breast cancer because the Hh pathway regulates physiologic PTHrP expression in the developing growth plate. Here, we show that Gli2 is expressed in several human cancer cell lines that cause osteolytic lesions in vivo and produce PTHrP (MDA-MB-231, RWGT2, and PC-3) but is not expressed in nonosteolytic cancer cell lines that do not secrete PTHrP (MCF-7, ZR-75, and T47D). Transient expression of Gli2 in MDA-MB-231 and MCF-7 breast cancer cells increased PTHrP promoter-luciferase activity dose dependently. Stable expression of Gli2 in MDA-MB-231 cells resulted in an increase in PTHrP protein in the conditioned medium. Alternatively, MDA-MB-231 cells stably transfected with Gli2-EnR, a repressor of Gli2 activity, exhibited a 72% to 93% decrease in PTHrP mRNA by quantitative real-time PCR when compared with control cells. To examine the effects of Gli2 on breast cancer–mediated osteolysis in vivo, athymic nude mice were inoculated with MDA-MB-231 cells stably expressing Gli2 or the empty vector. Following tumor cell inoculation via the left cardiac ventricle, Gli2-expressing tumors caused significantly more osteolysis. Together, these data suggest that PTHrP expression and osteolysis in vivo in human breast cancer cells is driven at least in part by Gli2. (Cancer Res 2006; 66(15): 7548-53)
Oncolytic Efficacy and Enhanced Safety of Measles Virus Activated by Tumor-Secreted Matrix Metalloproteinases
Authors: Springfeld Christoph , von Messling Veronika , Frenzke Marie , Ungerechts Guy , Buchholz Christian J. , Cattaneo Roberto
Published: August 2006

Cancer cells secrete matrix metalloproteinases (MMP) that degrade the extracellular matrix and are responsible for some hallmarks of malignant cancer. Many viruses, including a few currently used in oncolytic virotherapy clinical trials, depend on intracellular proteases to process their proteins and activate their particles. We show here for measles virus (MV) that particle activation can be made dependent of proteases secreted by cancer cells. The MV depends on the intracellular protease furin to process and activate its envelope fusion (F) protein. To make F protein activation cancer cell specific, we introduced hexameric sequences recognized by an MMP and identified the mutant proteins most effective in fusing MMP-expressing human fibrosarcoma cells (HT1080). We showed that an MMP inhibitor interferes with syncytia formation elicited by mutant F proteins and confirmed MMP-dependent cleavage by Edman degradation sequence analysis. We generated recombinant MVs expressing the modified F proteins in place of furin-activated F. These viruses spread only in cells secreting MMP. In nude mice, an MMP-activated MV retarded HT1080 xenograft growth as efficiently as the furin-activated MV vaccine strain. In MV-susceptible mice, the furin-activated virus caused lethal encephalitis upon intracerebral inoculation, whereas the MMP-activated did not. Thus, MV particle activation can be made dependent of proteases secreted by cancer cells, enhancing safety. This study opens the perspective of combining targeting at the particle activation, receptor recognition, and selective replication levels to improve the therapeutic index of MV and other viruses in ongoing clinical trials of oncolysis. (Cancer Res 2006; 66(15): 7694-700)
A Novel Functional Polymorphism in theTransforming Growth Factor-β2Gene Promoter and Tumor Progression in Breast Cancer
Authors: Beisner Julia , Buck Miriam B. , Fritz Peter , Dippon Jürgen , Schwab Matthias , Brauch Hiltrud , Zugmaier Gerhard , Pfizenmaier Klaus , Knabbe Cornelius
Published: August 2006

Transforming growth factor-β (TGF-β), a multifunctional growth factor, plays an important role in breast cancer. There is increasing evidence that enhanced expression of TGF-β promotes breast cancer progression contributing to metastasis and invasiveness of the tumor. We identified a functional polymorphism in the TGFB2 promoter, a 4-bp insertion at position −246 relative to the transcriptional start site (−246ins). Transient transfection experiments showed that the −246ins polymorphism significantly increased TGFB2 promoter activity in breast cancer cells. Electrophoretic mobility shift assays revealed binding of the transcription factor Sp1 to the −246ins allele. Overexpression of Sp1 enhanced promoter activity of the −246ins allele, demonstrating that Sp1 mediates transcriptional activation. Furthermore, the −246ins allele was associated with enhanced TGF-β2 expression in breast cancer tissue (P = 0.0005). To evaluate the role of the polymorphism in breast cancer, frequency of the −246ins allele was determined in breast cancer patients (n = 78) and healthy female controls (n = 143). No significant differences were found. However, the presence of the −246ins allele was associated with lymph node metastasis (P = 0.003). The −246ins allele was a significant predictor for lymph node metastasis independent of estrogen and progesterone receptor status in a multivariate logistic regression analysis (P = 0.0118, odds ratio, 5.18; 95% confidence interval, 1.44-18.62). We provide evidence that the TGFB2 −246ins polymorphism leads to enhanced TGF-β2 expression levels in vivo and might thereby contribute to tumor progression and development of metastases. (Cancer Res 2006; 66(15): 7554-61)
Mutation of Succinate Dehydrogenase Subunit C Results in Increased O2·−, Oxidative Stress, and Genomic Instability
Authors: Slane Benjamin G. , Aykin-Burns Nùkhet , Smith Brian J. , Kalen Amanda L. , Goswami Prabhat C. , Domann Frederick E. , Spitz Douglas R.
Published: August 2006

Mutations in genes coding for succinate dehydrogenase (SDH) subunits are believed to contribute to cancer and aging, but the mechanism for this is unclear. Hamster fibroblasts expressing a mutation in SDH subunit C (SDHC; B9) showed 3-fold increases in dihydroethidine and dichlorodihydrofluorescein (CDCFH2) oxidation indicative of increased steady-state levels of O2·− and H2O2, increases in glutathione/glutathione disulfide (indicative of oxidative stress), as well as increases in superoxide dismutase activity, relative to parental B1 cells. B9 cells also showed characteristics associated with cancer cells, including aneuploidy, increases in glucose consumption, and sensitivity to glucose deprivation–induced cytotoxicity. Expression of wild-type (WT) human SDHC in B9 cells caused prooxidant production, glucose consumption, sensitivity to glucose deprivation–induced cytotoxicity, and aneuploidy to revert to the WT phenotype. These data show that SDHC mutations cause increased O2·− production, metabolic oxidative stress, and genomic instability and that mutations in genes coding for mitochondrial electron transport chain proteins can contribute to phenotypic changes associated with cancer cells. These results also allow for the speculation that DNA damage to genes coding for electron transport chain proteins could result in a “mutator phenotype” by increasing steady-state levels of O2·− and H2O2. (Cancer Res 2006; 66(15): 7615-20)
Misexpression of Full-length HMGA2 Induces Benign Mesenchymal Tumors in Mice
Authors: Zaidi M. Raza , Okada Yasunori , Chada Kiran K.
Published: August 2006

The high-mobility group AT-hook 2 (HMGA2) protein is a member of the high-mobility group family of the DNA-binding architectural factors and participates in the conformational regulation of active chromatin on its specific downstream target genes. HMGA2 is expressed in the undifferentiated mesenchyme and is undetectable in their differentiated counterparts, suggesting its functional importance in mesenchymal cellular proliferation and differentiation. Interestingly, it is a frequent target of chromosomal translocations in several types of human benign differentiated mesenchymal tumors, including lipomas, fibroadenomas of the breast, salivary gland adenomas, and endometrial polyps. The translocations lead to a variety of HMGA2 transcripts, which range from wild-type, truncated, and fusion mRNA species. However, it is not clear whether alteration of the HMGA2 transcript is required for its tumorigenic potential. To determine whether misexpression of HMGA2 in differentiated mesenchymal cells is sufficient to cause tumorigenesis, we produced transgenic mice that misexpressed full-length or truncated human HMGA2 transcript under the control of the differentiated mesenchymal cell (adipocyte)–specific promoter of the adipocyte P2 (Fabp4) gene. Expression of the full-length HMGA2 transgene was observed in a number of tissues, which produced neoplastic phenotype, including fibroadenomas of the breast and salivary gland adenomas. Furthermore, transgenic misexpression of the truncated version of HMGA2, containing only the three DNA-binding domains, produced similar phenotypes. These results show that misexpression of HMGA2 in a differentiated mesenchymal cell is sufficient to cause mesenchymal tumorigenesis and is independent of the nature of the HMGA2 transcript that results from chromosomal translocations observed in humans. (Cancer Res 2006; 66(15): 7453-9)
Up-regulation of CYP26A1 in Adenomatous Polyposis Coli–Deficient Vertebrates via a WNT-Dependent Mechanism: Implications for Intestinal Cell Differentiation and Colon Tumor Development
Authors: Shelton Dawne N. , Sandoval Imelda T. , Eisinger Annie , Chidester Stephanie , Ratnayake Anokha , Ireland Chris M. , Jones David A.
Published: August 2006

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene seem to underlie the initiation of many colorectal carcinomas. Loss of APC function results in accumulation of β-catenin and activation of β-catenin/TCF–dependent transcription. Recent studies have implicated APC in controlling retinoic acid biosynthesis during normal intestinal development through a WNT-independent mechanism. Paradoxically, however, previous studies found that dietary supplementation of ApcMIN mice with retinoic acid failed to abrogate adenoma formation. While investigating the above finding, we found that expression of CYP26A1, a major retinoic acid catabolic enzyme, was up-regulated in ApcMIN mouse adenomas, human FAP adenomas, human sporadic colon carcinomas, and in the intestine of apcmcr mutant zebrafish embryos. Mechanistically, cyp26a1 induction following apc mutation is dependent on WNT signaling as antisense morpholino knockdown of tcf4 or injection of a dnLEF construct into apcmcr mutant zebrafish suppressed expression of cyp26a1 along with known WNT target genes. In addition, injection of stabilized β-catenin or dnGSK3β into wild-type embryos induced cyp26a1 expression. Genetic knockdown or pharmacologic inhibition of cyp26a1 in apcmcr mutant zebrafish embryos rescued gut differentiation defects such as expression of intestinal fatty acid–binding protein and pancreatic trypsin. These findings support a novel role for APC in balancing retinoic acid biosynthesis and catabolism through WNT-independent and WNT-dependent mechanisms. (Cancer Res 2006; 66(15): 7571-7)
Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among Endometrial Cancer Patients
Authors: Hampel Heather , Frankel Wendy , Panescu Jenny , Lockman Janet , Sotamaa Kaisa , Fix Daniel , Comeras Ilene , La Jeunesse Jennifer , Nakagawa Hidewaki , Westman Judith A. , Prior Thomas W. , Clendenning Mark , Penzone Pamela , Lombardi Janet , Dunn Patti , Cohn David E. , Copeland Larry , Eaton Lynne , Fowler Jeffrey , Lewandowski George , Vaccarello Luis , Bell Jeffrey , Reid Gary , de la Chapelle Albert
Published: August 2006

Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation–positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable. (Cancer Res 2006; 66(15): 7810-7)
Haploinsufficiency in DNA Polymerase β Increases Cancer Risk with Age and Alters Mortality Rate
Authors: Cabelof Diane C. , Ikeno Yuji , Nyska Abraham , Busuttil Rita A. , Anyangwe Njwen , Vijg Jan , Matherly Larry H. , Tucker James D. , Wilson Samuel H. , Richardson Arlan , Heydari Ahmad R.
Published: August 2006

This study uses a base excision repair (BER)–deficient model, the DNA polymerase β heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged β-pol+/− mice express 50% less β-pol transcripts and protein (P < 0.05) than aged β-pol+/+ mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in β-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged β-pol+/− mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of β-pol+/− mice exhibited lymphoid hyperplasia, whereas none of the β-pol+/+ exhibited this phenotype. β-pol+/− mice were also more likely to develop adenocarcinoma (2.7-fold increase; P < 0.05) and more likely to develop multiple tumors, as 20% of the β-pol+/− animals died bearing multiple tumors compared with only 5% of the β-pol+/+ animals (P < 0.05). In spite of accelerated tumor development, no gross effect of β-pol heterozygosity was seen with respect to life span. However, the survival curves for the β-pol+/+ and β-pol+/− mice are not identical. A maximum likelihood estimation analysis showed a modest but significant (P < 0.05) acceleration of the age-dependent mortality rate in β-pol+/− mice. Thus, the β-pol+/− mouse represents a model in which mortality rate and tumor development are accelerated and provides evidence supporting the role of genomic maintenance in both aging and carcinogenesis. (Cancer Res 2006; 66(15): 7460-5)
Activator Protein-1 Activity Regulates Epithelial Tumor Cell Identity
Authors: Gerdes Michael J. , Myakishev Maxim , Frost Nicholas A. , Rishi Vikas , Moitra Jaideep , Acharya Asha , Levy Michelle R. , Park Sang-won , Glick Adam , Yuspa Stuart H. , Vinson Charles
Published: August 2006

To examine the consequences of inhibiting activator protein-1 (AP-1) transcription factors in skin, transgenic mice were generated, which use the tetracycline system to conditionally express A-FOS, a dominant negative that inhibits AP-1 DNA binding. Older mice develop mild alopecia and hyperplasia of sebaceous glands, particularly around the eyes. When A-FOS was expressed during chemical-induced skin carcinogenesis, mice do not develop characteristic benign and malignant squamous lesions but instead develop benign sebaceous adenomas containing a signature mutation in the H-ras proto-oncogene. Inhibiting AP-1 activity after tumor formation caused squamous tumors to transdifferentiate into sebaceous tumors. Furthermore, reactivating AP-1 in sebaceous tumors results in a reciprocal transdifferentiation into squamous tumors. In both cases of transdifferentiation, individual cells express molecular markers for both cell types, indicating individual tumor cells have the capacity to express multiple lineages. Molecular characterization of cultured keratinocytes and tumor material indicates that AP-1 regulates the balance between the wnt/β-catenin and hedgehog signaling pathways that determine squamous and sebaceous lineages, respectively. Chromatin immunoprecipitation analysis indicates that c-Jun binds several wnt promoters, which are misregulated by A-FOS expression, suggesting that members of the wnt pathway can be a primary targets of AP-1 transcriptional regulation. Thus, AP-1 activity regulates tumor cell lineage and is essential to maintain the squamous tumor cell identity. (Cancer Res 2006; 66(15): 7578-88)
Effects of VLDL and Remnant Particles on Platelets
Authors: Olufadi Rasaq , Byrne Christopher D.
Published: August 2006

There is a considerable body of evidence supporting an association between hypertriglyceridaemia, a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade. Fibrinolysis is also less efficient when thrombin is generated. Thrombin induces thrombin activatable fibrinolysis inhibitor. Thrombin activatable fibrinolysis inhibitor is a carboxypeptidase that cleaves the carboxylic lysine residues on fibrin, thereby abolishing the critical binding site for tPA-plasminogen decreasing plasmin formation. Thus the evidence is supportive of dysregulated coagulation, and impaired fibrinolysis with a predisposition to atherothrombosis, in conditions such as the metabolic syndrome, in which there are increased concentrations of VLDL and remnant lipoproteins. The purpose of this review is to describe the current evidence supporting a procoagulant state induced by VLDL and remnant lipoproteins. The role of these lipoprotein classes in (1) platelet activation; (2) the intrinsic coagulation cascade, and (3) clot formation and fibrinolysis is discussed.
Lipoprotein-Associated Proteins Involved in Platelet Signaling
Authors: Korporaal Suzanne J.A. , Akkerman Jan-Willem N.
Published: August 2006

Platelets and lipoproteins are both key elements in the development of atherosclerosis and thrombosis. Based on their density, five classes of lipoproteins have been identified which all influence platelets via distinct mechanisms. The activation of platelets starts with binding of apolipoproteins to different platelet receptors and is followed by the activation of signaling pathways resulting in activation or inhibition of platelet functions like aggregation or secretion. In addition to apolipoproteins, lipoproteins are also associated to a large amount of proteins, enzymes and lipids that also can induce platelet activation or inhibition. This review provides a summary of the activation of signaling pathways after platelet–lipoprotein interactions initiated by lipoprotein-associated proteins and lipids.
Lipoprotein(a) and Thrombocytes: Potential Mechanisms Underlying Cardiovascular Risk
Authors: Discepolo William , Wun Ted , Berglund Lars
Published: August 2006

Plasma levels of lipoprotein(a), Lp(a), is an independent risk factor for cardiovascular disease. Lp(a) has many properties in common with low-density lipoprotein (LDL), including a cholesteryl ester-rich lipid core and the presence of one copy of apolipoprotein B-100; both apoB-100 and the lipid core are pro-atherogenic. In addition, Lp(a) contains a unique hydrophilic, carbohydrate-rich protein, apo(a), linked to apoB through a single disulfide bond connecting the C-terminal regions of the two proteins. The similarities between apolipoprotein(a), apo(a), and plasminogen has initiated numerous studies on the possible role of Lp(a) as a prothrombotic agent. Studies to date suggest that Lp(a) has antifibrinolytic and procoagulant properties. In this review, we summarize recent studies focused on the interaction between Lp(a) and platelets. Collectively, results to date illustrate that thrombogenicity associated with Lp(a) could be due to risk associated with the LDL moiety, with the apo(a) moiety, or from the combination of those in Lp(a). Present findings suggest that the various components of Lp(a) may impact to a varying degree on different underlying pathways involved in platelet activation and aggregation. On balance, results indicate an effect by Lp(a) on platelet function and future studies focused on specific Lp(a) components, such as the role of apo(a) and of the LDL-like lipid moiety, are needed.
Nutritional Status as a Risk Factor in Esophageal Surgery
Authors: Han-Geurts I.J.M. , Hop W.C. , Tran T.C.K. , Tilanus H.W.
Published: August 2006

Background: Nutritional condition is one of the factors determining postoperative outcome in esophageal surgery. This study explored the relation between preoperative nutritional status and postoperative infectious complications. Methods: From a prospective database, 400 patients who underwent esophageal resection for malignancy were selected. Preoperative nutritional status was assessed by body mass index, prognostic nutritional index (PNI), nutritional risk index (NRI) and weight loss. The association between nutritional parameters and postoperative complications and mortality, gender, age and hospitalization was assessed. Results: PNI and NRI differed between the patients with and without postoperative infectious complications (p = 0.031 and p = 0.009, respectively). However, receiver operating characteristic curves showed that PNI and NRI have a low predictive value for such complications. Also, no associations were found between nutritional parameters and in-hospital mortality. Although mean nutritional parameters were significantly lower, i.e. worse, in patients with neoadjuvant treatment as compared to no such treatment, the incidence of complications did not significantly differ between these treatment groups. Although PNI and NRI correlated negatively with age, no association was found between age and infectious complications. Multivariate analysis of various factors showed the male gender to be the only significant risk factor for development of infectious complications. Discussion: Preoperative nutritional status established by PNI, NRI, body mass index and weight loss has limited value in predicting complications following esophageal resection.
Effects of the Serotonin Type 2A, 3A and 3B Receptor and the Serotonin Transporter Genes on Paroxetine and Fluvoxamine Efficacy and Adverse Drug Reactions in Depressed Japanese Patients
Authors: Kato Masaki , Fukuda Tsuyoshi , Wakeno Masataka , Fukuda Kazuhiro , Okugawa Gaku , Ikenaga Yuka , Yamashita Megumi , Takekita Yoshiteru , Nobuhara Kenji , Azuma Junichi , Kinoshita Toshihiko
Published: August 2006

In this study, we tested the influence of the serotonin type 2A, 3A and 3B receptor genes (HTR2A, HTR3A, HTR3B) in addition to a polymorphism in the promoter region of the serotonin transporter (SERTPR), and investigated the different characteristics of clinical responses to paroxetine and fluvoxamine. A total of 100 Japanese patients affected by major recurrent depression were enrolled in a randomized 6-week study. The clinical response was evaluated using the Hamilton Rating Scale for Depression (HAM-D), and adverse drug reactions were assessed at each visit. Patients with the l allele of SERTPR showed a better response to SSRIs than s/s genotype carriers (p = 0.015–0.042), more significantly to fluvoxamine. The –1438G/G genotype of HTR2A was associated with a good response to SSRIs (p = 0.010–0.039), especially to fluvoxamine, and significantly with severe nausea in paroxetine-treated patients (p = 0.013). The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022–0.042), and more significantly in paroxetine-treated patients (p = 0.002–0.042). These effects were independent of one another. We replicated the finding that the SERPTR polymorphism was associated with a response to SSRIs. We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions. Furthermore, the effects of these polymorphisms varied from one SSRI to another and thus may depend on the characteristics of each SSRI.
Regional Quantification of White Matter Hyperintensity in Normal Aging, Mild Cognitive Impairment, and Alzheimer’s Disease
Authors: Chen Ya-Fang , Wang Huali , Chu Yong , Huang Yung-Chien , Su Min-Ying
Published: August 2006

Background/Aims: A quantitative method was applied to measure the volume of white matter hyperintensity (WMH) in different brain regions of subjects with Alzheimer’s disease (AD), mild cognitive impairment (MCI) and normal healthy age-matched controls, and the relationship between regional WMH and age and cognitive function was investigated. Methods: Fifty-six subjects were included in this study, 27 AD, 15 MCI and 14 normal age-matched controls. A user-friendly software was developed for WMH quantification in frontal, temporal, and parieto-occipital lobes. Mini-Mental State Examination and cognitive scores in performing naming, language fluency, and memory tasks were obtained for correlation analysis. Results: AD patients had the greatest total WMH volume, followed by MCI, then controls. However, there was a large variation within each group, and the difference did not reach a significant level. There was a positive linear correlation between the total WMH (p = 0.031) and the frontal WMH (p = 0.006) vs. age. After age correction the Boston Naming Test scores were negatively correlated with the total WMH volume in the AD (p = 0.03) and the control (p = 0.03) groups, and with the frontal WMH in controls (p = 0.01). Conclusion: We demonstrated a quantitative analysis method to measure regional WMH. Although WMH was not strongly associated with disease severity or cognition, it may provide a characteristic neuroimaging parameter in the study of AD development.
Targeting Pericytes Diminishes Neovascularization in Orthotopic Uveal Melanoma in Nerve/Glial Antigen 2 Proteoglycan Knockout Mouse
Authors: Ozerdem Ugur
Published: August 2006

In this investigation, we explored whether knockout of nerve/glial antigen 2 (NG2), a pericyte component, inhibited neovascularization and growth of uveal melanoma xenografts. For this, we used multichannel laser scanning confocal microscopy and quantitative image analysis. Orthotopic human uveal melanoma (OCM-1A) xenografts were induced in NG2 knockout and wild-type mice, which were immunosuppressed with cyclosporin A. Inhibition of pericytes through NG2 proteoglycan decreased neovascularization and tumor end volume, rendering pericytes and NG2 proteoglycan potential cellular and molecular therapeutic targets in uveal melanoma.
Combined Proton Beam Radiotherapy and Transpupillary Thermotherapy for Large Uveal Melanomas: A Randomized Study of 151 Patients
Authors: Desjardins L. , Lumbroso-Le Rouic L. , Levy-Gabriel C. , Dendale R. , Delacroix S. , Nauraye C. , Estève M. , Plancher C. , Asselain B.
Published: August 2006

Introduction: Exudation from the tumour scar and glaucoma can be major problems after proton beam irradiation of uveal melanoma and can sometimes lead to secondary enucleation. We conducted a randomized study to determine whether systematic transpupillary thermotherapy (TTT) after proton beam radiotherapy could have a beneficial effect. Patients and Method:Between February 1999 and April 2003, all the patients treated by proton beam radiotherapy for uveal melanomas ≧7 mm thick or ≧15 mm in diameter were included in this study after giving their informed consent. One half of the patients received proton beam radiotherapy alone (60 Gy in 4 fractions) and the other half received the same dose of proton beam radiotherapy followed by TTT at 1, 6 and 12 months. All the information concerning the initial tumour parameters, treatments and follow-up was recorded and a statistical analysis was performed. Results: We randomized 151 patients. The median follow-up was 38 months. The 2 groups of patients were similar in terms of age, gender and tumour characteristics. The patients treated with TTT showed a greater reduction of tumour thickness (p = 0.06), less retinal detachment at the latest follow-up (p = 0.14) and a lower secondary enucleation rate (p = 0.02). Discussion: The present study is the first randomized analysis to demonstrate a significant decrease in the secondary enucleation rate in patients treated with TTT after proton beam radiotherapy. Further studies should be performed to determine whether TTT could be beneficial to smaller tumours and to define its optimal dose.
Gd(ABE-DTTA), a Novel Contrast Agent, at the MRI-Effective Dose Shows Absence of Deleterious Physiological Effects in Dogs
Authors: Ruzsics Balázs , Surányi Pál , Kiss Pál , Brott Brigitta C. , Elgavish Ada , Saab-Ismail Nada H. , Simor Tamás , Elgavish Gabriel A.
Published: August 2006

The physiological effects of a novel MRI contrast agent, Gd(ABE-DTTA), were investigated in dogs, monitoring parameters in blood samples. Each animal (n = 8 in the short-term, n = 4 in the long-term group) underwent isoflurane anesthesia followed by the generation of myocardial infarction and received a contrast agent at the MRI effective dose. Blood samples were collected 24 and 48 h, and 7, 14, 28, 35, 49 and 56 days after contrast agent administration. No significant changes exceeding the normal range were detected in any of the investigated parameters except in alanine aminotransferase (ALT). ALT enzyme activity increased in the short-term group 24 and 48 h after agent administration as expected from the effect of isoflurane anesthesia. Between days 7 and 56 no elevation in ALT was observed. In dogs no substantial short- or long-term effect was observed on the investigated, physiological parameters after Gd(ABE-DTTA) administration at the MRI effective dose.
Metabolic Syndrome May Not Associate With Carotid Plaque in Subjects With Optimal, Normal, or High-Normal Blood Pressure
Authors: Ishizaka Nobukazu , Ishizaka Yuko , Hashimoto Hideki , Toda Ei-Ichi , Nagai Ryozo , Yamakado Minoru
Published: August 2006

Much evidence indicates that metabolic syndrome is a risk factor for the development of cardiovascular disease, but whether metabolic syndrome is an independent risk factor for early atherosclerosis in the individuals with only minor hemodynamic abnormalities, if any, is not well investigated. Here we have investigated the association between metabolic syndrome and carotid atherosclerosis in individuals with blood pressure of <140/90 mm Hg. Between 1994 and 2003, 8143 subjects underwent general health screening including carotid ultrasonography. Of 8143 individuals, 5661 individuals without antihypertensive medications who had blood pressure of <140/90 mm Hg were considered to have optimal, normal, or high-normal blood pressure. After adjustment for age, systolic blood pressure, body mass index, total and high-density lipoprotein cholesterol, triglycerides, fasting glucose, and smoking status, metabolic syndrome was not found to be an independent risk factor for carotid plaque (odds ratio: 1.65; 95% CI; 0.72 to 3.76 in women and odds ratio: 0.95; 95% CI: 0.70 to 1.28 in men) or for carotid intima-media thickening (odds ratio: 0.56; 95% CI: 0.18 to 1.72 in women and odds ratio: 0.93 95% CI: 0.62 to 1.38 in men) in these subjects. Thus, presence of metabolic syndrome may not increase the prevalence of carotid atherosclerosis independent of other cardiovascular risk factors in Japanese individuals with optimal, normal, or high-normal blood pressure.