bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractTransforming 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &gt;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

Abstract
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 &lt; 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 &lt; 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 &lt; 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 &lt; 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 &lt; 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

Abstract
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)
Assyrians in Iraq
Authors: Petrosian Vahram 
Published: August 2006

AbstractThe article examines the question of the Assyrian identity; certain problems pertaining to the history of the Assyrian-Kurdish relationships; the problem of the Assyrian autonomy; the role of the political parties of the Iraqi Assyrians; the status of the Assyrians in Iraqi Kurdistan; the Assyrians after the fall of Saddam Hussein's regime, and several other issues.
Comparison of Wake Model Simulations with Offshore Wind Turbine Wake Profiles Measured by Sodar
Authors: Barthelmie R. J. , Larsen G. C. , Frandsen S. T. , Folkerts L. , Rados K. , Pryor S. C. , Lange B. , Schepers G. 
Published: August 2006

Abstract
This paper gives an evaluation of most of the commonly used models for predicting wind speed decrease (wake) downstream of a wind turbine. The evaluation is based on six experiments where free-stream and wake wind speed profiles were measured using a ship-mounted sodar at a small offshore wind farm. The experiments were conducted at varying distances between 1.7 and 7.4 rotor diameters downstream of the wind turbine. Evaluation of the models compares the predicted and observed velocity deficits at hub height. A new method of evaluation based on determining the cumulative momentum deficit over the profiles is described. Despite the apparent simplicity of the experiments, the models give a wide range of predictions. Overall, it is not possible to establish any of the models as having individually superior performance with respect to the measurements.
A Comparative Study of Rainfall Retrievals Based on Specific Differential Phase Shifts at X- and S-Band Radar Frequencies
Authors: Matrosov Sergey Y. , Cifelli Robert , Kennedy Patrick C. , Nesbitt Steven W. , Rutledge Steven A. , Bringi V. N. , Martner Brooks E. 
Published: August 2006

Abstract
A comparative study of the use of X- and S-band polarimetric radars for rainfall parameter retrievals is presented. The main advantage of X-band polarimetric measurements is the availability of reliable specific differential phase shift estimates, KDP, for lighter rainfalls when phase measurements at the S band are too noisy to produce usable KDP. Theoretical modeling with experimental raindrop size distributions indicates that due to some non-Rayleigh resonant effects, KDP values at a 3.2-cm wavelength (X band) are on average a factor of 3.7 greater than at 11 cm (S band), which is a somewhat larger difference than simple frequency scaling predicts. The non-Rayleigh effects also cause X-band horizontal polarization reflectivity, Zeh, and differential reflectivity, ZDR, to be larger than those at the S band. The differences between X- and S-band reflectivities can exceed measurement uncertainties for Zeh starting approximately at Zeh &gt; 40 dBZ, and for ZDR when the mass-weighted drop diameter, Dm, exceeds about 2 mm. Simultaneous X- and S-band radar measurements of rainfall showed that consistent KDP estimates exceeding about 0.1° km−1 began to be possible at reflectivities greater than ∼26–30 dBZ while at the S band such estimates can generally be made if Zeh &gt; ∼35–39 dBZ. Experimental radar data taken in light-to-moderate stratiform rainfalls with rain rates R in an interval from 2.5 to 15 mm h−1 showed availability of the KDP-based estimates of R for most of the data points at the X band while at the S band such estimates were available only for R greater than about 8–10 mm h−1. After correcting X-band differential reflectivity measurements for differential attenuation, ZDR measurements at both radar frequency bands were in good agreement with each other for Dm &lt; 2 mm, which approximately corresponds to ZDR ≈ 1.6 dB. The ZDR-based retrievals of characteristic raindrop sizes also agreed well with in situ disdrometer measurements.
Intercomparisons and Aerosol Calibrations of 12 Commercial Integrating Nephelometers of Three Manufacturers
Authors: Heintzenberg J. , Wiedensohler A. , Tuch T. M. , Covert D. S. , Sheridan P. , Ogren J. A. , Gras J. , Nessler R. , Kleefeld C. , Kalivitis N. , Aaltonen V. , Wilhelm R-T. , Havlicek M. 
Published: August 2006

Abstract
This study determined measured and Mie-calculated angular signal truncations for total and backscatter TSI, Inc., nephelometers, as a function of wavelength and for particles of known size and composition. Except for the total scattering channels, similar agreements as in a previous study of measured and calculated truncations were derived for submicrometer test aerosols. For the first time, instrument responses were also determined for supermicrometer test aerosols up to 1.9 μm in geometric mean diameter. These supermicrometer data confirm the theoretical predictions of strong angular truncations of the total scatter signals in integrating nephelometers due to the limited range of measured forward scattering angles. Truncations up to 60% were determined for the largest measured particles. Rough empirical truncation corrections have been derived from the calibration data for Radiance Research and Ecotech nephelometers for which no detailed response characteristics exist. Intercomparisons of the nephelometers measuring urban atmospheric aerosols yield average deviations of the slope from a 1:1 relation with a TSI reference nephelometer of less than 7%. Average intercepts range between +0.53 and −0.19 Mm−1. For the Radiance Research and Ecotech nephelometers ambient regressions of the Radiance Research and Ecotech instruments with the TSI nephelometer show larger negative intercepts, which are attributed to their less well characterized optics.
Evaluation of Surface Shortwave Flux Estimates from GOES: Sensitivity to Sensor Calibration
Authors: Wonsick Margaret M. , Pinker Rachel T. , Meng Wen , Nguyen Louis 
Published: August 2006

Abstract
Parameters derived from satellite observations depend on the quality of the calibration method applied to the raw satellite radiance measurements. This study investigates the sensitivity of absolute reflectance, derived cloud cover, and estimated surface shortwave (SW) downward fluxes to two different calibration methods for the visible sensor aboard the eighth Geostationary Operational Environmental Satellite (GOES-8). The first method was developed at NOAA's National Environmental Satellite, Data, and Information Service (NESDIS), and the second at the NASA Langley Research Center. Differences in visible reflectance ranged from −0.5% to 3%. The average difference in monthly mean cloud amount was ∼3%, and the average difference in monthly mean shortwave downward flux was 5 W m−2. Differences in bias and rms of the SW fluxes when evaluated against ground station measurements were less than 3 W m−2. Neither calibration method was shown to consistently outperform the other. This evaluation yields an estimate of the errors in fluxes that can be attributed to calibration.
The Vav binding site of the non–receptor tyrosine kinase Syk at Tyr 348 is critical for β2 integrin (CD11/CD18)–mediated neutrophil migration
Authors: Schymeinsky Jurgen , Sindrilaru Anca , Frommhold David , Sperandio Markus , Gerstl Ronald , Then Cornelia , Mócsai Attila , Scharffetter-Kochanek Karin , Walzog Barbara 
Published: August 2006

AbstractLeukocyte adhesion via β2 integrins (CD11/CD18) activates the tyrosine kinase Syk. We found that Syk was enriched at the lamellipodium during N-formyl-Met-Leu-Phe–induced migration of neutrophil-like differentiated HL-60 cells. Here, Syk colocalized with Vav, a guanine nucleotide exchange factor for Rac and Cdc42. The enrichment of Syk at the lamellipodium and its colocalization with Vav were absent upon expression of a Syk kinase-dead mutant (Syk K402R) or a Syk mutant lacking the binding site of Vav (Syk Y348F). Live cell imaging revealed that both mutations resulted in excessive lamellipodium formation and severely compromised migration compared with control cells. Similar results were obtained upon down-regulation of Syk by RNA interference (RNAi) technique as well as in Syk–/– neutrophils from wild-type mice reconstituted with Syk–/– bone marrow. A pivotal role of Syk in vivo was demonstrated in the Arthus reaction, where neutrophil extravasation, edema formation, and hemorrhage were profoundly diminished in Syk–/– bone marrow chimeras compared with those in control animals. In the inflamed cremaster muscle, Syk–/– neutrophils revealed a defect in adhesion and migration. These findings indicate that Syk is critical for β2 integrin–mediated neutrophil migration in vitro and plays a fundamental role in neutrophil recruitment during the inflammatory response in vivo.
MicroRNAs: regulators of gene expression and cell differentiation
Authors: Shivdasani Ramesh A. 
Published: August 2006

AbstractThe existence and roles of a class of abundant regulatory RNA molecules have recently come into sharp focus. Micro-RNAs (miRNAs) are small (approximately 22 bases), non–protein-coding RNAs that recognize target sequences of imperfect complementarity in cognate mRNAs and either destabilize them or inhibit protein translation. Although mechanisms of miRNA biogenesis have been elucidated in some detail, there is limited appreciation of their biological functions. Reported examples typically focus on miRNA regulation of a single tissue-restricted transcript, often one encoding a transcription factor, that controls a specific aspect of development, cell differentiation, or physiology. However, computational algorithms predict up to hundreds of putative targets for individual miRNAs, single transcripts may be regulated by multiple miRNAs, and miRNAs may either eliminate target gene expression or serve to finetune transcript and protein levels. Theoretical considerations and early experimental results hence suggest diverse roles for miRNAs as a class. One appealing possibility, that miRNAs eliminate low-level expression of unwanted genes and hence refine unilineage gene expression, may be especially amenable to evaluation in models of hematopoiesis. This review summarizes current understanding of miRNA mechanisms, outlines some of the important outstanding questions, and describes studies that attempt to define miRNA functions in hematopoiesis.