bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological Significance of Prolactin in Gynecologic Cancers
Authors: Levina Vera V. , Nolen Brian , Su YunYun , Godwin Andrew K. , Fishman David , Liu Jinsong , Mor Gil , Maxwell Larry G. , Herberman Ronald B. , Szczepanski Miroslaw J. , Szajnik Marta E. , Gorelik Elieser , Lokshin Anna E. 
Published: June 2009

Abstract
There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, we show that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We show dramatically increased expression of PRL receptor in ovarian and endometrial tumors as well as in endometrial hyperplasia, signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors, indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen-activated protein kinase/ERK kinase 1, signal transducer and activator of transcription 3, CREB, ATF-2, and p53 and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial cells were chronically exposed to PRL, a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in severe combined immunodeficient-beige mice. Transformation efficiency was diminished by a Ras inhibitor, providing proof that PRL-induced transformation uses the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers. [Cancer Res 2009;69(12):5226–33]
N-myc Downstream Regulated Gene 1/Cap43 Suppresses Tumor Growth and Angiogenesis of Pancreatic Cancer through Attenuation of Inhibitor of κB Kinase β Expression
Authors: Hosoi Fumihito , Izumi Hiroto , Kawahara Akihiko , Murakami Yuichi , Kinoshita Hisafumi , Kage Masayoshi , Nishio Kazuto , Kohno Kimitoshi , Kuwano Michihiko , Ono Mayumi 
Published: June 2009

Abstract
N-myc downstream regulated gene 1 (NDRG1)/Cap43 expression is a predictive marker of good prognosis in patients with pancreatic cancer as we reported previously. In this study, NDRG1/Cap43 decreased the expression of various chemoattractants, including CXC chemokines for inflammatory cells, and the recruitment of macrophages and neutrophils with suppression of both angiogenesis and growth in mouse xenograft models. We further found that NDRG1/Cap43 induced nuclear factor-κB (NF-κB) signaling attenuation through marked decreases in inhibitor of κB kinase (IKK) β expression and IκBα phosphorylation. Decreased IKKβ expression in cells overexpressing NDRG1/Cap43 resulted in reduction of both nuclear translocation of p65 and p50 and their binding to the NF-κB motif. The introduction of an exogenous IKKβ gene restored NDRG1/Cap43-suppressed expression of melanoma growth-stimulating activity α/CXCL1, epithelial-derived neutrophil activating protein-78/CXCL5, interleukin-8/CXCL8 and vascular endothelial growth factor-A, accompanied by increased phosphorylation of IκBα in NDRG1/Cap43-expressing cells. In patients with pancreatic cancer, NDRG1/Cap43 expression levels were also inversely correlated with the number of infiltrating macrophages in the tumor stroma. This study suggests a novel mechanism by which NDRG1/Cap43 modulates tumor angiogenesis/growth and infiltration of macrophages/neutrophils through attenuation of NF-κB signaling. [Cancer Res 2009;69(12):4983–91]
Cancer Prevention: From 1727 to Milestones of the Past 100 Years
Authors: Lippman Scott M. , Hawk Ernest T. 
Published: June 2009

Abstract
The rich, multidisciplinary history of cancer prevention recounted here begins with surgical and workplace recommendations of the 1700s and ends with 2009 results of the enormous (35,535 men) Selenium and Vitamin E [prostate] Cancer Prevention Trial (SELECT). This history comprises a fascinating array of chemopreventive, vaccine, surgical, and behavioral science research, both preclinical and clinical. Preclinical milestones of cancer prevention include the 1913 and 1916 mouse studies by Lathrop and Loeb of cancer development associated with pregnancy or cancer prevention through castration (oophorectomy), preventing chemically induced mouse carcinogenesis as early as 1929, energy restriction studies in the 1940s, the 1950s discoveries and later molecular characterizations of field cancerization and multistep carcinogenesis, and the effects of angiogenesis inhibition in genetically engineered mice reported in 2009. The extraordinary panoply of clinical research includes numerous large and smaller chemoprevention studies of nutritional supplements, other dietary approaches, a Bacillus Calmette-Guérin trial in 1976, molecular-targeted agents, and agents to prevent infection-related cancers such as hepatitis B virus vaccine to prevent liver cancer in 1984. Clinical surgical prevention includes removal of intraepithelial neoplasia detected by screening (including Pap testing developed in 1929 and culposcopy for cervical premalignancy and colonoscopy and polypectomy to prevent colorectal cancer begun in the 1960s) and prophylactic surgeries, such as in Lynch syndrome patients begun in 1977. Behavioral studies include smoking cessation and control beginning in the 1950s, obesity control rooted in studies of 1841, and genetic-counseling and cancer-survivorship studies. This history of pioneering events may help in better understanding who we are and what we want to achieve as cancer prevention researchers and practitioners. [Cancer Res 2009;69(13):5269–84]
Targeting Tumor Endothelial Marker 8 in the Tumor Vasculature of Colorectal Carcinomas in Mice
Authors: Fernando Stephen , Fletcher Bradley S. 
Published: June 2009

Abstract
Tumor endothelial marker 8 (TEM8) is a recently described protein that is preferentially expressed within tumor endothelium. We have developed a fusion protein that targets TEM8 and disrupts tumor vasculature by promoting localized thrombosis. Fusion protein specificity and function were evaluated using Western blot analysis, ELISA, and enzymatic assays. A xenograft model of colorectal carcinoma was used to test the efficacy of targeted and control fusion proteins. Mice treated with the gene encoding anti-TEM8/truncated tissue factor exhibited a 53% reduction in tumor volume when compared with the untreated animals (P &lt; 0.0001; n = 10) and achieved a 49% increase in tumor growth delay by Kaplan-Meier analysis (P = 0.0367; n = 6). Immunohistochemistry confirmed tumor endothelial expression of TEM8, fusion protein homing to tumor vasculature, decrease in vessel density, and localized areas of thrombosis. These data support the hypothesis that targeting TEM8 can be an effective approach to influence tumor development by disrupting tumor vasculature. [Cancer Res 2009;69(12):5126–32]
Leucine Leucine-37 Uses Formyl Peptide Receptor–Like 1 to Activate Signal Transduction Pathways, Stimulate Oncogenic Gene Expression, and Enhance the Invasiveness of Ovarian Cancer Cells
Authors: Coffelt Seth B. , Tomchuck Suzanne L. , Zwezdaryk Kevin J. , Danka Elizabeth S. , Scandurro Aline B. 
Published: June 2009

Abstract
Emerging evidence suggests that the antimicrobial peptide, leucine leucine-37 (LL-37), could play a role in the progression of solid tumors. LL-37 is expressed as the COOH terminus of human cationic antimicrobial protein-18 (hCAP-18) in ovarian, breast, and lung cancers. Previous studies have shown that the addition of LL-37 to various cancer cell lines in vitro stimulates proliferation, migration, and invasion. Similarly, overexpression of hCAP-18/LL-37 in vivo accelerates tumor growth. However, the receptor or receptors through which these processes are mediated have not been thoroughly examined. In the present study, expression of formyl peptide receptor–like 1 (FPRL1) was confirmed on ovarian cancer cells. Proliferation assays indicated that LL-37 does not signal through a G protein–coupled receptor, such as FPRL1, to promote cancer cell growth. By contrast, FPRL1 was required for LL-37–induced invasion through Matrigel. The peptide stimulated mitogen-activated protein kinase and Janus-activated kinase/signal transducers and activators of transcription signaling cascades and led to the significant activation of several transcription factors, through both FPRL1-dependent and FPRL1-independent pathways. Likewise, expression of some LL-37–stimulated genes was attenuated by the inhibition of FPRL1. Increased expression of CXCL10, EGF, and PDGF-BB as well as other soluble factors was confirmed from conditioned medium of LL-37–treated cells. Taken together, these data suggest that LL-37 potentiates a more aggressive behavior from ovarian cancer cells through its interaction with FPRL1. (Mol Cancer Res 2009;7(6):907–15)
The MDM2-A Splice Variant of MDM2 Alters Transformation In vitro and the Tumor Spectrum in Both Arf- and p53-Null Models of Tumorigenesis
Authors: Volk Erin L. , Fan Liying , Schuster Katja , Rehg Jerold E. , Harris Linda C. 
Published: June 2009

Abstract
MDM2-A is a common splice variant of murine double minute 2 (MDM2) that is frequently detected in many tumor types. Our previous work has characterized MDM2-A as an activator of p53, and therefore, in a wild-type p53 background, this splice variant would be predicted to confer p53-dependent tumor protection. To test this hypothesis, we used Mdm2-a transgenic mice to assess transformation and tumorigenesis in tumor susceptible murine models. A MDM2-A–dependent decrease in transformation was observed in Arf-null mouse embryonic fibroblasts (MEF) or when wild-type MEFs were exposed to the carcinogen ethylnitrosourea. However, this reduced transformation did not confer tumor protection in vivo; Mdm2-a/Arf-null mice and ethylnitrosourea-treated MDM2-expressing mice developed similar tumor types with equivalent latency compared with their respective controls. Interestingly, when p53 was deleted, MDM2-A expression enhanced transformation of p53-null MEFs and altered tumor spectrum in vivo. In addition, p53-heterozygous mice that expressed MDM2-A developed aggressive mammary tumors that were not observed in p53-heterozygous controls. In conclusion, we found that although MDM2-A expression enhances p53 activity and decreases transformation in vitro, it cannot confer tumor protection. In contrast, MDM2-A seems to exhibit a novel transforming potential in cells where p53 function is compromised. These data show that MDM2 splice variants, such as MDM2-A, may provide protection against transformation of normal tissues having intact p53. However, when such splice variants are expressed in tumors that have defects in the p53 pathway, these isoforms may contribute to tumor progression, which could explain why their expression is often associated with aggressive tumor types. (Mol Cancer Res 2009;7(6):863–9)
The genetics of venous thromboembolism
Authors: Gohil Reya , Peck George , Sharma Pankaj 
Published: June 2009

SummaryWe conducted a systematic and comprehensive meta-analysis on all candidate genes to assess their genetic contribution to the aetiology of venous thromboembolism (VTE) (pulmonary embolism and deep venous thrombosis) in all ethnic groups. Electronic databases were searched until and including January 2008 for any candidate gene investigated in VTE. Odds ratios (OR) and 95% confidence intervals (CI) were determined for each gene disease association using fixed and random effect models. Our meta-analyses included ∼126,525 cases and 184,068 controls derived from 173 case-control studies, which included 21 genes (28 polymorphisms). Statistically significant associations with VTE were identified for factor V G1691A (OR 9.45; 95% CI 6.72–13.30, p<0.0001), factor V A4070G (OR 1.24; 95% CI
Evaluation of WRF and HadRM Mesoscale Climate Simulations over the U.S. Pacific Northwest*
Authors: Zhang Yongxin , Dulière Valérie , Mote Philip W. , Salathé Eric P. 
Published: June 2009

Abstract
This work compares the Weather Research and Forecasting (WRF) and Hadley Centre Regional Model (HadRM) simulations with the observed daily maximum and minimum temperature (Tmax and Tmin) and precipitation at Historical Climatology Network (HCN) stations over the U.S. Pacific Northwest for 2003–07. The WRF and HadRM runs were driven by the NCEP/Department of Energy (DOE) Atmospheric Model Intercomparison Project (AMIP)-II Reanalysis (R-2) data. The simulated Tmax in WRF and HadRM as well as in R-2 compares well with the observations. Predominantly cold biases of Tmax are noted in WRF and HadRM in spring and summer, while in winter and fall more stations show warm biases, especially in HadRM. Large cold biases of Tmax are noted in R-2 at all times. The simulated Tmin compares reasonably well with the observations, although not as well as Tmax in both models and in the reanalysis R-2. Warm biases of Tmin prevail in both model simulations, while R-2 shows mainly cold biases. The R-2 data play a role in the model biases of Tmax, although there are also clear indications of resolution dependency. The model biases of Tmin originate mainly from the regional models. The temporal correlation between the simulated and observed daily precipitation is relatively low in both models and in the reanalysis; however, the correlation increases steadily for longer averaging times. The high-resolution models perform better than R-2, although the nested WRF domains do have the largest biases in precipitation during the winter and spring seasons.
CALIPSO/CALIOP Cloud Phase Discrimination Algorithm
Authors: Hu Yongxiang , Winker David , Vaughan Mark , Lin Bing , Omar Ali , Trepte Charles , Flittner David , Yang Ping , Nasiri Shaima L. , Baum Bryan , Holz Robert , Sun Wenbo , Liu Zhaoyan , Wang Zhien , Young Stuart , Stamnes Knut , Huang Jianping , Kuehn Ralph 
Published: June 2009

Abstract
The current cloud thermodynamic phase discrimination by Cloud-Aerosol Lidar Pathfinder Satellite Observations (CALIPSO) is based on the depolarization of backscattered light measured by its lidar [Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP)]. It assumes that backscattered light from ice crystals is depolarizing, whereas water clouds, being spherical, result in minimal depolarization. However, because of the relationship between the CALIOP field of view (FOV) and the large distance between the satellite and clouds and because of the frequent presence of oriented ice crystals, there is often a weak correlation between measured depolarization and phase, which thereby creates significant uncertainties in the current CALIOP phase retrieval. For water clouds, the CALIOP-measured depolarization can be large because of multiple scattering, whereas horizontally oriented ice particles depolarize only weakly and behave similarly to water clouds. Because of the nonunique depolarization–cloud phase relationship, more constraints are necessary to uniquely determine cloud phase. Based on theoretical and modeling studies, an improved cloud phase determination algorithm has been developed. Instead of depending primarily on layer-integrated depolarization ratios, this algorithm differentiates cloud phases by using the spatial correlation of layer-integrated attenuated backscatter and layer-integrated particulate depolarization ratio. This approach includes a two-step process: 1) use of a simple two-dimensional threshold method to provide a preliminary identification of ice clouds containing randomly oriented particles, ice clouds with horizontally oriented particles, and possible water clouds and 2) application of a spatial coherence analysis technique to separate water clouds from ice clouds containing horizontally oriented ice particles. Other information, such as temperature, color ratio, and vertical variation of depolarization ratio, is also considered. The algorithm works well for both the 0.3° and 3° off-nadir lidar pointing geometry. When the lidar is pointed at 0.3° off nadir, half of the opaque ice clouds and about one-third of all ice clouds have a significant lidar backscatter contribution from specular reflections from horizontally oriented particles. At 3° off nadir, the lidar backscatter signals for roughly 30% of opaque ice clouds and 20% of all observed ice clouds are contaminated by horizontally oriented crystals.
The Role of Typhoon Songda (2004) in Producing Distantly Located Heavy Rainfall in Japan*
Authors: Wang Yongqing , Wang Yuqing , Fudeyasu Hironori 
Published: June 2009

Abstract
When Typhoon Songda (2004) was located southeast of Okinawa over the western North Pacific during 2–4 September 2004, a heavy rainfall event occurred over southern central Japan and its adjacent seas, more than 1200 km from the typhoon center. The Advanced Research version of the Weather Research and Forecast (WRF-ARW) model was used to investigate the possible remote effects of Typhoon Songda on this heavy precipitation event in Japan. The National Centers for Environmental Prediction (NCEP) global final (FNL) analysis was used to provide both the initial and lateral boundary conditions for the WRF model. The model was initialized at 1800 UTC 2 September and integrated until 1800 UTC 6 September 2004, during which Songda was a supertyphoon. Two primary numerical experiments were performed. In the control experiment, a bogus vortex was inserted into the FNL analysis to enhance the initial storm intensity such that the model typhoon had an intensity that was similar to that observed at the initial time. In the no-typhoon experiment, the vortex associated with Typhoon Songda in the FNL analysis was removed by a smoothing algorithm such that the typhoon signal did not appear at the initial time. As verified against various observations, the control experiment captured reasonably well the evolution of the storm and the spatial distribution and evolution of the precipitation, whereas the remote precipitation in Japan was largely suppressed in the no-typhoon experiment, indicting the significant far-reaching effects of Typhoon Songda. Songda enhanced the remote precipitation in Japan mainly through northward moisture transport into the preconditioned precipitation region by its outer circulation. The orographic forcing of the central mountains in Japan played a small role compared with Typhoon Songda in this extreme precipitation event.
“Jumpiness” of the ECMWF and Met Office EPS Control and Ensemble-Mean Forecasts
Authors: Zsoter Ervin , Buizza Roberto , Richardson David 
Published: June 2009

Abstract
This work investigates the inconsistency between forecasts issued at different times but valid for the same time, and shows that ensemble-mean forecasts are less inconsistent than corresponding control forecasts. The “jumpiness” index, the concepts of different forecast jumps—the “flip,” “flip-flop,” and “flip-flop-flip”—and the inconsistency correlation between time series of inconsistency indices are introduced to measure the consistency/inconsistency of consecutive forecasts. These new measures are used to compare the behavior of the ECMWF and the Met Office control and ensemble-mean forecasts for an 18-month period over Europe. Results indicate that for both the ECMWF and the Met Office ensembles, the ensemble-mean forecast is less inconsistent than the control forecast. However, they also indicate that the ensemble mean follows its corresponding control forecast more closely than the controls (or the ensemble means) of the two ensemble systems following each other, thus suggesting weaknesses in both ensemble systems in the simulation of forecast uncertainty due to model or analysis error. Results also show that there is only a weak link between forecast jumpiness and forecast error (i.e., forecasts with lower inconsistency do not necessarily have, on average, lower error).
Effects of Varying Rate of Signing on ASL Manual Signs and Nonmanual Markers
Authors: Wilbur Ronnie B. 
Published: June 2009

Spoken languages are characterized by flexible, multivariate prosodic systems. As a natural language, American Sign Language (ASL), and other sign languages (SLs), are also expected to be characterized in the same way. Artificially created signing systems for classroom use, such as signed English, serve as a contrast to natural sign languages. The present article explores the effects of changes in signing rate on signs, pauses, and, unlike previous studies, a variety of nonmanual markers. Rate was a main effect on the duration of signs, the number of pauses and pause duration, the duration of brow raises, the duration of licensed lowered brows, the number and duration of blinks, all of which decreased with increased signing rate. This indicates that signers produced their different signing rates without making dramatic changes in the number of signs, but instead by varying the sign duration, in accordance with previous observations (Grosjean, 1978, 1979). These results can be brought to bear on three different issues: (1) the difference between grammatical nonmanuals and non-grammatical nonmanuals; (2) the fact that nonmanuals in general are not just a modality effect; and (3) the use of some nonmanuals as pragmatically determined as opposed to overt morphophonological markers reflecting the semantic—syntax—pragmatic interfaces.
Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis
Authors: Semenza Gregg L. 
Published: June 2009

Abstract
Red blood cells deliver O2 from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O2-regulated α subunit and a constitutively expressed β subunit. Hydroxylation of HIF-1α or HIF-2α by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1α or HIF-2α by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2α have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.