bluuebunny/crossref_metadata_2025_split huggingface dataset:
Midkine Enhances Soft-Tissue Sarcoma Growth: A Possible Novel Therapeutic Target
Authors: Jin Zeming , Lahat Guy , Korchin Borys , Nguyen Theresa , Zhu Quan-Sheng , Wang Xuemei , Lazar Alexander J. , Trent Jonathan , Pollock Raphael E. , Lev Dina 
Published: August 2008

Abstract
Purpose: New therapeutic targets for soft-tissue sarcoma (STS) treatment are critically needed. Midkine (MK), a multifunctional cytokine, is expressed during midgestation but is highly restricted in normal adult tissues. Renewed MK expression was shown in several malignancies where protumorigenic properties were described. We evaluated the expression and function of MK in STS.
Experimental Design: Immunohistochemistry, reverse transcription-PCR, and Western blotting (WB) evaluated MK expression in human STS tissues and cell lines. WB and flow cytometry analyzed MK receptor expression. Cell growth assays evaluated the effect of MK on STS cell growth, and WB assessed MK downstream signaling. MK knock-in and knockout experiments further evaluated MK function. The growth of parental versus MK-transfected human fibrosarcoma cells was studied in vivo.
Results: MK was found to be overexpressed in a variety of human STS histologies. Using a rhabdomyosarcoma (RMS) tissue microarray, cytoplasmic and nuclear MK was identified; nuclear MK expression was significantly increased in metastases. Similarly, several STS cell lines expressed and secreted MK; RMS cells exhibited nuclear MK. STS cells also expressed the MK receptors protein tyrosine phosphatase ζ and lipoprotein receptor-related protein. MK significantly enhanced STS cell growth potentially via the Src and extracellular signal-regulated kinase pathways. STS cells stably transfected with MK exhibited increased growth in vitro and in vivo. MK-expressing human STS xenografts showed increased tumor-associated vasculature. Furthermore, MK knockdown resulted in decreased STS cell growth, especially in RMS cells.
Conclusion: MK enhances STS tumor growth; our results support further investigation of MK and its receptors as therapeutic targets for human STS.
Prognostic Effect of Epithelial and Stromal Lymphocyte Infiltration in Non–Small Cell Lung Cancer
Authors: Al-Shibli Khalid I. , Donnem Tom , Al-Saad Samer , Persson Magnus , Bremnes Roy M. , Busund Lill-Tove 
Published: August 2008

Abstract
Purpose: The major value of prognostic markers in potentially curable non-small cell lung cancer (NSCLC) should be to guide therapy after surgical resection. In this regard, the patients' immune status at the time of resection may be important and also measurable. The immune system has paradoxical roles during cancer development. However, the prognostic significance of tumor-infiltrating lymphocytes is controversial. The aim of this study is to elucidate the prognostic significance of epithelial and stromal lymphocyte infiltration in NSCLC.
Experimental Design: Tissue microarrays from 335 resected NSCLC, stage I to IIIA were constructed from duplicate cores of viable and representative neoplastic epithelial and stromal areas. Immunohistochemistry was used to evaluate the epithelial and stromal CD4+, CD8+, and CD20+ lymphocytes.
Results: In univariate analyses, increasing numbers of epithelial CD8+ (P = 0.023), stromal CD8+ (P = 0.002), epithelial CD20+ (P = 0.023), stromal CD20+ (P &lt; 0.001), and stromal CD4+ (P &lt; 0.001) lymphocytes correlated significantly with an improved disease-specific survival. No such relation was noted for epithelial CD4+ cells. Furthermore, a low level of stromal CD8+ lymphocyte infiltration was associated with an increased incidence of angiolymphatic invasion (P = 0.032). In multivariate analyses, a high number of stromal CD8+ (P = 0.043) and CD4+ (P = 0.002) cells were independent positive prognostic factors for disease-specific survival.
Conclusions: High densities of CD4+ and CD8+ lymphocytes in the stroma are independent positive prognostic indicators for resected NSCLC patients. This may suggest that these cells are mediating a strong antitumor immune response in NSCLC.
Deletion of 1p32-p36 Is the Most Frequent Genetic Change and Poor Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands
Authors: Rao Pulivarthi H. , Roberts Diana , Zhao Yi-Jue , Bell Diana , Harris Charles P. , Weber Randal S. , El-Naggar Adel K. 
Published: August 2008

Abstract
Purpose: Adenoid cystic carcinoma (ACC) is a relatively uncommon salivary gland malignancy known for its protean phenotypic features and pernicious clinical behavior. Currently, no effective therapy is available for patients with advanced nonresectable, recurrent, and/or metastatic disease. The purpose of this study is to identify prognostic factors other than tumor stage that can be used to predict the outcome of the patients with ACC.
Experimental Design: We used comparative genomic hybridization (CGH) to identify copy number aberrations in 53 primary ACCs. Array CGH and fluorescence in situ hybridization analysis was used to validate CGH results on selected cases. We correlated these copy number aberrations with clinicopathologic factors using Pearson's χ2 or by the two-tailed Fisher exact test. The disease-specific survival and disease-free intervals were generated by the Kaplan-Meier product limit method.
Results: Chromosomal losses (n = 134) were more frequent than gains (n = 74). The most frequent genetic change was the loss of 1p32-p36 in 44% of the cases followed by 6q23-q27, and 12q12-q14. The most frequently gained chromosomal regions were 8 and 18. Of the chromosomal aberrations, loss of 1p32-p36 was the only abnormality significantly associated with patient's outcome.
Conclusions: This study, for the first time, identifies loss of 1p32-p36 as a significant aberration in ACC. Molecular characterization of 1p32-36 region using the available genomic technologies may lead to the identification of new genes critical to the development of novel therapeutic targets for this disease copy number aberration.
Vandetanib Inhibits Growth of Adenoid Cystic Carcinoma in an Orthotopic Nude Mouse Model
Authors: Choi Sungweon , Sano Daisuke , Cheung Melvina , Zhao Mei , Jasser Samar A. , Ryan Anderson J. , Mao Li , Chen Wan-Tao , El-Naggar Adel K. , Myers Jeffrey N. 
Published: August 2008

AbstractPurpose: Adenoid cystic carcinoma (ACC) can often be controlled with surgery and postoperative adjuvant radiotherapy but is also characterized by late local recurrence and distant metastasis. No effective systemic therapeutic agents have been found to alter the natural history of ACC. Therefore, new therapeutic approaches are needed. In this study, we evaluated whether vandetanib (Zactima), a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinases, had antitumor efficacy in vitro and in an orthotopic nude mouse model of human ACC.Experimental Design: The in vitro effects of vandetanib were assessed in three ACC cell lines on cell growth, apoptosis, and VEGFR-2 and EGFR phosphorylation levels. The in vivo antitumor activity of vandetanib was examined in nude mice bearing parotid gland ACC tumors. The mice were treated for 4 weeks with vandetanib (50 mg/kg/d) or placebo (control). Tumors were resected at necropsy, and immunohistochemical and immunofluorescence staining were done.Results: In vitro, vandetanib caused dose-dependent inhibition of VEGFR-2 and EGFR phosphorylation in ACC cells. Vandetanib also inhibited the cell proliferation and induced their dose-dependent apoptosis. In vivo, mice in the vandetanib group had tumor volumes significantly lower than those in the control group (P &lt; 0.01). In addition, immunohistochemical staining showed a decrease in microvessel density and an increase in apoptosis of both tumor cells and endothelial cells within the tumor xenografts.Conclusion: These results suggest that vandetanib inhibits the growth of ACC in vitro and in vivo, making it a promising novel agent for the treatment of ACC.
Checkpoint Kinase 1 Down-Regulation by an Inducible Small Interfering RNA Expression System Sensitized In vivo Tumors to Treatment with 5-Fluorouracil
Authors: Ganzinelli Monica , Carrassa Laura , Crippa Francesca , Tavecchio Michele , Broggini Massimo , Damia Giovanna 
Published: August 2008

Abstract
Purpose: After DNA damage, checkpoints pathways are activated in the cells to halt the cell cycle, thus ensuring repair or inducing cell death. To better investigate the role of checkpoint kinase 1 (Chk1) in cellular response to different anticancer agents, Chk1 was knocked down in HCT-116 cell line and in its p53-deficient subline by using small interfering RNAs (siRNA).
Experimental Design: Chk1 was abrogated by transient transfection of specific siRNA against it, and stable tetracycline-inducible Chk1 siRNA clones were obtained transfecting cells with a plasmid expressing two siRNA against Chk1. The validated inducible system was then translated in an in vivo setting by transplanting the inducible clones in nude mice.
Results: Transient Chk1 down-regulation sensitized HCT-116 cells, p53−/− more than the p53 wild-type counterpart, to DNA-damaging agents 5-fluorouracil (5-FU), doxorubicin, and etoposide treatments, with no modification of Taxol and PS341 cytotoxic activities. Inhibition of Chk1 protein levels in inducible clones on induction with doxycycline correlated with an increased cisplatin and 5-FU activity. Such effect was more evident in a p53-deficient background. These clones were transplanted in nude mice and a clear Chk1 down-regulation was shown in tumor samples of mice given tetracycline in the drinking water by immunohistochemical detection of Chk1 protein. More importantly, an increased 5-FU antitumor activity was found in tumors with the double Chk1 and p53 silencing.
Conclusions: These findings corroborate the fact that Chk1 protein is a molecular target to be inhibited in tumors with a defective G1 checkpoint to increase the selectivity of anticancer treatments.
Production and Perception of Temporal Patterns in Native and Non-Native Speech
Authors: Bent Tessa , Bradlow Ann R. , Smith Bruce L. 
Published: August 2008

Abstract
Two experiments examined production and perception of English temporal patterns by native and non-native participants. Experiment 1 indicated that native and non-native (L1 = Chinese) talkers differed significantly in their production of one English duration pattern (i.e., vowel lengthening before voiced versus voice-less consonants) but not another (i.e., tense versus lax vowels). Experiment 2 tested native and non-native listener identification of words that differed in voicing of the final consonant by the native and non-native talkers whose productions were substantially different in experiment 1. Results indicated that differences in native and non-native intelligibility may be partially explained by temporal pat-tern differences in vowel duration although other cues such as presence of stop releases and burst duration may also contribute. Additionally, speech intelligibility depends on shared phonetic knowledge between talkers and listeners rather than only on accuracy relative to idealized production norms.
Storms and Lightning Activity in Greece during the Warm Periods of 2003–06
Authors: Mazarakis N. , Kotroni V. , Lagouvardos K. , Argiriou A. A. 
Published: August 2008

Abstract
Lightning activity over Greece during the warm season (May–September) of the years 2003–06 is investigated in relation to the synoptic meteorological conditions that prevailed in the region. The study is based on the use of cloud-to-ground lightning activity data from the Met Office Arrival Time Difference system and upper-air analyses from the European Centre for Medium-Range Weather Forecasts. Analysis of the spatial variability of lightning shows that the highest “relative” flash densities are observed in northern and western Greece and in central and western Peloponnissos. The relative flash density is correlated with elevation: it increases with elevation along the slopes of terrain features. The study of the synoptic patterns related to lightning is based on the analysis of 60 active days and 60 inactive days in terms of lightning activity over Greece. The days with high lightning activity are characterized by a short-wave trough at the 500-hPa level over the Ionian Sea. On the other hand, during the days with no lightning, a northwest flow prevails over Greece. It was also found that high lightning activity is related to high values of absolute vorticity, equivalent potential temperature, and convective available potential energy.
External Influences on Nocturnal Thermally Driven Flows in a Deep Valley
Authors: Schmidli Juerg , Poulos Gregory S. , Daniels Megan H. , Chow Fotini K. 
Published: August 2008

AbstractThe dynamics that govern the evolution of nighttime flows in a deep valley, California’s Owens Valley, are analyzed. Measurements from the Terrain-Induced Rotor Experiment (T-REX) reveal a pronounced valley-wind system with often nonclassical flow evolution. Two cases with a weak high pressure ridge over the study area but very different valley flow evolution are presented. The first event is characterized by the appearance of a layer of southerly flow after midnight local time, sandwiched between a thermally driven low-level downvalley (northerly) flow and a synoptic northwesterly flow aloft. The second event is characterized by an unusually strong and deep downvalley jet, exceeding 15 m s−1. The analysis is based on the T-REX measurement data and the output of high-resolution large-eddy simulations using the Advanced Regional Prediction System (ARPS). Using horizontal grid spacings of 1 km and 350 m, ARPS reproduces the observed flow features for these two cases very well. It is found that the low-level along-valley forcing of the valley wind is the result of a superposition of the local thermal forcing and a midlevel (2–2.5 km MSL) along-valley pressure forcing. The analysis shows that the large difference in valley flow evolution derives primarily from differences in the midlevel pressure forcing, and that the Owens Valley is particularly susceptible to these midlevel external influences because of its specific geometry. The results demonstrate the delicate interplay of forces that can combine to determine the valley flow structure on any given night.
Ocean Water Clarity and the Ocean General Circulation in a Coupled Climate Model
Authors: Gnanadesikan Anand , Anderson Whit G. 
Published: August 2008

Abstract
Ocean water clarity affects the distribution of shortwave heating in the water column. In a one-dimensional time-mean sense, increased clarity would be expected to cool the surface and heat subsurface depths as shortwave radiation penetrates deeper into the water column. However, wind-driven upwelling, boundary currents, and the seasonal cycle of mixing can bring water heated at depth back to the surface. This warms the equator and cools the subtropics throughout the year while reducing the amplitude of the seasonal cycle of temperature in polar regions. This paper examines how these changes propagate through the climate system in a coupled model with an isopycnal ocean component focusing on the different impacts associated with removing shading from different regions. Increasing shortwave penetration along the equator causes warming to the south of the equator. Increasing it in the relatively clear gyres off the equator causes the Hadley cells to strengthen and the subtropical gyres to shift equatorward. Increasing shortwave penetration in the less clear regions overlying the oxygen minimum zones causes the cold tongue to warm and the Walker circulation to weaken. Increasing shortwave penetration in the high-latitude Southern Ocean causes an increase in the formation of mode water from subtropical water. The results suggest that more attention be paid to the processes distributing heat below the mixed layer.
Recruiting and retaining pregnant women from a community health center at the US—Mexico border for the Mothers and Youth Access clinical trial
Authors: Ramos-Gomez Francisco , Chung Lisa H , Gonzalez Beristain Rocio , Santo William , Jue Bonnie , Weintraub Jane , Gansky Stuart 
Published: August 2008

Background Recruitment and retention in clinical trials of minorities is low, particularly in rural underserved populations. This has slowed progress in addressing racial/ethnic disparities in oral health. Purpose To describe factors associated with successful recruitment, and identify predictors of continued retention of pregnant women attending a community health center into a randomized controlled clinical trial to prevent early childhood caries. Methods The Mothers and Youth Access (MAYA) Trial recruited women in the second trimester of pregnancy. At baseline, consenting women completed an oral health questionnaire and received a dental exam and oral health counseling. Four months postpartum, women returned with their babies for randomization with follow up at 9-, 12-, 18-, 24-, 30-, and 36-month postpartum visits. To assess predictors of retention, data about respondents' demographics, and oral health-related knowledge, attitudes, and behaviors were obtained by questionnaire and analyzed by logistic and discrete time-to-event regression analyses. Results Of 556 predominantly Mexican-American women recruited at baseline, 195 (35%) were excluded after baseline for not meeting inclusion criteria; 361 (65%) continued to randomization. Factors such as race/ethnicity, annual household income, household composition, oral health-related knowledge and behaviors significantly related to retention until randomization. In multivariable models, women reporting a higher annual household income were less likely to be lost to attrition before randomization (odds ratio = 0.73, 95% confidence interval (CI) 0.60—0.89); while Mexican/Mexican-American women were less likely to be lost beyond randomization (hazard ratio = 0.53, 95% CI 0.26—1.08). Limitations Factors not measured at baseline may have been important in predicting attrition. The MAYA Trial is expected to finish by November 2008; therefore, complete results for total retention may differ from those reported here. Conclusions Recruitment and retention efforts for pregnant Hispanic women should place heavy emphasis on culture as ethnicity remained the only borderline significant predictor in postrandomization retention. Clinical Trials 2008; 5: 336—346. http://ctj.sagepub.com
Early participant attrition from clinical trials: role of trial design and logistics
Authors: Siddiqi Azfar-e-Alam , Sikorskii Alla , Given Charles W , Given Barbara 
Published: August 2008

Background Participant attrition from randomized controlled trials reduces the statistical power of the study and can potentially introduce bias. Early identification of potential causes of attrition can help reduce patient attrition. We performed secondary analyses of two trials involving cancer patients. Purpose To identify predictors of attrition during two early phases, i.e., from consent to screening (Phase-1), and from screening to intake interview (Phase-2) in two clinical trials. Methods Cancer patients undergoing chemotherapy were asked to enroll in one of two clinical trials. In each trial the benefits of a cognitive behavioral intervention were compared with a psycho-educational intervention to assist patients to manage cancer and treatment-related symptoms. Following consent patients were screened for their symptoms' severity to determine their eligibility. Results Of the 885 consenters 785 completed screening and of the 782 eligible for participation, 713 completed intake interview. In the first phase, longer delays between consent and first contact attempt, lower levels of patient education, minority race, and prolonged duration of screening increased the likelihood of dropping out with a significantly stronger effect on minorities than white patients. In the second phase, low education, being a minority, longer screening delays, and impact of symptom severity on enjoyment of life significantly increased probability of attrition. Limitations Participant reported causes of attrition were not modeled; however, exclusion of patients who died during the time period of this research meant that most patients leaving the study made a conscious decision to do so. Conclusions To assure preservation of external validity, the time between consent and randomization into the arms of a trial must be held to a minimum. Delays between contacts and run in time, that may include screening patients to assure they will benefit from a trial, must be balanced against rates of attrition. Compressing intervals between contacts is particularly important to retain minorities. Clinical Trials 2008; 5: 328—335. http://ctjsagepub.com
CCL25 increases thymopoiesis after androgen withdrawal
Authors: Williams Kirsten M. , Lucas Philip J. , Bare Catherine V. , Wang Jiun , Chu Yu-Waye , Tayler Ezekiel , Kapoor Veena , Gress Ronald E. 
Published: August 2008

AbstractAlthough studies have demonstrated that androgen withdrawal increases thymic size, molecular mechanisms underlying this expansion remain largely unknown. We show that decreased androgen signaling leads to enhanced immigration of bone marrow T-cell precursors, as manifested by both an early increase of early thymic progenitors (ETP) and improved uptake of adoptively transferred quantified precursors into congenic castrated hosts. We provide evidence that the ETP niche is enhanced after androgen withdrawal by proliferation of UEA+ thymic epithelial cells (TEC) and increased TEC production of CCL25, a ligand critical for ETP entry. Moreover, the greatest increase in CCL25 production is by UEA+ TEC, linking function of this subset with the increase in ETP immigration. Furthermore, blockade of CCL25 abrogated the effects of castration by impairing ETP entry, retarding immature thymocyte development, limiting increase of thymic size, and impairing increase of thymopoiesis. Taken together, these findings describe a cohesive mechanism underlying increased thymic productivity after androgen withdrawal.
Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c
Authors: Cohen Robert M. , Franco Robert S. , Khera Paramjit K. , Smith Eric P. , Lindsell Christopher J. , Ciraolo Peter J. , Palascak Mary B. , Joiner Clinton H. 
Published: August 2008

AbstractAlthough red blood cell (RBC) life span is a known determinant of percentage hemoglobin A1c (HbA1c), its variation has been considered insufficient to affect clinical decisions in hematologically normal persons. However, an unexplained discordance between HbA1c and other measures of glycemic control can be observed that could be, in part, the result of differences in RBC life span. To explore the hypothesis that variation in RBC life span could alter measured HbA1c sufficiently to explain some of this discordance, we determined RBC life span using a biotin label in 6 people with diabetes and 6 nondiabetic controls. Mean RBC age was calculated from the RBC survival curve for all circulating RBCs and for labeled RBCs at multiple time points as they aged. In addition, HbA1c in magnetically isolated labeled RBCs and in isolated transferrin receptor-positivereticulocytes was used to determine the in vivo synthetic rate of HbA1c. The mean age of circulating RBCs ranged from 39 to 56 days in diabetic subjects and 38 to 60 days in nondiabetic controls. HbA1c synthesis was linear and correlated with mean whole blood HbA1c (R2 = 0.91). The observed variation in RBC survival was large enough to cause clinically important differences in HbA1c for a given mean blood glucose.