bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma
Authors: Tone Alicia A. , Begley Heather , Sharma Monika , Murphy Joan , Rosen Barry , Brown Theodore J. , Shaw Patricia A. 
Published: July 2008

Abstract
Purpose: To identify molecular alterations potentially involved in predisposition to adnexal serous carcinoma (SerCa) in the nonmalignant fallopian tube epithelium (FTE) of BRCA1/2 mutation carriers, given recent evidence implicating the distal FTE as a common source for SerCa.
Experimental Design: We obtained and compared gene expression profiles of laser capture microdissected nonmalignant distal FTE from 12 known BRCA1/2 mutation carriers (FTEb) and 12 control women (FTEn) during the luteal and follicular phase, as well as 13 high-grade tubal and ovarian SerCa.
Results: Gene expression profiles of tubal and ovarian SerCa specimens were indistinguishable by unsupervised cluster analysis and significance analysis of microarrays. FTEb samples as a group, and four individual FTEb samples from the luteal phase in particular, clustered closely with SerCa rather than normal control FTE. Differentially expressed genes from these four samples relative to other FTEb samples, as well as differentially expressed genes in all FTEb luteal samples relative to follicular samples, were mapped to the I2D protein-protein interaction database, revealing a complex network affecting signaling pathways previously implicated in tumorigenesis. Two candidates, disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) and Ski-like (SKIL), were further validated by real-time reverse transcription–PCR and tissue arrays. FTEb luteal and SerCa samples expressed higher levels of oncogenic SKIL and decreased levels of tumor suppressor DAB2, relative to FTEb follicular samples.
Conclusions: These findings support a common molecular pathway for adnexal SerCa and implicate factors associated with the luteal phase in predisposition to ovarian cancer in BRCA mutation carriers.
Increased Prevalence ofEGFR-Mutant Lung Cancer in Women and in East Asian Populations: Analysis of Estrogen-Related Polymorphisms
Authors: Bell Daphne W. , Brannigan Brian W. , Matsuo Keitaro , Finkelstein Dianne M. , Sordella Raffaella , Settleman Jeff , Mitsudomi Tetsuya , Haber Daniel A. 
Published: July 2008

AbstractPurpose: Somatic mutations in the epidermal growth factor receptor (EGFR) gene occur in a subset of non–small-cell lung cancer (NSCLC) and are highly predictive of the clinical response to selective EGFR kinase inhibitors. The prevalence of EGFR-mutant NSCLC is appreciably higher in females than in males and in East Asian than in Caucasian populations. We hypothesized that these disparate frequencies may be attributable to underlying genetic modifiers. Given the coincident differences in sex and ethnic origin, we tested allozymatic variants of enzymes involved in estrogen biosynthesis and metabolism, encoded by polymorphic alleles known to differ in frequency between Caucasian and Asian populations, as modifying alleles.Experimental Design: We genotyped nine polymorphisms in the CYP1A1, CYP17A1, CYP19, HSD17B1, COMT, GSTM1, and GSTT1 genes, in a series of 100 Japanese NSCLCs, selected for equal representation of EGFR wild-type (wt) and EGFR-mutant cases, as well as male and female cases. Associations between polymorphic variants and the EGFR genotype and sex of NSCLC cases were examined using Fisher's exact test of significance.Results: Only CYP1A1*2C showed a difference in allele frequency that approached statistical significance. Heterozygotes were underrepresented among EGFR-mutant cases compared with EGFR-wt cases (27% versus 47%, P = 0.08), with a concurrent trend toward overrepresentation of CYP1A1*2CIle/Ile homozygotes among EGFR-mutant cases as compared with EGFR-wt cases (69% versus 51%, P = 0.13).Conclusion: Within the power of this study, our findings suggest that the selected polymorphic variants in the estrogen biosynthesis and metabolism pathways are unlikely to be major genetic modifiers of the prevalence of EGFR-mutant NSCLC.
DNA Damage Detection and Repair Pathways—Recent Advances with Inhibitors of Checkpoint Kinases in Cancer Therapy
Authors: Ashwell Susan , Zabludoff Sonya 
Published: July 2008

Abstract
Insights from cell cycle research have led to the hypothesis that tumors may be selectivity sensitized to DNA-damaging agents, resulting in improved antitumor activity and a wider therapeutic margin. The theory relies primarily on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway, resulting in reliance on S and G2 phase checkpoints for DNA repair and cell survival. The S and G2 phase checkpoints are predominantly regulated by checkpoint kinase 1; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway that allows for DNA repair and cell survival. There is now a large body of preclinical evidence showing that checkpoint kinase inhibitors do indeed enhance the efficacy of both conventional chemotherapy and radiotherapy, and several agents have recently entered clinical trials. Excitingly, additional therapeutic opportunities for checkpoint kinase inhibitors continue to emerge as biology outside their pivotal role in cell cycle arrest is further elucidated.
Combined Inhibition of c-Src and Epidermal Growth Factor Receptor Abrogates Growth and Invasion of Head and Neck Squamous Cell Carcinoma
Authors: Koppikar Priya , Choi Seung-Ho , Egloff Ann Marie , Cai Quan , Suzuki Shinsuke , Freilino Maria , Nozawa Hiroshi , Thomas Sufi M. , Gooding William E. , Siegfried Jill M. , Grandis Jennifer R. 
Published: July 2008

Abstract
Purpose: Increased expression and/or activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and poor prognosis in many cancers, including head and neck squamous cell carcinoma (HNSCC). Src family kinases, including c-Src, mediate a variety of intracellular or extracellular signals that contribute to tumor formation and progression. This study was undertaken to elucidate the role of c-Src in the growth and invasion of HNSCC and to determine the effects of combined targeting of EGFR and Src kinases in HNSCC cell lines.
Experimental Design: HNSCC cells were engineered to stably express a dominant-active form of c-Src and investigated in cell growth and invasion assays. The biochemical effects of combined treatment with the Src inhibitor AZD0530, a potent, orally active Src inhibitor with Bcr/Abl activity, and the EGFR kinase inhibitor gefitinib were examined, as well as the consequences of dual Src/EGFR targeting on the growth and invasion of a panel of HNSCC cell lines.
Results: HNSCC cells expressing dominant-active c-Src showed increased growth and invasion compared with vector-transfected controls. Combined treatment with AZD0530 and gefitinib resulted in greater inhibition of HNSCC cell growth and invasion compared with either agent alone.
Conclusions: These results suggest that increased expression and activation of c-Src promotes HNSCC progression where combined targeting of EGFR and c-Src may be an efficacious treatment approach.
Functional Variants of the NEIL1 and NEIL2 Genes and Risk and Progression of Squamous Cell Carcinoma of the Oral Cavity and Oropharynx
Authors: Zhai Xiaodong , Zhao Hui , Liu Zhensheng , Wang Li-E , El-Naggar Adel K. , Sturgis Erich M. , Wei Qingyi 
Published: July 2008

Abstract
Purpose: Human DNA glycosylases NEIL1 and NEIL2 participate in oxidized base excision repair and protect cells from DNA damage. NEIL1 (MIM:608844) and NEIL2 (MIM:608933) variants may affect their protein functions, leading to altered cell death and carcinogenesis. To date, only one reported study has investigated the association between NEIL1 and NEIL2 polymorphisms and cancer risk.
Experimental Design: Genotype and haplotypes of the NEIL1 NT_010194.16:g.46434077G&gt;T (rs7182283) and g.46438282C&gt;G (rs4462560) and NEIL2 NT_077531.3:g.4102971C&gt;G (rs804270) polymorphisms were determined for 872 patients with newly diagnosed squamous cell carcinomas of the oral cavity and oropharynx (SCCOOP) and 1,044 cancer-free non–Hispanic white control subjects frequency-matched by age and sex. Crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression, and false-positive report probabilities were also calculated.
Results: We found no overall differences in the frequencies of alleles, genotypes, and haplotypes of NEIL1 g.46434077G&gt;T and NEIL1 g.46438282C&gt;G polymorphisms between cases and controls. However, the NEIL2 g.4102971CC genotype was associated with a significantly increased risk of SCCOOP (adjusted OR, 1.30; 95% CI, 1.02-1.65); this increase in risk was the highest among current alcohol drinkers (adjusted OR, 1.87; 95% CI, 1.28-2.72), particularly in patients with oropharyngeal cancer (adjusted OR, 1.35; 95% CI, 1.04-1.76). The NEIL2 g.4102971CC genotype was also significantly associated with SCCOOP of advanced stages.
Conclusions: Polymorphisms of the NEIL2 gene may be markers for risk and progression of SCCOOP, particularly in patients with oropharyngeal cancer. Larger studies are needed to confirm our findings.
Multiple Mechanisms of Telomere Maintenance Exist and Differentially Affect Clinical Outcome in Diffuse Malignant Peritoneal Mesothelioma
Authors: Villa Raffaella , Daidone Maria Grazia , Motta Rosita , Venturini Lorenza , De Marco Cinzia , Vannelli Alberto , Kusamura Shigeki , Baratti Dario , Deraco Marcello , Costa Aurora , Reddel Roger R. , Zaffaroni Nadia 
Published: July 2008

AbstractPurpose: This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM).Experimental Design: In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy.Results: Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA−, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versus TA−, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy.Conclusions: Our results indicate that both known telomere maintenance mechanisms, TA and ALT, are present in DMPM and differentially affect patient prognosis.
Dendritic Cell Vaccination with Xenogenic Polypeptide Hormone Induces Tumor Rejection in Neuroendocrine Cancer
Authors: Papewalis Claudia , Wuttke Margret , Seissler Jochen , Meyer Yvonne , Kessler Caroline , Jacobs Benedikt , Ullrich Evelyn , Willenberg Holger S. , Schinner Sven , Baehring Thomas , Scherbaum Werner A. , Schott Matthias 
Published: July 2008

Abstract
Purpose: No relevant breakthrough has yet been achieved in the identification of tumor antigens in many neuroendocrine cancer types that exist, such as malignant gastrinoma, insulinoma, or medullary thyroid carcinoma. The aim of this study was to proof the concept of dendritic cell immunization with a tumor cell-specific polypeptide hormone as a target molecule in a transgenic mouse model for medullary thyroid carcinoma (Ret/Cal mice).
Experimental Design: Ret/Cal mice were repeatedly immunized for up to 6 months with amino acid–modified (xenogenic) calcitonin-pulsed dendritic cells. Xenogenic calcitonin was chosen for immunization due to its higher immunogenicity as compared with murine calcitonin.
Results: Lymph nodes from control protein-immunized mice did not show any macroscopic abnormalities, whereas tumor peptide-treated mice revealed in general profoundly enlarged lymph nodes. In tetramer analysis of paratumorous lymph nodes, 1.9% to 3.1% of all infiltrating CD8+ T cells were specific for one of three tumor epitopes tested. Analysis of the activated IFN-γ-secreting component in splenic cells revealed an average of 2.8% tumor epitope-specific CD8+ cells. Immunohistochemistry revealed strong CD8+ tumor infiltration in calcitonin-vaccinated mice. In addition, these cells also showed strong in vitro lysis capacity at up to 63.3%. Most importantly, calcitonin-immunized mice revealed largely diminished tumor outgrowth (−74.3%) compared with control mice (P &lt; 0.0001). Likewise, serum calcitonin levels in calcitonin-vaccinated Ret/Cal mice were lower than in the control group.
Conclusion: These results have a major effect, as they are the first to establish a role for xenogenic polypeptide hormones as target molecules for immunotherapy in endocrine malignancies.
Motor-induced Suppression of the Auditory Cortex
Authors: Aliu Sheye O. , Houde John F. , Nagarajan Srikantan S. 
Published: July 2008

Abstract
Sensory responses to stimuli that are triggered by a self-initiated motor act are suppressed when compared with the response to the same stimuli triggered externally, a phenomenon referred to as motor-induced suppression (MIS) of sensory cortical feedback. Studies in the somatosensory system suggest that such suppression might be sensitive to delays between the motor act and the stimulus onset, and a recent study in the auditory system suggests that such MIS develops rapidly. In three MEG experiments, we characterize the properties of MIS by examining the M100 response from the auditory cortex to a simple tone triggered by a button press. In Experiment 1, we found that MIS develops for zero delays but does not generalize to nonzero delays. In Experiment 2, we found that MIS developed for 100-msec delays within 300 trials and occurs in excess of auditory habituation. In Experiment 3, we found that unlike MIS for zero delays, MIS for nonzero delays does not exhibit sensitivity to sensory, delay, or motor-command changes. These results are discussed in relation to suppression to self-produced speech and a general model of sensory motor processing and control.
The Long Road to Automation: Neurocognitive Development of Letter–Speech Sound Processing
Authors: Froyen Dries J. W. , Bonte Milene L. , van Atteveldt Nienke , Blomert Leo 
Published: July 2008

Abstract
In transparent alphabetic languages, the expected standard for complete acquisition of letter–speech sound associations is within one year of reading instruction. The neural mechanisms underlying the acquisition of letter–speech sound associations have, however, hardly been investigated. The present article describes an ERP study with beginner and advanced readers in which the influence of letters on speech sound processing is investigated by comparing the MMN to speech sounds presented in isolation with the MMN to speech sounds accompanied by letters. Furthermore, SOA between letter and speech sound presentation was manipulated in order to investigate the development of the temporal window of integration for letter–speech sound processing. Beginner readers, despite one year of reading instruction, showed no early letter–speech sound integration, that is, no influence of the letter on the evocation of the MMN to the speech sound. Only later in the difference wave, at 650 msec, was an influence of the letter on speech sound processing revealed. Advanced readers, with 4 years of reading instruction, showed early and automatic letter–speech sound processing as revealed by an enhancement of the MMN amplitude, however, at a different temporal window of integration in comparison with experienced adult readers. The present results indicate a transition from mere association in beginner readers to more automatic, but still not “adult-like,” integration in advanced readers. In contrast to general assumptions, the present study provides evidence for an extended development of letter–speech sound integration.
Parameterization of Eddy Fluxes near Oceanic Boundaries
Authors: Ferrari Raffaele , McWilliams James C. , Canuto Vittorio M. , Dubovikov Mikhail 
Published: July 2008

Abstract
In the stably stratified interior of the ocean, mesoscale eddies transport materials by quasi-adiabatic isopycnal stirring. Resolving or parameterizing these effects is important for modeling the oceanic general circulation and climate. Near the bottom and near the surface, however, microscale boundary layer turbulence overcomes the adiabatic, isopycnal constraints for the mesoscale transport. In this paper a formalism is presented for representing this transition from adiabatic, isopycnally oriented mesoscale fluxes in the interior to the diabatic, along-boundary mesoscale fluxes near the boundaries. A simple parameterization form is proposed that illustrates its consequences in an idealized flow. The transition is not confined to the turbulent boundary layers, but extends into the partially diabatic transition layers on their interiorward edge. A transition layer occurs because of the mesoscale variability in the boundary layer and the associated mesoscale–microscale dynamical coupling.
Response of the Antarctic Circumpolar Current to Atmospheric Variability
Authors: Sallée J. B. , Speer K. , Morrow R. 
Published: July 2008

Abstract
Historical hydrographic profiles, combined with recent Argo profiles, are used to obtain an estimate of the mean geostrophic circulation in the Southern Ocean. Thirteen years of altimetric sea level anomaly data are then added to reconstruct the time variable sea level, and this new dataset is analyzed to identify and monitor the position of the two main fronts of the Antarctic Circumpolar Current (ACC) during the period 1993–2005. The authors relate their movements to the two main atmospheric climate modes of the Southern Hemisphere: the Southern Annular Mode (SAM) and the El Niño–Southern Oscillation (ENSO). The study finds that although the fronts are steered by the bathymetry, which sets their mean pathway on first order, in flat-bottom areas the fronts are subject to large meandering because of mesoscale activity and atmospheric forcing. While the dominant mode of atmospheric variability in the Southern Hemisphere, SAM, is relatively symmetric, the oceanic response of the fronts is not, showing substantial regional differences. Around the circumpolar belt the fronts vary in latitude, exposing them to different Ekman transport anomalies induced by the SAM. Three typical scenarios occur in response to atmospheric forcing: poleward movement of the frontal structure in the Indian Basin during positive SAM events, an equatorward movement in the central Pacific, and an intensification without substantial meridional movement in the Indo-Pacific basin. The study also shows the geographical regions that are dominated by a SAM or ENSO response at low and high frequencies.
A Coupled Air–Sea Response Mechanism to Solar Forcing in the Pacific Region
Authors: Meehl Gerald A. , Arblaster Julie M. , Branstator Grant , van Loon Harry 
Published: July 2008

Abstract
The 11-yr solar cycle [decadal solar oscillation (DSO)] at its peaks strengthens the climatological precipitation maxima in the tropical Pacific during northern winter. Results from two global coupled climate model ensemble simulations of twentieth-century climate that include anthropogenic (greenhouse gases, ozone, and sulfate aerosols, as well as black carbon aerosols in one of the models) and natural (volcano and solar) forcings agree with observations in the Pacific region, though the amplitude of the response in the models is about half the magnitude of the observations. These models have poorly resolved stratospheres and no 11-yr ozone variations, so the mechanism depends almost entirely on the increased solar forcing at peaks in the DSO acting on the ocean surface in clear sky areas of the equatorial and subtropical Pacific. Mainly due to geometrical considerations and cloud feedbacks, this solar forcing can be nearly an order of magnitude greater in those regions than the globally averaged solar forcing. The mechanism involves the increased solar forcing at the surface being manifested by increased latent heat flux and evaporation. The resulting moisture is carried to the convergence zones by the trade winds, thereby strengthening the intertropical convergence zone (ITCZ) and the South Pacific convergence zone (SPCZ). Once these precipitation regimes begin to intensify, an amplifying set of coupled feedbacks similar to that in cold events (or La Niña events) occurs. There is a strengthening of the trades and greater upwelling of colder water that extends the equatorial cold tongue farther west and reduces precipitation across the equatorial Pacific, while increasing precipitation even more in the ITCZ and SPCZ. Experiments with the atmosphere component from one of the coupled models are performed in which heating anomalies similar to those observed during DSO peaks are specified in the tropical Pacific. The result is an anomalous Rossby wave response in the atmosphere and consequent positive sea level pressure (SLP) anomalies in the North Pacific extending to western North America. These patterns match features that occur during DSO peak years in observations and the coupled models.
Effects of Black Carbon Aerosols on the Indian Monsoon
Authors: Meehl Gerald A. , Arblaster Julie M. , Collins William D. 
Published: July 2008

Abstract
A six-member ensemble of twentieth-century simulations with changes to only time-evolving global distributions of black carbon aerosols in a global coupled climate model is analyzed to study the effects of black carbon (BC) aerosols on the Indian monsoon. The BC aerosols act to increase lower-tropospheric heating over South Asia and reduce the amount of solar radiation reaching the surface during the dry season, as noted in previous studies. The increased meridional tropospheric temperature gradient in the premonsoon months of March–April–May (MAM), particularly between the elevated heat source of the Tibetan Plateau and areas to the south, contributes to enhanced precipitation over India in those months. With the onset of the monsoon, the reduced surface temperatures in the Bay of Bengal, Arabian Sea, and over India that extend to the Himalayas act to reduce monsoon rainfall over India itself, with some small increases over the Tibetan Plateau. Precipitation over China generally decreases due to the BC aerosol effects. There is a weakened latitudinal SST gradient resulting from BC aerosols in the model simulations as seen in the observations, and this is present in the multiple-forcings experiments with the Community Climate System Model, version 3 (CCSM3), which includes natural and anthropogenic forcings (including BC aerosols). The BC aerosols and consequent weakened latitudinal SST gradient in those experiments are associated with increased precipitation during MAM in northern India and over the Tibetan Plateau, with some decreased precipitation over southwest India, the Bay of Bengal, Burma, Thailand, and Malaysia, as seen in observations. During the summer monsoon season, the model experiments show that BC aerosols have likely contributed to observed decreasing precipitation trends over parts of India, Bangladesh, Burma, and Thailand. Analysis of single ensemble members from the multiple-forcings experiment suggests that the observed increasing precipitation trends over southern China appear to be associated with natural variability connected to surface temperature changes in the northwest Pacific.