bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three-Dimensional Collagen I Promotes Gemcitabine Resistance in Pancreatic Cancer through MT1-MMP–Mediated Expression of HMGA2
Authors: Dangi-Garimella Surabhi , Krantz Seth B. , Barron Morgan R. , Shields Mario A. , Heiferman Michael J. , Grippo Paul J. , Bentrem David J. , Munshi Hidayatullah G. 
Published: December 2010

Abstract
One of the hallmarks of human pancreatic ductal adenocarcinoma (PDAC) is its pronounced type I collagen-rich fibrotic reaction. Although recent reports have shown that the fibrotic reaction can limit the efficacy of gemcitabine chemotherapy, the underlying mechanisms remain poorly understood. In this article, we show that the type I collagen allows PDAC cells to override checkpoint arrest induced by gemcitabine. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3-dimensional collagen microenvironment have minimal Chk1 phosphorylation and continue to proliferate in the presence of gemcitabine. Collagen increases membrane type 1 matrix metalloproteinase (MT1-MMP)–dependent ERK1/2 phosphorylation to limit the effect of gemcitabine. Collagen also increases MT1-MMP–dependent high mobility group A2 (HMGA2) expression, a nonhistone DNA-binding nuclear protein involved in chromatin remodeling and gene transcription, to attenuate the effect of gemcitabine. Overexpression of MT1-MMP in the collagen microenvironment increases ERK1/2 phosphorylation and HMGA2 expression, and thereby further attenuates gemcitabine-induced checkpoint arrest. MT1-MMP also allows PDAC cells to continue to proliferate in the presence of gemcitabine in a xenograft mouse model. Clinically, human tumors with increased MT1-MMP show increased HMGA2 expression. Overall, our data show that collagen upregulation of MT1-MMP contributes to gemcitabine resistance in vitro and in a xenograft mouse model, and suggest that targeting MT1-MMP could be a novel approach to sensitize pancreatic tumors to gemcitabine. Cancer Res; 71(3); 1019–28. ©2010 AACR.
Human Papillomavirus E7 Enhances Hypoxia-Inducible Factor 1–Mediated Transcription by Inhibiting Binding of Histone Deacetylases
Authors: Bodily Jason M. , Mehta Kavi P.M. , Laimins Laimonis A. 
Published: December 2010

Abstract
Infection by human papillomaviruses (HPV) leads to the formation of benign lesions, warts, and in some cases, cervical cancer. The formation of these lesions is dependent upon increased expression of proangiogenic factors. Angiogenesis is linked to tissue hypoxia through the activity of the oxygen-sensitive hypoxia-inducible factor 1α (HIF-1α). Our studies indicate that the HPV E7 protein enhances HIF-1 transcriptional activity whereas E6 functions to counteract the repressive effects of p53. Both high- and low-risk HPV E7 proteins were found to bind to HIF-1α through a domain located in the N-terminus. Importantly, the ability of E7 to enhance HIF-1 activity mapped to the C-terminus and correlated with the displacement of the histone deacetylases HDAC1, HDAC4, and HDAC7 from HIF-1α by E7. Our findings describe a novel role of the E7 oncoprotein in activating the function of a key transcription factor mediating hypoxic responses by blocking the binding of HDACs. Cancer Res; 71(3); 1187–95. ©2010 AACR.
Data Assimilation of Cloud-Affected Radiances in a Cloud-Resolving Model
Authors: Polkinghorne Rosanne , Vukicevic Tomislava 
Published: December 2010

AbstractAssimilation of cloud-affected infrared radiances from the Geostationary Operational Environmental Satellite-8 (GOES-8) is performed using a four-dimensional variational data assimilation (4DVAR) system designated as the Regional Atmospheric Modeling Data Assimilation System (RAMDAS). A cloud mask is introduced in order to limit the assimilation to points that have the same type of cloud in the model and observations, increasing the linearity of the minimization problem. A series of experiments is performed to determine the sensitivity of the assimilation to factors such as the maximum-allowed residual in the assimilation, the magnitude of the background error decorrelation length for water variables, the length of the assimilation window, and the inclusion of other data such as ground-based data including data from the Atmospheric Emitted Radiance Interferometer (AERI), a microwave radiometer, radiosonde, and cloud radar. In addition, visible and near-infrared satellite data are included in a separate experiment. The assimilation results are validated using independent ground-based data. The introduction of the cloud mask where large residuals are allowed has the greatest positive impact on the assimilation. Extending the length of the assimilation window in conjunction with the use of the cloud mask results in a better-conditioned minimization, as well as a smoother response of the model state to the assimilation.
Sumatriptan as a treatment for cyclic vomiting syndrome: A clinical trial
Authors: Hikita Toshiyuki , Kodama Hiroko , Kaneko Sono , Amakata Kaori , Ogita Kaori , Mochizuki Daishi , Kaga Fumiaya , Nakamoto Natsue , Fujii Yasushi , Kikuchi Akira 
Published: December 2010

Background and objective Cyclic vomiting syndrome (CVS) is associated with migraine. This study aimed to evaluate the efficacy of sumatriptan in treating CVS. Methods Twelve patients were enrolled in this trial. Sumatriptan was administered either subcutaneously [(age × 4 + 20)/100×3mg] or by nasal spray (NS; 20 mg). Response to the treatment was classified as complete, effective, or noneffective. Results Eleven patients, who presented with 35 attacks, were treated by subcutaneous injection of sumatriptan. The treatment was responsive in 19 attacks. The efficacy of sumatriptan was high in attacks that occurred in cases with a family history of migraine compared to those without (p = .0482). Five patients were treated with sumatriptan NS for six attacks. The treatment was completely responsive in two of six attacks. We observed no adverse effects associated with sumatriptan treatment in this trial. Conclusions We conclude that sumatriptan has potential efficacy in treating of patients with CVS.
The (AAT)n repeat of the cannabinoid CB1 receptor gene influences disease progression in relapsing multiple sclerosis
Authors: Rossi Silvia , Buttari Fabio , Studer Valeria , Motta Caterina , Gravina Paolo , Castelli Maura , Mantovani Vilma , De Chiara Valentina , Musella Alessandra , Fiore Stefania , Masini Silvia , Bernardi Giorgio , Maccarrone Mauro , Bernardini Sergio , Centonze Diego 
Published: December 2010

Background: Genetic and pharmacological inactivation of cannabinoid CB1 receptors (CB1Rs) exacerbates disease course in experimental autoimmune encephalomyelitis, suggesting that CB1Rs might play a role in the neurodegenerative damage associated with multiple sclerosis (MS). Objectives: To see whether CNR1 gene polymorphism could influence disease progression in relapsing–remitting MS. Methods: The genotype of 350 patients for the number of AAT repeats was characterized and correlation studies were performed with measures of disease severity and progression. Results: MS patients with the homozygous genotype for long AAT repeats in the CNR1 gene had more severe disease and higher risk of progression. These subjects had significantly higher scores on both the progression index and the MS severity scale. Furthermore, the percentage of patients with MS functional composite score progression or Bayesian Risk Estimate for MS (BREMS) score ≥2 (considered at very high risk of secondary progression) was significantly higher in the AAT long group than in the short group, while the frequency of patients with BREMS score ≤−0.63 (very likely to remain progression-free) was not significantly different between the two groups, although lower in the long group. Finally, the frequency of patients prescribed a second-line treatment was significantly higher among subjects of the AAT long group, providing a further, indirect indication of higher disease severity. Conclusions: The results of the present investigation point to CB1R as an important modulator of disease severity in relapsing MS subjects.
Structural determinants of vascular endothelial growth factor-D receptor binding and specificity
Authors: Leppänen Veli-Matti , Jeltsch Michael , Anisimov Andrey , Tvorogov Denis , Aho Kukka , Kalkkinen Nisse , Toivanen Pyry , Ylä-Herttuala Seppo , Ballmer-Hofer Kurt , Alitalo Kari 
Published: December 2010

AbstractVascular endothelial growth factors (VEGFs) and their tyrosine kinase receptors (VEGFR-1-3) are central mediators of angiogenesis and lymphangiogenesis. VEGFR-3 ligands VEGF-C and VEGF-D are produced as precursor proteins with long N- and C-terminal propeptides and show enhanced VEGFR-2 and VEGFR-3 binding on proteolytic removal of the propeptides. Two different proteolytic cleavage sites have been reported in the VEGF-D N-terminus. We report here the crystal structure of the human VEGF-D Cys117Ala mutant at 2.9 Å resolution. Comparison of the VEGF-D and VEGF-C structures shows similar extended N-terminal helices, conserved overall folds, and VEGFR-2 interacting residues. Consistent with this, the affinity and the thermodynamic parameters for VEGFR-2 binding are very similar. In comparison with VEGF-C structures, however, the VEGF-D N-terminal helix was extended by 2 more turns because of a better resolution. Both receptor binding and functional assays of N-terminally truncated VEGF-D polypeptides indicated that the residues between the reported proteolytic cleavage sites are important for VEGF-D binding and activation of VEGFR-3, but not of VEGFR-2. Thus, we define here a VEGFR-2–specific form of VEGF-D that is angiogenic but not lymphangiogenic. These results provide important new insights into VEGF-D structure and function.
Application of Wavelet Packet Transform to detect genetic polymorphisms by the analysis of inter-Alu PCR patterns
Authors: Cardelli Maurizio , Nicoli Matteo , Bazzani Armando , Franceschi Claudio 
Published: December 2010

AbstractBackgroundThe analysis of Inter-Alu PCR patterns obtained from human genomic DNA samples is a promising technique for a simultaneous analysis of many genomic loci flanked by Alu repetitive sequences in order to detect the presence of genetic polymorphisms. Inter-Alu PCR products may be separated and analyzed by capillary electrophoresis using an automatic sequencer that generates a complex pattern of peaks. We propose an algorithmic method based on the Haar-Walsh Wavelet Packet Transformation (WPT) for an efficient detection of fingerprint-type patterns generated by PCR-based methodologies. We have tested our algorithmic approach on inter-Alu patterns obtained from the genomic DNA of three couples of monozygotic twins, expecting that the inter-Alu patterns of each twins couple will show differences due to unavoidable experimental variability. On the contrary the differences among samples of different twins are supposed to originate from genetic variability. Our goal is to automatically detect regions in the inter-Alu pattern likely associated to the presence of genetic polymorphisms.ResultsWe show that the WPT algorithm provides a reliable tool to identify sample to sample differences in complex peak patterns, reducing the possible errors and limits associated to a subjective evaluation. The redundant decomposition of the WPT algorithm allows for a procedure of best basis selection which maximizes the pattern differences at the lowest possible scale. Our analysis points out few classifying signal regions that could indicate the presence of possible genetic polymorphisms.ConclusionsThe WPT algorithm based on the Haar-Walsh wavelet is an efficient tool for a non-supervised pattern classification of inter-ALU signals provided by a genetic analyzer, even if it was not possible to estimate the power and false positive rate due to the lacking of a suitable data base. The identification of non-reproducible peaks is usually accomplished comparing different experimental replicates of each sample. Moreover, we remark that, albeit we developed and optimized an algorithm able to analyze patterns obtained through inter-Alu PCR, the method is theoretically applicable to whatever fingerprint-type pattern obtained analyzing anonymous DNA fragments through capillary electrophoresis, and it could be usefully applied on a wide range of fingerprint-type methodologies.
Novel variation associated with species range expansion
Authors: Buckley James , Bridle Jon R , Pomiankowski Andrew 
Published: December 2010

Abstract
When species shift their ranges to track climate change, they are almost certain to experience novel environments to which they are poorly adapted. Otaki and co-workers document an explosion of wing pattern variation accompanying range expansion in the pale grass blue butterfly. This pattern can be replicated in the laboratory using artificial selection on cold shocked pupae, at temperature extremes typical of recently colonized environments. We discuss how this phenotypic plasticity may be associated with successful colonization and how significant local adaptation is likely to re-establish developmental control. Integrating knowledge of trait plasticity into current genetic models of adaptation is central to our understanding of when and where a colonising population will be able to persist and adapt in novel surroundings.
Arabidopsis brassinosteroid biosynthetic mutant dwarf7-1exhibits slower rates of cell division and shoot induction
Authors: Cheon Jinyeong , Park So-Young , Schulz Burkhard , Choe Sunghwa 
Published: December 2010

AbstractBackgroundPlant growth depends on both cell division and cell expansion. Plant hormones, including brassinosteroids (BRs), are central to the control of these two cellular processes. Despite clear evidence that BRs regulate cell elongation, their roles in cell division have remained elusive.ResultsHere, we report results emphasizing the importance of BRs in cell division. An Arabidopsis BR biosynthetic mutant,dwarf7-1, displayed various characteristics attributable to slower cell division rates. We found that theDWARF4gene which encodes for an enzyme catalyzing a rate-determining step in the BR biosynthetic pathways, is highly expressed in the actively dividing callus, suggesting that BR biosynthesis is necessary for dividing cells. Furthermore,dwf7-1showed noticeably slower rates of callus growth and shoot induction relative to wild-type control. Flow cytometric analyses of the nuclei derived from either calli or intact roots revealed that the cell division index, which was represented as the ratio of cells at the G2/M vs. G1 phases, was smaller indwf7-1plants. Finally, we found that the expression levels of the genes involved in cell division and shoot induction, such asPROLIFERATING CELL NUCLEAR ANTIGEN2(PCNA2) andENHANCER OF SHOOT REGENERATION2(ESR2), were also lower indwf7-1as compared with wild type.ConclusionsTaken together, results of callus induction, shoot regeneration, flow cytometry, and semi-quantitative RT-PCR analysis suggest that BRs play important roles in both cell division and cell differentiation in Arabidopsis.
CCAAT/Enhancer Binding Protein-delta (C/EBP-delta) regulates cell growth, migration and differentiation
Authors: Yu Xueyan , Si Junling , Zhang Yingjie , DeWille James W 
Published: December 2010

Abstract

Background
CCAAT/enhancer binding protein-delta (C/EBP-delta) is a member of the highly conserved C/EBP family of basic region leucine zipper transcription factors. C/EBP family members regulate cell growth and differentiation and "loss of function" alterations in C/EBPs have been reported in a variety of human cancers. C/EBP-delta gene expression is upregulated by G0 growth arrest, IL-6 family cytokines and endotoxin treatments. C/EBP-delta exhibits properties of a tumor suppressor gene, including reduced expression and promoter methylation-induced silencing in transformed cell lines and primary tumors. In addition, C/EBP-delta gene expression is repressed by c-Myc, an oncogene that is over-expressed in a wide range of human cancers. "ChIP-chip" studies demonstrated that C/EBP-delta functions as a transcriptional activator of target genes that function in intracellular signal transduction, transcription, DNA binding/repair, cell cycle control, cell adhesion, and apoptosis. Despite progress in determining the biochemical functions of C/EBP-delta, the specific cellular defects that are induced by C/EBP-delta "loss of function" alterations are poorly understood. This study investigated the impact of C/EBP-delta "loss of function" alterations on growth arrest, migration/invasion and differentiation in nontransformed mouse mammary epithelial cells (MECs) and primary mouse embryo fibroblasts (MEFs).

Results
C/EBP-delta siRNA transfected MECs exhibited ~90% reduction in C/EBP-delta mRNA and protein levels. C/EBP-delta siRNA treatment resulted in defective growth arrest as demonstrated by persistently elevated BrdU labeling, 3H-thymidine incorporation and cyclin D1 levels in response to growth arrest treatments. C/EBP-delta siRNA treatment also resulted in increased migration/invasion and defective differentiation. C/EBP-delta knockout MEFs exhibited defective growth arrest and increased proliferation/migration. Re-introduction of C/EBP-delta expression restored the growth arrest response of C/EBP-delta knockout MEFs. Finally, deletion of the C/EBP-delta DNA binding domain or the C/EBP-delta bZIP domain resulted in the loss of C/EBP-delta growth inhibition in clonogenic assays.

Conclusions
This study demonstrates that C/EBP-delta functions in the regulation of critical cell fate determining programs such as growth arrest, migration, and differentiation. These results support the tumor suppressor function of C/EBP-delta and identify potential mechanisms in which "loss of function" alterations in C/EBP-delta could promote cell transformation and tumorigenesis.
The ERK MAP kinase-PEA3/ETV4-MMP-1 axis is operative in oesophageal adenocarcinoma
Authors: Keld Richard , Guo Baoqiang , Downey Paul , Gulmann Christian , Ang Yeng S , Sharrocks Andrew D 
Published: December 2010

Abstract

Background
Many members of the ETS-domain transcription factor family are important drivers of tumourigenesis. In this context, their activation by Ras-ERK pathway signaling is particularly relevant to the tumourigenic properties of many ETS-domain transcription factors. The PEA3 subfamily of ETS-domain transcription factors have been implicated in tumour metastasis in several different cancers.

Results
Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in oesophageal adenocarcinomas and determined their role in oesophageal adenocarcinoma cell function. PEA3 plays an important role in controlling both the proliferation and invasive properties of OE33 oesophageal adenocarcinoma cells. A key target gene is MMP-1. The ERK MAP kinase pathway activates PEA3 subfamily members and also plays a role in these PEA3 controlled events, establishing the ERK-PEA3-MMP-1 axis as important in OE33 cells. PEA3 subfamily members are upregulated in human adenocarcinomas and expression correlates with MMP-1 expression and late stage metastatic disease. Enhanced ERK signaling is also more prevalent in late stage oesophageal adenocarcinomas.

Conclusions
This study shows that the ERK-PEA3-MMP-1 axis is upregulated in oesophageal adenocarcinoma cells and is a potentially important driver of the metastatic progression of oesophageal adenocarcinomas.
The effects of obesity and polycystic ovary syndrome on serum lipocalin-2 levels: a cross-sectional study
Authors: Panidis Dimitrios , Tziomalos Konstantinos , Koiou Ekaterini , Kandaraki Eleni A , Tsourdi Elena , Delkos Dimitrios , Kalaitzakis Emmanuil , Katsikis Ilias 
Published: December 2010

AbstractBackgroundLipocalin-2 is a novel adipokine that appears to play a role in the development of insulin resistance. Serum lipocalin-2 levels are elevated in obese patients. Obesity and insulin resistance are cardinal characteristics of the polycystic ovary syndrome (PCOS). However, there are limited data on serum lipocalin-2 levels in patients with PCOS. The aim of the present study was to assess serum lipocalin-2 levels in PCOS.MethodsWe studied 200 patients with PCOS and 50 healthy female volunteers.ResultsSerum lipocalin-2 levels were slightly higher in women with PCOS compared with controls (65.4 +/- 34.3 vs. 60.3 +/- 26.0 ng/ml, respectively) but this difference did not reach statistical significance. In contrast, lipocalin-2 levels were higher in overweight/obese women with PCOS than in normal weight women with the syndrome (76.2 +/- 37.3 vs. 54.5 +/- 27.2 ng/ml, respectively; p < 0.001). Serum lipocalin-2 levels were also higher in overweight/obese controls compared with normal weight controls (70.1 +/- 24.9 vs. 50.5 +/- 23.7 ng/ml, respectively; p = 0.004). In the total study population (patients with PCOS and controls), lipocalin-2 levels were independently correlated with the body mass index (p < 0.001). In women with PCOS, lipocalin-2 levels were independently correlated with the waist (p < 0.001).ConclusionsObesity is associated with elevated serum lipocalin-2 levels. In contrast, PCOS does not appear to affect lipocalin-2 levels.
Waist to hip ratio and trunk to extremity fat (DXA) are better surrogates for IMCL and for visceral fat respectively than for subcutaneous fat in adolescent girls
Authors: Savgan-Gurol Eray , Bredella Miriam , Russell Melissa , Mendes Nara , Klibanski Anne , Misra Madhusmita 
Published: December 2010

Abstract

Background
Increased visceral adipose tissue (VAT) and intramyocellular lipids (IMCL) are associated with increased metabolic risk. Clinical and DXA body composition measures that are associated with VAT are generally even more strongly associated with subcutaneous adipose tissue (SAT) reflecting general adiposity, and thus are not specific for VAT. Measures more strongly associated with VAT than SAT (thus more specific for VAT), and predictors of IMCL have not been reported.

Subjects/Methods
We studied 30 girls 12-18 years; 15 obese, 15 normal-weight. The following were assessed: (1) anthropometric measures: waist circumference at the umbilicus and iliac crest (WC-UC and WC-IC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), (2) DXA measures: total fat, percent body fat (PBF), percent trunk fat (PTF), trunk-to-extremity fat ratio (TEFR), (3) MRI and 1H-MRS: VAT and SAT (L4-L5), soleus-IMCL.

Results

Group as a whole:
WC, trunk fat and PBF were more strongly associated with SAT than VAT; none were specific for VAT. In contrast, PTF and TEFR were more significantly associated with VAT (r = 0.83 and 0.81 respectively, p <0.0001 for both) than SAT (r = 0.77 and 0.75, p < 0.0001 for both). Strongest associations of S-IMCL were with WHR (r = 0.66, p = 0.0004).
Subgroup analysis:
In obese girls, WHR and WHtR were more strongly correlated with VAT (r = 0.62 and 0.82, p = 0.04 and 0.001) than SAT (r = 0.41 and 0.73, p not significant and 0.007), and for DXA measures, PTF and TEFR were more significantly associated with VAT (r = 0.70 and 0.72, p = 0.007 and 0.006) than SAT (r = 0.52 and 0.53, p = 0.07 and 0.06). In controls, PTF and TEFR were more strongly correlated with VAT (r = 0.79, p = 0.0004 for both) than SAT (r = 0.71 and 0.72, p = 0.003 for both). WHR was associated with IMCL in obese girls (r = 0.78, p = 0.008), but not controls.

Conclusion
Overall, WHR (anthropometry), and PTF and TEFR (DXA) are good surrogates for IMCL and for visceral fat respectively in adolescent girls.