bluuebunny/crossref_metadata_2025_split huggingface dataset:
The use of pooled vs serial urine samples to measure urine protein:creatinine ratios
Authors: LeVine Dana N. , Zhang Daowen , Harris Tonya , Vaden Shelly L. 
Published: July 2009

Background:Evaluation of serial urine protein:creatinine (UPC) ratios is important in prognosticating chronic kidney disease and monitoring response to therapeutic interventions. Owing to random biologic variation in dogs with stable glomerular proteinuria, multiple determinations of UPC ratios often are recommended to reliably assess urine protein loss. This can be cost‐prohibitive.Objective:The purpose of this study was to evaluate agreement between the mean of 3 UPC ratios obtained on 3 separate urine samples per dog and a single UPC ratio obtained when aliquots of the separate samples were pooled and analyzed as 1 sample.Methods:Three separate urine samples were collected from each of 25 dogs, both client‐owned and members of a research colony. Protein and creatinine concentrations were measured in the supernatant of each sample using a biochemical analyzer, and the mean of the 3 UPC ratios was calculated. A 1.0 mL aliquot of each of the 3 samples from each dog was pooled to create a fourth sample for that dog, and the UPC ratio of the pooled sample was similarly determined. Agreement and correlation between the mean and pooled UPC ratios were assessed using Bland–Altman difference plots and regression analysis, respectively.Results:The UPC ratio in the pooled samples was highly correlated (r=.9998,P<.0001) with the mean UPC ratio of the 3 separate samples. Strong agreement between results was demonstrated; a UPC ratio from a pooled sample was at most ±20% different than the mean UPC ratio obtained from 3 separate samples.Conclusions:Measuring the UPC ratio in a pooled sample containing equal volumes of several different urine specimens from the same dog provides a reliable and cost‐effective alternative to assessing multiple UPC ratios on several specimens from the same dog.
In Vivo and In Vitro Evidence of the Involvement of CXCL1, a Keratinocyte‐Derived Chemokine, in Equine Laminitis
Authors: Faleiros R.R. , Leise B.B. , Westerman T. , Yin C. , Nuovo G.J. , Belknap J.K. 
Published: July 2009

Background:C‐X‐C motif ligand 1 (CXCL1) is an important chemokine of epithelial origin in rodents and humans.Objectives:To assess in vivo and in vitro the regulation of CXCL1 in equine laminitis.Animals:Twenty adult horses.Methods:Real‐time quantitative polymerase chain reaction (PCR) was used to assess expression of CXCL1 in samples of laminae, liver, skin, and lung from the black walnut extract (BWE) model of laminitis, and in cultured equine epithelial cells (EpCs). Tissue was obtained from control animals (CON, n = 5), and at 1.5 hours (early time point [ETP] group, n = 5), at the onset of leukopenia (developmental time point [DTP] group, n = 5), and at the onset of lameness (LAM group, n = 5) after BWE administration. EpCs were exposed to Toll‐like/Nod receptor ligands, oxidative stress agents, and reduced atmospheric oxygen (3%). In situ PCR was used to localize the laminar cell types undergoing CXCL1 mRNA expression.Results:Increases in laminar CXCL1 mRNA concentrations occurred in the ETP (163‐fold [P= .0001]) and DTP groups (21‐fold [P= .005]). Smaller increases in CXCL1 expression occurred in other tissues and organs. In cultured EpCs, increases (P< .05) in CXCL1 mRNA concentration occurred after exposure to lipopolysaccharide (LPS [28‐fold]), xanthine/xanthine oxidase (3.5‐fold), and H2O2(2‐fold). Hypoxia enhanced the LPS‐induced increase in CXCL1 mRNA (P= .007). CXCL1 gene expression was localized to laminar EpCs, endothelial cells, and emigrating leukocytes.Conclusion and Clinical Importance:These findings indicate that CXCL1 plays an early and possibly initiating role in neutrophil accumulation in the BWE laminitis model, and that laminar keratinocytes are an important source of this chemokine. New therapies using chemokine receptor antagonists may be indicated.
Linear‐Accelerator‐Based Modified Radiosurgical Treatment of Pituitary Tumors in Cats: 11 Cases (1997–2008)
Authors: Sellon R.K. , Fidel J. , Houston R. , Gavin P.R. 
Published: July 2009

Objective:Determine the efficacy and safety of a linear‐accelerator‐based single fraction radiosurgical approach to the treatment of pituitary tumors in cats.Design:Retrospective study.Animals:Eleven client‐owned cats referred for treatment of pituitary tumors causing neurological signs, or poorly controlled diabetes mellitus (DM) secondary either to acromegaly or pituitary‐dependent hyperadrenocortism.Procedures:Cats underwent magnetic resonance imaging (MRI) of the brain to manually plan radiation therapy. After MRI, modified radiosurgery was performed by delivering a single large dose (15 or 20 Gy) of radiation while arcing a linear‐accelerator‐generated radiation beam around the cat's head with the pituitary mass at the center of the beam. Eight cats were treated once, 2 cats were treated twice, and 1 cat received 3 treatments. Treated cats were evaluated for improvement in endocrine function or resolution of neurological disease by review of medical records or contact with referring veterinarians and owners.Results:Improvement in clinical signs occurred in 7/11 (63.6%) of treated cats. Five of 9 cats with poorly regulated DM had improved insulin responses, and 2/2 cats with neurological signs had clinical improvement. There were no confirmed acute or late adverse radiation effects. The overall median survival was 25 months (range, 1–60), and 3 cats were still alive.Conclusions and Clinical Importance:Single fraction modified radiosurgery is a safe and effective approach to the treatment of pituitary tumors in cats.
Stimulating the GPR30 Estrogen Receptor with a Novel Tamoxifen Analogue Activates SF-1 and Promotes Endometrial Cell Proliferation
Authors: Lin Benjamin C. , Suzawa Miyuki , Blind Raymond D. , Tobias Sandra C. , Bulun Serdar E. , Scanlan Thomas S. , Ingraham Holly A. 
Published: July 2009

Abstract
Estrogens and selective estrogen receptor (ER) modulators such as tamoxifen are known to increase uterine cell proliferation. Mounting evidence suggests that estrogen signaling is mediated not only by ERα and ERβ nuclear receptors, but also by GPR30 (GPER), a seven transmembrane (7TM) receptor. Here, we report that primary human endometriotic H-38 cells express high levels of GPR30 with no detectable ERα or ERβ. Using a novel tamoxifen analogue, STX, which activates GPR30 but not ERs, significant stimulation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways was observed in H-38 cells and in Ishikawa endometrial cancer cells expressing GPR30; a similar effect was observed in JEG3 choriocarcinoma cells. STX treatment also increased cellular pools of phosphatidylinositol (3,4,5) triphosphate, a proposed ligand for the nuclear hormone receptor SF-1 (NR5A1). Consistent with these findings, STX, tamoxifen, and the phytoestrogen genistein were able to increase SF-1 transcription, promote Ishikawa cell proliferation, and induce the SF-1 target gene aromatase in a GPR30-dependent manner. Our findings suggest a novel signaling paradigm that is initiated by estrogen activation of the 7TM receptor GPR30, with signal transduction cascades (PI3K and MAPK) converging on nuclear hormone receptors (SF-1/LRH-1) to modulate their transcriptional output. We propose that this novel GPR30/SF-1 pathway increases local concentrations of estrogen, and together with classic ER signaling, mediate the proliferative effects of synthetic estrogens such as tamoxifen, in promoting endometriosis and endometrial cancers. [Cancer Res 2009;69(13):5415–23]
Kinome Profiling in Pediatric Brain Tumors as a New Approach for Target Discovery
Authors: Sikkema Arend H. , Diks Sander H. , den Dunnen Wilfred F.A. , ter Elst Arja , Scherpen Frank J.G. , Hoving Eelco W. , Ruijtenbeek Rob , Boender Piet J. , de Wijn Rik , Kamps Willem A. , Peppelenbosch Maikel P. , de Bont Eveline S.J.M. 
Published: July 2009

Abstract
Progression in pediatric brain tumor growth is thought to be the net result of signaling through various protein kinase-mediated networks driving cell proliferation. Defining new targets for treatment of human malignancies, without a priori knowledge on aberrant cell signaling activity, remains exceedingly complicated. Here, we introduce kinome profiling using flow-through peptide microarrays as a new concept for target discovery. Comprehensive tyrosine kinase activity profiles were identified in 29 pediatric brain tumors using the PamChip kinome profiling system. Previously reported activity of epidermal growth factor receptor, c-Met, and vascular endothelial growth factor receptor in pediatric brain tumors could be appreciated in our array results. Peptides corresponding with phosphorylation consensus sequences for Src family kinases showed remarkably high levels of phosphorylation compared with normal tissue types. Src activity was confirmed applying Phos-Tag SDS-PAGE. Furthermore, the Src family kinase inhibitors PP1 and dasatinib induced substantial tumor cell death in nine pediatric brain tumor cell lines but not in control cell lines. Thus, this study describes a new high-throughput technique to generate clinically relevant tyrosine kinase activity profiles as has been shown here for pediatric brain tumors. In the era of a rapidly increasing number of small-molecule inhibitors, this approach will enable us to rapidly identify new potential targets in a broad range of human malignancies. [Cancer Res 2009;69(14):5987–95]
Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes
Authors: Pinnix Chelsea C. , Lee John T. , Liu Zhao-Jun , McDaid Ronan , Balint Klara , Beverly Levi J. , Brafford Patricia A. , Xiao Min , Himes Benjamin , Zabierowski Susan E. , Yashiro-Ohtani Yumi , Nathanson Katherine L. , Bengston Ana , Pollock Pamela M. , Weeraratna Ashani T. , Nickoloff Brian J. , Pear Warren S. , Capobianco Anthony J. , Herlyn Meenhard 
Published: July 2009

Abstract
The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (NIC) was exploited to determine if Notch activation is a “driving” event in melanocytic transformation or instead a “passenger” event associated with melanoma progression. NIC-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. NIC-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease. [Cancer Res 2009;69(13):5312–20]
Differential Response of Glioma Cells to FOXO1-Directed Therapy
Authors: Lau Cara J. , Koty Zaf , Nalbantoglu Josephine 
Published: July 2009

Abstract
Gliomas are the most common adult primary brain tumors, and the most malignant form, glioblastoma multiforme, is invariably fatal. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is altered in most glioblastoma multiforme. PTEN, an important negative regulator of the PI3K-Akt pathway, is also commonly mutated in glioma, leading to constitutive activation of Akt. One ultimate consequence is phosphorylation and inactivation of FOXO forkhead transcription factors that regulate genes involved in apoptosis, cell cycle arrest, nutrient availability, DNA repair, stress, and angiogenesis. We tested the ability of a mutant FOXO1 factor that is not subject to Akt phosphorylation to overcome dysregulated PI3K-Akt signaling in two PTEN-null glioma cell lines, U87 and U251. Adenovirus-mediated gene transfer of the mutant FOXO1 successfully restored cell cycle arrest and induced cell death in vitro and prolonged survival in vivo in xenograft models of human glioma (33% survival at 1 year of animals bearing U251 tumors). However, U87 were much more resistant than U251 to mutant FOXO1-induced death, showing evidence of increased nuclear export and Akt-independent phosphorylation of FOXO1 at S249. A cyclin-dependent kinase 2 inhibitor decreased phosphorylation of S249 and rendered U87 cells significantly more susceptible to mutant FOXO1-induced death. Our results indicate that targeting FOXO1, which is at the convergence point of several growth factor receptor tyrosine kinase pathways, can effectively induce glioma cell death and inhibit tumor growth. They also highlight the importance of Akt-independent phosphorylation events in the nuclear export of FOXO1. [Cancer Res 2009;69(13):5433–40]
β1 Integrin Cytoplasmic Variants Differentially Regulate Expression of the Antiangiogenic Extracellular Matrix Protein Thrombospondin 1
Authors: Goel Hira Lal , Moro Loredana , Murphy-Ullrich Joanne E. , Hsieh Chung-Cheng , Wu Chin-Lee , Jiang Zhong , Languino Lucia R. 
Published: July 2009

Abstractβ1 integrins play an important role in regulating cell proliferation and survival. Using small interfering RNA or an inhibitory antibody to β1, we show here that, in vivo, β1 integrins are essential for prostate cancer growth. Among the five known β1 integrin cytoplasmic variants, two have been shown to differentially affect prostate cell functions. The β1A variant promotes normal and cancer cell proliferation, whereas the β1C variant, which is down-regulated in prostate cancer, inhibits tumor growth and appears to have a dominant effect on β1A. To investigate the mechanism by which β1C inhibits the tumorigenic potential of β1A, we analyzed changes in gene expression in cells transfected with either β1C or β1A. The results show that β1C expression increases the levels of an extracellular matrix protein, thrombospondin 1 (TSP1), an angiogenesis inhibitor. TSP1 protein levels are increased upon β1C expression in prostate cancer cells as well as in β1-null GD25 cells. We show that TSP1 does not affect proliferation, apoptosis, or anchorage-independent growth of prostate cancer cells. In contrast, the newly synthesized TSP1, secreted by prostate cancer cells expressing β1C, prevents proliferation of endothelial cells. In conclusion, our novel findings indicate that expression of the β1C integrin variant in prostate glands prevents cancer progression by up-regulation of TSP1 levels and inhibition of angiogenesis. [Cancer Res 2009;69(13):5374–82]
microRNA miR-196a-2 and Breast Cancer: A Genetic and Epigenetic Association Study and Functional Analysis
Authors: Hoffman Aaron E. , Zheng Tongzhang , Yi Chunhui , Leaderer Derek , Weidhaas Joanne , Slack Frank , Zhang Yawei , Paranjape Trupti , Zhu Yong 
Published: July 2009

Abstract
Increasing evidence has suggested that microRNAs (miRNA) play an important role in tumorigenesis. As transcriptional regulators, altered miRNA expression may affect many cancer-related biological pathways, indicating that miRNAs can function as tumor suppressors and/or oncogenes. We first performed a genetic association analysis by screening genetic variants in 15 miRNA genes and detected that a common sequence variant in hsa-miR-196a-2 (rs11614913, C→T) was significantly associated with decreased breast cancer risk (for homozygous variant: odds ratio, 0.44; 95% confidence interval, 0.28-0.70). Hypermethylation of a CpG island upstream (-700 bp) of the miR-196a-2 precursor was also associated with reduced breast cancer risk (odds ratio, 0.35; 95% confidence interval, 0.15-0.81). By delivering expression vectors containing either wild-type or mutant precursors of miR-196a-2 into breast cancer cells, we showed that this variant led to less efficient processing of the miRNA precursor to its mature form as well as diminished capacity to regulate target genes. A whole-genome expression microarray was done and a pathway-based analysis identified a cancer-relevant network formed by genes significantly altered following enforced expression of miR-196a-2. Mutagenesis analysis further showed that cell cycle response to mutagen challenge was significantly enhanced in cells treated with variant miR-196a-2 compared with cells treated with the wild-type. Taken together, our findings suggest that miR-196a-2 might have a potentially oncogenic role in breast tumorigenesis, and the functional genetic variant in its mature region could serve as a novel biomarker for breast cancer susceptibility. [Cancer Res 2009;69(14):5970–7]
T-Regulatory Cells Shift from a Protective Anti-Inflammatory to a Cancer-Promoting Proinflammatory Phenotype in Polyposis
Authors: Gounaris Elias , Blatner Nichole R. , Dennis Kristen , Magnusson Fay , Gurish Michael F. , Strom Terry B. , Beckhove Philipp , Gounari Fotini , Khazaie Khashayarsha 
Published: July 2009

Abstract
T-regulatory (Treg) cells play a major role in cancer by suppressing protective antitumor immune responses. A series of observations (from a single laboratory) suggest that Treg cells are protective in cancer by virtue of their ability to control cancer-associated inflammation in an interleukin (IL)-10–dependent manner. Here, we report that the ability of Treg cells to produce IL-10 and control inflammation is lost in the course of progressive disease in a mouse model of hereditary colon cancer. Treg cells that expand in adenomatous polyps no longer produce IL-10 and instead switch to production of IL-17. Aberrant Treg cells from polyp-ridden mice promote rather than suppress focal mastocytosis, a critical tumor-promoting inflammatory response. The cells, however, maintain other Treg characteristics, including their inability to produce IL-2 and ability to suppress proliferation of stimulated CD4 T cells. By promoting inflammation and suppressing T-helper functions, these cells act as a double-edged knife propagating tumor growth. [Cancer Res 2009;69(13):5490–7]
A “Vascular Normalization Index” as Potential Mechanistic Biomarker to Predict Survival after a Single Dose of Cediranib in Recurrent Glioblastoma Patients
Authors: Sorensen A. Gregory , Batchelor Tracy T. , Zhang Wei-Ting , Chen Poe-Jou , Yeo Priscilla , Wang Meiyun , Jennings Dominique , Wen Patrick Y. , Lahdenranta Johanna , Ancukiewicz Marek , di Tomaso Emmanuelle , Duda Dan G. , Jain Rakesh K. 
Published: July 2009

Abstract
Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti–vascular endothelial growth factor (VEGF) therapy can “normalize” brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We used advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging–measured changes in vascular permeability/flow (i.e., Ktrans) and in microvessel volume, and the change of circulating collagen IV levels, all after a single dose of cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma. Changes in Ktrans, microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival (P &lt; 0.05). When we combined these three parameters into a “vascular normalization index,” we found that it closely associated with overall survival (ρ = 0.54; P = 0.004) and progression-free survival (ρ = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials. [Cancer Res 2009;69(13):5296–300]
MDA-MB-435 and M14 Cell Lines: Identical but not M14 Melanoma?
Authors: Chambers Ann F. 
Published: July 2009

Abstract
A controversy has arisen over the past several years about the true origin of the human MDA-MB-435 cell line. Originally described as a human breast cancer cell line, subsequent expression array studies instead suggested a gene expression profile consistent with a melanoma origin. Subsequent karyotype and comparative genomic hybridization studies supported the idea that current stocks of both MDA-MB-435 cells and M14 melanoma cells must be identical cell lines, and the conclusion was drawn that both cell lines were in fact M14 melanoma cells. However, an alternate conclusion based on these data is that both cell lines are indeed identical, but are in fact MDA-MB-435 breast cancer cells. There is evidence that many cell lines can display “lineage infidelity” and that assignment to tissue type is unreliably made based on expression patterns. Evidence from the literature is presented here that is inconsistent with both lines being of M14 melanoma origin, but rather is consistent with both cell lines being of MDA-MB-435 breast cancer origin. [Cancer Res 2009;69(13):5292–3]
Base excision repair of reactive oxygen species–initiated 7,8-dihydro-8-oxo-2′-deoxyguanosine inhibits the cytotoxicity of platinum anticancer drugs
Authors: Preston Thomas J. , Henderson Jeffrey T. , McCallum Gordon P. , Wells Peter G. 
Published: July 2009

AbstractAnticancer therapy with cisplatin and oxaliplatin is limited by toxicity and onset of tumor resistance. Both drugs form platinum-DNA cross-linked adducts, and cisplatin causes oxidative DNA damage including the 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxodG) lesion. To assess oxidative DNA damage as a mechanism of cisplatin and oxaliplatin cytotoxicity, 8-oxodG–directed base excision repair was stably enhanced in human embryonic kidney cells by FLAG-tagged expression of human oxoguanine glycosylase 1 (α-OGG1) or its functional homologue, Escherichia coli formamidopyrimidine glycosylase (fpg). Both drugs increased reactive oxygen species and 8-oxodG levels, and cytotoxicity was decreased by antioxidant pretreatment. Ectopic expression of α-OGG1 or fpg in cell clones increased nuclear and mitochondrial 8-oxodG repair, and reduced death by reactive oxygen species initiators (H2O2, menadione) and both platinum drugs. Exposure to oxaliplatin caused a more marked and sustained block of cell proliferation than exposure to cisplatin. We conclude that the 8-oxodG lesion is cytotoxic, and base excision repair a likely determinant of risk. The greater antitumor efficacy of oxaliplatin seems unrelated to oxidative DNA damage, suggesting a novel strategy for improving the therapeutic index in cancer therapy. [Mol Cancer Ther 2009;8(7):2015–26]