bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue–diet discrimination factors and turnover of stable carbon and nitrogen isotopes in white-footed mice (Peromyscus leucopus)
Authors: DeMots Rachel L. , Novak James M. , Gaines Karen F. , Gregor Aaron J. , Romanek Christopher S. , Soluk Daniel A. 
Published: October 2010

Stable isotope analysis has become an increasingly valuable tool in investigating animal ecology. Here we document the turnover rates for carbon in the liver, muscle, and whole blood tissue, as well as the tissue–diet discrimination values for carbon and nitrogen isotopes in the liver, whole blood, muscle, and hair, of the white-footed mouse ( Peromyscus leucopus (Rafinesque, 1818)). A 168-day diet-switching experiment was conducted with a laboratory population of white-footed mice. The δ13C values for all tissues deviated less than 1‰ from those of the diet except for whole blood, which had a slightly higher tissue–diet discrimination factor of 1.8‰. All tissues were enriched in 15N by approximately 3‰ relative to the diet except for liver tissue, which was 4.5‰ higher than the dietary δ15N value. Turnover rates for tissues of white-footed mice were ranked liver > whole blood > muscle. The half-lives calculated for liver tissue differed significantly between the two diet switches performed in this experiment. We demonstrate that there is potential for variation in tissue–diet discrimination values and tissue turnover rates between even closely related species. These findings highlight the importance of determining species-specific estimates of these parameters prior to the use of stable isotope analysis in field investigations of animal ecology.
Crypsis influences escape decisions in the Round-tailed Horned Lizard (Phrynosoma modestum)
Authors: Cooper, William E. , Sherbrooke Wade C. 
Published: October 2010

Flight initiation distance (predator–prey distance when escape begins) increases as predation risk increases. Prey should have longer flight initiation distance when their background, movement, or current posture reduces crypsis. Flight initiation distance of ectotherms may increase at lower body temperature to compensate for slower running speed. However, for cryptic prey, fleeing might increase the probability of being detected. The Round-tailed Horned Lizard ( Phrynosoma modestum Girard, 1852) is eucryptic and resembles small stones. We predicted that flight initiation distance by P. modestum is shorter among stones than on uniform sand. Because movement and upright posture disrupt crypsis, we predicted that flight initiation distance is greater after movement and when standing than when still and lying on the ground. As predicted, flight initiation distances were shorter on a rocky than sandy area, when lying flat than standing, and while immobile than after moving. We measured running speed and flight initiation distance to determine relationships among body temperature, speed, and escape decisions. Running speed and flight initiation distance were reduced at lower body temperature, suggesting that crypsis reinforced by immobility is more advantageous than longer flight initiation distance for cool, slow lizards. The lizards adjusted escape decisions to current effectiveness of crypsis and escape ability.
EXISTENCE AND BEHAVIOR OF SOLUTION TO SOME CHEMOTAXIS MODEL WITH INTERACTING SPECIES
Authors: LI JUN-FENG , LIU WEI-AN 
Published: October 2010

In this paper, we study a chemotaxis system involving two interacting species as follows: [Formula: see text] with some initial and boundary conditions. We prove the existence of solution to the problem whose behavior is concerned with reference to some systems through sup-sub-solution method.
The Oncoprotein c-Ski Functions as a Direct Antagonist of the Transforming Growth Factor-β Type I Receptor
Authors: Ferrand Nathalie , Atfi Azeddine , Prunier Céline 
Published: October 2010

Abstract
The oncoprotein c-Ski has been implicated in the negative regulation of transforming growth factor-β (TGF-β) signaling owing to its ability to repress Smad transcriptional activity via recruitment of a transcriptional corepressor complex containing histone deacetylases. However, c-Ski has also been shown to localize to the cytoplasm, raising the interesting possibility that it might disable TGF-β signaling through alternative mechanisms. Here, we provide evidence that c-Ski can restrict TGF-β signaling by interacting directly with the activated TGF-β type I receptor (TβRI). We explored the physiologic relevance of the c-Ski/TβRI interaction and found that it can culminate in a constitutive association of TβRI with a nonfunctional R-Smad/Smad4 complex. Based on these findings, we hypothesize that the interaction between c-Ski and TβRI might interfere with nuclear translocation of the R-Smad/Smad4 complex, thereby attenuating TGF-β signaling. Such a mechanism may play a crucial role in tumor progression, because many tumors that express high levels of c-Ski also display impaired nuclear accumulation of Smads. Cancer Res; 70(21); 8457–66. ©2010 AACR.
Protein Tyrosine Phosphatase Receptor Type γ Is a Functional Tumor Suppressor Gene Specifically Downregulated in Chronic Myeloid Leukemia
Authors: Della Peruta Marco , Martinelli Giovanni , Moratti Elisabetta , Pintani Davide , Vezzalini Marzia , Mafficini Andrea , Grafone Tiziana , Iacobucci Ilaria , Soverini Simona , Murineddu Marco , Vinante Fabrizio , Tecchio Cristina , Piras Giovanna , Gabbas Attilio , Monne Maria , Sorio Claudio 
Published: October 2010

Abstract
Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease. Protein tyrosine phosphatase receptor type γ (PTPRG) is a tumor suppressor gene and a myeloid cell marker expressed by CD34+ cells. Downregulation of PTPRG increases colony formation in the PTPRG-positive megakaryocytic cell lines MEG-01 and LAMA-84 but has no effect in the PTPRG-negative cell lines K562 and KYO-1. Its overexpression has an oncosuppressive effect in all these cell lines and is associated with myeloid differentiation and inhibition of BCR/ABL-dependent signaling. The intracellular domain of PTPRG directly interacts with BCR/ABL and CRKL, but not with signal transducers and activators of transcription 5. PTPRG is downregulated at the mRNA and protein levels in leukocytes of CML patients in both peripheral blood and bone marrow, including CD34+ cells, and is reexpressed following molecular remission of disease. Reexpression was associated with a loss of methylation of a CpG island of PTPRG promoter occurring in 55% of the patients analyzed. In K562 cell line, the DNA hypomethylating agent 5-aza-2′-deoxycytidine induced PTPRG expression and caused an inhibition of colony formation, partially reverted by downregulation of PTPRG expression. These findings establish, for the first time, PTPRG as a tumor suppressor gene involved in the pathogenesis of CML, suggesting its use as a potential diagnostic and therapeutic target. Cancer Res; 70(21); 8896–906. ©2010 AACR.
Basal and Treatment-Induced Activation of AKT Mediates Resistance to Cell Death by AZD6244 (ARRY-142886) in Braf-Mutant Human Cutaneous Melanoma Cells
Authors: Gopal Y.N. Vashisht , Deng Wanleng , Woodman Scott E. , Komurov Kakajan , Ram Prahlad , Smith Paul D. , Davies Michael A. 
Published: October 2010

Abstract
The majority of melanomas show constitutive activation of the RAS-RAF-MAP/ERK kinase (MEK)-mitogen-activated protein kinase (MAPK) pathway. AZD6244 is a selective MEK1/2 inhibitor that markedly reduces tumor P-MAPK levels, but it produces few clinical responses in melanoma patients. An improved understanding of the determinants of resistance to AZD6244 may lead to improved patient selection and effective combinatorial approaches. The effects of AZD6244 on cell growth and survival were tested in a total of 14 Braf-mutant and 3 wild-type human cutaneous melanoma cell lines. Quantitative assessment of phospho-protein levels in the Braf-mutant cell lines by reverse phase protein array (RPPA) analysis showed no significant association between P-MEK or P-MAPK levels and AZD6244 sensitivity, but activation-specific markers in the phosphoinositide 3-kinase (PI3K)-AKT pathway correlated with resistance. We also identified resistant cell lines without basal activation of the PI3K-AKT pathway. RPPA characterization of the time-dependent changes in signaling pathways revealed that AZD6244 produced durable and potent inhibition of P-MAPK in sensitive and resistant Braf-mutant cell lines, but several resistant lines showed AZD6244-induced activation of AKT. In contrast, sensitive cell lines showed AZD6244 treatment–induced upregulation of PTEN protein and mRNA expression. Inhibition of AKT, TORC1/2, or insulin-like growth factor I receptor blocked AZD6244-induced activation of AKT and resulted in synergistic cell killing with AZD6244. These findings identify basal and treatment-induced regulation of the PI3K-AKT pathway as a critical regulator of AZD6244 sensitivity in Braf-mutant cutaneous melanoma cells and the novel regulation of PTEN expression by AZD6244 in sensitive cells, and suggest new combinatorial approaches for patients. Cancer Res; 70(21); 8736–47. ©2010 AACR.
Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer
Authors: Bianchini Giampaolo , Iwamoto Takayuki , Qi Yuan , Coutant Charles , Shiang Christine Y. , Wang Bailang , Santarpia Libero , Valero Vicente , Hortobagyi Gabriel N. , Symmans W. Fraser , Gianni Luca , Pusztai Lajos 
Published: October 2010

Abstract
Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative, 7 in HER2+, and 28 in ER−/HER2− cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER−/HER2− cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER+/HER2− cancers, but not in ER−/HER2− or HER2+ cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER+/HER2− and HER2+ tumors and also predicted higher probability of pCR in HER2+ cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype. Cancer Res; 70(21); 8852–62. ©2010 AACR.
Activation of Forkhead Box O Transcription Factors by Oncogenic BRAF Promotes p21cip1-Dependent Senescence
Authors: de Keizer Peter L.J. , Packer Leisl M. , Szypowska Anna A. , Riedl-Polderman Paulien E. , van den Broek Niels J.F. , de Bruin Alain , Dansen Tobias B. , Marais Richard , Brenkman Arjan B. , Burgering Boudewijn M.T. 
Published: October 2010

Abstract
Oncogene-induced senescence (OIS) is a potent tumor-suppressive mechanism that is thought to come at the cost of aging. The Forkhead box O (FOXO) transcription factors are regulators of life span and tumor suppression. However, whether and how FOXOs function in OIS have been unclear. Here, we show a role for FOXO4 in mediating senescence by the human BRAFV600E oncogene, which arises commonly in melanoma. BRAFV600E signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-Jun NH2 terminal kinase–mediated activation of FOXO4 via its phosphorylation on Thr223, Ser226, Thr447, and Thr451. BRAFV600E-induced FOXO4 phosphorylation resulted in p21cip1-mediated cell senescence independent of p16ink4a or p27kip1. Importantly, melanocyte-specific activation of BRAFV600E in vivo resulted in the formation of skin nevi expressing Thr223/Ser226-phosphorylated FOXO4 and elevated p21cip1. Together, these findings support a model in which FOXOs mediate a trade-off between cancer and aging. Cancer Res; 70(21); 8526–36. ©2010 AACR.
Cancer Stem Cells in the Central Nervous System – A Critical Review
Authors: Prestegarden Lars , Enger Per Øyvind 
Published: October 2010

Abstract
The cancer stem cell hypothesis postulates that tumors arise from, and are maintained by, a small subpopulation of cancer stem cells. This concept has recently become increasingly controversial, following a series of conflicting results. The cell-surface epitope CD133 has been proposed as a brain cancer stem cell marker, whereas a growing number of studies clearly show a tumorigenic potential among CD133− cells as well. Diverging results suggest that assays for isolating cancer stem cells impose a selection bias on which cells are defined as cancer stem cells. Here, we highlight some recent developments, with an emphasis on reports that call for caution in the acceptance of the brain cancer stem cell hypothesis. Cancer Res; 70(21); 8255–8. ©2010 AACR.
Tumorigenic and Metastatic Activity of Human Thyroid Cancer Stem Cells
Authors: Todaro Matilde , Iovino Flora , Eterno Vincenzo , Cammareri Patrizia , Gambara Guido , Espina Virginia , Gulotta Gaspare , Dieli Francesco , Giordano Silvia , De Maria Ruggero , Stassi Giorgio 
Published: October 2010

Abstract
Thyroid carcinoma is the most common endocrine malignancy and the first cause of death among endocrine cancers. We show that the tumorigenic capacity in thyroid cancer is confined in a small subpopulation of stem-like cells with high aldehyde dehydrogenase (ALDHhigh) activity and unlimited replication potential. ALDHhigh cells can be expanded indefinitely in vitro as tumor spheres, which retain the tumorigenic potential upon delivery in immunocompromised mice. Orthotopic injection of minute numbers of thyroid cancer stem cells recapitulates the behavior of the parental tumor, including the aggressive metastatic features of undifferentiated thyroid carcinomas, which are sustained by constitutive activation of cMet and Akt in thyroid cancer stem cells. The identification of tumorigenic and metastagenic thyroid cancer cells may provide unprecedented preclinical tools for development and preclinical validation of novel targeted therapies. Cancer Res; 70(21); 8874–85. ©2010 AACR.
Transcriptome Analysis Reveals that p53 and β-Catenin Alterations Occur in a Group of Aggressive Adrenocortical Cancers
Authors: Ragazzon Bruno , Libé Rossella , Gaujoux Sébastien , Assié Guillaume , Fratticci Amato , Launay Pierre , Clauser Eric , Bertagna Xavier , Tissier Frédérique , de Reyniès Aurélien , Bertherat Jérôme 
Published: October 2010

AbstractAdrenocortical carcinoma (ACC) is a rare disease with an overall poor but heterogeneous prognosis. This heterogeneity could reflect different mechanisms of tumor development. Gene expression profiling by transcriptome analysis led to ACC being divided into two groups of tumors with very different outcomes. Somatic inactivating mutations of the tumor suppressor gene TP53 and activating mutations of the proto-oncogene β-catenin (CTNNB1) are the most frequent mutations identified in ACC. This study investigates the correlation between p53 and β-catenin alterations and the molecular classification of ACC by transcriptome analysis of 51 adult sporadic ACCs. All TP53 and CTNNB1 mutations seemed to be mutually exclusive and were observed only in the poor-outcome ACC group. Most of the abnormal p53 and β-catenin immunostaining was also found in this group. Fifty-two percent of the poor-outcome ACC group had TP53 or CTNNB1 mutations and 60% had abnormal p53 or β-catenin immunostaining. Unsupervised clustering transcriptome analysis of this poor-outcome group revealed three different subgroups, two of them being associated with p53 or β-catenin alterations, respectively. Analysis of p53 and β-catenin target gene expressions in each cluster confirmed a profound and anticipated effect on tumor biology, with distinct profiles logically associated with the respective pathway alterations. The third group had no p53 or β-catenin alteration, suggesting other unidentified molecular defects. This study shows the important respective roles of p53 and β-catenin in ACC development, delineating subgroups of ACC with different tumorigenesis and outcomes. Cancer Res; 70(21); 8276–81. ©2010 AACR.
cIAP2 Upregulated by E6 Oncoprotein via Epidermal Growth Factor Receptor/Phosphatidylinositol 3-Kinase/AKT Pathway Confers Resistance to Cisplatin in Human Papillomavirus 16/18–Infected Lung Cancer
Authors: Wu Heng-Hsiung , Wu Jeng-Yuan , Cheng Ya-Wen , Chen Chi-Yi , Lee Ming-Ching , Goan Yih-Gang , Lee Huei 
Published: October 2010

Abstract
Purpose: Inhibitors of antiapoptosis protein (IAP) have been implicated in the resistance to cisplatin. Therefore, verifying which pathway is involved in cIAP2 upregulation may be helpful in finding a feasible pathway inhibitor to increase the chemotherapeutic efficacy in human papillomavirus (HPV)–infected lung cancer.
Experimental Design: Specific inhibitors of different pathways were used to verify which pathway is involved in cIAP2 transcription. cIAP2 promoter fragments with various deletions and/or mutations were constructed by site-directed mutagenesis. cIAP2, epidermal growth factor receptor (EGFR), and phospho-AKT (p-AKT) expressions in 136 lung tumors were evaluated by immunohistochemistry.
Results: Our data show that two NF-κB (−209 to −200 and −146 to −137) and one CREB (cyclic AMP–responsive element binding protein; −52 to −42) binding sites in cIAP2 promoter region were responsible for cIAP2 upregulated by E6 in TL-1 cells. Moreover, CREB was phosphorylated by EGFR/phosphatidylinositol 3-kinase (PI3K) pathway. To test the involvement of cIAP2 on cisplatin resistance, IC50 was lowered to 8.6 μmol/L in TL-1 cells with cIAP2 short hairpin RNA (shRNA) transfection and compared with 39.7 μmol/L in TL-1 cells with nonspecific shRNA. Pretreatment with EGFR or PI3K inhibitor in TL-1 cells diminished the resistance to cisplatin. Among the tumor groups, cIAP2 expression correlated significantly with HPV16/18 E6, EGFR, and p-AKT. We followed up 46 of 136 patients who had tumor recurrence and/or metastasis and underwent chemotherapy. Tumors with cIAP2-positive immunostaining were associated with a poorer tumor response to chemotherapy compared with those with negative immunostaining.
Conclusions: cIAP2 upregulated by E6 via EGFR/PI3K/AKT cascades may contribute to cisplatin resistance, revealing that the EGFR or PI3K inhibitor combined with cisplatin may improve the chemotherapeutic efficacy in HPV-infected lung cancer. Clin Cancer Res; 16(21); 5200–10. ©2010 AACR.
MicroRNA Expression Profiling of Exfoliated Colonocytes Isolated from Feces for Colorectal Cancer Screening
Authors: Koga Yoshikatsu , Yasunaga Masahiro , Takahashi Amane , Kuroda Junichiro , Moriya Yoshihiro , Akasu Takayuki , Fujita Shin , Yamamoto Seiichiro , Baba Hideo , Matsumura Yasuhiro 
Published: October 2010

AbstractTo reduce the colorectal cancer (CRC) mortality rate, we have reported several CRC screening methods using colonocytes isolated from feces. Expression analysis of oncogenic microRNA (miRNA) in peripheral blood was recently reported for CRC detection. In the present study, we conducted miRNA expression analysis of exfoliated colonocytes isolated from feces for CRC screening. Two hundred six CRC patients and 134 healthy volunteers were enrolled in the study. miRNA expression of the miR-17-92 cluster, miR-21, and miR-135 in colonocytes isolated from feces as well as frozen tissues was analyzed by quantitative real-time PCR. The expression of the miR-17-92 cluster, miR-21, and miR-135 was significantly higher in CRC tissues compared with normal tissues. The exfoliated colonocytes of 197 CRC patients and 119 healthy volunteers were analyzed because of the presence of sufficient miRNA concentration. miR-21 expression did not differ significantly between CRC patients and healthy volunteers (P = 0.6). The expression of miR-17-92 cluster and miR-135 was significantly higher in CRC patients than in healthy volunteers (P &lt; 0.0001). The overall sensitivity and specificity by using miRNA expression was 74.1% (146/197; 95% confidence interval, 67.4-80.1) and 79.0% (94/119; 95% confidence interval, 70.6-85.9), respectively. Sensitivity was dependent only on tumor location (P = 0.0001). miRNA was relatively well conserved in exfoliated colonocytes from feces both of CRC patients and healthy volunteers. miRNA expression analysis of the isolated colonocytes may be a useful method for CRC screening. Furthermore, oncogenic miRNA highly expressed in CRC should be investigated for CRC screening tests in the future. Cancer Prev Res; 3(11); 1435–42. ©2010 AACR.
The Origins and Implications of Intratumor Heterogeneity
Authors: Michor Franziska , Polyak Kornelia 
Published: October 2010

Abstract
Human tumors often display startling intratumor heterogeneity in various features including histology, gene expression, genotype, and metastatic and proliferative potential. This phenotypic and genetic heterogeneity plays an important role in neoplasia, cancer progression, and therapeutic resistance. In this issue of the journal (beginning on page 1388), Merlo et al. report their use of molecular data from 239 patients with Barrett's esophagus to evaluate the propensity of major diversity indices for predicting progression to esophageal adenocarcinoma. This work helps elucidate the implications of molecular heterogeneity for the evolution of neoplasia. Cancer Prev Res; 3(11); 1361–4. ©2010 AACR.
Spatial Attention Determines the Nature of Nonverbal Number Representation
Authors: Hyde Daniel C. , Wood Justin N. 
Published: October 2010

Abstract
Coordinated studies of adults, infants, and nonhuman animals provide evidence for two systems of nonverbal number representation: a “parallel individuation” system that represents individual items and a “numerical magnitude” system that represents the approximate cardinal value of a group. However, there is considerable debate about the nature and functions of these systems, due largely to the fact that some studies show a dissociation between small (1–3) and large (&gt;3) number representation, whereas others do not. Using event-related potentials, we show that it is possible to determine which system will represent the numerical value of a small number set (1–3 items) by manipulating spatial attention. Specifically, when attention can select individual objects, an early brain response (N1) scales with the cardinal value of the display, the signature of parallel individuation. In contrast, when attention cannot select individual objects or is occupied by another task, a later brain response (P2p) scales with ratio, the signature of the approximate numerical magnitude system. These results provide neural evidence that small numbers can be represented as approximate numerical magnitudes. Further, they empirically demonstrate the importance of early attentional processes to number representation by showing that the way in which attention disperses across a scene determines which numerical system will deploy in a given context.